TUTORIAL - keywords
Keynote Presentation: eurUS.brain tutorial definitive text
Slide 1-5: overview
Text on the slides. Overview of the tutorial on slide 1.
- many images used are adapted by courtesy of the authors and the publisher:
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological
record. A Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org ©
2015
- other references are on the slides and in the last slide of the tutorial, also old images that are copyright free
- recommended web based information of anatomy:
- https://www.neurosurgicalatlas.com/ http://www.neuroanatomy.ca
- some textual reading available in Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester.
Handb Clin Neurol 171:245-289.
- where appropriate latin nomenclature has been preserved; CUS = cranial ultrasound
cranial ultrasound (CUS) tutorial
eurUS.brain mission
eurUS.brain members
why do we need to use CUS if we have MRI available ?
conditions we can study well with ultrasound
Slide 6: serial ultrasound findings complete the clinical findings
Serial cranial ultrasound is most informative if performed by investigators who can read the clinical situation.
Slide 7: developmental processes - in the timeline of pregnancy - associated
to timely disorders
Specific timely context determines vulnerability to several insults, resulting in specific brain changes per
period.
Slide 8: timeline of developmental processes in the human brain
Overview of the complexity of brain development, based on several sources.
Bystron I, Blakemore C, Rakic P (2008) Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev
Neurosci 9:110–22.
Keunen K, Counsell SJ, Benders MJ (2017) The emergence of functional architecture during early brain development.
Neuroimage 2017.
Ouyang M, Dubois J, Yu Q, Mukherjee P, Huang H (2019) Delineation of early brain development from fetuses to infants with
diffusion MRI and beyond. Neuroimage 185:836-850.
van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ, Rowitch DH, Nijboer CH (2018) Origin and
dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury. Glia 66(2):221-238.
Volpe JJ (2008) Neurology of the Newborn. Philadelphia: WB Saunders Company.
Slide 9: different structures are more or less visible; clinical relevance of
injury varies per structure
Recommended clinical background for this tutorial:
An introduction to clinical neonatal neurology: Garcia-Alix A, Arnaez J, Agut T, Alarcon A (2014) Neonatal neurology at
a glance https://www.researchgate.net/publication/275641777_Neonatal_Neurology_At_a_Glance
Slide 10: the main brain segments as they develop
Schemes in this tutorial are adapted, with permission of the author and publisher, after Smith CG, van der Kooy
DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press. The schemes here show how images from
this book (top) are adapted and used in this tutorial. This slide depicts the main brain segments in
development, the midline and the olfactory area. The Basic Neuroanatomy handbook is focused on adult brain
anatomy, but several schemes clearly illustrate issues in development.
Slide 11: sectional planes and fontanels available for insonation
For a more complete understanding of the complex subject of developmental neuroanatomy (of sulci, gyri and
lobes), we emphasize the importance of reading papers published on the subject. In this tutorial we summarize
the key concepts. It should be mentioned that this reference list is not complete, but provides an overview of
the topic.
To optimize the ultrasound examination for assessing anatomical landmarks, it is best to use several fontanels.
Insonation in an orderly fashion involves scanning from the anterior fontanel (first coronal anterior to
posterior), from the mastoid fontanel, and when appropriate also from the axial and/or posterior fontanel.
General References to brain anatomy
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Alkadhi H, Kollias SS (2004) Pli de passage fronto-pariétal moyen of Broca separates the motor homunculus. Am J
Neuroradiol 25: 809-812.
Ref to Broca P (1888) Descriptions élémentaires des circonvolutions cérébrales de l'homme. Mémoires
d'Antropologie. Memo Paris: C. Reinwald 707-804.
Ref to Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt
1-167.
Ref to Cunningham DJ (1892) The fissure of Rolando. Contributions to the surface anatomy of the cerebral
hemispheres. Cunningham memoirs no 7. Dublin: Academy Press, 161-193.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
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161-192. Extensive reference to older literature.
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Cohen-Sacher B, Lerman-Sagie T, Lev D, Malinger G (2006) Sonographic developmental milestones of the fetal cerebral
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Slide 12: cerebral lobes and primary sulci
Being able to locate the borders of each lobe is important to correctly describe the location of brain injuries
seen on imaging. Although the knowledge of brain (surface) anatomy should not be considered definitive, it is
unlikely that large brain regions as depicted here will be renamed following further research.
The frontal lobe is posteriorly demarcated by the central groove on the convexity; an anterior coronal section
can display a number of sulci and gyri against the orbital roof: the gyrus rectus is situated against the falx at
the fronto-orbital surface, with the olfactory sulcus just beside it (a short linear density rising from below the
midline, upwards and laterally away from it, on which rests the olfactory tract); the external orbital sulcus will
be found laterally at the base of this lobe. Mesially the posterior border is the central sulcus encircled by the
paracentral lobule, itself bordered posteriorly by the ramus supramarginalis of the cingular groove.
Some anatomists have referred to pre- and postcentral gyri together as the central lobe. Functionally it seems
logical to contain the precentral cortex with primary motor areas as belonging to the frontal lobe, and the
postcentral sensory area as part of the parietal lobe (multi-sensory association).
The parietal lobe extends from the central sulcus to the indentation of the parieto-occipital sulcus; the
intraparietal sulcus starts at the postcentral sulcus on the cerebral convexity, penetrating the parietal lobe
behind the lateral sulcus: in between lies the supramarginal gyrus; the angular gyrus is situated between the
intraparietal sulcus and the superior temporal sulcus. Those anatomical landmarks can be located by means of
extremely parasagittal and postatrial coronal sections; on the mesial hemisphere the parietal lobe consists
mainly of the precuneus, above the parieto-occipital sulci.
The occipital lobe is least accessible from the anterior fontanel; it is often not possible to recognize the
calcarine sulcus, but the experienced sonographer may suspect its presence on a juxta-sagittal section: this
lobe shows up as a hypoechoic zone (cuneus) behind the parieto-occipital sulcus. The optic radiation: an
elongated elliptic hyperechoic area between the posterior end of the lateral fissure and the upper third of the
atrium, best visible in preterms up to about 34 weeks PMA.
The temporal lobe lies underneath thalamus and striatum, in between them is the transverse fissure (of
Bichat); the posterior demarcation of this lobe is an upstanding line starting from the occipital notch; the
temporal excursion of the optic radiation is often affected by injury.
The insula of Reil has been called the fifth lobe by some anatomists.
Many also separate limbic cortex (gyrus cinguli and gyrus parahippocampalis) as a sixth, limbic lobe with it’s
specific functions.
The lobes with association cortex have specifically expanded in primates. They are frontal and parietal lobes
mainly, outside the sensory, motor and visual cortical areas.
Ragsdale CW, Grove EA (2001) Patterning the mammalian cerebral cortex. Current Opinion in Neurobiology 11: 50-58.
Slide 13: fissures, sulci and annectant gyri
Top left: right lateral views of the brain. F, O, T, the frontal, occipital, and temporal poles. At 8
postfertilizational weeks (stage 23), the insula (red)) is still visible on the surface. The long sweeping arrow
shows how the frontal and temporal lobes will become ‘‘wrapped’’ around the structures (e.g., corpus
striatum) deep to the insula. At approximately 25 weeks PMA the insula is gradually becoming buried by the
three (named) opercula (arrows).
Mangin JF, Le Guen Y, Labra N, Grigis A, Frouin V, Guevara M, Fischer C, Rivière D, Hopkins WD, Régis J, Sun ZY (2019) “Plis
de passage" Deserve a Role in Models of the Cortical Folding Process. Brain Topogr. 2019 Oct 3.
O’Rahilly R, Müller F (2006) The Embryonic Human Brain. An Atlas of Developmental Stages, third ed. Wiley-Liss, Hoboken,
NJ.
O’Rahilly R, Müller F (2008) Significant features in the early prenatal development of the human brain. Ann Anat 190:
105-118.
The term fissure has been applied for brain grooves in two different definitions: to describe the separation of
the olfactory pallium from the neopallium (explaining an ontogenetically early sulcus rhinalis) and to describe
extracerebral space hidden by the folding brain. We adhere to the second definition here.The lateral fissure is
only in part the result of opercularisation, and can thus be considered in part fissure and in part sulcus (see
below). Fissures are large demarcating structures, developing due to sequestration of the extracerebral space
by growing brain. The interhemispheric and transverse fissures develop when the hemispheres meet in the
midline (with the falx in between) and when the temporal lobes meet mesencephalon and diencephalon
respectively. In the second trimester the initially broad hippocampal sulcus develops into a tight depression
that is obliterated as the infolding of hippocampus takes place: this hippocampal sulcus could thus also be
named an obliterated fissure.
Sulci on the contrary develop from within the deep brain substance itself. Although growth of the brain is the
common imperative in development of fissures and sulci, the mechanisms behind them are different.
From very early on, during development of primary sulci in second and third trimester, many sulci have
transverse elevations buried in them at a more or less perpendicular angle with them. These annectant or
submerged gyri are likely to be early functional systems, following connection between adjacent cortical
regions.
Slide 14: the historical difficulty of depicting and naming cerebral surface
anatomy
The subsequent text is adapted from Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb ClinNeurol 171:245-289.
Development of cerebral sulci and gyri is an orderly process, to be observed with fetal imaging or by serial
postnatal imaging following preterm birth. The process of primary sulcation/gyration (english term folding)
occurs mainly between 19 and 32 weeks of gestation (review Nishikuni et al. 2013), driven by complex forces in
cortex, underlying white matter and germinal matrix (Sawada et al. 2012, Zilles et al. 2013, Lewitus et al.
2013, Altman and Bayer 2015, Striedter et al. 2015, Im and Grant 2017). Development of the six cortical layers
occurs during the first half of this period, coinciding with increasing thickness of subplate, in itself driven not
only by thalamo-cortical but also by commissural and cortico-cortical contacts (Vasung et al. 2016). The
thickest subplate is formed in perisylvian associative cortical areas. Further post-primary sulcation, beyond 32
weeks of gestation until a peak of gyrification in the latter part of the first year of life, is driven by
specialisation of regions that generate mechanical forces in and immediately below the cortex. After 32 weeks
most secondary (around 33w) and tertiary (around term) sulci are formed, and primary sulci further mature by
becoming deeper and tighter. As gyration proceeds the volume of white matter increases, the relative volume
of the ventricles decreases, the stratified transitional fields disappear and matrix areas shrink.
Based on cerebral growth and the developmental pattern in cynomolgus monkeys, the gyrification process can
be divided into four stages (Sawada et al. 2012): stage 1 (human 14-24w PMA, sulcus calcarinus, parietooccipitalis, cinguli) demarcation of cerebral lobes and limbic gyri; emergence of cortico-cortical long
associative fibers; stage 2 (human 24-31w PMA; sulcus centralis, temporalis superior, collateralis, precentralis)
demarcation of primary neocortical gyri; expansion of cerebrum; stage 3 (human more than 32w) emergence of
secondary and tertiary sulci; stage 4. growth of sulcal length and depth and cortical maturation. Growth peaks
accompany primary and secondary gyration.
Primary sulci mature in a particular sequence before the 32nd week of gestation (Chi et al. 1977, FeessHiggins and Larroche 1987). The surface first indents, later deepens into a groove with banks and finally
bifurcates at the ends of the groove, starting around 30 weeks gestation. Secondary and tertiary sulci develop
after the 31st week (Slagle et al. 1989). Bending (tortuosity) of primary sulci starts around 30 weeks (Worthen
et al. 1986). All over the brain (submerged or surfaced) annectant gyri, french term “plis de passage”, connect
adjacent brain areas often perpendicular to the sulci (Broca 1888, Cunningham 1892, Retzius 1896, with
references to contemporary and preceding authors). Further research is needed to understand whether these
submerged connections predict later functional specialisation.
How to approach the complex anatomical description of the brain surface is still a matter of research and
debate. This slide shows simplifications of the convexity surface by different researchers.
Slide 15: primary gyration peaks during viable preterm life
Retzius G (1896) Das Menschenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
The subsequent text is adapted from Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb ClinNeurol 171:245-289.
Primary gyration starts around 16 w PMA (calcarine and parieto-occipital sulcus), but is especially active
between 24 and 34 weeks. At around 22 weeks the brain is still almost entirely lissencephalic on the convexity.
Detailed attention to the brain surface in imaging is the only way to study gyration in life. The lag between
development at postmortem and detection with fetal MRI is well documented (Levine and Barnes PD 1999,
Girard and Gambarelli 2001). A fetal Total Maturation Score scale with MRI has been proposed to assess
morphologic brain maturity of fetuses between 25 and 35 weeks GA in a clinical setting: sulcation of frontal,
occipital and insular cortex, as well as presence and depth of superior and inferior temporal sulcus can be used
as a part of the score (Vossough et al. 2013). On ultrasound scans an early indication of a developing sulcus is a
broad band of echospeckle upon tangential insonation. Fetal sonography shows the interhemispheric fissure at
the 8th and the lateral fissure at the 19th week. The lateral fissure, in fact not a parenchymal sulcus but the
result of opercularisation of the developing insula, develops after 15 w. By 22 weeks calcarine and parietooccipital sulci should be visible with ultrasound. The frontal part of the cingulate, the central and calcarine
sulci appear on cranial ultrasound before the 24th week. Toi et al. in 2004 studied sulcation with
transabdominal ultrasound in 50 normal fetuses, postmenstrual ages ranging from 15.6 to 29.6 weeks: the
earliest PMA at which specific sulci could be seen in any fetus were: parieto-occipital fissure 18.5 weeks,
calcarine sulcus 18.5 weeks, cingulate sulcus 23.2 weeks and convexity sulci 23.2 weeks; the PMA at which
these sulci were always visible were as follows: parieto-occipital fissure > 20.5 weeks, calcarine sulcus > 21.9
weeks, cingulate sulcus > 24.3 weeks and convexity sulci > 27.9 weeks; the circular sulcus at the margin of the
insula was initially smooth but became angular after about 17 weeks by parieto-temporal opercularisation
which means that initially the insula/operculum angle in an axial plane is obtuse, that an acute angle is first
evident at 23.2 weeks and in all fetuses older than 24.5 weeks. Pistorius et al. in 2010 described feasibility of
mapping folding in fetuses, using practical scores per different sectional plane. In routine clinical practice
evaluation of sulcus parieto-occipitalis, calcarinus and cinguli is possible, in addition to measurements at the
insula of Reil and lateral fissure. In preterm infants a composite ultrasound score has als been proposed but not
validated in prospective research (Murphy et al. 1989).
Sulcus cinguli develops on neonatal ultrasound from 24 w onwards as single or multiple but discontinuous lines;
it becomes one line at 28 to 33 w first in its anterior part and develops multiple branches after 33 w. The
cingulate sulcus begins below the rostrum, it sweeps around the genu paralleling the corpus callosum. It
separates the medial frontal gyrus from the cingulate gyrus below. It ends with a constant supramarginal
branch cutting in on the convexity of the parietal lobe, separating precuneus from the paracentral lobule. The
marginal ramus has a constant relationship to the central sulcus, being formed between 24 weeks and term.
The cingulate sulcus appears duplicated in about 1/3 of the hemispheres, mainly in its anterior segment, by the
presence of a paracingulate sulcus (Paus et al. 1996, Spasojevic et al. 2010). This doubling of the anterior
cingulate sulcus occurs twice as often on the left versus right. Interruptions are frequently (around 1/3) noted
along its course. These interruptions lead to transitional gyri between mesial frontal cortex and cingulate
gyrus, the “plis de passage fronto-limbiques of Broca”. A small posterior branch points in the direction of the
subparietal sulcus with which it may anastomose. A branch (paracentral sulcus) extending up from the
cingulate sulcus in the region in front of the paracentral lobule is present in about 1/2.
The pericentral sulci mainly develop between 20 and 24 weeks (Afif et al. 2014). Sensorimotor cortex develops
in stages. The central cerebral sulcus is first identified (at postmortem) at 18 w, the right appearing before the
left; it is first identifiable in its inferior part, it develops contemporary but independent from the central
insular sulcus. At early stages, the projection from the inferior extremity of the central sulcus is located
anterior to that of the superior extremity of the central insular sulcus. The precentral cerebral sulcus is first
observed at 20–22 w, usually in two separate parts, and the postcentral sulcus at 22–24 w. On CUS they make
their appearance one or two weeks later. According to Cunningham (1892) the sulcus centralis usually cuts the
upper convexity in adults; in 2/5 it ends near or just at the convexity. On the mesial hemisphere, when
present, the sulcus ends with a backward curve, never joining the ramus supramarginalis of the sulcus cinguli,
the large sulcus that ends behind it and invariably cuts the convexity to reach the lateral hemisphere. The
sulcus centralis nears the convexity around 30 w of gestation. At the lower end, the sulcus centralis ends just
above the lateral fissure in the majority; in 1/5 it is connected to the lateral fissure. In most fetuses the lower
two thirds of the sulcus form from a large early shallow fissure, later followed by a deep pit or depression for
the upper third. This deeper depression near the convexity joins the lower larger fissure soon after
appearance. The elevated intervening part has been referred to as the "pli de passage frontoparietal moyen" by
Broca. It is this elevation that my remain relatively large and high in some brains, leading to division of the
central groove (De Bisschop et al. 2019). The elevated portion corresponds to an area of motor development
for the contralateral hand. Although a comparable double origin exists for the precentral sulcus, the two
precentral sulci in general remain separate throughout development.
The insula of Reil, initially exposed, develops at the cleavage between frontal and temporal lobe in which
branches from the carotid artery reach the brain surface in early fetal life. Later on, opercularisation, the
covering of the insula by rapidly growing cerebral parenchyma, renders the insula at term no longer visible
from the surface. Insular sulci are visible by 34 w on ultrasound, but develop between 28 and 34 w, usually two
short sulci anterior to the central sulcus. At 24 weeks PMA the surrounding cortex overlaps the posterior part of
the sylvian region, with only partial covering of the anterior insula and the anterior peri-insular sulcus. The
superior part of the anterior insula is gradually hidden by development of the fronto-orbital opercula. The
central cerebral artery arises from the central insular artery (branch of the superior division of the MCA).
Timeline according to Afif et al. 2007 and 2014
central sulci
13-17w GA
18-19 w GA
insular sulci
stage 1: appearance of the first sulcus
stage 1: appearance of the inferior part of the
central cerebral sulcus
stage 2: development of the pericentral lateral
regions and beginning of opercularization
stage 2: development of the periinsular sulci
stage 3: central sulci and
opercularization of the insula
24-26w GA
stage 3: development of parietal and temporal
cortices; covering of the postcentral insular region
stage 4: covering of the posterior insula
27-28w GA
stage 4: maturation of the central cerebral regions
stage 5: closure of the posterior sylvian
fissure
20-22 w GA
Clinically relevant variations. Although it is well acknowledged that cortical folding varies between individuals
(Turner 1948, Chi et al. 1977, Naidich et al. 1994 ), and that the right hemisphere usually matures before the
left with respect to gyration (Chi et al. 1977 on the basis of postmortem findings, Kasprian et al. 2011 using
fetal MRI, Afif et al. 2014 on the basis of postmortem findings, Zhang et al. 2015 based on MR findings), there
are few perinatal in vivo reports of the importance and cause of such individual variation outside of the
context of disorders of migration (see below). The exception is the study of cingular groove development with
CUS by Slagle et al. In 1989. The study of clinically relevant variation of primary sulci is, even with MRI, still in
an early stage.
Abnormal development
Changes induced by lesions. Focal cortical brain injury can directly alter final gyral morphology during either
primary or post-primary gyration. Any significant lesion of the cortex itself, be it an arterial or venous infarct,
watershed injury, inflammation or other, changes gross cortical morphology. In postmortem descriptions this is
referred to as ulegyria, i.e atrophy and alteration in shape of gyri (Friede 1989, Paneth et al. 1994). When
lesions to the cortex occur before the end of the brunt of neuroblast migration (around 25 w) they lead to focal
interruption of cortical formation, histologically often referred to as polymicrogyria, the existence of far too
many erratic small gyri in a specific region (Friede 1989).
Deep lesions may on the other hand also alter the cortical plate above it. Perinatal human clastic deep brain
lesions, below subplate and cortex, like a medullary venous infarct in a preterm infant at 23-25 weeks can
cause macroscopically recognizable cortical dysplasia in the form of polymicrogyria (Govaert et al. 2006). At
postmortem, changes in the cerebral cortex have been reported above bilateral deep white matter lesions
referred to with the term leukomalacia (Marin-Padilla 1996 and 1997), now lumped under the umbrella
“punctate white matter lesions”. A maturational delay but not an alteration in shape (compared to the normal
detailed description from a discontinuous sulcus around 26w, to continuity by 30w and branching in the
following 4 weeks) was documented by postnatal sonographic study of the developing cingular groove following
unilateral medullary venous infarction in preterm infants with GA below 32w (Slagle et al. 1989).
Changes by preterm delivery. MR has described diffuse altered gyrification in preterm infants. Using MRI with
dedicated post-processing (mainly using the inner cortex to white matter border), it has been demonstrated
that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to
singletons, whereas the gyrification of IUGR newborns is discordant to normal development, with a more
pronounced reduction of surface in relation to a given sulcation index (Dubois et al. 2008). Using global surface
measurements, an effect of preterm birth on cortical folding can be shown (Lefèvre et al. 2016). MR studies
start to focus on specific regional variations (Kersbergen et al. 2016), confirming the higher pace of right versus
left sulcation of postmortem studies. Postmortem studies have demonstrated since long that hemispheres in
the third trimester are already asymmetric at the level of Heschl gyri, planum temporale and superior temporal
sulcus (STS). In a cross-sectional neonatal MRI study, Dubois et al. 2010 aimed to blindly and automatically map
early asymmetries over the immature cortex, in 25 newborns from 26 to 36 weeks of gestational age.
Asymmetries were highlighted in three specific cortical regions: a deeper sulcus temporalis superior on the
right side, a larger posterior region of the lateral fissure on the left side, ipsilateral to a larger left planum
temporale. Such study confirms in vivo that perisylvian regions are asymmetric from early on, suggesting their
anatomical specificity for the emergence of functional lateralization in language processing prior to language
exposure.
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Slide 16: primary gyration summarized in a 3D model
The convexity of a 3D model (term) based mainly on descriptions by Retzius and Cunningham. Compare with an
historical image after Gratiolet, where postnatal progression of gyral complexity is illustrated.
Slide 17: primary gyration and lobes in a 3D model against Brodmann areas
After text and images by Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. Dublin
University Press.
With extensive reference to older literature.
Left Brodmann histological areas simplified (Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S,
White LE (2012) Neuroscience. Fifth edition. Sinauer associates.).
Compare with a sulcal map automatically derived from MRI studies of the brain surface with clear delineation
of the main sulci and brain regions: Yang Z, Carass A, Chen C, Prince JL (2012) Simultaneous Cortical Surface
Labeling and Sulcal Curve Extraction. Proc SPIE Int Soc Opt Eng 8314:831414.
Slide 18: a commercial 3D model of the adult brain surface
https://3d4medical.com/apps/brain-pro
Slide 19: timeline of primary gyration at postmortem inspection
A picture of the development of sulci, mainly based on Chi et al. 1977.
Afif A, Bouvier R, Buenerd A, Trouillas J, Mertens P (2007) Development of the human fetal insular cortex: study of the
gyration from 13 to 28 gestational weeks. Brain Struct Funct 212: 335-346.
Afif A, Trouillas J, Mertens P (2014) Development of the sensorimotor cortex in the human fetus: a morphological
description. Surg Radiol Anat 37: 153-160.
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The fissure of Rolando. pp
161-192. Extensive reference to older literature.
Knowledge of the time lag between imaging and postmortem inspection is illustrated in a reference below. In
isolated fetal ventriculomegaly the time lage between postmortem and fetal MRI detection of sulci seems to be
doubled from around 2 to 4 weeks.
time lag between appearance of sulcus between anatomy and fetal MRI
group
mean time lag ±
sd (w)
range (w)
normal brain
1.9 ± 2.2
0-8
mild ventriculomegaly
4.4 ± 3.2
0-8
p value
< 0.1
Hahner N, Puerto B, Perez-Cruz M, Policiano C, Monterde E, Crispi F, Gratacos E, Eixarch E (2017) Altered cortical
development in fetuses with isolated nonsevere ventriculomegaly assessed by neurosonography. Prenatal Diagnosis 38:
365-375.
Slide 20: development of individual primary sulci at postmortem exam:
average PMA of appearance
Nishikuni K, Carvalhal Ribas G (2013) Study of fetal and postnatal morphological development of the brain sulci. J
Neurosurg Pediatrics 11: 1-11.
Two hundred fourteen brain hemispheres from 107 human brain specimens were examined to evaluate the
timing of sulcal formation. These brains were obtained from cadavers ranging in age from 12 weeks of
gestation to 8 months of postnatal life. All primary sulci are formed during fetal life. The appearance of each
sulcus follows a characteristic timing pattern, which may be used as one of the reliable guides pertinent to
gestational age and normal fetal development. The order of appearance of the sulci, and the number and
percentages found were as follows: longitudinal cerebral fissure at 12 weeks (10/10, 100%); callosal sulcus at
12 weeks (10/10, 100%); hippocampal sulcus at 15 weeks (7/10, 70%); lateral sulcus at 17 weeks (20/22,
90.9%); circular insular sulcus at 17 weeks (18/22, 81.8%); olfactory sulcus at 17 weeks (18/22, 81.8%);
calcarine sulcus at 17 weeks (14/22, 63.6%); parietooccipital sulcus at 17 weeks (11/22, 50%); cingulate sulcus
at 19 weeks (16/20, 80%); central sulcus at 21 weeks (22/38, 57.9%); orbital sulcus at 22 weeks (9/16, 56.2%);
lunate sulcus at 24 ± 2 weeks (12/16, 75%); collateral sulcus at 24 ± 2 weeks (8/16, 50%); superior frontal
sulcus at 25 ± 2 weeks (5/6, 83.3%); rhinal sulcus at 25 ± 2 weeks (3/6, 50%); precentral sulcus at 26 ± 3 weeks
(2/4, 50%); postcentral sulcus at 26 ± 3 weeks (2/4, 50%); superior temporal sulcus at 26 ± 3 weeks (2/4, 50%);
central insular sulcus at 29 ± 2 weeks (4/4, 100%); intraparietal sulcus at 29 ± 2 weeks (2/4, 50%);
paraolfactory sulcus at 29 ± 2 weeks (2/4, 50%); inferior frontal sulcus at 30 ± 3 weeks (2/4, 50%); transverse
occipital sulcus at 30 ± 3 weeks (2/4, 50%); occipitotemporal sulcus at 30 ± 3 weeks (2/4, 50%); marginal
branch of the cingulate sulcus at 30 ± 3 weeks (2/4, 50%); paracentral sulcus at 30 ± 3 weeks (2/4, 50%);
subparietal sulcus at 30 ± 3 weeks (2/4, 50%); inferior temporal sulcus at 31 ± 3 weeks (3/6, 50%); transverse
temporal sulcus at 33 ± 3 weeks (6/8, 75%); and secondary sulcus at 38 ± 3 weeks (2/4, 50%).
Slide 21: human newborn versus adult monkey brain
Lessons learnt from primate experiments are inherently important because of the similarity in gyration
between the term human brain and the mature primate brain.
Slide 22: human gyration at 32w PMA
Details of sulci in the human preterm infant at 32w PMA, when most primary sulci are present in their basic
linear form without ramifications. Compare with the almost lissencephalic convexity at 23w PMA.
Slide 23: gyrification mechanisms
Mechanistic explanations for cortical folding tend to focus either on forces external to the developing cortex or
on intrinsic forces. The latter models tend to emphasize axonal tension, differential proliferation or
differential tangential expansion of developing structures that are bonded to one another. Various explanations
are not mutually exclusive (Striedter et al. 2015).
The first cortical folds usually develop into the final deepest parts of sulci, and are termed sulcal pits on fetal
MRI (Im and Grant 2017). A sulcal pit can be identified in a sulcal catchment basin by using structural
information of small connecting gyri (the focal elevation of the sulcal bottom, also called an annectant gyrus
submerged or not), as described above for the “pli fronto-pariétal moyen” in the central groove. The first
major folds appear to show greater spatial invariance during development as they deepen and have a stronger
spatial covariance with functional areas under closer genetic control than later developing sulci. Invariant
sulcal pit distributions across individuals may be due to the stability of the human-specific protomap. The
clinical relevance of the relation between annectant gyri, sulcal pits and definitive sulci constitutes a recent
research field.
Current insights into the role of the outer subventricular zone in gyral development (Lewitus et al. 2013, Zilles
et al. 2013, Striedter et al. 2015), explain how deep brain lesions may indeed alter primary gyration. Primary
gyration is driven by genetic mechanisms that control proliferation of cells in the outer subventricular zone. A
discrepant conical expansion of cells in this zone occurs under future gyral crowns. The number of cells
produced and their spreading lead to gyral folding. Basal radial glia are progenitors forming transit-amplifying
progenitors in the OSVZ.
Beyond 32 w post-primary sulcation continues until around 1 year of age after term birth and is also driven by
external in addition to intrinsic, genetic factors. Sulcal length and width increase in this stage. Tension in
immediate subcortical white matter then becomes important, whereas such tension is not (or less ?) relevant to
primary gyration. Primary gyration does co-occur with early development of long associative tracts but is not
related to myelination. In evolution there seems to be an advantageous trend that favors folding over cortical
thickening.
The stage of likely interference with primary gyration is in the fetal (20-23 w) and early preterm (24-32 w)
phases of cerebral development when thalamocortical, callosal and cholinergic afferents first connect to outer
subplate targets and wait before connecting targets in the deep cortical plate (Kostovic and Jovanov-Milosevic
2006). This is a period of massive cell production in ventricular and subventricular zones, during which the
subplate is large by abundant extracellular matrix and by early synapse formation, and when surface negative
large EEG transients emerge from this subplate. It is also a period of vigorous structural plasticity. It precedes
cortico-cortical connectivity around 33-35 w GA and later reorganization following disappearance of transient
structures. The time window in which interference can exist with gyration was determined by experimental
study. It was demonstrated by applying frontal cortical resections in primates during gestation that not only
local but also distant changes (in the remote occipital areas on both sides, even with unilateral lesions) occur
in the formation of primary sulci: new and deep sulci appear, consequent not to abnormal prolongation of
neurogenesis but to rerouting of thalamocortical fibers coming from the mediodorsal thalamic nucleus
(Goldman-Rakic PS 1980). This remote change in primary sulci only occurs when fetuses are lesioned before
E124 for rhesus monkeys (equivalent age around PMA 30 weeks in humans), because mediodorsal thalamic
nuclei transsynaptically whither when their cortical target is lesioned after that moment. In summary there is
need to focus on the effect of deep brain lesions on primary gyration.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
de Vareilles H, Rivière D, Mangin JF, Dubois J. Development of cortical folds in the human brain: An attempt to review
biological hypotheses, early neuroimaging investigations and functional correlates. Dev Cogn Neurosci. 2023: 61:101249.
Goldman-Rakic PS (1980) Morphological consequences of prenatal injury to the primate brain. Progress in Brain Research 53:
3-19.
Kostovic I, Jovanov-Milosevic N (2006) The development of cerebral connections during the first 20-45 weeks' gestation.
Seminars in Fetal and Neonatal Medicine 11: 415-422.
Lewitus E, Kelavaand I, Huttner WB (2013) Conical expansion of the outer subventricular zone and the role of neocortical
folding in evolution and development . Frontiers in human neuroscience. Volume7|Article424 |1-10.
Sawada K, Fukunishi K, Kashima M, Saito S, Sakata-Haga H, Aoki I, Fukui Y (2012) Fetal Gyrification in Cynomolgus Monkeys:
A Concept of Developmental Stages of Gyrification. The anatomical record 295: 1065-1074.
Striedter GF, Srinivasan S, Monuki ES (2015) Cortical folding: when, where, how, and why? Annu Rev Neurosci. 38:291-307.
White T, Su S, Schmidt M, Kao C-Y, Sapiro G (2010) The development of gyrification in childhood and adolescence. Brain
Cogn 72(1): 36-55.
Zilles K, Palomero-Gallagher N, Amunts K (2013) Development of cortical folding during evolution and ontogeny. Trends in
Neurosciences, Vol. 36, No. 5.
Slide 24: gyrification index, differential proliferation and diverging radial fibers
Gyrification index.
Zilles K, Palomero-Gallagher N, Amunts K (2013) Development of cortical folding during evolution and ontogeny. Trends in
Neurosciences, Vol. 36, No. 5.
Shimony JS, Smyser CD, Wideman G, Alexopoulos D, Hill J, Harwell J, Dierker D, van Essen DC, Inder TE, Neil JJ (2016)
Comparison of cortical folding measures for evaluation of developing human brain. Neuroimage 125; 780-790.
Cortical folding of the human brain starts around the 16th week of gestation, increases rapidly during the first
trimester, and reaches a transient maximum between weeks 66 and 80 postconception. From this time on, the
GI declines by 18% from a maximal value of 3.03 to the adult level, which is reached at an age of almost 23
years.The mechanisms underlying this developmental course are not sufficiently understood, but it may be
speculated that perinatal pruning with programmed cell death and reduction of cell numbers and connectivity
may lead to the GI reduction. However, the decrease in GI continues into adulthood, whereas the perinatal
overshooting of synaptic density seems to reach a plateau much earlier than the GI.
Sulcal depth versus gyrification index: Shimony et al. 2016. 22 Measures of cortical folding were evaluated, 20
derived from local curvature (curvature-based measures) and two based on other features (sulcal depth and
gyrification index). Cortical surfaces were reconstructed from 12 term control and 63 preterm infants. Preterm
infants underwent 2–4 MR imaging sessions between 27 and 42 weeks postmenstrual age (PMA). Term infants
underwent a single MR imaging session during the first postnatal week. One group of 38 preterms infants had
no/minimal abnormalities on qualitative assessment of conventional MR images. The second group (25 infants)
consisted of infants with injury on conventional MRI at term equivalent PMA. Only left hemispheres were used.
For both preterm infant groups, all folding measures increased or decreased monotonically with increasing
PMA, but only sulcal depth and gyrification index differentiated preterm infants with brain injury from those
without. No curvature-based measure distinguished between the groups, whereas sulcal depth distinguished
term control from injured preterm infants and gyrification index distinguished all three groups: sulci in preterm
infants are shallower, more so in injured than in uninjured preterms. When incorporating total cerebral volume
into the statistical model, sulcal depth no longer distinguished between the groups, though gyrification index
distinguished between all three groups and positive shape index distinguished between the term control
(average 2.05) and uninjured preterm (average 1.8) groups. Though curvature-based measures change during
this period, they were not sensitive for detecting the differences in folding associated with brain injury and/or
preterm birth.
In contrast, gyrification index was effective in differentiating these groups.
Grey matter hypothesis of cortical folding.
The subventricular zone of the fetal hemisphere is subdivided into an inner (ISVZ) and outer (OSVZ)
subventricular zone.The OSVZ is a proliferative region outside the ventricular zone that contains a lineage of
neural stem and transit-amplifying intermediate progenitor cells and expands considerably between gestational
weeks 11 and 16 in humans, immediately before the onset of cortical folding. The OSVZ modifies the trajectory
of the migrating immature neurons by a recently discovered cell type, the unipolar intermediate radial glia cell
(IPC) , which is a self-amplifying progenitor cell that generates a radially oriented scaffold in addition to the
scaffold formed by the classical apical and bipolar radial glia cells. The proliferation of IPCs could be a driving
force for the early tangential expansion of the fetal cortex and its folding. The subplate zone plays an
important role in gyrification. It is characterized by a slow and long-lasting developmental period. SP has its
largest dimension subjacent to late maturing and folding association cortices. It contains transient
corticocortical and callosal connections before they enter the cortical plate. The protracted development and
the dimension of the SP can explain the regional heterochronicity of cortical folding and the numerous, mainly
smaller-sized gyri in the multimodal association regions, as well as the early interaction between cell
proliferation and migration and the influence of fiber tension on folding. SP seems to be the structure that
links the mechanisms behind the cellular proliferation and mechanical tension hypotheses.
In species with gyrencephalic brains, the radial fiber scaffold may display two conformations: parallel or
divergent (Borrell and Reillo 2012). If radial fibers are parallel, the massive number of neurons generated by
cortical progenitors will migrate in parallel trajectories and accumulate on thick layers, without tangential
dispersion. If radial fibers are divergent, migrating neurons follow divergent trajectories. This results in the
tangential dispersion of radially migrating neurons, increasing the degree of cortical folding. In this second
model, radial fibers from bRG intercalate between full-span fibers of aRG cells.
Borrell V, Reillo I (2012) Emerging Roles of Neural Stem Cells in Cerebral Cortex Development and Evolution. Develop
Neurobiol 72: 955– 971.
Lewitus E, Kelavaand I, Huttner WB (2013) Conical expansion of the outer subventricular zone and the role of neocortical
folding in evolution and development . Frontiers in human neuroscience. Volume7|Article 424 |1-10.
Tension-based hypothesis.
Tension above or below certain thresholds stimulates axonal elongation or retraction, respectively. Because
axons build the fiber tracts, gyrification can be explained by connectivity, more specifically by the 3D courses
and the viscoelastic properties of fiber tracts. The first connections between cortical and other cortical and
subcortical regions are visible during subplate development, and are maintained during migration and in the
mature cortex via synapses that provide high adhesiveness of preto postsynaptic structures. There are many
more tangentially organized (relative to the cortical surface) cortico-cortical than radially organized corticosubcortical connections in the human forebrain. Consequently, the original tension hypothesis predicted an
outward folding caused by strong cortico-cortical and weak cortico-subcortical connections, and an inward
folding caused by an inverse relationship. Moreover, folding makes the path between different interconnected
cortical sites as short as possible. Tension is found in radially as well as tangentially arranged axons in white
matter tracts below gyri and sulci, and in radially arranged axons in gyri. Contrary to the original tension
hypothesis, tension is not found across developing gyri. Thus, tension cannot pull on the opposite walls of a
gyrus and does not lead to an outward folding during initiation, nor when sustaining and maintaining folds.
Axonal tension (arrows) is distributed circumferentially across subcortical white matter (dashed arrows), but
radially in the subplate and gyral folds (filled arrows).
Mechanical forces in the cortex play a role in development of post-primary gyration, after 31 w GA.
A mechanical mathematical model of cortical folding.
Budday S, Raybaud C, Kuhl E ((2014) A mechanical model predicts morphological abnormalities in the developing human
brain. Scientific reports 4: 5644.
Recent studies tried to unify several hypotheses of cortical folding and provide mathematical synthetic models.
Using nonlinear field theories of mechanics supplemented by the theory of finite growth, one can model the
human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing
inner core. This approach seamlessly integrates two competing hypotheses for cortical folding: axonal tension
and differential growth. This model was calibrated using MR images from very preterm neonates. The model
predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the
gyrification index, the ratio between the total and exposed surface area, these abnormalities agree with the
classical pathologies of lissencephaly and polymicrogyria.
There is evidence that mechanical factors are recognized as potential driving force for cortical folding, with
controversies around two competing hypotheses, axonal tension and differential growth. Axonal tension, a
mechanism to bring functionally related units close together, disagrees with dissection experiments, which
confirm the existence of axonal tension but not along the predicted directions. Differential growth, a
mechanism to release residual stress by surface buckling, agrees with stress distribution in dissection
experiments, however, not with realistic stiffness ratios. Here both mechanisms are unified in a model with a
morphogenetically growing outer surface and stretch-driven growing inner core.
There is a general agreement that cortical growth is almost entirely morphogenetic, independent of
mechanical factors. But rapidly growing biological membranes like the cortex may induce mechanical
instabilities, associated with large deformations of the overall system. This creates extreme subcortical
deformation, which this model captures in the form of the elastic volume stretch. Subcortical growth is a result
of stretch-driven axon elongation. On the cellular level, chronic axonal overstretch activates mechanotransduction pathways, which result in a gradual increase in axonal length, an increase in the number of
microtubules and neurofilaments, cytoplasm and plasma membrane, while the ultrastructure and diameter of
the growing axon remain virtually unchanged. Axonal growth is self-regulating: as the axon grows, it reduces its
stretch, and thereby regulates its length. In this model stretch rather than tension is suggested as the driving
mechanism for subcortical growth. Misbalanced cortical and subcortical growth creates morphological
abnormalities. Abnormally slowly growing cortices allow axons to almost instantaneously respond to growthinduced subcortical deformation so that no folds emerge. Abnormally fast growing cortices reduce the sulcal
depth, decrease the gyrification index, and provoke the formation of secondary folds.
Slide 25: thalamo-cortical anchors at primary sulci
Thalamo-cortical anchors.
Early radiation fibers from the thalamic relay nuclei and the pulvinar anchor the expanding neocortex,
deepening of the sulci and elevating the bank of these gyri as the neocortex expands. Coronal section of the
neocortex in a GW29 fetus (260 mm): early fibers anchored in the thalamus (red lines) are hypothesized to
serve as “guide wires” that resist expansion while neurons migrating and fibers growing towards the neocortex
(arrows) elevate the expanding cortex at the unanchored sites. Note that at the presumed anchored sites the
white matter tends to remain narrow. The cortical surface is smooth before gyrification. In the region where
thalamic fibers arrive early, the cortical surface becomes anchored. That region becomes the depth of the
future sulcus. As later arriving fibers and neurons reach the adjacent areas, the pressure exerted causes the
cortical surface to bulge at adjacent unanchored sites.
A putative example of such anchor is the interoceptive thalamocortical tract that “fixates” the upper margin of
the insular fundus, to facilitate opercularisation (Evrard 2019). One idea is that slow spinal axonal traffic with
interoceptive information is kept as close as possible to thalamus because of it’s vital homeostatic function.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA.
Evrard HC (2019) The Organization of the Primate Insular Cortex. Front Neuroanat 13:43.
Slide 26: sulcation landmarks in fetal MRI
Girard N, Gambarelli D (2001) Normal fetal brain. Magnetic resonance imaging. An atlas with anatomic correlations.
Brunelle F, Show D eds. Rickmansworth, UK.
Abe S, Takagi K, Yamamoto T, Okuhata Y, Kato T (2003) Assessment of cortical gyrus and sulcus formation using MR images in
normal fetuses. Prenat Diagn 23(3):225-31.
Fetal MRI studies have gradually developed predictive properties for alter outcome. In fetuses exposed to
maternal psychological stress a negative effect could be measured of stress on size of the left hippocampal
volume (Wu et al. 2020). In the same study development of sulci in frontal and temporal lobes seemed
accelerated in relation to stress factors.
Wu Y, Lu YC, Jacobs M, Pradhan S, Kapse K, Zhao L, Niforatos-Andescavage N, Vezina G, du Plessis AJ,
Limperopoulos C (2020) Association of Prenatal Maternal Psychological Distress With Fetal Brain Growth,
Metabolism, and Cortical Maturation. JAMA Netw Open 3(1):e1919940.
Slide 27: the critical period for thalamo-cortical interaction lies before ~30 w
PMA: alteration of distant primary gyration in a monkey model
Goldman-Rakic PS (1980) Morphological consequences of prenatal injury to the primate brain. Progress in Brain Research 53:
3-19. References ibidem. Text adapted from this paper.
Critical period of fissural development and genesis of connections.
In rhesus monkey, the convolutional pattern of the brain begins to take shape around the end of the second and
early third trimester of gestation. The first primary grooves to develop are the Sylvian and Rolandic. In the
monkey they appear around E100. During the last-third of gestation, all other primary and most secondary sulci
become either well delineated or at least clearly recognizable so that at the end of this period the adult
cerebral fissural pattern is established.
This period which seems to be critical for the development of the normal fissural pattern, appears to coincide
with the time interval over which there is an influx of thalamic and corticocortical afferents into the cortex.
According to studies on the development of the visual system in monkeys, the thalamocortical innervation of
the occipital lobe occurs between E91 and E124 (Rakic 1979). Other thalamic connections in the primate brain
invade their cortical targets over the same period of time. Corticocortical and callosal fibers innervate the
cortex somewhat later - roughly between E124 and E150 (Goldman-Rakic 1980). Thus, cerebral sulcation begins
about the same time that thalamo-cortical afferents invade the cortex and sulci shape their mature pattern
during the time of major ingrowth of corticocortical connections. Anomalous features in the sulcal pattern can
be experimentally induced only in the brains of monkeys that have been operated on before the end of this
period.
The correspondence in the timetable of development of fissures and the innervation of the cortical plate
suggests that these two events may in some way be causally related. This hypothesis may explain how a
disruption of a rather small part of the cortex could produce widespread changes which encompass the entire
cerebral surface of both hemispheres. If prefrontal neurons are removed before their axons have reached their
ipsilateral cortical targets, which are in the adjacent prefrontal cortex and in distant destinations of the
temporal and parieto-occipital cortex, these target structures will be deprived of a considerable portion of
their normal input which would subject them to unusual forces resulting from the abnormal numbers and
arrangement of ingrowing fibers. Furthermore, since transneuronal degeneration occurs more extensively in
immature than mature brain, it may be expected that neurons in the cortical target regions that are deprived
of their normal input would degenerate in greater numbers and proportions in fetal than in more mature
animals. Finally, this effect would be transferred via callosal neurons to corresponding loci in the opposite
hemisphere which would also degenerate or become rearranged - resulting in local mirror-symmetric changes
in homotopic cortical zones.
This sequence of events is a working hypothesis which could explain location, timetable and symmetry of
abnormal convolutions. Thus, the abnormal fissures tend to be located in target areas of the prefrontal corticocortical efferent system and are notably absent in areas such as the sensorimotor cortex which are devoid of
direct prefrontal projections. The abnormal sulci develop just before these connections are fully formed.
Finally, their bilateral distribution follows the circuitry that could be affected by transneuronal processes as
outlined above. According to this model, protection from transneuronal degenerative processes occurs with the
collateralization of afferent and efferent systems. Thalamic neuronal survival than leads to abnormal wiring.
Slide 28: fetal and neonatal MRI studies of the effect of prematurity on
sulcation
A summary of several MRI studies of fetal and preterm sulcation. Some contradiction is present.
Clouchoux C, Kudelski D, Gholipour A, Warfield SK, Viseur S, Bouyssi-Kobar M, Mari JL, Evans AC, du Plessis AJ,
Limperopoulos C (2012) Quantitative in vivo MRI measurement of cortical development in the fetus. Brain Struct Funct
217(1):127-39.
Dubois J, Benders M, Borradori-Tolsa C, Cachia A, Lazeyras F, Ha-Vinh Leuchter R, Sizonenko SV, Warfield SK, Mangin JF,
Hüppi PS (2008) Primary cortical folding in the human newborn: an early marker of later functional development. Brain
131(Pt 8):2028-41.
Dubois J, Benders M, Lazeyras F, Borradori-Tolsa C, Leuchter RH, Mangin JF, Hüppi PS (2010) Structural asymmetries of
perisylvian regions in the preterm newborn. NeuroImage 52; 32–42.
Engelhardt A, Inder TE, Alexopoulos D, Dierker DL, Hill J, Van Essen D, Neil JJ (2015) Regional Impairments of Cortical
Folding in Premature Infants. Ann Neurol 77; 154-162.
Im K, Grant PE (2017) Sulcal pits and patterns in developing human brains. Neuroimage 1-10.
Kersbergen KJ, Leroy F, Išgum I, Groenendaal F, de Vries LS, Claessens NH, van Haastert IC, Moeskops P, Fischer C, Lee HJ,
Kwon H, Kim JI, Lee JY, Lee JY, Bang S, Lee J-M (2021) The cingulum in vry preterm infants relates to language and socialemotional impairment at 2 years of term-equivalent age. NeuroImage Clinical 29; 102528.
Mangin JF, Viergever MA, Dubois J, Benders MJ (2016) Relation between clinical risk factors, early cortical changes, and
neurodevelopmental outcome in preterm infants. Neuroimage 142:301-310.
Lefèvre J, Germanaud D, Dubois J, Rousseau F, de Macedo Santos I, Angleys H, Mangin JF, Hüppi PS, Girard N, De Guio F
(2016) Are Developmental Trajectories of Cortical Folding Comparable Between Cross-sectional Datasets of Fetuses and
Preterm Newborns? Cereb Cortex 26(7):3023-35.
Zubiaurre-Elorza L, Soria-Pastor S, Junque C, Vendrell P, Padilla N, Rametti G, Bargallo N, Botet F (2009) Magnetic
resonance imaging study of cerebral sulci in low-risk preterm children. Int J Devl Neuroscience 7; 559-565.
Slide 29: annectant gyri reintroduced in the “sulcal root” model
Cachia A, Roell M, Mangin JF, Sun ZY, Jobert A, Braga L, Houde O, Dehaene S, Borst G (2018) How interindividual differences
in brain anatomy shape reading accuracy. Brain Struct Funct 223:701–712
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The fissure of Rolando. pp
161-192. Extensive reference to older literature.
Mangin JF, Le Guen Y, Labra N, Grigis A, Frouin V, Guevara M, Fischer C, Rivière D, Hopkins WD, Régis J, Sun ZY (2019) "Plis
de passage" Deserve a Role in Models of the Cortical Folding Process. Brain Topogr 32(6):1035-1048.
Regis J, Mangin J, Ochiai T, Frouin V, Riviere D, Cachia A, Tamura M, Samson Y (2005) “Sulcal root” generic model: a
hypothesis to overcome the variability of the human cortex folding patterns. Neurol Med Chir 45:1–17.
Pli de passage phenomenon, namely annectant gyri buried in the depth of the main sulci.
“Plis de passage” could become an interesting benchmark for models of the cortical folding process, linking
modern biological models of cortical folding to the development of the Pli de Passage Frontal Moyen (PPFM) in
the middle of the central sulcus. Nine interrupted central sulci in the Human Connectome Project dataset were
detected and used to explore the organization of the hand sensorimotor areas in this rare configuration of the
PPFM.
The plis de passage appear in the earliest stages of development and should be regarded as a character of
cortical organization that could help decipher gyrification. The origin of the variability of their depth is
unclear, but findings on the PPFM lead to a simple hypothesis: when the tangential expansion creating the
bridging gyrus occurs early enough relative to the orthogonal expansion fathering the main sulcus, the pli de
passage can resist burial, for instance thanks to T-shape local folding patterns. This chronological hypothesis
may suggest that the depth of plis de passage is an epiphenomenon. A recent result has shown that another
superficial pli de passage in the visual word form area has a positive impact on reading skills (Cachia et al.
2018).
U-fiber organization must be impacted by the depth of plis de passage: the existence of a pli de “passage”
reaching the brain surface may increase the amount of axons connecting the functional areas located on both
side of the sulcus. Are some of the plis de passage specific to humans ? Cunningham mentioned in his seminal
work that he observed some plis de passage in chimp and orang brains (Cunningham 1890-1892). Hence, there
may exist a marked tendency in the human brain towards the breaking up of the main sulci into two or more
component parts by the formation of deep or superficial annectant gyri, but it may just be related to brain
size. Interruption of a sulcus by large annectant gyri can be depicted with both ultrasound and MRI.
Slide 30: typical annectant gyri in cranial ultrasound
Typical annectant gyri in cranial ultrasound sections of a term infant.
Slide 31: an attempt at postnatal scoring of surface development using
ultrasound
Murphy NP, Rennie J, Cooke RWI (1989) Cranial ultrasound assessment of gestational age in low birthweight infants. Archives
of Disease in Childhood 64: 569–572.
The only (not recent) published attempt at scoring gyration using cranial ultrasound in preterm infants in
neonatal intensive care.
Slide 32: nomenclature of sulci on a term brain
Term brain from Retzius with comprehensive naming of sulci, nomenclature conform to to ten Donkelaar et al.
2019.
brain images at term from Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA
Norstedt 1-167.
ten Donkelaar HJ, Tsourio-Mazoyer N, Mai JK (2019) Toward a common terminology for the gyri and sulci of the human
cerebral cortex. Frontiers in Neuroanatomy 12: artil 93.
Update on gyral anatomy with myeloarchitectonic areas (Nieuwenhuys et al. 2015).
Nieuwenhuys R, Broere CA, Cerliani L (2015) A new myeloarchitectonic map of the human neocortex based on data from the
Vogt-Vogt school. Brain Struct Funct 220(5):2551-73.
The end stage of gyrification results in complex gyration dividing the cortex in parcels with morphological and
functional unique character. Local differences in the spatial organization of myelinated fibres render it possible
to recognize areas with a different myeloarchitecture. The data available are adequate and sufficient for the
composition of a myeloarchitectonic map of the entire human neocortex: the resultant map includes 180
myeloarchitectonic areas, 64 frontal, 30 parietal, 6 insular, 17 occipital and 63 temporal. The designation of
various areas with simple Arabic numbers, introduced by Oscar Vogt for frontal and parietal cortices, has been
extended over the entire neocortex. Combined with the results of the detailed cytoarchitectonic and receptor
architectonic studies by Karl Zilles and Katrin Amunts and their associates, this yields a comprehensive
‘supermap’ of the structural organization of the human neocortex. How much of this relates to the preterm or
term neonate is unclear.
Slide 33: connections of the amygdala
Gloor P (1997) The temporal lobe and limbic system. Oxford University press.
Netter FH (1986) The CIBA Collection of Medical Illustrations. Vol. 1. Nervous System. Part I: Anatomy and Physiology. West
Caldwell, NJ: CIBA Pharmaceutical.
Nieuwenhuys R, Voogd J, van Huijzenz C (1988) The human central nervous system. Third revised edition. Springer-Verlag.
Digital version by Martin Hirsch named ‘Interbrain’.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, White LE (2012) Neuroscience. Fifth edition. Sinauer
associates.
Connections of the amygdala based on images adapted from several references.
The corticomedial group of subnuclei has connections with the olfactory bulb and the olfactory nuclei. The
basolateral group, large in humans and growing in volume as the primate species developed, has connections
with the cerebral cortex, especially the orbital and medial prefrontal cortex and the association cortex of the
anterior temporal lobe. The central group of nuclei is characterized by connections with hypothalamus and
brainstem, including such visceral sensory structures as the nucleus of the solitary tract and the parabrachial
nucleus. Other projections are to ventral striatum and to the mediodorsal nucleus of thalamus. The anterior
cingulate and frontal cortex are clearly part of the limbic system. The amygdala take part in a complex group
of nuclei under the anterior commissure that extend from the amygdala to the septum, together called ventral
(basal) forebrain: the bed nucleus of the stria terminalis and the sublenticular substantia innominata are
together referred to as extended amygdala.
The amygdala (specifically, the basolateral group of nuclei) participate in a “triangular” circuit linking
amygdala, thalamic mediodorsal nucleus (directly and indirectly via the ventral parts of the basal ganglia), and
orbital and medial prefrontal cortex. These complex interconnections allow direct interactions between the
amygdala and prefrontal cortex, as well as indirect modulation via the ventral basal ganglia. Cortical inputs
provide information about highly processed visual, auditory, somatosensory, visceral sensory, gustatory, and
olfactory stimuli. Considering these connections, the amygdala emerge as a nodal point in a network that links
together the cortical and subcortical brain regions involved in emotional processing. Thus, highly subjective
feelings can be plausibly conceived as the product of an emotional working memory that sustains neural
activity related to the processing of these various elements of emotional experience. Detecting the intentions
of others and fear are such emotional aspects controled in the frontolimbic system. Evidence is consistent with
the idea that the right hemisphere is more intimately (but not isolated) concerned with the perception and
expression of emotions than is the left hemisphere.
Most neutral sensory inputs are relayed to principal neurons in the amygdala by projections from sensory
processing areas that represent objects (e.g. faces). If these sensory inputs depolarize neurons at the same
time as inputs that represent other sensations with primary reinforcing value, then associative learning occurs
by strengthening synaptic linkages. Long-term potentiation is the mechanism behind this type of learning.
Slide 34: olfactory cortex
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
Golgi C (1875) Sulli fina struttura dei bulbi olfattorii. Riv. sper. freniat. Reggio-Emilia 1:66-78.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
Sarnat HB, Flores-Sarnat L, Wei XC 2017) Olfactory Development, Part 1: Function, From Fetal Perception to Adult WineTasting. J Child Neurol 32(6):566-578.
Sarnat HB, Flores-Sarnat L (2017) Olfactory Development, Part 2: Neuroanatomic Maturation and Dysgeneses. J Child Neurol
32(6):579-593.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Testut L, Latarjet A (1948) Traité d’anatomie Humaine, Vol. 2. Paris: Doin.
Olfactory system based on images adapted from several references.
The olfactory chemical sensor system is already active in preterm infants around 28w PMA: pure aromatic
testing under the nostrils during quit sleep or drowsiness can elicit a reflex of swallowing or a withdrawal
response e.g. to peppermint oil. Nostrils are usually patent at viable preterm age. An accessory olfactory bulb
(the vomeronasal organ of rodents) disappears in the middle trimester. An extension of the lateral ventricle the olfactory recessus - into the area of the olfactory bulb, obliterates in late second trimester, but
occasionally hydrocephalus (e.g. with preterm IVH) may cause opening of this recessus. The nasal olfactory
epithelium develops in early third trimester, with specific receptor proteins present around 28w PMA. Odorants
stimulate protrusions of these cells and open coupled G protein receptors which send axon potentials to the
olfactory bulb. From the nasal mucosa, unmyelinated axons cross the lamina cribrosa (they are the cranial
nerve nr 1), guided by specific glial ensheathing cells, and make synapses with the glomeruli at the base of the
olfactory bulb. Glomeruli are odorant-specific. Dendrites of mitral neurons in these glomeruli pick up signals
from the nasal epithelium. These signals converge on bulb mitral neurons. The neurons in the olfactory bulb
have a columnar organisation with limited lateral connections. Many olfactory receptor cells in the nose are
specific to one odor, and humans still have a large genetic library of odor receptors (around 400 different ones,
compared to around 1200 in dogs). The main output from the olfactory bulb (an interaction between mitral,
tuft and granule neurons takes place locally) is to the anterior olfactory nucleus in the olfactory bulb and tract
(akin to thalamic relay for other sensory systems), to the pyriform cortex, to the amygdala, to the entorhinal
cortex (indirectly to MD thalamus), to the contralateral olfactory bulb via the anterior commissure, to septal
nuclei and hypothalamus. The bulb neurons are present from around 18w PMA, but mature marker expression
occurs around term (NeuN, and LFB for myelin after term birth). Progenitors (vimentin positive) both in the
nasal epithelium and in the olfactory bulb, remain productive throughout life, explaining recuperation of
olfaction following e.g. infection. A regeneration cycle takes between 1 and 2 months. During fetal
development the progenitor cells migrate along the rostral migratory stream from the gangllionic eminences
into the olfactory bulb. This plasticity is also related to the idea that the olfactory bulb is capable of
generating epileptic olfactory seizure auras.
In coronal sonograms and coronal T2 MRI of good quality, the olfactory sulci can be depicted readily. MRI can
also show the olfactory tract itself.
Specific mutations can exclude odors from activity (specific anosmias). Total anosmia exists with arhinia
(absent nose base) and with arhinencephaly (wich can be unilateral). Syndromes with arhinencephaly: CHARGE
association (CHD7, 22q11.2), Kallman - de Morsier syndrome, septo-optic dysplasia, Waardenburg s.,
aneuploidies (48xxx+21) and holoprosencaphlies. Enlargement of the olfactory bulb by dysplasia is seen in
hemimegalencephaly and orbitofrontal cortical dysplasia.
Slide 35: ventral forebrain
Gloor P (1997) The temporal lobe and limbic system. Oxford University press.
Haines DE (2004) Neuroanatomy: An Atlas of Structures, Sections, and Systems. Sixth Edition. Lippincott,
Williams & Wilkins.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
The ventral forebrain is a collective term, replacing the former name of substantia innominata. It refers to the
area containing the septal nuclei (with the nu. accumbens septi), the ventral striatum and pallidum with the
anterior and inferior fused parts of nucleus lentiformis also called nucleus accumbens septi), the (cholingergic)
basal nucleus of Meynert and its anterior connected nu. of the diagonal band. This part of the forebrain is not
mentioned in lesion descriptions, but is accessible to inspection with cranial ultrasound. It is situated between
the septal area and the insular limen. Because of the presence of arterial perforators the surface is called area
perforata anterior. Inferior striate veins descend to this area and contribute to the formation of the basal vein
of Rosenthal. The extended amygdala, part of the ventral forebrain, are discussed with the amygdala.
Slide 36: hippocampus
Braak H, Braak E, Yilmazer D, Bohl J (1996) Functional anatomy of human hippocampal formation and related
structures. J Child Neurol 11; 265-275.
Gloor P (1997) The temporal lobe and limbic system. Oxford University press.
Insausti R, Amaral DG (2004) Hippocampal formation. in Paxinos G, Mai JK (Eds.), The Human Nervous System,
second ed. Elsevier, Amsterdam, pp. 871-914.
McDonald AJ, Mott DD (2017) Functional neuroanatomy of amygdalohippocampal interconnections and their
role in learning and memory. J Neurosci Res 95: 797-820.
O’Rahilly R, Müller F (2006) The Embryonic Human Brain. An Atlas of Developmental Stages, third ed. WileyLiss, Hoboken, NJ.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Šimić G, Krsnik Ž, Knezović V, Kelović Z, Mathiasen ML, Junaković A, Radoš M, Mulc D, Španić E, Quattrocolo G,
Hall VJ, Zaborszky L, Vukšić M, Olucha Bordonau F, Kostović I, Witter MP, Hof PR (2022) Prenatal development
of the human entorhinal cortex. J Comp Neurol 530(15):2711-2748.
Testut L, Latarjet A (1948) Traité d’anatomie Humaine, Vol. 2. Paris: Doin.
Hippocampus based on images adapted from several references.
the pes hippocampi or pes of the hippocampus (pes hippocampi) showing the hippocampal digitations
(digitationes hippocampi); thes leave impressions in the ventricle floor (the paw) and form external digitations
in the uncal notch; the pes forms the head or anterior segment (caput or pars anterior) and it bends towards
the midline at the junction with the body
the body or middle segment (corpus or pars media)
the tail or posterior segment (cauda or pars posterior) that also approaches the midline
the gyri of Anders Retzius or subsplenial gyri (dentes subiculi or gyri subspleniales) described by Gustav Retzius
(Retzius 1896), a series of small bumps marking the caudal limit of the CA1 field.
The parahippocampal gyrus meets the retrosplenial region caudally. Two obliquely oriented small gyri are
located above and deep to the gyri of Andreas Retzius. The medial one is the fasciola cinerea, the visible
caudal end of the dentate gyrus. The lateral gyrus, corresponding to the caudal end of the CA3 field, is the
gyrus fasciolaris. Gyrus dentatus extends rostrally into the bundle of Giacomini that crosses the uncus and
separates the apex of the uncus (CA3, former gyrus intralimbicus) from the gyrus uncinatus (CA1). Caudally the
gyrus dentatus extends into the fasciola cinerea as it becomes the induseum griseum covering the corpus
callosum.
Entorhinal cortex covers the area between sulcus rhinalis (and collateralis) and gyrus uncinatus; in adults cell
islands in layer 2 of the entorhinal cortex creat a verrucous (lattice-like) change of the surface of the rostral
gyrus parahippocampalis. This verrucous surface differs considerably between individuals. Between temporal
neocortex and entorhinal cortex is the transentorhinal region in the depth of the sulcus rhinalis, a portal of
entry for information to the hippocampus. Cytoarchitectural differentiation of the entorhinal cortex begins in
the 10th week of gestation in a superficial magnocellular layer in the deep part of the marginal zone (Simic et
al. 2022). Lamination in the entorhinal cortex differs clearly from neocortex. Up to 13w PMA there is a compact
cortex with a superfical magnocellular layer and a deeper larger layer ith smaller cells, below which waves of
migrating neurons create dense and sparse zones. At 14 w PMA the superficial lamina dissecans (LD) is visible,
which divides the cortical plate into the lamina principalis externa (LPE) and interna (LPI). Dendrites and axons
in the lamina dissecans belong to the layer above it. In the 16th week the LPE changes into vertical cell-dense
and cell-sparse zones with a caudorostral gradient. In the rostral LPE some cell islands start to form. At 20 w an
adult-like cytoarchitectural organization is visible, MBP-expressing oligodendrocytes first appear in the fimbria
and the perforant path (PP) penetrates the subiculum to reach its molecular layer and travels along through
the Cornu Ammonis fields to reach the suprapyramidal blade of the dentate gyrus, whereas the entorhinaldentate branch perforates the hippocampal sulcus about 2–3 weeks later. Lamination at 20w separates
entorhinal from neo-cortex which is still compact in the temporal lobe. At 20w cell islands are very clear in the
LPE and characteristic of permanent entorhinal cortex, the interposited clear zones contain ingrowing axons.
The LPI probably corresponds to the subplate of neocortex in formation. The first AChE reactivity (innervation
of the entorhinal cortex) appears as longitudinal stripes at 23 w in layers I and II of the rostrolateral entorhinal
cortex and then also as AChE-positive in-growing fibers in islands of superficial layer III and layer II neurons. At
40 w myelination of the perforant path starts as patchy MBP-immunoreactive oligodendrocytes and their
processes.
The efferent hippocampal system is mainly from subiculum via fimbria and fornix. The fimbria form behind the
sulcus hippocampi and uncal apex, to run caudally and become the crura fornicis at the splenium. The uncal
recessus, the mesial extenison of the temporal horn into the uncus, becomes a slit at the junction between
amygdala and pes hippocampus in the uncus; this recessus can often be seen in neonatal sonograms.
The limbic loop is fed by extensive sensory association cortical areas that project to the lateral prefrontal
cortex for planning and organisation of motor behaviour. The excursion along the limbic loop (maibly to
entorhinal cortex) adds emotional weight to behaviour and this is strongly related to memory. Hippocampus
plays a rôle in declarative (explicit, conscious) memory formation and storage: a cognitive map of acquired
kowledge is organised by hippocampus. The main information feeder is the entorhinal cortex, itself informed
by association, limbic, insular and prefrontal cortex. The entry into the hippocampus (to dentate gyrus
projection neurons) is via the perforant path. The main efferent is the gyrus cinguli via fornix and mammillary
bodies plus anterior thalamus, but storage is also organised in association cortices and ventral striatum as well
as amygdala play their rôle.
The interaction between amygdala and hippocampal formation is complex. Direct (reciprocal) connections are
between amygdalar nuclei and subiculum plus ammon's horn, indirect connections via entorhinal cortex are to
dentate gyrus. Basolateral nuclei in amygdala modulate consolidation of memories with emotional experience.
Fear conditioning and extinction are mediated by special fear and extinction neurons in the basolateral
nucleus. The amygdalohippocampal complex also generates synchronous electrocortical oscillations of differing
nature: (1) slow oscillations (1 Hz) during slow wave sleep (memory consolidation ?) and in anesthaesia; (2)
theta rythms (4-8 Hz) related to fear processing; (3) fast gamma oscillations (40-100 Hz) during appetitive
learning when information from neocortex is transferred to the hippocampus. These oscillations are formed by
glutamatergic pyramidal neurons but with a feedforward long range GABAergic modulation prior to it. Selective
absence of the amygdalar contribution (as in Urbach-Wiethe disease) eliminates declarative memory of
emotional material only, sparing memorisation of neutral material. This amygdalohippocampal network is
involved in memory dysfunction as in Alzheimer disease and in temporal lobe epilepsy.
Slide 37: hypothalamus
Hypothalamus based on images adapted from Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn.
Toronto: Collamore Press.
McNaughton N, Vann SD (2022) Construction of complex memories via parallel distributed cortical-subcortical iterative
integration. Trends Neurosci 45(7):550-562.
Slide 38: neurogenesis timelines in the embryonic and early fetal period;
neuromeres, focus on diencephalon
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Kahle W (1951) Studies on the matrix phases and the local differences in maturation in the embryonic human brain; I. The
matrix phases in general. Dtsch Z Nervenheilkd. 166(4):273-302.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Development of the matrix layer in various parts of the human brain during the first four intrauterine months.
Phases: formation, increase, decrease and depletion with ependyma formation. The diencephalic neuromere is
part of the prosencephalon, which contains diencephalon and telencephalon. The diencephalic neuromere
contains thalamus, subthalamus and metathalamus. Hypothalamus is telencephalic, but has also been referred
to as rostral diencephalon.
Slide 39: from structural definition of diencephalic nuclei to descriptions
based on molecular gradients (dorsoventral and longitudinal)
Coggeshall R E (1964) A study of diencephalic development in the albino rat. J Comparative Neurology 122:241-269.
In rat the diencephalon is divided by a vertical groove (anterior diencephalic fold, later EML external medullary
lamina) into a ventral hypothalamic part continuous with telencephalon, and a dorsal part continuous with
midbrain anterior and middle folds delimit a wedge-shaped piece of diencephalic wall in which dorsal and
ventral thalamus form behind the middle diencephalic fold develops epithalamus and this fold becomes the FR
fasciculus retroflexus. The eponyms dorsal and ventral, morphologically correct initially, are no longer used.
Scholpp S, Lumsden A (2010) Building a bridal chamber: development of the thalamus. Trends in Neurosciences 33: 373–380.
The MDO is induced at the interface of the Fez-positive prethalamus anlage and the Otx-positive MDO/
thalamus anlage. Following induction, the principal signal of the MDO – Shh – is expressed from ventral to
dorsal, possibly limited dorsally by RA signaling from the epithalamus. Shh expression within the MDO is limited
anteroposteriorly by the repressive function of neighboring transcription factors, Fez and Irx; expression of Fez
and Irx establish prethalamic and thalamic anlagen as different fields, determining their subsequent response
to Shh signaling from the MDO.
Slide 40: the diencephalic neuromere at the end of the embryonic period
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Puelles L, Harrison M, Paxinos G, Charles Watson C (2013) A developmental ontology for the mammalian brain based on the
prosomeric model. Trends in Neurosciences, October 2013, Vol. 36, No. 10
The segmental organization of the developing brain.
A diagram of a lateral view of developing mouse brain, adapted from Puelles et al. 2013. The telencephalon is
divided into pallium and subpallial regions. The septal roofplate extends from the telencephalic roof to the
developing anterior commissure. Within the terminal hypothalamus, the eye vesicle, the neurohypophysis, and
the mamillary bodies are differentiating. Within the peduncular hypothalamus, the subthalamic nucleus is
developing. The dark line represents the alar–basal boundary, also in the midbrain and diencephalon. In the
diencephalon, this molecular boundary is for a short distance pulled to the diencephalic roof as the zona
limitans (ZLi)(also called mid-diencephalic organizer), which separates p2 and p3 at alar plate levels. The
diagram shows that the developing substantia nigra extends rostrally from the midbrain into the diencephalon.
The caudal diencephalon is subdivided into three neuromeres P1-P3. Secondary organizers are further
illustrated below in the simplified scheme.
Slide 41: thalamus end of the embryonic period in a scheme of neuromeres
Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
Realistic presentation of the thalamus at the end of the embryonic period. Diencephalic neuromeres P1-P3 as
in the previous slide.
The human rostral diencephalon is subdivided into four dorsoventral zones: epithalamus, (dorsal) thalamus,
ventral thalamus and subthalamus. Hypothalamus is telencephalic according to recent molecular analyses, but
has been referred to before as the rostral diencephalon.
Epithalamus gives origin to habenular nuclei and pineal gland (epiphysis). The habenular nuclei receive their
main afferents from limbic structures (septum, hypothalamus) via the stria medullaris. The principal efferent
pathway of the habenular nuclei is the habenulo-interpeduncular tract (also known as fasciculus retroflexus or
bundle of Meynert). The habenular nuclei, the stria medullaris and the habenulo-interpeduncular tract can be
clearly distinguished before the end of the second month.
The dorsal thalamus or thalamus proper occupies initially only a narrow zone of the diencephalic wall, but this
primordium grows out and differentiates into a large nuclear complex.
During early development, prethalamus occupies a considerable sector of the wall of the diencephalon. Its
matrix zone, which never attains the width of that of the dorsal thalamus, is depleted by the end of the tenth
week.
The subthalamus, characterized by very early depletion of its ventricular matrix, produces the subthalamic
nucleus and the internal and external parts of globus pallidus.
A germinative zone lying caudally to the mamillary recess is responsible for formation of the neurons of the
subthalamic nucleus. From this site of origin, the neurons migrate radially and then tangentially and dorsally
along the marginal zone of the ventral diencephalon.
The hypothalamus forms the floor and contributes to development of the lateral walls of the third ventricle.
Its upper boundary is marked on the ventricular side by a shallow groove, the hypothalamic sulcus. The
primordia of most hypothalamic nuclei can be distinguished by the end of the third month, the lateral and
posterior hypothalamic areas as well as the supraoptic and paraventricular nuclei differentiate early (9 weeks),
and the suprachiasmatic nucleus cannot be clearly distinguished before the 23rd week.
Slide 42: nuclear separation in human thalamus in the early fetal period
Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
Transverse sections through rostral and caudal diencephalon of a human embryo of about 48 mm. Text adapted
from this reference.
The dorsal thalamus or thalamus proper occupies initially only a narrow zone of the diencephalic wall, but this
primordium grows out and differentiates into a large nuclear complex. In early embryonic stages, the thalamotelencephalic plane is more or less transversely oriented, but gradually it assumes a longitudinal orientation.
Afferent and efferent fibres connecting thalamus with the telencephalon accumulate in the ventral part of the
enlarged telodiencephalic contact zone to form the hemispheric stalk. Rostrolaterally, this fibre mass is
directly continuous with the internal capsule and caudally with the pes pedunculi. The early embryonic free
lateral surface of thalamus rotates to become its caudal surface. This apparent vanishing of the free lateral
wall of the thalamus is accompanied by caudal displacement of the anlage of the dorsal lateral geniculate
nucleus. Late in development, the enormous outgrowth of the pulvinar leads to a further ventral displacement
of the dorsal lateral geniculate nucleus.
Differentiation of the thalamus begins late and progresses slowly in comparison with the development of
ventral thalamus and hypothalamus. During the second half of the second month and the first half of the third
month, the thalamic anlage is characterized by the presence of a wide and compact ventricular zone, a cellrich mantle layer and a narrow marginal zone. The most superficial part of the mantle zone is occupied by a
sheet of densely packed cells, the thalamic plate. The dorsal lateral geniculate nucleus, which differentiates
much earlier than the remaining thalamic nuclei, develops from this plate.
The thalamic ventricular zone combines features of a ventricular matrix (interkinetic nuclear migration) with
those of subventricular matrix (proliferation in situ). Only by this combination is the thalamic anlage able to
produce the enormous number of cells required for the huge thalamic nuclear complex. Nuclear differentiation
begins at the end of the third month and 2 months later most of the adult thalamic nuclei can be readily
recognized. The central median nucleus appears shortly after the dorsal lateral geniculate nucleus and the
expansion of the pulvinar occurs relatively late.
The investigations of Rakic et al. have shown that the human thalamus, after diencephalic mitotic activity has
ceased, in addition receives a massive influx of neuroblasts from the ganglionic eminence, i.e. a proliferative
zone in the basal telencephalon. These elements form a compact, medially directed stream, which is
designated as the corpus gangliothalamicum. Its constituent cells, which are all GABAergic, contribute to the
expansion of those thalamic nuclei that project selectively to the association cortex, i.e. the medial and
pulvinar nuclei. This additional complement of neurons is imported to the thalamus during a protracted period
of fetal development, extending from the 15th to the 34th week. A comparable telo-diencephalic migratory
stream has not been identified in any other mammalian species investigated so far.
During early development, prethalamus occupies a considerable sector of the wall of the diencephalon. Its
matrix zone, which never attains the width of that of the dorsal thalamus, is depleted by the end of the tenth
week. The dorsal and ventral thalami are separated by a cell-free band, the zona limitans intrathalamica.
Within this zone, the lamina medullaris externa develops. A similar, but less conspicuous limiting zone
separates the ventral thalamus from the subthalamus and becomes the fasciculus thalamicus. The column of
grey matter between these two limiting zones represents the ventral thalamic primordium, from which the
ventral lateral geniculate nucleus, zona incerta and thalamic reticular nucleus develop, nuclei which share
GABA as a transmitter of (most of) their neurons. These nuclei differentiate early; they are already clearly
distinguishable in the second half of the third month, during which time the dorsal thalamus is still represented
by an undifferentiated primordium. Due to the expansion of the thalamic nuclear complex, the thalamic
reticular nucleus is transformed into a thin shell of neurons covering this complex rostrally, laterally and
ventrally.
Slide 43: progressive segregation of thalamic nuclei between 10 and 14
weeks PMA
Kahle W (1956). Zur Entwicklung des menschlichen Zwischenhirnes. Studien über die Matrixphasen und die örtlichen.
Reifungsunterschiede im embryonalen menschlichen Gehirn. II. Mitteilung. Dtsch Z Nervenheilk. 175, 259–318.
Mai JK, Ashwell KWS (2004) Fetal Development of the Central Nervous System. In The Human Nervous System, Second
Edition. Elsevier (USA).
Within thalamus a lateral and medial territory are recognizable at the beginning of the fetal period. In the
medial part, differentiation is delayed; in the lateral part, the ventral lateral geniculate body can be
recognized at 10 weeks. Between 10 and 14 weeks, segregation of neurons into different thalamic nuclei
begins, whereby first the lateral geniculate nucleus, then the centrum medianum and the mediodorsal nucleus
are distinguished. After 14 weeks all major thalamic nuclei can be recognized.
The definitive cytological organization is reached between 16 and 18 weeks in most parts of the thalamus,
except in pulvinar which is then still poorly developed. Cells for the pulvinar appear to proliferate in the
lateral ventricular eminence from which they enter the thalamus by a transient cell layer termed the corpus
gangliothalamicum. This structure is located under the external surface of the developing pulvinar of fetuses
from the 18th to the 34th week (Rakic and Sidman, 1969).
Molecular markers separate thalamic nuclei.
Calretinin-immunoreactive structures include the intralaminar nuclei (labeled from 16 weeks), the anteroventral and limitans nuclei (from 18 weeks), and the mediodorsal nucleus (from 22 weeks).
Calbindin immunoreactivity is helpful for the discrimination of thalamic cell groups. It is a reliable marker from
14 weeks for the ventrolateral parts of the ventroanterior and ventrolateral nuclei, and also in the
ventromedial nucleus.
The SMI-32 antibody stains neurons in the ventro-posterior lateral nucleus (VPL) from 21 weeks, in the
magnocellular part of the ventroanterior nucleus between 23 and 39 weeks, and in the anterior part of the
ventrolateral nucleus (VLA) and ventromedial nucleus (VM, lateral leaf) between 23 and 27 weeks.
SMI-32 IR thus enables to distinguish VPLs from those adjacent nuclei that are positive for calbindin. SMI-32 IR
is also found in the centrum medianum and parafascicular nucleus (CM/PF) complex.
CD15 labeling appears in the dorsal thalamus at 14 weeks, and it is not associated with radial glial processes
but with the neuropil in differentiating prospective nuclei. The occurrence of this granular CD15 labeling is
very precise in time and specific for each nucleus. It progresses from the centrum medianum and the ventral
nuclear group to the lateral and medial geniculate nuclei (16 weeks), the medial division of the ventroposterior
nucleus (VPM), and the limitans nucleus. VPL and VPM are recognized by the high CD15 reactivity and the
sharply demarcated borders between both nuclei. The pulvinar becomes progressively labeled after 20 weeks.
Slide 44: sources of cortical and thalamic GABAergic neurons in man
Coletti AM, Singh D, Kumar S, Shafin TN, Briody PJ, Babbitt BF, Pan D, Norton ES, Brown EC, Kahle KT, Del Bigio MR, Conover
JC (2018) Characterization of the ventricular-subventricular stem cell niche during human brain development. Development
145(20):dev170100.
Jones EG (2007) The Thalamus. Cambridge University Press.
Kubo KI, Deguchi K (2020) Human neocortical development as a basis to understand mechanisms underlying
neurodevelopmental disabilities in extremely preterm infants. J Obstet Gynaecol Res 46(11):2242-2250.
Letinic K, Rakic P (2001) Telencephalic origin of human thalamic GABAergic neurons. Nat Neurosci. Sep;4(9):931-6.
Miyoshi G (2018) Elucidating the developmental trajectories of GABAergic cortical interneuron subtypes. Neuroscience
Research 10.1016/j.neures.2018.09.012
Molnár Z, Clowry GJ, Šestan N, Alzu'bi A, Bakken T, Hevner RF, Hüppi PS, Kostović I, Rakic P, Anton ES, Edwards D, Garcez P,
Hoerder-Suabedissen A, Kriegstein A (2019) New insights into the development of the human cerebral cortex. J Anat.
235(3):432-451.
Paredes MF, James D, Gil-Perotin S, Kim H, Cotter JA, Sandoval K, Rowitch DH, Xu D, McQuillen PS, Garcia-Verdugo J-M,
Huang EJ, Alvarez-Buylla A (2016) Extensive migration of young neurons into the infant human frontal lobe. Science 354;
aaf7073.
Rakić P, Sidman RL (1969) Telencephalic origin of pulvinar neurons in the fetal human brain. Z Anat Entwicklungsgesch.
129(1):53-82.
Generation of gamma-aminobutyric acid (GABA)ergic cortical interneurons in human. Between 8 and 12 postconceptual weeks (PCW) expression of early ‘GABAergic’ genes associated with ventral telencephalic domains
in rodents is also very low in the human dorsal telencephon, but ‘GABAergic’ genes expressed in late progenitor
and post-mitotic cells shower higher expression, particularly in frontal temporal cortex. Interneuron migration
pathways proposed to be more prominent in human than mouse, include an anterior pathway from caudal
ganglionic eminence (CGE) to frontal cortex and a medial pathway from septum to frontomedial cortex. A
source of late GABAergic neurons is an Arc of progenitors along the lateral ventricles. This source generates
GABAergic cells along a radial migratory route at least for five months after birth (Paredes et al. 2016).
Human brain development proceeds via a sequentially transforming stem cell population in the ventricularsubventricular zone (V-SVZ)(Coletti et al. 2018). The multi-ciliated ependymal epithelium replaces stem cells
at the ventricular surface starting from around 20w PMA in humans. A distinctive stem cell retention pattern in
humans causes ependymal cells to populate the surface of the ventricle in an occipital-to-frontal wave. Stem
cells with an apical process in contact with the ventricle between adjacent ependymal cells, are gradually
reduced as radial glial cells stop their asymmetric division and finally become ependymal cells. By 7 months
few stem cells remain detected, paralleling the decline in neurogenesis. In adolescence and adulthood, stem
cells and neurogenesis are not observed along the lateral wall, contrary to findings in the rat e.g. Volume,
surface area and curvature of the lateral ventricles (gradual concave areas formed after birth in the frontal
lobe wall) all change during fetal development but stabilize after 1 year, corresponding with the wave of
ependymogenesis and stem cell reduction. The volume of the ventricles plateaus at 1-3 years whereas the total
brain volume increases further during childhood. This may have consequences for entities such as congenital
hydrocephalus, where extension of the ventricle surface may prematurely exhaust SVZ progenitors with an
apical contact at the lumen.
Corpus gangliothalamicum: early descriptions of the development of the human thalamus gave little reason
for believing that pulvinar was derived from anything other than the diencephalic wall which gives rise to the
rest of the dorsal thalamic nuclei. In 1969, however, Rakic and Sidman discovered in human fetuses what
appeared to be a massive influx of young neurons into the vicinity of the pulvinar from a proliferative region in
the wall of the telencephalon. They found that proliferation peaks in the diencephalic wall between 8 and 15
weeks in the human fetus and at the end of that period most thalamic nuclear groups except the pulvinar are
large and separated by various fiber bundles and medullary laminae. They were able to show that diencephalic
proliferation had ceased after about 15 weeks. Enlargement and differentiation of pulvinar occur well after 15
weeks and it is thought that this is accounted for by an influx of differentiated but young (bipolar) neurons
from the ganglionic eminence, a highly proliferative part of the wall of the lateral ventricle overlying the
developing caudate nucleus and in the early stages of development closely adjacent to the thalamus. Beween
16 and 34 weeks streams of bipolar cells could be observed in sectioned material passing from the ganglionic
eminence, under the region of the stria terminalis and into the dorsal part of the thalamus. These streams of
cells were named corpus gangliothalamicum. It was thought that it is they which contribute to the late
development of the pulvinar and it was speculated that they might also contribute cells to cortical areas with
which the pulvinar nuclei are connected, for these cortical areas also seem to develop late in relation to the
rest of the cortex (Rakic 1977). The ganglionic eminence does not appear to contribute telencephalic cells to
the pulvinar of other primates. There is no evidence to indicate that the thalamus of other mammals includes
cells that have their origins in the telencephalon and no evidence that elements of midbrain origin contribute
to the thalamus.
Slide 45: a complete view of brain neurogenesis; thalamic neurogenesis
highlighted
An overview of neurogenetic sources and some timing associated with them. Thalamic neurogenesis in red.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Letinic K, Rakic P (2001) Telencephalic origin of human thalamic GABAergic neurons. Nat Neurosci. Sep;4(9):931-6.
Jones EG (2007) The Thalamus. Cambridge University Press.
Mai JK, Ashwell KWS (2004) Fetal Development of the Central Nervous System. In The Human Nervous System, Second
Edition. Elsevier (USA).
Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
Slide 46: layering of the fetal brain mantle
Bystron I, Blakemore C, Rakic P (2008) Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev
Neurosci 9:110–22.
Meyer G, González-Gómez M (2018) The Subpial Granular Layer and Transient Versus Persisting Cajal-Retzius Neurons of the
Fetal Human Cortex. Cereb Cortex 28(6):2043-2058.
Rakic P, Arellano JI, Breunig J (2009) Development of the primate cerebral cortex. In Gazzaniga (ed) The cognitive
neurosciences, MIT press.
An overview of development of the cerebral cortex with revisitation of the nomenclature by the Boulder
committee. The image and scheme upper left are representative of the mantle layers at 17 weeks PMA. OSVZ
and ISVZ stand for outer and inner subventricular zone. MZ stands for marginal zone with Cajal-Retzius cells,
SG stands for subpial granular layer.
Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially from the
periolfactory subventricular zone all over the neocortex. At 14 to 18 gestational weeks, the SGL grows to attain
maximum prominence around midgestation. At 20-25 GW, a transient cell type in the MZ expresses glutamate
decarboxylase (GAD) and calretinin, and extends a varicose plexus surrounding somata of large transient CajalRetzius neurons (tCRN), potentially modulating their activity. Around 30 GW, after the disappearance of SGL a
population of persisting subpial, perivascular Cajal-Retzius neurons (pCRN) appears and remains into adult life
in the walls of sulci.
Timing of cortical genesis in the human
Stage I
Initial formation of the cortical plate (approximately the 6th to the 10th fetal weeks).
During the 7th fetal week, postmitotic cells begin to migrate from the ventricular zone outward to form a new
accumulation of cells at the junction of the intermediate and marginal zones. By the middle of this period,
synapses are present (in a bilaminar setting) above and below the cortical plate in the marginal zone and in the
pre-subplate which both contain early maturing neurons.
Stage II
Primary condensation of the cortical plate (approximately the 10th and 11th fetal weeks).
The cortical plate increases in thickness, becomes more compact, and is clearly demarcated from the fiber-rich
part of the intermediate zone, which seems to have fewer cells per unit volume, indicating that the first major
wave of migration is almost spent. This stage ends when layers 5 and 6 (the deep layers) are generated in most
regions of the cortex.
Stage III
Bilaminate cortical plate (most pronounced during the 11th to the 13th fetal week).
The uniform and compact cortical plate of the second stage becomes subdivided into an inner zone occupied
mainly by cells with relatively large, somewhat widely spaced oval nuclei and an outer zone of cells with
densely packed, darker, bipolar nuclei. This heterogeneity results from the advanced maturation of the deeplying neurons that had arrived at the cortical plate during earlier developmental stages, plus the addition of a
new wave of somas of immature neurons that take up more superficial positions. This period is characterized
by the appearance of the cell-sparse, fiber-rich subplate zone situated below the cortical plate, particularly
wide in the regions subjacent to the association areas.
Stage IV
Secondary condensation (from the 13th to the 15th fetal week).
During this period of gestation, the ventricular zone becomes progressively thinner, while the subventricular
zone remains relatively wide. The cortical plate again condensates into a uniform appearance. At the end of
this stage, an accumulation of large cells appears below the cortical plate, and the subplate zone enlarges
further, with early regional differences (also in the prefrontal cortex). For the fontal lobe a specific
transcription factor expressed here is bFGF. Thalamic input is present at this stage, in the subplate, but most
axons entering the subplate and cortex are from the basal forebrain (cholinergic) and from the brainstem
tegmentum (mono-aminergic). Endogenous oscillations emerge in subplate, independent of sensory input.
Stage V
Prolonged stage of cortical maturation (from the 16th fetal week, well into the postnatal period).
By the fifth month, relatively few neuronal precursors seem to be proliferating in the reduced ventricular zone
of the human cerebral hemispheres. However, the interneurons, which continue to be generated in the
subventricular zone and ganglionic eminence, are still being added to the cortex between the 20th and 25th
weeks of gestation. Most neurons of the human neocortex are generated before the beginning of the third
trimester of gestation, no neyrons are generated in the cortex itself. Toward term, the ventricular zone
disappears, the subplate zone dissolves, and as the intermediate zone transforms into the white matter, only a
vestige of the subplate cells remain as interstitial neurons. Glial cells produced in the SVZ including
oligodendorgcytes, largely outnumber neurons. After cortical neurons have settled in their final positions, their
differentiation, including the formation of synapses, proceeds for a long time and reaches a peak only during
the second postnatal year.
Slide 47: growth trajectory of thalamic axons into the subplate
Development of the cortex is highly influenced by an interaction of thalamic axons, first within subplate and
later within the cortical plate. Thalamic axons eventually develop into thalamic radiations. The initial
orientation is guided by molecules in subpallium and in the pallial-subpallial boundary. There exist special
corridor cells that come from the lateral ganglionic eminence LGE to organise a corridor for thalamic axons as
they shake hands with cortical axons from the areas that will be connected to them.
Time points indicate the approximate time at each turn-point.
Krsnik Ž, Majić V, Vasung L, Huang H, Kostović I (2017) Growth of Thalamocortical Fibers to the Somatosensory Cortex in the
Human Fetal Brain. Front Neurosci. 2017 Apr 27;11:233.
Kostović I, Judas M (2010) The development of the subplate and thalamocortical connections in the human foetal brain.
Acta Paediatr 99(8):1119-27.
Thalamocortical (TH-C) fiber growth begins during the embryonic period and is completed by the third
trimester of gestation in humans. TH-C axon outgrowth occurs as early as 7.5 PCW in the ventrolateral part of
the thalamic anlage. Between 8 and 9.5 PCW, TH-C axons form massive bundles that traverse the diencephalictelencephalic boundary. From 9.5 to 11 PCW, thalamocortical axons pass the periventricular area at the pallialsubpallial boundary and enter intermediate zone in radiating fashion. Between 12 and 14 PCW, TH-C axons,
aligned along the fibers from the basal forebrain, continue to grow for a short distance within the deep
intermediate zone and enter the deep CP, parallel with SP expansion. Between 14 and 18 PCW, TH-C aons
interdigitate with callosal fibers, running shortly in the sagittal stratum and spreading through the deep SP
("waiting" phase). From 19 to 22 PCW, TH-C axons accumulate in the superficial SP below the somatosensory
cortical area; this occurs 2 weeks earlier than in the frontal and occipital cortices. Between 23 and 24 PCW,
AChE-reactive TH-C axons penetrate the CP concomitantly with its initial lamination. Between 25 and 34 PCW,
AChE reactivity of the CP exhibits an uneven pattern suggestive of vertical banding, showing a basic 6-layer
pattern. Human thalamocortical axons show prolonged growth (4 months), and somatosensory fibers precede
the ingrowth of fibers destined for frontal and occipital areas. TH-C axons are early factors in SP and CP
morphogenesis and synaptogenesis and may regulate cortical somatosensory system maturation.
The central portion of voluminous thalamic fibers within the cerebral stalk (“Hemispherenstiel” of Hochstetter
and His), found in both histological and MR tractographic images, is a characteristic feature of the growth
trajectory at the telencephalic-diencephalic borders and more lateral pallial-subpallial border, below the
ganglionic eminence. Strategic points along the growth trajectory are essential for initial pathfinding. The
pallial-subpallial border is important for cortical GABAergic neuron migration. When TH-C fibers pass this
crucial morphogenetic border during the early fetal period, they enter another important crossroad area in the
periventricular space. Afterward, they fan out to form the prominent radiation that grows rather directly to
the midlateral cortex, showing short distance trajectory in the deep stratum of the intermediate zone. This
radiating growth of somatosensory TH-C fibers allows earlier interactions (1–2 weeks) with the transient SP
zone and earlier penetration of the CP (around 23 PCW). The TH-C fibers to the somatosensory cortex approach
the SP 1–2 weeks earlier than other cortical areas, and this period may correspond to the developmental
window necessary for ingrowth of callosal fibers to the somatosensory cortex.
Simultaneous interaction of TH-C axons with the subplate and CP neurons after 24 PCW explains transient
electrophysiological phenomena such as large electric waves and form an anatomical basis for early nociceptive
influence on the cortex. Early involvement of thalamic afferents in synaptic oscillatory activity of the SP
indicates a transient influence on cortical circuitry formation.
In very preterm infants younger than 24 PCW (i.e. 26 weeks of gestation), thalamo-cortical afferents
accumulate in the superficial subplate. This creates a substrate for thalamic input and action potentials are
generated under the influence of cortical neurotransmitters, including monoaminergic and cholinergic arousal
and activating systems. These first stages are not sensory-driven.
Between 24 and 26 PCW, thalamocortical afferents invade the cortical plate of corresponding target areas and
the first synapses appear within the cortical plate in a deep-to-superficial fashion. This turns cortex into a
processing system, a.o. for pain afferents. There is no cortical processing and no “feeling of pain” before 25
weeks of gestation, but after that moment evoked potentials can be recorded in sensory, visual, auditory and
frontal cortex. Innervation of deep cortical layers revealed by AChE-histochemistry closely correlates with the
appearance of synapses under electron microscopy.
Between 29 and 32 PCW, thalamocortical axons establish synapses with cortical plate layer IV neurons and
become sensory-driven. This coincides with primary gyration and differentiation of the cortical plate in the sixlayered celtype. The subplate remains thicker than the cortical plate. Dendrites are rapidly produced in the
cortex. Pain pathways to cortex are functional and NIRS monitoring can detect this. Function readily follows
anatomical development. Callosal axons grow through the periventricular zone, i.e. its so-called internal
segment and penetrate the subplate. At the bottom of cortical sulci subplate is resolved faster than in gyral
crowns. Thalamocortical axons dominate the corona radiata, radial at midlevel, sagittal at frontal and occipital
poles.
The period between 33 and 35 PCW is characterized by interhemispheric synchronization and a gradual
resolution of the subplate. From 36 PCW to the term, there is maturation of long intra-hemispheric
(associative) and interhemispheric (callosal) cortico-cortical connectivity. The subplate is still present, but it’s
delineation becomes increasingly difficult on in vivo MR due to a significant decrease in the amount of
hydrophyllic extracellular matrix, the decrease of fractional isotropy in the subplate and the appearance of the
corona radiata. It is probable that prominent size and prolonged existence of the subplate in associative
cortical regions are related to a large amount of cortico-cortical associative connections in humans.
The developmental importance of the subplate in preterm infants is reflected in (a) presence throughout the
fetal period, (b) the fact that subplate is the thickest cortical layer reaching its peak in preterm infants
between 22 and 34 weeks of gestation. The pathogenesis and the anatomical substrate of deleterious effects of
the hypoxic-ischaemic lesion of the subplate are not known. Injury to neurons, but also to the extracellular
matrix may alter axonal guidance and connectivity. This is in accordance with findings of MRI studies
demonstrating that thalamocortical axons in the somatosensory cortex may be re-routed if the developmental
lesion occurs during the ‘waiting’ period, that is, before they enter the cortical plate.
Based on the existing evidence, the period of developmental vulnerability of the TH-C fibers exists between
22 and 28 PCW, which is earlier than the vulnerability of the associative fiber system.
Moln r Z, Higashi S, L pez-Bendito G (2003) Choreography of Early Thalamocortical Development. Cerebral Cortex 13:661–
669.
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á
Thalamic axons, which carry most of the information from the sensory environment, are amongst the first
projections to reach the cerebral cortex during embryonic development. It has been proposed that the scaffold
of early generated cells in the ventral thalamus, internal capsule and preplate play a pivotal role in their
deployment through sharp gene expression boundaries. In Tbr1, Gbx2, Pax6 knock out mice both thalamic and
corticofugal projections fail to traverse the striatocortical junction. In both Emx2 and Pax6 knock out brains,
the misrouted thalamic afferents are accompanied by displacements of the pioneering projections from the
internal capsule. Regardless of their altered route, thalamic afferents in the reeler and L1 knock out mice
seem to be able to redistribute themselves on the cortical sheet and establish normal periphery-related
representation in somatosensory cortex.
Hanashima C, Molnár Z, Fishell G (2006) Building Bridges to the Cortex. Cell. 125. 24-7.
Historically, the navigation of thalamocortical axons was thought to depend on area-specific attracting signals
from different cortical regions. Because such area-specific signals had not been found in organotypic
cocultures, it was suggested that some of the guidance cues must lie outside the cortex. The early-born
cortical preplate axons descend from the cortex and extend into the internal capsule (striatocortical junction
and ventral telencephalon) before thalamocortical projections reach this region. These observations led to the
“handshake hypothesis,” in which thalamocortical and corticothalamic fibers guide each others' reciprocal
navigation. In this model, thalamocortical axons intermingle with corticothalamic fibers and use this scaffold as
they grow past one another en route to their respective targets within the cortex and the dorsal thalamus.
Gezelius H, Lopez-Bendito G (2016) Thalamic neuronal specification and early circuit formation. Develop Neurobiol 77:
830-843
Thalamocortical axons exit thalamus rostrally and turn laterally at the diencephalic-telencephalic boundary
(DTB) due to Slit2 repulsion. After crossing the cortico-striatal boundary (CSB), thalamocortical axons turn
again and grow below the cortical plate until their respective target areas.
Slide 48: the complexity of axons preceding tract formation: white matter
segments and functional tract types
Isasegi IZ, Rados M, Krsnik Z, Rados M, Benjak V, Kostovic I (2018) Interactive histogenesis of axonal strata and proliferative
zones in the human fetal cerebral wall. Brain Structure and Function 223:3919–3943.
Based on text of the previous slide, this scheme depicts different fiber types in the stratum sagittale and in the
multilaminar axonal-cellular compartment.
Slide 49: different views on layering of the fetal mantle
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Ayala R, Shu T, Tsai LH. (2007) Trekking across the brain: the journey of neuronal migration. Cell. Jan 12;128(1):29-43.
Butts BD, Houde C, Mehmet H. (2008) Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis:
implications for normal development and disease. Cell Death Differ. Jul;15(7):1178-86.
Isasegi IZ, Rados M, Krsnik Z, Rados M, Benjak V, Kostovic I (2018) Interactive histogenesis of axonal strata and proliferative
zones in the human fetal cerebral wall. Brain Structure and Function 223:3919–3943.
Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci.
32:149-84.
Kuhn S, Gritti L, Crooks D, Dombrowski Y. (2019) Oligodendrocytes in Development, Myelin Generation and Beyond. Cells.
Nov 12;8(11).
Murugan M, Ling E-A, Kaur C (2013) Dysregulated glutamate uptake by astrocytes causes oligodendroglia death in hypoxic
periventricular white matter damage. Molecular and Cellular Neuroscience 56; 342-354.
Nadarajah B, Parnavelas JG. (2002) Modes of neuronal migration in the developing cerebral cortex. Nat Rev Neurosci.
Jun;3(6):423-32.
Between 8.5 and 11 PCW, thalamocortical fibers from the intermediate zone (IZ) are initially dispersed
throughout the subventricular zone (SVZ), while sizeable axonal “invasion” occurred between 12.5 and 15 PCW
followed by callosal fibers which “delaminated” the ventricular zone-inner SVZ from the outer SVZ (OSVZ).
During midgestation, the SS extensively invaded the OSVZ, separating cell bands, and a new multilaminar
axonal-cellular compartment (MACC) is formed, increasing in complexity of the MACC in preterm infants. The
addition of associative fibers and the formation of the centrum semiovale separates the SS from the subplate.
Histogenetical changes in the MACC, and consequently, delineation of the SS on MRI, may serve as a relevant
indicator of white matter microstructural integrity in the developing brain.
A comparable but different approach to the study of these layers in fetal white matter is in the work of Altman
and Bayer. Between 24 and 32 weeks GA ongoing events comprise growth of axons, maximal growth of the
subplate and entrance of thalamic afferents into the developing cortex. Layering of the cerebral mantle,
including development of white matter and its tracts, follows complex cell production in germinal matrix
(Kriegstein and Alvarez-Buylla 2009). Specifically, during early brain development neuroepithelial cells divides
in both a symmetric and an asymmetric fashion in order to regenerate the stem cell compartment of the VZ
and to generate neurons. Neuronal migration leads to formation of the primordial plexiform layer or pre-plate
(PP) located just underneath the pia mater (Bystron et al. 2008). Subsequent migrating neurons form the
cortical plate (layers II to VI) in an “inside-out” manner splitting the preplate in an outer layer, the “marginal
zone” (MZ or layer I) containing the Cajal-Retzius cells and in the subplate (SP). Beneath the SP the
intermediate zone (IZ) is mainly formed by afferent and efferent fibers while just underneath it, the
subventricular zone (SVZ) is constituted by actively proliferating cells that gives rise to neuronal IPCs and glia
mainly in late gestation and in post-natal life (Nadarajah et al. 2002, Ayala et al. 2007).
As cells migrate between GW 9 and 20 there are concentric fields that become apparent in future white
matter: stratified transitional fields (STF, Altman and Bayer 2015). Early in this period Cajal-Retzius cells,
present in the subpial layer, orchestrate cortical plate formation. This is also the period of formation of fibers
in corticofugal, thalamocortical and commissural networks; diffusible molecules and axonal growth and
sprouting are intense during this period of cell migration. Early fibers are the optic radiation and the
sensorimotor tracts to the future pericentral area.
Cells sejourning and forming early fiber contacts form six transitional fields: STF 1: deep white matter, STF 2:
large pyramidal neurons for layer V and VI, STF 3: layer IV granular neurons (with columnar “honeycomb”
appearance in some areas), STF 4: fibers in different directions, STF 5: small pyramidal cells for layers II and
III, STF 6 callosal fibers.
Between 10.5 and 13 w GA thalamocortical fibers from the intermediate zone (IZ) are initially dispersed
throughout the subventricular zone (SVZ). Thalamocortical axonal “invasion” takes place between 12.5 and 15
w GA and is followed by callosal fiber invasion which separates the inner from the outer SVZ (Isazegi te al.
2018).
Oligodendrocyte precursors, the major myelin forming cells, are subject to stage-specific vulnerability (preoligodendrocyte stage) being selectively affected by different insults based on the maturation stage and with
glutamatergic excitotoxic cell death as common pathway (Butts et al. 2008, Murugan et al. 2013, Kuhn et al.
2019).
Slide 50: postmortem 3T MRI of fetal white and grey matter in axial and
coronal T2W fast spin-echo sequences
Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb Clin Neurol 171:245-289.
Top: Postmortem magnetic resonance imaging (PMMRI) performed on a 3.0 T scanner of non-fixed in situ fetal
brains assessed within 24h from death. Axial T2-weighted (T2W) fast spin-echo (FSE) images performed on
fetuses from 19th to 28th gestational week (gw) studied after therapeutic termination of pregnancy (TOPs) due
to extracranial abnormalities or after spontaneous intrauterine death. From left to right are depicted a 19th
(A), 20th (B), 21st (C), 22nd (D), 28th (E) gw brain fetuses respectively. It can be seen the laminar organization
of the cerebral hemispheres and signal changes of the posterior limb of the internal capsule (PLIC) with respect
to the surrounding brain structures at different gestational ages. Between 19 and 20 gw the PLIC (*) is clearly
more hypointense compared to the adjacent thalami (white arrow) and the lentiform nuclei (black arrow).
From 21 to 22 gw due to the progressively more hypointense signal of the mesial part of the lentiform nuclei
and the antero-lateral part of the thalami, the contrast between the PLIC and these structures decrease. At 28
gw the PLIC is relatively hyperintense compared to the thalami and nuclei pallidi.
Bottom: Coronal T2W-FSE PMMRI images of the same fetuses as in figure 1 in which it can be seen again the
signal changes of the PLIC (*) with respect to the adjacent brain structures between 19 and 28 gw. The laminar
organization of the cerebral hemispheres at different gw is clearly visible as well. From 19 to 28 gw the
cerebral hemispheres show transient layers from the pia to the ventricle that becomes progressively less
separate and more blurred into each other. From 19 to 22 gw the cerebral hemispheres show the following
transient layers: marginal zone (MZ), cortical plate (CP), subplate (SP), intermediate zone (IZ). The SP is no
longer visible at 28 gw when a clear demarcation between the SB and the IZ doesn’t exist anymore. The
markedly hypointense layer recognizable along the ependymal surface of the thalami-caudate notch and at the
level of the temporal horn of the lateral ventricle corresponds to the germinal matrix (GM) and is well evident
from 19 to 28 gw although progressively smaller.
Slide 51: commissural and projection fibers
Fibers are organised into tracts, with several large functional subtypes.
Slide 52: projection tracts of the internal capsule
ten Donkelaar H, van der Vliet T (2014) Overview of the Development of the Human Brain and Spinal Cord. Ch 1 in: ten
Donkelaar HJ, Lammens M, Hori A: Clinical Neuroembryology: Development and Developmental Disorders of the Human
Central Nervous System.
The corticospinal tract is an important fiber bundle in the internal capsule.
Pyramidal tract development drives motor development and is therefore of interest to cerebellar development
(Ten Donkelaar et al. 2014). Fibers from layer V in the perirolandic area (sensory asw ell as motor) and in
premotor and cingulate cortex, form the corticospinal tract (CST). The level of decussation in the lower
medulla is reached by fibers around the end of the embryonic period. Such fibers have to be chemically guided
in a complex manner, from origin (pre- and suplate at first and later cortical plate, semaphorins), via internal
capsule (netrins 1, slit 2, NRx2.1) to spinal cord, through decussation (absence of a vimentin-positive midline
glial septum). Fasciculation (L1CAM) and prevention of back-crossing in the cord (ephrins) are further essential
steps. The lower spinal cord is reached by fibers around 29w GA. Direct cortico-motoneuronal connection in the
human is late (around 6 months of age) in monkeys compared to humans (just before term). Humans thereafter
have a very prolonged myelination stage (up to the age of 2 years), explaining discrepancy between early
target contact and late functional maturation (skilled finger movements). The shift in shortened electrical
response speed from bilateral around birth to unilateral and crossed, happens between 3 and 18 months of life.
Variations are common (normal partial decussation in 67 %): asymmetrical decussation, absence of decussation.
Slide 53: the mature posterior limb with tracts at the level of thalamus and
striatum, relation of tracts to SMA and PMA
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press. “Modified and included with
permission of the publisher.”
The posterior limb of the internal capsule and its tracts.
Slide 54: cortical tracts involved in motor function
Almasri O (2011) An essay on the human corticospinal tract: history, development, anatomy and connections. Neuroanatomy
10; 1-4.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, White LE (2012) Neuroscience. Fifth edition. Sinauer
associates.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press. “Modified and included with
permission of the publisher.”
The medial ventral horn contains lower motor neurons that govern posture, balance, locomotion and orienting
movements of the head and neck during visual fixation. These medial motor neurons receive descending input
from pathways that originate mainly in the brainstem, course through the anterior-medial white matter of the
spinal cord, and then terminate bilaterally.: reticulospinal, vestibulospinal and tectospinal tracts. The lateral
ventral horn contains lower motor neurons that mediate the expression of skilled voluntary movements of the
distal extremities. These lateral motor neurons receive a major descending projection from the contralateral
motor cortex via the main (lateral) division of the corticospinal tract, which runs in the lateral white matter of
the spinal cord and from the rubrospinal tract.
The term motor cortex is commonly restricted to the primary motor cortex located in the precentral gyrus and
the paracentral lobule. The primary motor cortex can be distinguished from a complex mosaic of adjacent
“premotor” areas both cytoarchitectonically and by the low intensity of current necessary to elicit
movements by electrical stimulation in this region. The pyramidal cells of cortical layer 5 are the upper motor
neurons of the primary motor cortex. Among these neurons are the Betz cells, which are the largest neurons
(by soma size) in the human CNS. In the human CNS they account for no more than 5% of the axons that project
from the motor cortex to the spinal cord. Despite their small numbers, Betz cells play an important role in the
activation of lower motor neurons that control muscle activities in the distal extremities. The remaining
smaller, non-Betz pyramidal neurons of layer 5 are found in the primary motor cortex and in each division of
the premotor cortex. The axons of these upper motor neurons descend in the corticobulbar (also called
corticonuclear) and corticospinal tracts, terms that are used to distinguish axons that terminate in the
brainstem (“bulbar”) or spinal cord. The components of this upper motor neuron pathway that innervate
cranial nerve nuclei, the reticular formation, and the red nucleus (that is, the corticobulbar tract) leave the
pathway at the appropriate levels of the brainstem. There is also a massive corticobulbar projection that
terminates among nuclei in the base of the pons that project in turn to the cerebellum; this projection is often
called the corticopontine tract. Just before entering the spinal cord, about 90% of the corticospinal axons
decussate to form the lateral corticospinal tract. The remaining 10% constitute the bilateral ventral (anterior)
corticospinal tract. The ventral corticospinal pathway arises primarily from dorsal and medial regions of the
motor cortex that serve trunk and proximal limb muscles—the same divisions of the motor cortex that give rise
to projections to the reticular formation. Some of the lateral corticospinal axons (including those derived from
Betz cells) synapse directly on α motor neurons that govern distal extremities: this privileged contact is
restricted to a subset of α motor neurons that supply the muscles of the forearm and hand. This distribution
implies a special role for the lateral corticospinal tract in the control of the hands. It explains the limited
recovery in humans after damage to the motor cortex or some component of this pathway. Some ability to
perform voluntary movements reappears, but they are presumably mediated by residual corticospinal inputs
and by motor centers in the brainstem, and are crude for the most part. Some components of the corticobulbar
and corticospinal projections are derived from layer 5 neurons in somatosensory regions of the anterior parietal
lobe and terminate among local circuit neurons near the sensory trigeminal nuclei and dorsal column nuclei of
the brainstem, and in the dorsal horn of the spinal cord. They are likely involved in modulating the
transmission of proprioceptive signals and other mechanosensory inputs relevant to sensory perception and the
monitoring of body movements.
Focus on the function of nucleus ruber.
Gruber P, Gould DJ (2010) The red nucleus: past, present and future. Neuroanatomy 9, 1-3
RNm nucleus ruber magnocellular:
- this part is phylogenetically regressive
- regression parallels acquisition of bipedal stance
- this regression parallels expansion of the corticospinal tract, and then the rubrospinal tract becomes a
backup motor pathway mainly for influencing upper limb control in primates
- this tract is predominant in fetus and newborn.
RNp nucleus ruber parvocellular:
- greater movement repertoire (independent arm-hand movements) in mammals induces more extensive
development of neocerebellum and of this part of the red nucleus
- this is integrated in a loop cerebellum - red nucleus - inferior olive: triangle de Molaret
- this loop is not only active in motor but also in sensory activity e.g. for coordinated finger movements,
object discrimination
- rôle in antinociceptive response, perhaps also in migraine.
Cacciola A, Milardi D, Basile GA, Bertino S, Calamuneri A, Chillemi G, Paladina G, Impellizzeri F, Trimarchi F,
Anastasi G, Bramanti A, Rizzo G. The cortico-rubral and cerebello-rubral pathways are topographically
organized within the human red nucleus. Sci Rep. 2019 Aug 20;9(1):12117.
The Red Nucleus (RN) is a large nucleus located in the ventral midbrain: it is subdivided into a small caudal
magnocellular part (mRN) and a large rostral parvocellular part (pRN). These distinct structural regions are part
of functionally different networks and show distinctive connectivity features: the mRN is connected to the
interposed nucleus, whilst the pRN is mainly connected to dentate nucleus, cortex and inferior olivary
complex. The pRN and mRN cannot be distinguished using conventional MRI, but high-quality structural and
diffusion MRI data permit connectivity-based segmentation of the human RN. The RN can be subdivided
according to its connectivity into two clusters: a large ventrolateral one, mainly connected with the cerebral
cortex and the inferior olivary complex, and a smaller dorsomedial one, mainly connected with the interposed
nucleus.
Slide 55: the nucleus ruber in the mesencephalic crossroad of fibers
Fiber tracts near the red nucleus.
Triangle de Molaret: dentate nucleus to red nucleus to inferior olive.
Slide 56-58: histological myelination sequence; leukomalacia of the preterm
brain
Although up to now myelination cannot be studied with CUS, in this slide an overview is given of sequences of
myelination in postmortem study. This information is needed to study quality and quantity of myelination with
MRI, often performed in confirmation of lesions detected with ultrasound.
Preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and
economic burden. The risks are inversely proportional to maturity at birth. In the majority of extremely
preterm infants (<28 weeks' gestation), injury is associated with exposure to multiple inflammatory perinatal
triggers that include antenatal infection (i.e., chorioamnionitis), hypoxia-ischaemia, and various postnatal
injurious triggers (i.e., oxidative stress, sepsis, mechanical ventilation, haemodynamic
instability, effects of drugs)(Ophelders et al. 2020). These perinatal insults cause a self-perpetuating cascade of
peripheral and cerebral inflammation that plays a critical role in the etiology of diffuse white and grey matter
injuries that underlies a spectrum of connectivity deficits in survivors from extremely preterm birth. Even
survivors without CP and with normal IQ can develop specific deficits in motor coordination, attention,
language and learning. Candidates for clinical trials are total body hypothermia for moderate preterms,
suppletion of stem cells to control the local inflammatory response (both innate and acquired), suppletion of
annexin A1 to stabilise the blood-brain barrier, trophic support of the pre-oligodendrocyte … Timing of such
treatment will be much more complex than for cooling in the context of intrapartum asphyxia, where the
molecular cascade is relatively well known.
PVL can be classified in two patterns: focal necrosis (cystic PVL) and a more diffuse and cell-specific lesion to
premyelinating oligodendrocytes accompanied by astrogliosis and microgliosis (diffuse leukomalacia). In both
conditions, oligodendrocyte precursors (the major myelin forming cells), undergo changes in morphology and
antigenic profile expressing several different superficial antigen over times. Pre-OLs refers to both the 04positive, 01-negative pre-oligodendrocyte and the 01-positive immature oligodendrocyte. The 04-positive cell
comprises approximately 90% of the oligodendroglial population until about 28 weeks of gestation but even at
term accounts for 50%. The 01-positive cell accounts for only about 10% of the oligodendroglial population of
the premature infant but is also vulnerable. The 01-positive cell does not reach 50% of the total
oligodendroglial population until term in the human brain. From animal experiments and clinical experience
preterm white matter at 28-30 weeks PMA is especially vulnerable. There is regional heterogeneity in white
matter development that explains prefential damage to deep white matter, most vulnerable seems to be the
subcentral area. The final lesion is due to loss of axons and due to insufficient myelination. Primary white
matter damage leads to secondary grey matter changes in cortex and thalamus, explaining associated grey
matter “dysmaturation”. The cortex above a cystic whte matter lesions is severely aletered. There is no doubt
that imaging (ideally with both ultrasound in series and with a TEQ MRI scan) can predict some aspects of
outcome following preterm white matter injury (Martinez-Biarge et al. 2016 and 2019). Categories of injury
include: Ia focal non-cystic lesions numbering < 6 foci, Ib focal non-cystic lesions numbering more than 6 foci, II
limited small cyst formation, III extensive cystic change near the ventricles, IV extensive cystic change near the
ventricles but also extending into the subcortex. The risk of CP in grades I and II is about 1/10 and 9/10 in
groups III and IV.
The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischaemia and
systemic infection/inflammation, both of which are common occurrences in premature infants. Cofactors are
partial-pressure passivity of the cerebral circulation and postnatal acute hypocarbia. In animal models
inflammation (e.g. induced by LPS) potentiates the effects of hypoperfusion. The potentiation has caused
subthreshold ischaemic insults to still lead to white matter injury.
Three downstream mechanisms are documented: microglial activation, excitotoxicity and free radical attack.
Elucidation of these factors has lead to experimental (and limited clinical) study of early treatment of white
matter injury. These cells are subject to stage-specific vulnerability (pre-oligodendrocyte stage, pre-OL) being
selectively affected by different insults based on the maturation stage and with glutamatergic excitotoxic cell
death as common pathway and via free radical injruy to the oligodendrocyte (Butts et al. 2008, Volpe et al.
2011, Murugan et al. 2013, Kuhn et al. 2019). Although these lost pre-oligodendrocytes may be replaced in
focal circumscript lesions by new cells from the subventricular zone and/or by abundant local proliferation, the
latter seem not to follow the normal developmental trajectory to produce mature myelin.
As for the possible excitotoxic mechanism, in a postmortem report the presence of NMDA receptors in human
control brains over a long postconceptional range into adulthood, were compared with 10 instances of white
matter injury (although very few with typical PVL around 30w PMA) (Jantzie et al. 2015). In normal white
matter, NR1 and NR2B levels were highest in the preterm period compared with adult. In gray matter, NR2A and
NR3A expression were highest near term. NR2A was significantly elevated in PVL white matter, with reduced
NR1 and NR3A in gray matter compared with uninjured controls. These data suggest increased NMDAR-mediated
vulnerability during early brain development due to an overall upregulation of individual receptors subunits, in
particular, the presence of highly calcium permeable NR2B-containing and magnesium-insensitive NR3A
NMDARs. These data agree with an intrinsic prenatal vulnerability to glutamate-mediated injury.
Neuroimaging data suggest that VLBW infants are exposed to recurrent hypoxic-ischaemic and infectious/
inflammatory insults. With both recurrent upstream insults inhibition of pre-OL development could occur by
persistent toxicity to pre-OLs or by direct activation of receptors on pre-OLs to inhibit development.
With recurrent hypoxia-ischaemia all three downstream mechanisms persist. Accumulation of DAMPs (danger
associated molecular products) with recurrent hypoxia-ischaemia would result in both microglial activation and
inhibition of pre-OL maturation via TLRs. Similarly, activation of the downstream mechanisms of excitotoxicity
and microglial activation by recurrent hypoxia-ischaemia would cause persistence of ROS/RNS and free radical
attack.
Major maturation-dependent factors underlying the three downstream mechanisms in PVL (Volpe et al. 2011)
- Free radical attack
Vulnerability of pre-OLs to free radical attack
Abundant production of both ROS and RNS in PVL (by pre-OLs, microglia, astrocytes)
Delayed development of antioxidant defenses in pre-OLs - Acquisition of Fe2+ by pre-OLs
- Excitotoxicity
Vulnerability of pre-OLs to excitotoxicity
Exuberant expression of major glutamate transporter (source of glutamate) by pre-OLs
Exuberant expression on soma of pre-OLs of AMPA receptors, which are deficient in the GluR2 subunit
and therefore are Ca2+ -permeable
Exuberant expression on neurites of pre-OLs of NMDA receptors, which also are Ca2+ -permeable
Likely mechanism of excitotoxicity is receptor dependent generation of ROS/RNS and non-receptor
dependent glutathion depletion
- Microglial activation
Central role of microglia in free radical generation
Microglia, especially abundant in PVL; potent sources of ROS/RNS
Presence of TLRs on microglia; activation results in release of free radicals
Maturation-dependent concentration of microglia in normal cerebral white matter
Microglial activation releases potentially injurious cytokines
TNFalpha derived from microglia in diffuse PVL
TNFalpha potentiates the maturation-dependent toxicity to pre-OLs by interferon gamma
(interferon gamma expressed in astrocytes in diffuse PVL and its receptor expressed in
pre-OLs)
Microglial activation impairs glutamate transport and accentuates excitotoxicity
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Slide 59: development of commissures
Nomenclature and development of the commissures.
from Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Slide 60: development of corpus callosum on two anchors
Modified from Barkovich AJ, Raybaud C. Pediatric Neuroimaging , 5th ed. Philadelphia: LWW; 2012:371–372.
- in week 8, olfactory commissural fibers cross the midline through the ventral aspect of the lamina reuniens
-
to form the anterior commissure; in the following weeks, fibers develop between the anterior mediobasal
cortex (septal nuclei) and the future hippocampus to form the ipsilateral fornix
about week 11, some fornical fibers cross the midline in the dorsal portion of the lamina reuniens and form
the hippocampal commissure; during week 12, the corticoseptal boundary becomes defined at the medial
edge of the future neocortex and a glial sling forms along this boundary
by week 13, three commissural sites have been established: anterior commissure, hippocampal commissure
and glial sling
depending on their origin, early neocortical commissural fibers cross the midline along the anterior
commissure (temporo-occipital fibers), the glial sling (frontal fibers), or the hippocampal commissure
(parieto-occipitotemporal fibers); corpus callosum grows by adding further commissural fibers and forms a
single continuous structure stretched between the anterior commissure and the hippocampal commissure; it
circumscribes the future septum pellucidum; later, development of the frontal lobes results in posterior
growth of the anterior corpus callosum, which displaces the hippocampal commissure and the splenium
backward above the velum interpositum (roof above the third ventricle), stretching the body of the fornix
Slide 61: development of commissures: anomalies and functional end stage
Development of commissures: anomalies and functional end stage.
Raybaud C (2010) The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy,
development, and malformation. Neuroradiology (2010) 52:447–477.
Slide 62: archicortex and paleocortex displacement by development of the
corpus callosum; hippocampal curling
Basma J, Guley N, Michael Ii L, et al. (January 23, 2020) The Evolutionary Development of the Brain As It Pertains to
Neurosurgery. Cureus 12(1): e6748.
Gloor P (1997) The temporal lobe and limbic system. Oxford University press.
Archicortex and paleocortex are displaced by development of the corpus callosum; hippocampal curling is a
time-related event:
- the dentate gyrus curls medially at the tip of the hippocampal formation
- the entorhinal cortex is also shifted medially
- the cornu ammonis is moved laterally, forming an "S" shape on coronal sections
- dentate gyrus loses its connection with the hippocampus proper and curls as an independent C structure
around the end of the latter
- entorhinal cortex and parahippocampal gyrus (from the dorsal pallium) move medial relative to the
hippocampus
- the limbic rotation moves the hippocampus from the roof to the floor of the ventricle.
Slide 63: thalamic regions and their cortical projections (functional loops)
Jones EG (2007) The Thalamus. Cambridge University Press.
Mai JK, Majtanik M (2019) Toward a common terminology for the thalamus. Frontiers in Neuroanatomy 12: article 114.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, White LE (2012) Neuroscience. Fifth edition. Sinauer
associates.
Sherman SM, Guillery RW (2001) Exploring the thalamus. Academic Press.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Thalamus plays a role in many brain functions, including: (i) processing and integration of sensory information;
(ii) regulation of consciousness, arousal, awareness, emotion and attention; and (iii) modulation of the
pyramidal and extrapyramidal motor systems. In addition to relaying information, the nuclei control executive
networks and regulate complex behaviors, such as flexibility and reward-directed behavior. Many aspects of
thalamic function are but partially understood (Sherman and Guillery 2001, Jones 2007).
Thalamic nuclei are grouped into functional regions: sensory, motor, limbic, intralaminar and associative
nuclei. A specific rôle is played by the thalamic reticular nucleus. Thalamus is the largest structure of the
diencephalon. It has two parts: (1) the allothalamic part (midline nuclei + centre-median-parafascicular
complex + intralaminar region); (2) the isothalamic part, which is the bulk of thalamus, containing many nuclei
(50-60 in number per side), with “bushy” neurons and “microneurons”, and with most of its reciprocal
connections directed to the cortex. The reticular nucleus (in prethalamus) and the intralaminar nuclei project
diffusely to many areas of the cortex and have been coined “nonspecific” nuclei. The central nuclei project not
only to cortex but also back to striatum. There are in addition connections between thalamus and the
amygdala.
The internal medullary lamina (lamella) divides thalamus into four major areas: a medial region on one side
and a (ventro-)lateral region on its other side. The anterior part of the internal medullary lamina splits into
two lamellae, which surround the anterior region. The cell groups resident within the internal medullary
lamina in the caudal part are named intralaminar nuclei, where the lamella splits over the large “centre
médian”. Behind these four regions, the fifth is a large posterior region, less well delineated at its anterior
end. To these five regions can be added both lateral geniculates (referred to as metathalamus), the
paramedian region, the regio basalis and the thalamic reticular nucleus as separate functional units.
A thalamic 'region' is a gross topographic division corresponding to a large functional cortical area. A 'territory'
is defined as the cerebral space filled by afferent endings from one source.
Slide 64: anatomy of thalamus: nuclei and tracts
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Scheme adapted from Smith and van der Kooy 1985 to show the main thalamic regions, their nuclei and the
afferent and cortical efferent connections.
Slide 65: anatomy and function of thalamus: nuclei, drivers and modulators
Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
Sherman SM, Guillery RW (2001) Exploring the thalamus. Academic Press.
Scheme adapted from Nieuwenhuys et al. 2008 to show the main thalamic regions, their nuclei and the tracts
in relation to the internal capsule.
On the right a summarizing scheme of a thalamic triad, to explain the diferrence between drivers and
modulators, between glutamatergic stimulating neurotransmission and GABAergic inhibitory neurotransmission.
Relay cells express these complex events by either tonic or burst firing. Driver neurons (relaying information
via ionotropic glutamate receptors) are controlled by modulator neurons (relaying information via
metabotropic glutamate receptors) and interneurons within every nucleus.
Slide 66: connectivity and functional diversity of thalamus
Jones EG (2007) The Thalamus. Cambridge University Press. Nakagawa Y (2019) Development of the thalamus: From early
patterning to regulation of cortical functions. Wiley Interdiscip Rev Dev Biol 8(5):e345.
Sherman SM, Guillery RW (2001) Exploring the thalamus. Academic Press.
Steriade M (2005) Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends in Neurosciences 28; 317-324.
Usrey WM, Sherman SM (2019) Corticofugal circuits: Communication lines from the cortex to the rest of the brain. J Comp
Neurol 527(3):640-650.
Connectivity and function of thalamus.
Two distinct orders of thalamic nuclei are proposed on the basis of their afferent fibres (drivers) from
ascending pathways and/or from the cerebral cortex (Sherman and Guillery 2001, Jones 2007, Nakagawa et al.
2019, Usrey and Sherman 2019): (i) first-order nuclei receive primary afferent fibres from ascending subcortical
pathways and receive corticothalamic afferents from cortical layer 6, which also sends branches to the
reticular nucleus; (ii) higher order nuclei receive primary afferents from pyramidal neurons of cortical layer 5,
lacking a branch to the reticular nucleus, and they transmit information about the output of one cortical area
to another cortical area (association and limbic nuclei), which can be between first order and higher order
cortical area or between two higher order cortical areas. The difference is the driver input, which is
subcortical for a first order relay and from layer 5 of cortex for a higher order relay. A feature of driver inputs
to thalamus is a thick axon with a large terminal innervating a proximal dendritic site, often in complex
synaptic zones known as glomeruli. Thus all thalamic relays receive an input from layer 6 of cortex, which is
mostly feedback, but higher order relays in addition receive a layer 5 input from cortex, which feeds
information forward to other cortical areas.
The topographic organisation of the subcortical afferents at the level of the thalamic nuclei is mainly
contralateral, but some nuclei have bilateral subcortical afference.
Pyramidal cells in cortical layers 5 and 6 are the only cells with axons that leave the cortex to influence
thalamus. Layer 6 cells provide modulatory feedback input to all thalamic nuclei. Layer 5 cells provide driving
input to higher-order thalamic nuclei and do not innervate first-order nuclei. Higher-order nuclei innervated by
layer 5 cells thus seem to be involved with cortico-thalamo-cortical communication. The layer 5 axons branch
to also target subcortical structures that interact with the external environment.
Interaction between thalamus and cerebral cortex is crucial to understand the EEG. Corticofugal projections
provide positive feedback to the “correct” thalamic input, while at the same time suppressing irrelevant
information: a given thalamic neuron receives excitation from a small cortical area that shares the same
stimulus selectivity (“egocentric selection”). The cortico-thalamo-cortical loops amplify cortical oscillations
(fast synchronous rhythms), but thalamoic neurons control the slow oscillations. Within thalamus exist powerful
mechanisms that promote synchronous and phasic 3 Hz activity. In normal circumstances inhibitory synaptic
responses, including those from the thalamic reticular nucleus, are required for this network synchronisation.
Thalamic reticular neurons in burst mode synchronise thalamic and cortical activity during slow wave sleep and
some forms of epilepsy, but on the contrary they fire in tonic mode in wake or during REM sleep (Steriade
2005). Precisely how injury to thalamus or disruption of the thalamic reticular nucleus in the newborn lead to
pediatric sleep associated epilepsy is not clear, but the entity is well recognized.
Slide 67: subthalamic functional loops
Subthalamic functional loops. Subthalamus plays a rôle in three functional loops and is therefore not just a
motor integrator. Information from cortex via globus pallidus (ansa lenticularis and fasciculus lenticularis) and
from brainstem (nucleus ruber and substantia nigra) is integrated in subthalamus for further processing in
thalamus and hypothalamus. This area is dense with tracts.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Slide 68: germinal matrix development and fragility, corrolary of neurogenesis
(end stage of the protomap)
Upper left image after Kinoshita Y, Okudera T, Tsuru E, Yokota A. Volumetric analysis of the germinal matrix and lateral
ventricles performed using MR images of postmortem fetuses. AJNR Am J Neuroradiol. 2001 Feb;22(2):382-8.
Lower left image after Paneth N, Rudelli R, Kazam E, Monte W (1994) Brain Damage in the Preterm Infant. Clinics in
Developmental Medicine No. 131. London: Mac Keith Press.
Text also available from Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb Clin Neurol
171:245-289.
Raets MM, Dudink J, Govaert P (2015) Neonatal disorders of germinal matrix. J Matern Fetal Neonatal Med 28 Suppl
1:2286-90.
Germinal matrix
Between 24 and 32 weeks of gestational age (GA) brain maturation is at a critical stage with ongoing events
such as growth of axons, maximal growth of the subplate and entrance of thalamic afferents into the
developing cortex. The germinal matrix (GM) or subventricular zone is a richly vascularized, transient layer at
the surface of the ventricles, which is present in the fetal brain between 8 and 36 weeks of gestation (1). GM
volume (GMV) reaches its maximum at 23-26 weeks gestational age (1-3). Scott et al. studied 48 MRI scans of
39 fetuses in utero between 20-31 weeks of gestation. Using motion-corrected, automatic segmentation they
showed that GMV peaks at 25 weeks GA, which is corroborated by histological studies (4,5). Reduction of this
volume occurs site specific and is continues until the subventricular zone regresses at 36 weeks. Part of the
subventricular zone persists as a source of progenitor cells, providing interneurons for the olfactory bulb as
well as oligodendrocytes through adulthood (6). GM is considered the ‘factory’ for production of most brain
cells: glutamatergic projection neurons, GABAergic interneurons and oligodendroglial as well as astroglial
precursors in the latter part of pregnancy. After 15 weeks the subventricular zone becomes the predominant
site of cell generation, forming ganglionic eminences along the lateral walls of the frontal horns of the lateral
ventricles (5,7). Neuroblasts derived from the eminences migrate tangentially to reach the cortical anlage
along a scaffold of radial glial fibers. GE precursor cells first migrate laterally (radially) and then change
direction, entering tangential migration. Tangential migration is also seen in thalamic pulvinar as interneurons
there arise from the telencephalic GM and migrate to the diencephalon during 5-8 months of gestation. As GM
is a major source for oligodendrocytes, their number can be reduced and differentiation impaired due to
haemorrhage; this may contribute to white matter injury (7).
GM vulnerability and GMH
The fragility of vessels in GM is well known but partly understood. Haemodynamic factors seem to cause wall
rupture in small venules in many preterm infants (8). Preterm brain haemorrhage occurs primarily in GM (GMH
or germinal matrix haemorrhage) but neither in cortex nor in white matter (WM)(9). Matrix vascular density is
increased compared to parenchyma of WM and cerebral cortex (10). The vascular network of GM is complex,
but regular anatomic schemes such as arterioles, capillaries and veins are not present (11). GM vasculature
drains along subependymal veins, in which medullary veins from the deep white matter coalesce between
matrix and caudate head (12). At 23 weeks of GA thin-walled subependymal veins are well identified in GM;
they mature with increasing GA (11,12). Pericytes are diminished in these vessels in human fetuses and preterm
infants: both coverage and density were reduced in GM vasculature compared with WM and cortex (13). In the
mouse, pericytes mature with delayed presence of desmin-positive pericyte coverage (rôle in cell stability) in
germinal matrix (24); contrary to the human the number of pericytes in mice germinal matrix is not lower than
in cortex; vascular maturation is by increasing number of vessels parallel to matrix size, not by enlargement of
vessels. Blood-brain barrier (BBB) components include endothelial tight junctions, astrocyte end-feet
coverage, basal lamina and capillary pericytes: all play a role in stabilisation of microvessels. Weakness of any
of those components can predispose to GMH (14). Changes in BBB permeability correlate with the distribution
of tight junction proteins (15), although the maturational rôle of tight junctions in development of GMH is still
controversial. In human brains pecimens at 24 weeks tight junction roteins like ZO-1, claudin and occludin are
present in germinal matrix (thin discontinuous lines), but they are more abundant in cortical vessels (thick lines
and nodes)(22). El-Khoury et al. (9) studied perivascular coverage by astrocyte end-feet in GM compared with
WM and cerebral cortex from 16 to 40 weeks GA. They documented decreased expression of the glial fibrillary
acidic protein (GFAP) in end-feet along the vasculature of the GM compared with WM and cerebral cortex
between 24-32 weeks GA. End-feet coverage possibly plays a role in the fragility of GM vasculature.
Laminin, type IV collagen and heparin sulphate proteoglycan perlecan form the basal lamina of cerebral
vasculature. Together with the basal lamina, fibronectin, present in extracellular matrix, also plays a role in
providing structural stability of vessels. Xu et al. (14) found that fibronectin protein levels in the GM were
significantly lower than WM or cerebral cortex. Fibronectin levels in WM and cortex increased significantly with
advancing GA, but not in GM. The expression of type IV collagen chains and perlecan are not different between
cortex, WM or GM (16). Laminin α1 had a higher expression in GM compared with WM and cortex, the other
chains did not differ. However, mutations in type IV collagen are known to cause fetal brain haemorrhage,
hydrocephalus, porencephaly, cerebellar destruction and arterial aneurysms (17). Prenatal lung ripening with
glucocorticoids (GC) has contributed to increased survival and less morbidity in preterm infants. The incidence
of GMH-IVH is reduced by 50%. In a histopathological study of rabbits and human fetuses, prenatal GCs
stabilized GM vasculature through suppressed angiogenesis, pruned neovasculature and enhanced pericyte
coverage (18). In animal studies indomethacin inhibits prostaglandin synthesis and decreases cerebral blood
flow. Ment et al. demonstrated that indomethacin in beagle pups led to increased deposition of collagen V and
laminin, and this increase stability of the basal lamina probably explains the reduction in incidence of IVH (19).
In a mouse model of limited GMH (not large IVH and no venous infarction) where GMH was created in anterior
subventricular matrix on one side with injection of blood of the mouse itself, it was demonstrated that there is
an increase of transient amplifying progenitors cells (21). This increased cell production seems to exhaust the
cell lines prematurely, because in the cortex above the lesion neurons do not increase in number.
Oligodendroglial differentiation (after increased proliferation on the lesion side) is also reduced in this model,
best observed in the corpus callosum near the ventricle. Cell death is not conspicuous in this model that shows
how GMH may interfere with cell maturation in neuronal and glial lines.
The association of cuffs of matrix cells above the caudate head, to veins crossing through matrix, is important
for two reasons (23). The close relation between veins and matrix cells is another argument in support of the
hypothesis that most GMH instances follow distension of veins in the matrix, and not primary thrombosis.
Secondly, the matrix cells form a cuff around the vein, the cuff itself is borderd by a glial scaffold and from
this perimeter processes extend to the vessel itself. This provides corridors for cell migration well documented
in matrix and in surrounding parenchyma. This guided migration by glial processes resembles chain migration,
e.g. in the corpus gangliothalamicum for thalamus.
Using staining with alklaine phosphatase (arteries and capillaries, not veins) and collagen A4 (all vessels)
Anström et al. challenge the old idea that capillary fragility is the main reason for bleeding in preterm
germinal matrix (25). In fact there are three different vascular areas in matrix. A superficial subpendymal
network has predominantly venous vessels organised in a plexus of around 50 µm thick. A central area is vesselpoor but it has small arteries, venules and capillaries, some with alignement perpendicular to the ependymal
line; in this area clusters of matrix cells may form a package lined by vessels and glial (GFAP-positive) fibers,
whereas other areas lack this clustering and have vessels oriented in all directions. Finally, near the caudate
head both veins and arteries form a dense cluster of vessels. There is no evidence of interarterial border zones
in this study. Capillaries in the matrix do not differ in maturity from those in cortex, but many small veins with
somewhat larger caliber are prdsent, and they are the most likely site of vessel disruption in preterm GMH, not
the capillaries.
In summary fragility of GM microvasculature is not likely due to lack of collagen, laminin or perlecan.
Fibronectin is significantly lower in GM compared with WM and cortex and therefore might play a role. Tight
junction protein levels in GM are comparable with WM and cortex levels, however these tight junctions are
immature at 23 weeks of gestation and mature with increasing GA. Perivascular coverage by astrocyte end-feet
is immature in GM. Prenatal use of GCs stabilizes GM vasculature. Prophylactic use of indomethacin might have
a protective effect on the development of GMH. The description of the complex interaction between clinical
risk factors and maturation in development of GMH/IVH is beyond our discussion here (20).
1. Kinoshita Y, Okudera T, Tsuru E, Yokota A. Volumetric analysis of the germinal matrix and lateral ventricles performed
using MR images of postmortem fetuses. AJNR Am J Neuroradiol. 2001 Feb;22(2):382-8.
2. Battin MR, Maalouf EF, Counsell SJ, Herlihy AH, Rutherford MA, Azzopardi D, et al. Magnetic resonance imaging of the
brain in very preterm infants: visualization of the germinal matrix, early myelination, and cortical folding. Pediatrics. 1998
Jun;101(6):957-62.
3. Habas PA, Kim K, Corbett-Detig JM, Rousseau F, Glenn OA, Barkovich AJ, et al. A spatiotemporal atlas of MR intensity,
tissue probability and shape of the fetal brain with application to segmentation. Neuroimage. 2010 Nov 1;53(2):460-70.
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brain tissues estimated from 3D reconstructed in utero MRI. Int J Dev Neurosci. 2011 Aug;29(5):529-36.
5. Del Bigio MR. Cell proliferation in human ganglionic eminence and suppression after prematurity-associated
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nervous system. J Neurochem. 2008 Sep;106(6):2272-87.
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22. Anstrom JA, Thore CR, Moody DM, Brown WR (2007) Immunolocalzation of tight junction proteins in blood vessels in
human germinal matrix and cortex. Histochem. Cell Biol 127; 205-213.
23. Anstrom JA, Thore CR, Moody DM, Challa VR, Block SM, Brown WR (2005) Germinal matrix cells associate with veins and
a glial scaffold in the human fetal brain. Developmental Brain Research 160; 96-100.
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Slide 69: progenitors and cerebral cortical cell neurogenesis in a protomap,
early mantle layering
García-Moreno F, Molnár Z (2015) Subset of early radial glial progenitors that contribute to the development of
callosal neurons is absent from avian brain. Proc Natl Acad Sci U S A 112(36):E5058-67.
Meyer G, González-Gómez M (2018) The heterogeneity of human in subpallium neurons. Semin Cell Dev Biol
76:101-111.
Montiel JF, Wang WZ, Oeschger FM, Hoerder-Suabedissen A, Tung WL, García-Moreno F, Holm IE, Villalón A,
Molnár Z (2011) Hypothesis on the dual origin of the Mammalian subplate. Front Neuroanat. 5:25.
Price D, Jarman A, Mason J, Kind P (2001) Building brains: an Introduction to neural development, first edition.
John Wiley & sons.
CRN are the first (or at least very early) neurons of the developing cortex, characterized by presence of reelin
that interacts with migrating neurons on their lipoprotein ApoER2 and VLDR (initiating Dab1 adaptor protein).
This system organizes layering of the cortex with the typical inside-out migration. Transient (t) and persisting
(p) Cajal-Retzius neurons (CRN) share the expression of Reelin and Tbr1 (present in all pallial glutamatergic
cells), complemented by p73, calretinin, CXCR4 and NOS. They differ in their moment of appearance, fate and
morphology (Meyer and Gonzalez-Gomez 2018). Initially tCRNs come from cortical neuroepithelium at 5w PMA
and are deposited in collumns perpendicular to the surface above the preplate. Additional sources of CRNs are:
basal forebrain and septum, the pallial cortical hem (parallel to explosion of the SVZ in the ganglionic
eminences), the thalamic eminence, the amygdalar hem, the ventral cortical hem and the subpial granular
layer. tCRN form an axon plexus in the low marginal zone, which innervates the apical dendritic tufts of
pyramidal cells tCRNs may serve as a migration substrate and waiting compartment for interneurons descending
from the subpial granular layer (SGL) into the cortical plate. Around midgestation, the SGL also gives rise to a
transient interneuron type, the miniature neuron, that provides GABAergic innervation of tCRN, which
eventually, through diverse signaling pathways involving p73, contribute to the demise of tCRN (in part due to
the changing character of GABAergic transmittors from stimulating to inhibiting rôle, interfering with the life/
death protein p73) and the breakdown of their plexus (starting around 23-25w PMA). Around 25-27 wPMA the
reelin signal seems no longer needed as the migration of neurons is nearly complete. The pCRN appear in the
last trimester of gestation and may derive from committed CRN progenitors which migrate with the SGL from
the periolfactory forebrain. They lack the horizontal CR plexus, and may be implicated in cortical folding,
distribution of blood vessels and plasticity of microcircuits in the molecular layer. NO from mature CRNs can
play a rôle in vasoactivity during sulcation (expression mainly in the dept and walls of a sulcus in formation).
Germinal matrix is the third trimester equivalent (derivative) of the neuroepithelium, which is present along
the ventricles and in the (sub)pallial germinative zones. The neocortex is entirely built from a protomap of
neurogenetic events in the neuroepithelium. First cells are produced asymmetrically in the ventricular zone,
then symmetrically in the subventricular zone. Following migration to the subplate, preplate and later into the
definitive cortical plate, these cells produce the complex layering of the cerebral cortex mainly just before
and after viable preterm age. During migration they explain in part the complex layering of the intermediate
zone, the later white matter. Not only neurons (with neurotransmitter synthesis) but also glial cells stem from
the same progenitor cells.
RGC (Emx2+) can renew themselves, be directly neurogenic (asymetric division with one daughter cell as a
neuroblast) and be indirectly neurogenic (one daughter cell is an intermediate progenitor cell that will divide
in the SVZ). Pyramidal neurons are generated in a temporal sequence, with all radial glial cells (RGCs)
contributing to both lower and upper neocortical layers. A subgroup of fate-restricted RGCs in the early
neocortex generates only upper-layer neurons (Garcia-Moreno and Molnar 2015). The lineage of selected Emx2+
RGCs has sequential and fate-restricted programs in mouse. Among a large assortment of sequentially
programmed RGCs in the mouse brain, a subset of self-renewing Cux2+ progenitors lack neurogenic potential
during the earliest phase of corticogenesis, but after a delay generate callosal upper-layer neurons and glia.
Neurogenic delay of selected RGCs (“heterochrony”) may be unique to mammals and possibly associated with
the evolution of the corpus callosum. This delayed division plays a rôle in expansion of the supragranular
layers.
Corticofugal and thalamo-cortical axons extend toward each other at early stages but both stop short of their
ultimate targets: corticofugal projections from subplate and layer VI accumulate in the thalamic reticular
nucleus (TRN) and thalamo-cortical projections accumulate in subplate.Toward the middle of the first postnatal
week (in rodents) corticofugal and corticopetal axons enter the thalamus (Th) and cortical plate (CP),
respectively, where they arborize and establish their contacts with their ultimate targets in thalamus and
neocortex.
Slide 70: from patterning centers and gradients in the neuroepithelial
protomap to different areas in the cortex
Rakic P, Ayoub AE, Breunig JJ, Dominguez MH (2009) Decision by division: making cortical maps. Trends in Neurosciences
Vol.32 No.5
Rakic and coworkers explain how cortical areas develop from a periventricular neuroepithelial protomap. The
first sign of cortical regionalization is the emergence of molecular gradients in the embryonic cerebral vesicles.
The onset of diversification of neural stem cells in the proliferative VZ coincides with the appearance of
patterning centers, which exert their influence in a rostro-caudal and medio-lateral extent. Patterning centres
express gradients of progenitors based on the genetic expression of different molecules. Before refinement of
the cortex by experience, a set of markers already organise the primitive neocortex. Graded expression
patterns of factors is responsible for shaping the ultimate neocortical landscape that is highly partitioned and
specialized. A greater list is available at: http://rakiclab.med.yale.edu/pages/molecules.php.
Id2: Inhibitor of DNA binding 2
Lhx2: LIM homeobox 2
Lmo3: LIM domain only 3
ROR-ß: retinoid-related orphan receptor ß
Slide 71: neurogenesis and gliogenesis from the same precursors in the
neuroepithelial protomap
Hoerder-Suabedissen A, Molnar Z (2015) Development, evolution and pathology of neocortical subplate neurons.
Neuroscience 16: 133-146.
Meyer G, González-Gómez M (2018) The Subpial Granular Layer and Transient Versus Persisting Cajal-Retzius Neurons of the
Fetal Human Cortex. Cereb Cortex 28(6):2043-2058.
Molnár Z, Clowry GJ, Šestan N, Alzu'bi A, Bakken T, Hevner RF, Hüppi PS, Kostović I, Rakic P, Anton ES, Edwards D, Garcez P,
Hoerder-Suabedissen A, Kriegstein A (2019) New insights into the development of the human cerebral cortex. J Anat.
235(3):432-451.
Sarnat HB (2021) Transitory and vestigial structures of the developing human nervous system. Pediatric Neurology 12;
86-101.
Neuroepithelial cells (NPCs) undergo symmetric cell division to produce an initial pool of cortical progenitors
that later transform into ventricular radial glia cells (vRGCs). vRGCs begin asymmetric cell division to generate
another vRGC and a projection neuron that migrates radially from the ventricular zone (VZ) along the basal
process of a RGC into the cortical plate (CP). The earliest born neurons migrate to form the preplate. Later
migrating neurons split the preplate into the marginal zone (MZ) and subplate (SP). As neurogenesis proceeds,
diverse subtypes of neurons are generated through the successive asymmetric division of RGCs. Early-born
projection neurons settle in the deep layers (layers 5 and 6). Some populations of RGC daughter cells become
intermediate progenitor cells (IPCs) or outer radial glial cells (oRGCs) in the subventricular zone (SVZ).
After the neurogenic stages, the radial scaffold detaches from the apical surface and vRGCs become gliogenic,
generating astrocytes, or transform into ependymal cells.
Tangential migration of interneurons is observed in the MZ, intermediate zone (IZ) and SVZ.
Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially from the
periolfactory subventricular zone (near the rhinencephalic ventricle) to spread all over the neocortex by 16w
PMA (not at hippocampus). At 14 to 18 gestational weeks, the SGL grows to attain maximum prominence around
midgestation. After 22w the layer regresses to be rudimentary at term. The astocytes in the SGL probably
function in arresting cells in their radial migration process, to avoid overmigration into the pial layer.
At 20-25 w PMA, a transient cell type in the MZ expresses glutamate decarboxylase (GAD) and calretinin, and
extends a varicose plexus surrounding somata of large transient Cajal-Retzius neurons (tCRN), potentially
modulating their activity. Around 30 GW, after the disappearance of SGL a population of persisting subpial,
perivascular Cajal-Retzius neurons (pCRN) appears and remains into adult life in the walls of sulci.
The early marginal zone contains mature large Cajal-Retzius neurons, which form a synaptic plexus before the
first wave of radial neuroblast migration begins, from the same origin of later GABAergic thalamic neurons.
Other sites of origin of Cajal-Retzius cells also have been identified. These early-maturing neurons secrete the
extracellular glycoprotein Reelin (RLN), essential for the normal inside out positioning of radial migratory
neurons. The cortical plate forms from radial and tangential migration in the middle third of the primitive
marginal zone. The superficial third of the primitive marginal zone containing Cajal- Retzius neurons becomes
the molecular zone or layer 1 of the mature cerebral cortex. Cajal-Retzius cells occur only in the neocortex,
not in the hippocampus or in any subcortical structures. Cajal-Retzius neurons are GABAergic and are strongly
immunoreactive for calcium-binding proteins such as calretinin and parvalbumin. These neurons form long
transverse axons within the molecular zone of the maturing cortex.
A rôle for the reelin pathway is discovered in experimental genetic work, in the control of cell positioning in
the developing central nervous system and this predicts a pattern of cytoarchitectural alteration in patients
carrying alterations in the Reelin/lipoprotein receptor/Dab1 pathway, as well as Reln mutations causing
lissencephaly. Cajal-Retzius neurons are not, therefore, transitory neurons but remain as scattered vestiges
when their function in lamination of the cortex is completed.
Slide 72: subplate at viable preterm age
Hoerder-Suabedissen A, Molnar Z (2015) Development, evolution and pathology of neocortical subplate
neurons. Neuroscience 16: 133-146.
Kubo KI, Deguchi K (2020) Human neocortical development as a basis to understand mechanisms underlying
neurodevelopmental disabilities in extremely preterm infants. J Obstet Gynaecol Res 46(11):2242-2250.
Montiel JF, Wang WZ, Oeschger FM, Hoerder-Suabedissen A, Tung WL, García-Moreno F, Holm IE, Villalón A,
Molnár Z (2011) Hypothesis on the dual origin of the Mammalian subplate. Front Neuroanat. 5:25.
Price D, Jarman A, Mason J, Kind P (2011) Building brains: an Introduction to neural development, first edition.
John Wiley & sons.
Neocortical excitatory neurons are generated from the radial glial cells in the VZ, and these early-born neurons
invade the preplate. Migrating late-born neurons move past the SP, splitting this layer away from the Cajal–
Retzius cells. Therefore, the preplate is split into a superficial marginal zone (future layer I), in which the
Cajal–Retzius cells remain adjacent to the pial surface, and a deep SP. Reelin, a molecule secreted from the
Cajal–Retzius cells, is thought to play an essential role in controlling the arrangement of the neurons that later
form the cortical plate. With progression of development, neurons are generated not only in the VZ but also in
the subventricular zone (SVZ). The neurons generated in the SVZ are finally distributed in all layers of the
cortex, but many neurons are especially localized in the superficial layers (layers II and III). In the primate
(including human) fetal brains, the SVZ is further subdivided into two regions, the outer SVZ (OSVZ) and the
inner SVZ (ISVZ). The SVZ is prominently expanded in human fetal brains and contains numerous progenitor
cells. These cells extend long radial processes toward the pial surface. They have been named as OSVZ radial
glia-like (oRG) cells. Their number is significantly higher in primates, including humans. Consequently, OSVZ
supplies a large amount of neurons, especially to the superficial layers of the neocortex.
Subplate mot likely contains both ancestral and newly derived cell populations: originally derived from a
phylogenetically ancient structure in the dorsal pallium of stem amniotes, subplate subsequently expanded
with additional cell populations in the synapsid lineage to support an increasingly complex cortical plate
development (Montiel et al. 2011). The subplate in humans appears from around 14 w PMA. TBR1+ neurons are
continuously added to the subplate between 14 and 25 w PMA. By 6 months post term age, the subplate is no
longer recognizable. Neurons in large quantities have been dispersed or have disappeared due to programmed
cell death, but the fact that this disappearance is regionally inhomogenous suggests some selectivity in the
continued function around term and in the first months of life.
In rodents, the width of the SP remains smaller than that of the CP throughout neurodevelopment. In contrast,
in humans, the width of the SP increases, becoming severalfold greater in width than the CP between 22 and
28 GWs (peak width around 24w and disappearance after 32w PMA). However, after 26–28 GWs, the ‘waiting’
fibers start to invade the upper-lying CP to establish ‘wirings’ to their targets and the SP gradually resolves and
decreases in size, in parallel with the development of gyri and sulci in the neocortex. Approximately 10–20% of
the SP neurons survive and remain in the WM as the so-called interstitial white matter neurons.
The neurons of the subplate mature earlier than most surrounding neurons, and it was proposed that this
makes them particularly vulnerable to hypoxic injury during late gestation and in the perinatal period. Preterm
birth or perinatal hypoxic–ischaemic injuries are risk factors for both epilepsy and schizophrenia. Recent
evidence suggests that subplate cells do not die in excess compared to other deep-layer neurons in rat model
ischaemia. Similar cell death across all cortical layers is also reported following oxygen–glucose deprivation in
an in vitro assay. There is no particular imaging correlate of specific subplate injury in the perinatal period (so
far).
Subplate neurons have also been investigated for their contribution to epilepsy, autism, bipolar disorder and
schizophrenia.
Drug-resistant epilepsy is often accompanied by cortical dysplasias, in which large groups of cells may be
abnormally located within white matter.
Excess numbers of neurons within the superficial white matter have been documented in post-mortem samples
from some (not all) patients with schizophrenia. Interstitial white matter neurons (identified by NADPH
diaphorase (NADPHd) staining) were abnormally distributed in the dorsolateral prefrontal cortex of brains from
patients with schizophrenia.
Post-mortem histopathological analysis of autistic brains revealed various cellular and structural abnormalities.
Supernumerary mature-looking neurons in white matter (presumed to be interstitial neurons) were identified in
a number of adult brains of patients with autism. MRI of brains of patients with autism spectrum disorders
revealed an indistinct boundary between grey and white matter, possibly also indicating supernumerary
subplate neurons.
Vasung L, Lepage C, Rados M, Pletikos M, Goldman JS, Richiardi J, Raguz M, Fischi-Gomez E, Karama S, Hupi PS,
Evans AC, Kostovic I (2016) Quantitative and Qualitative Analysis of Transient Fetal Compartments during
Prenatal Human Brain Development. Frontiers in Neuroanatomy, vol 10, article 11.
A study of subplate thickness (and other brain substructures) in postmortem 3T MRI findings. Standardised
images at 24 and 30w PMA clearly show peak size of the subplate. After 28w PMA the subplate decreases in
size. Around 10-20 % of subplate neurons survive in subcortical white matter (interstitial neurons).
Slide 73: subplate function in early neocortical development
Dereymaker A (2017) Automated EEG analysis to quantify brain function in preterm and term neonates, thesis
KULeuven.
Luhmann HJ, Kanold PO, Molnar Z, Vanhatalo S (2022) Early brain activity: translations between bedside and
laboratory. Progress in Neurobiology 213; 102268.
Luhmann HJ, Kirischuk S, Kilb W (2018) The superior function of the subplate in early neocortical development.
Frontiers in Neuroanatomy 12; art 97.
Milh M et al. (2007) Rapid cortical oscillations and early motor activity in premature human neonate. Cereb.
Cortex 17, 1582–1594.
Montiel JF, Wang WZ, Oeschger FM, Hoerder-Suabedissen A, Tung WL, García-Moreno F, Holm IE, Villalón A,
Molnár Z (2011) Hypothesis on the dual origin of the Mammalian subplate. Front Neuroanat. 5:25.
Molnar Z, Luhmann HJ, Kanold PO (2020) Transient cortical circuits match spontaneous and sensory-driven
activity during development. Science 370, eabb2153, 1-9.
Subplate is not just a “waiting” zone for thalamo-cortical fibers. Subplate postmigratory neurons (SPN) have a
large morphological variety, resembling later layer 6B neurons. Axonal arborisation is dense in the subplate, but
axons also extend into the cortex and subcortex. Subplate neurons can be glutamatergic as well as GABAergic.
GABAergic neurons contain a parvalbumin-positive subgroup, a somatostatin subgroup and a 5HT3a (serotonin)
subgroup. A fraction (< 20 %) of subplate neurons survives in adulthood with longe-range connections from the
lower cortical layers or the subcortical white matter (layer 6b, 7 or subgriseal layer); these neurons are
integrated int synaptic networks (rôle in cortical state transitions ?). The remainder is lost via programmed cell
death, in part due to pruning of thalamic input.
Subplate neurons lack a distinct common molecular marker, although at least seven genes are known to be
specifically expressed in subplate neurons: neurexophillin 4, nuclear receptor related 1, complexin 3, inositol
phosphate 4 phosphatase II, connective tissue growth factor, 5HT 1D receptor and tumor protein D52-like 1.
Nurr 1 and Cplx3 are glutamatergic neuron-specific. TBR1+ neurons are continuously added to the subplate
between 14 and 25 w PMA.
In primates the majority of SPNs are generated before the cortical plate has been formed and the generation of
the SP continues until around mid-gestation. The invasion of monoamine, basal forebrain, thalamocortical and
corticocortical axons may regulate the region-dependent dispersion of SPNs. The majority of early born SPNs
are generated in the ventricular zone. A subpopulation of early born SPNs is generated in the rostromedial
telencephalic wall. Other GABAergic SPNs originate in the medial ganglionic eminence to reach the developing
neocortex via tangential migration. Subplate neurons, among the first excitatory cortical neurons, are involved
in neurotransmission and produce burst firing. They are spontaneously active (depolarisation waves via
connexin hemichannels) but also susceptible to mild sensory stimulation via afferents. This occurs long before
thalamic axons reach definitive cortical layer 4.
Input:
Glutamatergic: thalamocortical (e.g. sound evoked responses), from other subplate neurons (probably active in
amplification of incoming thalamocortical activity), from the developing cortical plate.
GABAergic: from other subplate neurons, from cortical areas (even callosal projections; one is from deep
cortical layers and another projection is from the entire cortex).
Other: nicotinic, cholinergic (organising oscillatory events), glycine (modulating excitability), purines (from
astrocytes), serotonin.
Output:
within subplate
long distance: cortex (glutamatergic to layers 1 and 4, GABAergic to CRNeurons) (auditory, somatosensory),
dorsal thalamus via internal capsule, contralateral hemisphere via corpus callosum, colliculus superior.
Early functions.
SPNs probably do not generate, but rather instruct (transmit and amplify) activity patterns (in rodents) (in
somatosensory, visual, auditory and motor cortex):
- spindle bursts with a frequency of 10–25 Hz (recorded with EEG in preterm infants)
- early gamma oscillations with a frequency of 30–50 Hz; the current sink of this early activity is located in the
inner layer of the cortical plate (future layer 4) and in the SP.
This activity probably regulates maturation of intracortical inhibition and is the blueprint for development of
thalamocortical activity. There may also be some control of radial neuronal migration in subplate, which may
play a rôle in some epilepsies.
Hypoxia-ischaemia damages the subplate in newborn rats, which may influence later plasticity. The most likely
clinical correlate of SP injury is preterm white matter damage, where a depressed EEG background and a
reduction in burst activity have been documented (Pogledic et al. 2014, Ranasinghe et al. 2015: references in
Milh et al. 2007).
Direct evidence for pathological changes of different cellular elements (neurons, glia, ECM, and axons) of the
SP during hypoxic-ischaemic episodes in the fetal or preterm human brain is lacking. Lesions of the voluminous
thalamo-cortical fibers may partly explain the reduction of cerebral volume in infants born prematurely. Based
on the existing evidence, a period of developmental vulnerability of these fibers may exist between 22 and 28
PCW, earlier than the vulnerability of the associative fiber system.
Developmental stages in spontaneous activity:
1. Cajal-Retzius and subplate neurons at 17-23 w PMA discharge faster action potentials at higher frequency
than cortical plate neurons; this activity is isolated and asynchronous, occurs via gap junctions;
2. subplate and cortical neurons electrically coupled by gap junctions generate: local synchronized activity
(driven by thalamus, which is not yet activated from brainstem) in small networks or propagating activity
waves; subplate neurons pioneer both thalamocortical and corticothalamic connections;
3. discharges become faster and local networks (subplate dependent) discharge in synchronized bursts with
delta-activity (spindle bursts) or gamma-bursts; cortical oscillations (in specific circuits) and giant depolarising
potentials emerge; these bursts are spontaneous, thalamus driven or driven by other cortical areas; transient
early-born neurons start to disappear; higher-order thalamic nuclei seem to provide most early projections to
matched cortical areas (the default mode) whereas primary sensory areas are induced by sensory activity at
later ages; this early period is characterized by a high degree of multisensory projections, especially to higherorder thalamic nuclei; first-order thalamic projec- tions target L4 and provide inputs to L6a; higher-order
thalamic inputs target L5 and L1; only first-order thalamic nuclei provide collaterals to nucleus reticularis
thalami; L5 projections first provide input to higher order thalamic nuclei, this default system is overruled by
later sensory experience;
4. appearance of adult-like sparse desynchronized activity independent of transient neurons and circuits, due
to progressively stronger impact of peripheral sensory input.
Disorders of subplate function.
The spread of spontaneous activity in the thalamocortical network and cerebral cortex is broader in the human
preterm as compared with the term infant, evident from resting-state EEG connectivity in the 8- to 15-Hz
frequency band (spindle burst). Sensory, motor, default mode, frontoparietal, and executive control networks
develop at different rates, before the sensory periphery is fully functional. Subplate is fully integrated into
cortical circuits and may influence resting-state networks before term birth. It is postulated that early
transient circuits form the basis for activity patterns in the preterm and that the pathophysiological
persistence of these circuits is involved in the manifestation of neurological and psychiatric disorders: these
early networks are vulnerable to hypoxia-ischaemia and to drugs like valproic acid; in temporal lobe epilepsy
persisting subplate neurons may play a rôle in pathogenesis.
Subtypes of subplate neurons probably mediate lemniscal, paralemniscal and nonlemniscal development:
alterations in different subplate circuits may cause different diseases, some of higher-order thalamic
dysfunction and others due to network asynchrony. Persistent subplate and Cajal-Retzius neurons might play a
role in cognitive disorders.
Maturation of the EEG.
Dereymaker A (2017) Automated EEG analysis to quantify brain function in preterm and term neonates, thesis
KULeuven.
Luhmann HJ, Kanold PO, Molnar Z, Vanhatalo S (2022) Early brain activity: translations between bedside and
laboratory. Progress in Neurobiology 213; 102268.
In the neonatal EEG, bursting activity is a clearly identifiable and mechanistically distinct form of brain
activity. Burst description covers burst occurrence (burst percentage), interburst intervals, its fluctuation as an
index of sleep state, the internal structures of the burst such as frequency content or waveform shape.
Neuronal interactions in the EEG signal can be studied by estimating phase synchrony and amplitude
correlations, also referred to as intrinsic coupling mode. These coupling modes take place within or between
oscillatory frequencies across brain-wide networks. It is now well established that several networks may coexist to give rise to various higher brain functions, while each network reveals also a highly dynamic changing
pattern over different time scales. In the context of early development, a particularly interesting mode is
phase-amplitude coupling (a.k.a. nestedness) (Vanhatalo et al. 2005), which implies correlation between higher
frequency amplitude and lower frequency phase.
At the cortical level various forms of activity (spontaneous and induced) intermingle, and their electrical
signatures are diverse. Work in rodents has revealed that centrally generated events show higher
synchronization and larger amplitude than peripherally generated events. One hallmark of cortical spontaneous
activity is its oscillatory nature. The frequency content of the oscillations changes with development. Although
the developing brain shows age-dependent patterns of continuous EEG activity and elaborate EEG classification schemes for preterm and full-term infants exist, animal studies suggest that the subdivision of the
various activity patterns into distinct events can be questioned. In clinical settings it seems to be more
appropriate to see the ongoing activity patterns of the immature brain as a singular class of discrete events
termed “spontaneous activity transients” (SATs) (for review Vanhatalo and Kaila, 2006).The temporal structure
of certain events is generally far more complex than thought from superficial “by eye analysis”. The amplitude
of high-frequency activity may be coupled to the phase of a slower oscillation (phase-amplitude coupling or
nested oscillation). Spindle bursts and delta brushes are examples of such nested oscillations in the EEG that
can be easily identified. However, the EEG analyses become more challenging when the neuronal activity is
very slow (as in infraslow activity) or when the high-frequency component exceeds 30 Hz. Local evoked activity
often triggers network-wide reactions.
In early premature infants, EEG shows very low amplitude continuous activity interrupted by brief high
amplitude bursts, spontaneous activity transients (SATs), with nested oscillatory activity at higher frequencies.
The SATs are poorly synchronized between hemispheres. At term age, the continuous EEG activity has become
higher amplitude and the SAT events are longer duration, more complex and more synchronized across cortical
areas. At post-neonatal age, the EEG activity shows continuous activities at higher frequencies and the
intermittent SAT type activities have disappeared.
A particular type of cortical bursting in an early preterm infant is readily seen in the EEG signal after
somatosensory, visual or auditory stimulation, which all result in a largescale complex event near the
corresponding sensory cortices. These events interact with the cortical bursts that occur without external
sensory stimulation, and recent animal work suggests that the subplate is centrally involved.
Rakic P, Arellano JI, Breunig J (2009) Development of the primate cerebral cortex. In Gazzaniga (ed) The cognitive
neurosciences, MIT press.
Early human frontal lobe development
Circuitry
Activity
Embryonic
6–7 PCW
Nonsynaptic preplate network
Oscillating, spontaneous
Type of Activity
Early fetal
8–14 PCW
Two synaptic strata, in SP and
Transient spontaneous
MZ; cholinergic (basal forebrain) modulated by monoamines
and monoaminergic (tegmentum)
afferents; regional differences
Endogenous (not sensory
dependent)
Midfetal and
late fetal
15–23 PCW
Transient lamination in marginal
zone, prominent SP with
synaptogenesis (60 %
glutamatergic, 40 % GABAergic),
no layer IV yet in CP; output to
striatum, pons and spinal cord;
highly developed subventricular
zone producing neurons and glial
cells
Transient spontaneous,
modulated by extrinsic
thalamic afferents and
axons from basal forebrain
and amygdala
Endogenous + brain stem
and cholinergic basal
forebrain (not sensory
dependent)
Early
preterm
24–32 PCW
The peak of SP, afferents in CP
from thalamus (non-sensory MD
nucleus for frontal lobe), MZ has
sublayers and a subpial granular
layer, initial lamination in the
cortical plate; predominantly
glial cell production in SVZ
Transient circuitry
(subplate, intrinsic) and
permanent (cortical plate)
thalamocortical afferents
coexist; output to striatum
(Muratoff bundle) into
developing striatal cell
islands; increasing
projection and commissural
fibers
Endogenous; SATs emerge
from around 24w,
transform around 30w and
disappear near term; first
general movements
Late preterm 33–35 PCW
Primary gyration achieved,
secondary gyration active; CP
layers differ from mature
pattern; synaptogenesis in CP,
pyramidal differentiation,
cytoarchitectonic belts;
decreasing SP size parallel to
development of white matter in
corona radiata; glial cell
production but still migrating
late-arriving neurons
Second wave of dendritic
differentiation in the
cortical plate; coexistence
of increasingly permanent
and transient circuitry;
exuberant callosal fiber
formation and developing
long associative fascicles,
external capsule and
cingulate fasciculus
Sensory-sensitive
asynchrony (EEG) but in
general more continuous
EEG; synaptic production
independent of afferent
input ?; switched cortical
dipole (now predominantly
superficial generation of
electrical activity);
writhing general
movements
Neonatal
1–2 months
Tertiary gyration; long afferents
within the target; layer V
pyramids differentiation;
ubiquitous granular layer IV;
wide transition layer VI to
disappearing subplate
Permanent circuitry with
transient elements;
extensive dendtritic
formation in CP and SP,
rapidly increasing number
of synapses
Sensory-sensitive
synchrony (rapidly
changing electrical
activity), few remaining
SATs; experience
expectant but still low
attention span
Early infancy
2–6 months
Reorganization of corticocortical
pathways; rapid synaptogenesis
and spinogenesis (dendritic
differentiation of pyramidal
neurons); retraction of
exuberant pathways, e.g. in
corpus callosum (starts before
birth)
Permanent circuitry with
resolving transient
elements; explosive
synaptic density
Sensory-driven, layer V
centered
Late infancy
7–12 months
Long connectivity established;
layer III pyramids “dormant”
until 16 months of life
(association neurons); areal
differentiation; granulardysgranular differentiation;
initial differentiation of
inhibitory neurons; no longer SP
Initial “cognitive” circuitry
with early environmentally
driven executive functions
due to cortico-cortical
activity
Sensory-driven; columnar
processing
Early
childhood
12–24
months
Maturity of layer III pyramids and
local circuits; maximal
synaptogenesis
Cognitive
Environmentally driven;
extrinsic-intrinsic through
local circuitry
Slide 74: nomenclature and location of three different types of pallial cortex
Basma J, Guley N, Michael Ii L, et al. (January 23, 2020) The Evolutionary Development of the Brain As It
Pertains to Neurosurgery. Cureus 12(1): e6748.
Briscoe SD, Ragsdale CW (2019) Evolution of the Chordate Telencephalon. Curr Biol. 29(13):R647-R662.
Gloor P (1997) The temporal lobe and limbic system. Oxford University press.
Medina L, Abellán A, Desfilis E (2022) Evolving Views on the Pallium. Brain Behav Evol 96(4-6):181-199.
Montiel JF, Aboitiz F (2015) Pallial patterning and the origin of the isocortex. Front Neurosci 9:377.
Puelles L, Harrison M, Paxinos G, Charles Watson C (2013) A developmental ontology for the mammalian brain
based on the prosomeric model. Trends in Neurosciences, October 2013, Vol. 36, No. 10
The cortex of the pallium develops in different types, as depicted in several schemes. The initial neural tube
areas that generate different cortices, are called medial, dorsal and lateral pallium, striato-amygaloid gray and
septal area. Observe early fiber collections like the medial forebrain bundle and its lateral counterpart (the
internal capsule). The rhinal sulcus is at the border between neocortex and paleocortex (olfactory cortex),
anterior to the sulcus collateralis. Below left: anterior left view on a 3D drawing of the pallium. Amygdala
derive from telencephalon, but diencephalic neurons migrate into it as well.
The pallium model is an ongoing challenge from a phylogenetic point of view (Medina et al. 2021). A
hexapartite model currently best represents homology sequences. Isolation, based on cell and tissue
characteristics, but mainly on expression of genes, of functional morphogenetic units has created a prosomeric
model (Puelles et al. 2013) in which further study focuses on the subdivions of pallium. In the hexapartite
model 6 units have been isolated: medial, dorsal, dorsolateral, lateral, ventral and ventrocaudal.
An ancestral mammal is inferred to have possessed a highly developed olfactory bulb and olfactory cortex,
with a compact neocortex located dorsally (Briscoe and Ragsdale 2019). This small neocortex nonetheless
contained a range of neocortical areas shared to all extant mammals. The primary visual area (V1) receives
lemniscal visual input (relay through the lateral geniculate nucleus), whereas the middle temporal visual area
(MT) receives input from a separate, parallel visual pathway that relays through the optic tectum and then the
thalamic lateral posterior nucleus. All mammals share a primary auditory area (A1), a primary somatosensory
area (S1) and an adjoining second somatosensory area (S2). Mammals with a highly expanded neocortex, such
as humans, have a larger proportion of non-primary-sensory and higher order association cortex, e.g. prefrontal
cortex.
In all mammals, the cerebral cortex includes the 6-layered neocortex and the 3-layered hippocampal and
olfactory cortices. Cerebral organization in the opossum, a marsupial, is thought to be representative of that in
mammals. The small, smooth opossum neocortex is demarcated from the relatively large olfactory cortex by a
deep rhinal sulcus. Size increase in mammals is principally in the tangential dimension and not in the radial
dimension, such that neocortex thickness varies by only about two-fold. The relatively tiny human olfactory
and hippocampal cortices are displaced into the temporal lobe by the expansion of the highly folded
neocortex. An extensive neocortical white matter of myelinated axons sits below the neuronal cell bodies of
the neocortical grey matter. The neocortex of mammals has some homologous components: radial glial cells for
neuronal migration, gene duplication for increased neuronal prodution (notch-2 and ARHGAP11B are human
specific), construction of a canonical circuit in the cortex with input neurons (layre 4), output neurons (layer 5
and 6) and local IT (intratelencephalic, in upper layers) neurons. Further expansive development in mammals is
most found in upper cortical layers.
Non-vertebrate chordates already pssess a forebrain with a single inflation or cerebral vesicle, with some
regionalisation. Some non-vertebrates lack this specialisation. All vertebrates develop a rostral brain with
paired telencephalon. Birds develop a pallium without neocortex, in stead the higher functions are organised
in the DVR (dorsal ventricular ridge) and in the Wulst, both nuclear complexes.
Slide 75: striatum develops in accord with expansion of pallium;
opercularisation follows differential growth of neocortex versus insula
Just like thalamus, phylogenetically, striatum expands together with neocortex, lateral and superior to
thalamus. Unlike thalamus, which can be recognized to some extent, any border of striatum is difficult to
depict with ultrasound. Differential expansion of neocortex versus insular cortex leads to bulging of the
cerebral lobes around the insula and later covering (opercularisation) with formation of the lateral fissure.
Slide 76: different types of cortex in pallium, from immature to mature
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Beul SF, Hilgetag CC (2015) Towards a “canonical” agranular cortical microcircuit. Frontiers in Neuroanatomy 8; 129-136.
Kubo KI, Deguchi K (2020) Human neocortical development as a basis to understand mechanisms underlying
neurodevelopmental disabilities in extremely preterm infants. J Obstet Gynaecol Res 46(11):2242-2250.
Marin-Padilla M (2014) The mammalian neocortex new pyramidal neuron: a new conception. Frontiers in Neuroanatomy 7;
art 51.
Sarnat HB, Flores-Sarnat L (2013) Radial micro-columnar cortical architecture: maturational arrest or focal cortical
dysplasia ? Pediatr Neurol 48:259e270.
Sarnat HB (2021) Transitory and vestigial structures of the developing human nervous system. Pediatric Neurology 12;
86-101.
Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Tau GZ, Peterson BS (2010) Normal development of brain circuits. Neuropsychopharmacology reviews 35; 147-168.
Usrey WM, Sherman SM (2017) Corticofugal circuits: communication lines from the cortex to the rest of the brain. J Comp
Neurol 527; 640-650.
van den Heuvel MP, Scholtens LH, Feldman Barrett L, Hilgetag CC, de Reus MA (2015) Bridging Cytoarchitectonics and
Connectomics in Human Cerebral Cortex. J Neurosci 35(41):13943-8.
Although some layering is clearly present in the definitive cortex at 24w PMA, the maturation of this part of the
brain into functional columns perpendicular to the surface with specific layers (parallel to the surface) is
largely beyond 24w PMA. This is consequent to thalamo-cortical interaction. The normal architecture of the
cerebral cortical plate in the first half of gestation is microcolumnar rather than horizontal; horizontal
lamination is superimposed from about 22 weeks (Sarnat 2021). The histopathological hallmark of International
League Against Epilepsy FCD Ia is persistence of the microcolumnar pattern. This transitory pattern persisting
into late fetal and postnatal life may be considered a “maturational arrest”. This pattern also occurs as FCD
IIId adjacent to porencephalic cysts, due to infarction from middle cerebral artery occlusion before
midgestation, and it also occurs in a generalized distribution involving all lobes of the cortex in certain
prenatal onset genetic/metabolic disorders.
The mature cortical types are schematically presented. Pyramidal cells, from ependymal origin, are generated
mainly between 8 and 15 weeks PMA and following migration they settle in the preplate, thus separating the
first cortical layer (marginal layer with CR cells) from the subplate. The maximum number of neurons (of
course measured after the peak of neurogenesis) is reached around 28 w PMA. The second wave of apoptosis
(first wave is in late first trimester in ventricular zone) begins around 19w PMA and leads to a reduction in
neuronal number in third trimester. Neuronal migration roughly coincides with this dynamic. Progressively more
later pyramidal cells settle above the first pyramidal layer P1, the latter becomes layer V of the mature
cortex. All pyramidal cells extend a large apical dendrite to the first layer and keep that connection. These
dendrites grow from 15 µm at 8 w PMA over 275 µm at 15w to 1500 µm at term. The number of spines per
apical dendrite increase from a few at 15w to around 2000 at term. As these pyramidal cells progressively find
the cortex, astrocytes and vessels grow into the same area. The number of pyramidal cell layers in humans (up
to seven layers) is higher than in primates and lower mammals, suggesting that the complexity of motor and
cognitive behaviour in man is correlated to the growing potential of neocortical pyramidal cells. Pyramidal
strata after P1 form at 20w (P2), at 25w (P3), at 30w (P4), at 35w (P5) and at term (P6). The seventh
pyramidal contingent forms after birth.
Gray matter volume increases in third trimester and early childhood, not due to increase in neuronal numbers,
but due to increase in neuronal size, glial proliferation and myelination plus synaptic remodelling. Mature
myelin is present in the rolandic area and the optic radiation around 35w PMA, in the acoustic radiation around
term.
Depending on the specific cortical region, cortical layer I is formed between GA weeks 24-34, and layers III and
IV between GA weeks 32-34. Pyramidal neurons are derived from radial glial cells and reside in a number of
layers within the same minicolumn. Short-range connections bind cells of nearby minicolumns horizontally and
cells of differing lyers within each column vertically.
Synaptogenesis in the cortical plate peaks around 34w PMA. Dendritic arborisation peaks in the first two years
after birth, especially in layers II and III, peaking in the third year of life; the number of dendrites declines
after the brain growth plateau ends around 6 years. Brain metabolism is most active between 4 and 10 years of
age.
Schematically: layers II and III send cortical afferents, with layer II projecting more locally and layer III more
distant. Layers V and VI project to subcortical regions, with layer VI projecting primarily to the thalamus and
layer V projecting to brainstem, midbrain and basal ganglia.
- Layer VI contains pyramidal cells with rich dendritic arbors and excitatory axons to the thalamus. The lower
part (often called layer VIb has the remaining cells of the subplate).
- Layer V contains the largest pyramidal cells, which send excitatory projections to basal ganglia, brainstem
and spinal cord.
- Layer IV: isocortical (homotypic) regions contain a granular layer IV and are involved in higher-order sensory
processing. Allocortical (heterotypic) regions lack layer IV and are typical of limbic cortices. Excitatory
neurons in layer IV, such as pyramidal and spiny stellate cells, are targets of thalamic input, the main input
from subcortical afferents.
- Layer III neurons receive convergent inputs from inhibitory interneurons within this layer and from deeper
-
layers. Layer III pyramidal cells project to ipsilateral and contralateral (commissural) cortical regions. The
size of the neurons in this corresponds with cortico-cortical connectivity on diffusion weighted MRI (van den
Heuvel et al. 2015).
Layer II receives diverse inputs but contains smaller pyramidal neurons that send projection to less distant
ipsilateral cortical areas.
Layer I receives axons originating from other cortical regions on apical dendrites of pyramidal cells. This
layer also has Cajal-Retzius cells.
Usrey and Sherman 2017:
Layer VI neurons
- modulator for all thalamic nuclei (for first and higher order; for glutamatergic and GABAergic neurons in
thalamus and thalamic reticular nucleus); glutamatergic on distal dendrites outside glomeruli; effect via
ionotropic and metabotropic receptors with low probability of transmitter release; basis of oscillations
between thalamus and cortex in alpha-range; feed forward function e.g. creating spatial attention (spotlight
function)
- axon collaterals to the layers of the cortex that receive thalamic input in that area thin and weakly
myelinated axons
Layer V neurons
- driver for higher order thalamic nuclei (mediodorsal, pulvinar …) often firing in burst mode; glutamatergic on
proximal dendrites in glomeruli (triadic synapses); effect via ionotropic receptors with high probability of
release; not necessarily to thalamic nucleus that projects to that cortical area (there may be hierarchical
processing)
- efference copy (anticipatory circuit making) of message for spinal cord to local cortical neighbouring areas,
other thalamic nuclei (transthalamic pathway), striatum, bulbospinal control centers
- large and thickly myelinated axons
- provide around half of all synapses on relay cells
- parallel processing streams (e.g. parvocellular, magnocellular and koinocellular for retino-geniculo-calcarine
processing of vision).
A canonical agranular cortical microcircuit exists of excitatory to excitatory cell connections (layers 2/3 to 5)
(reciprocal), excitatory to inhibitory connections (layers 2/3 to 5) and a small precentage of interlaminar
inhibitory to inhibitory connections of all types (Beul and Hilgetag 2015). This provides interlaminar recurrent
inhibition and excitation. Interlaminar inhibitory to excitatory connection is not substantial.
Slide 77: consciousness
Frohlich J, Bayne T, Crone JS, DallaVecchia A, Kirkeby-Hinrup A, Mediano PAM, Moser J, Talar K, Gharabaghi A, Preissl H
(2023) Not with a "zap" but with a “beep": Measuring the origins of perinatal experience. Neuroimage 30;273:120057.
Hudson AJ (2009) Consciousness: physiological dependence on rapid memory access. Frontiers in Bioscience 14, 2779-2800
Lagercrantz H, Changeux J-P (2009) The emergence of human consciousness: from fetal to neonatal life. Pediatric Research
65; no 3; 255-260.
Although consciousness has no accepted definition, also because the word is not identical to words
representing the same in other languages, it can be stated that it is a global network function that mainly
depends on thalamo-cortical interaction and on tonic activation by the reticular formation and some areas of
the insula and frontal cortex. Arousal (wakefulness, sustained attention) depends on the ascending reticular
activating system (ARAS) and on immediate coupling of sensory input to memorised items: awareness of
previous input is imperative to conscious behaviour. Thus circumscribed it can be inferred that minimal
consciousness is present in preterm infants and fetuses of around 26w PMA, when cortical activation by sound
emerges.
The neurons of the dorsal thalamic pathway and their neurotransmitters originate from the cholinergic
pedunculopontine tegmental and laterodorsal tegmental nuclei in the posterior midbrain and anterior pons
region. They project to nuclei in thalamus: intralaminar nuclei, relay nuclei and the reticular nucleus.
The ventral hypothalamic pathway, through the lateral hypothalamic area, is formed of fibers from the
noradrenergic locus coeruleus in the pons and by fibers of the serotonergic dorsal and median raphé nuclei and
the dopaminergic ventral tegmental area in the midbrain. These are joined in the hypothalamus by projections
from a number of nuclei in the lateral hypothalamic area, especially the histaminergic tuberomammillary
nucleus and the peptidergic orexin neurons, and by projections from the basal forebrain region inhibitory
GABAergic neurons and cholinergic neurons, to target neurons throughout the cortex.
The question of when consciousness, or subjective experience, begins in human development remains
incompletely answered, though boundaries can be set using current knowledge from developmental
neurobiology and recent investigations of the perinatal brain (Frohlich et al. 2023). While newborn infants are
the archetypal subjects for studying early human development, researchers may also benefit from fetal
studies, as the womb is, in many respects, a more controlled environment than the cradle. The earliest
possible timepoint when subjective experience might begin is likely the establishment of thalamocortical
connectivity at 26 weeks gestation, as the thalamocortical system is necessary for consciousness according to
most theoretical frameworks. To infer at what age and in which behavioral states consciousness might emerge
following the initiation of thalamocortical pathways, sPCI [sensory perturbational complexity index (sPCI) based
on auditory ("beep-and-zip"), visual ("flash-and-zip"), or even olfactory ("sniff-and-zip") cortical perturbations]
and similar techniques, based on EEG, MEG, and fMRI, to estimate the perinatal brain's state of consciousness.
Slide 78: ontogeny of cortical seizure activity
Carrasco M, Stafstrom CE (2018) How Early Can a Seizure Happen? Pathophysiological Considerations of Extremely
Premature Infant Brain Development. Dev Neurosci. 40(5-6):417-436.
Within the microcolumns neurons become organised in such a way that from a certain stage of develoment,
seizures can be generated there (Carrasco and Stafstrom 2018). Issues are complex when considering seizures
in premature infants. The clinical and electrographic phenomenology of seizures in extremely preterm infants
reflects the specific pathophysiology of brain development in that age window. The gestational age at which a
seizure can first occur is uncertain. Specifically, before 28 w PMA synapse formation is not robust, synchronized
activity and neuronal oscillations have not yet developed, and excitation via glutamate and GABA synaptic
activity has not yet become engaged. At P0–2 and earlier in rodents (corresponding to 24-26w PMA in humans,
neurons are immature and ion channels show activity that is random and spontaneous, derived from voltagegated calcium channels. By P1–3 (27-28w PMA), some cells are interconnected via gap junctions (expressing
connexins) and produce local synchronized neural activity in the form of spindle bursts and gamma bursts in
the surface EEG. By P4–10 (28-40w PMA) chemical synapses form, mediated by both glutamate and GABA; GABA
is excitatory at an early stage; synchronised activity gradually propagates in networks of increasing scale
(cENOs, cortical early network oscillations, peaking around 30w PMA develop into cGDPS, cortical giant
depolarising potentials, peaking around 35w PMA). After P10 (after term), neurons and circuits are more
mature (dark gray): GABA becomes hyperpolarizing and inhibitory, and neural firing is desynchronized, cGDPs
disappear. Hemispheric synchrony sets on (under brainstem control) around 30w PMA, and becomes stronger by
commissural activity after 34w PMA.
Field potential recording of spindle bursts have a peak amplitude of ∼100 µV and duration of ∼200 ms. Field
potential recording of gamma bursts have a peak amplitude of ∼200 µV and duration of ∼500 ms. Intracellular
recording of cENOs (cortical early network oscillations) have a duration of ∼5 s. Intracellular recording of cGDPs
have a duration of ∼0.5 s.
Around 28w PMA the EEG has a typical tracé discontinu, high amplitude irregular and asynchronous bursts
alternate with flat interburst intervals that become increasingly shorter. Seizures in preterm infants are often
generated in the context of IVH with sequelae and infection, not asphyxia or metabolic disorders. They have
certain characteristics:
- the reported incidence varies (depending on methods of definition and detection) from 5 to around 50 %
below 30-32w PMA;
- focal onset is occipital rather than frontal: limited ability to propagate seizure activity; earlier maturation of
the occipital region ?;
- most seizures are subclinical (>50%): differences from normal movements are subtle; coupling of discharges
to the motor system is immature; there are effects of GABAergic drugs used e.g. for sedation
- seizures are shorter: there is a limited ability to sustain seizure activity.
Late preterm and term infants are especially prone to seizures, contrary to ELBW preterms. Ion channel
development proceeds from first calcium-cannels to later sodium and potassium currents. Once the latter
channels are expressed in the cortical plate, repititive firing becomes possible. Membrane properties change
due to this progression of channel expression and due to transition to chemical synapses. Gradually more
glutamate receptors of the NMDA-type (GluN1 and especially GluN2b) become expressed with a peak around
37w PMA in white matter and in cortical areas. The Mg++-block at these receptors is present from 26w PMA, but
becomes inceasingly operational in the third trimester, so that in theory magnesium may reduce excitability
near term. Glutamate receptors expressing AMPA are also overexpressed near term, except for the GluA2
receptor and this absence may also add to excitability near term.
GABA receptors mediate excitation (mainly trophic actions and not synaptic function), which gradually changes
to inhibition in the third trimester. Around term both patterns of activity coexist. This explains why GABAergic
drugs can cause myoclonic seizures throughout the third trimester. The switch to inhibition is probably related
to expression of chloride-channels like KCC2. This transition is gradual and regionally heterogeneous. Even if
GABA receptors can still be excitatory at term, glutamatergic excitation is considerably stronger.
Although MBP is expressed in thalamus and internal capsule around 20w PMA, cortical expression of MBP (in
mature myelin) gradually increasses after 24w PMA. The largely absent mature myelin contributes to difficult
propagation of seizures in preterm infants.
Slide 79: summary of functional anatomy of the reticular formation
Petrovický P, N mcová V, ten Donkelaar HJ, Overeem S, Vos P (2011) The Reticular Formation and Some Related Nuclei. in
Hans J. ten Donkelaar: Clinical Neuroanatomy Brain Circuitry and Its Disorders, Springer Verlag.
The reticular formation is a heterogeneous region, strategically placed to modulate and control tracts
connecting the spinal cord to the forebrain, autonomic brainstem centers, eye movements and motor control
by the cerebellum and nucleus ruber. Ascending connections in the ARAS govern consciousness states and sleep.
The central tegmental tract connects reticular fibers to thalamus and other forebrain nuclei, as well as
connects nucleus ruber to inferior olive.
Slide 80: realistic images of the reticular formation and some of its special
nuclei involved in the ARAS
from Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological
record. A Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The
Laboratory of Developmental Neurobiology, Inc. Ocala, FL 34481, USA.
ě
Reticular formation nuclei depicted on the neuronal elements in a brain at 26w PMA.
Slide 81: longitudinal columnar anatomy of the human reticular formation
Scheme adapted from Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
The reticular formation is complicated but a columnar subdivision in four different subparts is widely accepted:
I the median (raphe) and paramedian nuclei
II the medial reticular formation (with large cells)
III the lateral reticular formation
IV the intermediate reticular formation between II and III with monoaminergic and cholinergic nuclei other
than serotonin.
These subparts are composed of many nuclei present in the tegmentum of mesencephalon, pons and medulla
oblongata. Some specific nuclei are: locus coeruleus with NOR neurotransmission, pedunculopontine and lateral
dorsal tegmental nucleus with acetylcholine as neurotransmitter, the respiratory nucleus of the pre-Bötzinger
complex in the medulla.
In the wide interpretation of functions of the reticular formation other nuclei are included: nucleus ruber,
inferior olive and precerebellar nuclei of the brainstem.
Slide 82: more anatomic details of the human reticular formation related to
the ARAS and to emotional behaviour
Venkatraman A, Edlow BL, Immordino-Yang MH (2017) The brainstem in emotion: a review. Frontiers in Neuroanatomy 11;
article 15.
The ascending network (ARAS) is composed chiefly of the spinothalamic tracts projections to brainstem nuclei,
which transmit sensory information from the body to rostral structures.
The descending motor network is subdivided into medial projections from the reticular formation that
modulate the gain of inputs impacting emotional salience, and lateral projections from the periaqueductal
gray, hypothalamus and amygdala that activate characteristic emotional behaviors.
The brainstem hosts a group of modulatory pathways, such as those arising from the raphe nuclei
(serotonergic), ventral tegmental area (dopaminergic) and locus coeruleus (noradrenergic), which coordinate
interactions between ascending and descending networks. Integration of signaling occurs at all levels of the
brainstem, whereafter progressively more complex integration occurs in hypothalamus and thalamus, which in
turn provide input for the highest level of integration to the frontal, insular, cingulate and other regions of the
cerebral cortex.
Via these bidirectional interactions, the human brainstem contributes to the evaluation of sensory information
and to fixed-action pattern responses that together constitute a spectrum of possible emotions.
Ascending (sensory): spinothalamic tracts (anterolateral pathway for nociceptive and temperature-related
signals); medial forebrain bundle; nucleus of the tractus solitarius; parabrachial nuclear complex of the RF;
several thalamic nuclei (VPm, IL, MD), hypothalamus and amygdala; interoception at anterior insular and
pregenual cingulate cortex, somato-sensory perception in rolandic areas.
Descending (emotional motor system): Lateral: periaqueductal gray and its projections in ponto-medullary
tegmentum (fight or flight, freezing …); Medial: caudal raphe nuclei, locus coeruleus and their projections
(descending pain modulation, muscle function level-setting for arousal levels.
Modulatory: raphe nuclei (serotonergic); locus coeruleus (noradrenergic); ventral tegmental area
(dopaminergic); pedunculopontine and laterodorsal tegmental nuclei (cholinergic).
Slide 83: the parabrachial nuclei as part of the ARAS (essential to prevent
coma states)
Venkatraman A, Edlow BL, Immordino-Yang MH (2017) The brainstem in emotion: a review. Frontiers in Neuroanatomy 11;
article 15.
The main parabrachial nuclei are the medial parabrachial nucleus, the lateral parabrachial nucleus and the
subparabrachial nucleus (also known as the Kölliker-Fuse nucleus). The subparabrachial nucleus regulates
breathing rate. It receives signals from the cardio-respiratory part of the solitary nucleus and sends signals to
the lower medulla oblongata, the spinal cord, the amygdala and lateral hypothalamus.
The parabrachial nuclei receive visceral afferents from the solitary nucleus, which contain taste information
and information about the remainder of the body. The subnuclei also receive input from the spinal and
trigeminal dorsal horn, concerned with pain and other visceral sensations.
Many subsets of neurons in the parabrachial complex contain specific neuropeptides and carry out distinct
functions. For example, a population of neurons in the external lateral parabrachial subnucleus that contain
the neurotransmitter calcitonin gene-related peptide (CGRP) appears to be critical for relaying information
about hypoxia or hypercapnia (e.g. as by sleep apnea) to forebrain sites to wake the brain up. Glutamatergic
neurons in the parabrachial nuclei, along with glutamatergic neurons in the pedunculopontine tegmental
nucleus, are critical for producing a waking state. Lesions of these neurons cause irreversible coma.
Slide 84: the serotonergic raphe system
Broadbelt KG, Paterson DS, Rivera KD, Trachtenberg FL, Kinney HC (2010) Neuroanatomic relationships between the
GABAergic and serotonergic systems in the developing human medulla. Auton Neurosci 154(1-2):30-41.
Kinney HC, Broadbelt KG, Haynes RL, Rognum IJ, Paterson DS (2011) The serotonergic anatomy of the developing human
medulla oblongata: implications for pediatric disorders of homeostasis. J Chem Neuroanat 41(4):182-99.
Randall BB, Paterson DS, Haas EA, Broadbelt KG, Duncan JR, Mena OJ, Krous HF, Trachtenberg FL, Kinney HC (2013)
Potential asphyxia and brainstem abnormalities in sudden and unexpected death in infants. Pediatrics 132(6):e1616-25.
Xu G, Broadbelt KG, Haynes RL, Folkerth RD, Borenstein NS, Belliveau RA, Trachtenberg FL, Volpe JJ, Kinney HC (2011) Late
development of the GABAergic system in the human cerebral cortex and white matter. J Neuropathol Exp Neurol
70(10):841-58.
Top: diagram of the topography of the caudal 5-HT system in the human infant medulla.
The caudal serotonergic (5-HT) system is a critical component of a medullary ‘‘homeostatic network’’ that
regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia.
Anatomically the caudal 5-HT system in the human medulla comprises neurons in the raphe (raphe obscurus,
raphe magnus and raphe pallidus), extra-raphe (gigantocellularis, paragigantocellularis lateralis, intermediate
reticular zone, lateral reticular nucleus, nucleus subtrigeminalis) and along the ventral surface (arcuate
nucleus). These 5-HT neurons are positioned adjacent to the respiratory and other autonomic activity related
nuclei in the medulla whose responses they modulate.
Below left: Biochemistry pathaway in a serotonergic neuron and developmental serotonopathies of the caudal
(as well as rostral) 5-HT domain associated with homeostatic imbalances.
Below right: diagram of the caudal 5-HT system and its relationship to homeostatic regulation. This system: (1)
receives sensory input about the internal milieu via the nucleus of the solitary tract (visceral sensory) in the
autonomic nervous system, as well as its own chemo- and glucose receptors in close relationship to arteries
and/or cerebrospinal fluid; (2) modulates adjustments to homeostatic stresses via its projections to the major
medullary effector nuclei (hypoglossal nucleus; nucleus of the solitary tract; dorsal motor nucleus of the vagus;
preBötzinger complex, phrenic nucleus in the cervical spinal cord; intermediolateral column in the thoracic
spinal cord); (3) receives modulatory input itself from the hypothalamus a other limbic forebrain sites relevant
to sleep/wake cycle regulation and cardiorespiratory effects via receptor-mediated interactions with diverse
neurotransmitters and neuromodulators.
Interaction with the cytokine system which is critical to homeostasis in its mediation of ‘‘protective’’ sickness
behaviors and cellular defenses against tissue damage.
Slide 85: the cortical cells and (brainstem plus other) systems that make for
consciousness; cortical microcolumns
Hudson AJ (2009) Consciousness: physiological dependence on rapid memory access. Frontiers in Bioscience 14, 2779-2800.
The reticular activating system is essential to the diurnal sleep/wake cycle. Patients with severe brain
damage, especially to the midbrain, are comatose and the sleep/wake cycle is absent. Some less severely
injured patients who display very limited mental and physical responses, are diagnosed as either in a
‘persistent vegetative state’ or a ‘minimally conscious state’ and in both the sleep/wake cycle, and accordingly
the ARAS, are intact. Such patients with intact sleep/wake cycle generally have extensive cerebral cortical
damage which shows the influence the cortex has on consciousness.
Without memories dating from very early life all subsequent sensory input would be without meaning or effect.
It is proposed that it is sensory input applied to memory as it is stored throughout the cerebral cortex, together
with the driving force of the ascending arousal system, which forms a basis for consciousness. A difficulty with
a concept of consciousness based on memory has been to define a neural system that is capable of matching
continuously shifting sensory inputs to memory.
Inhibition of arousal is essential for sleep.
The ventrolateral preoptic nucleus (VLPO) in the hypothalamus contains the inhibitory neurotransmitter GABA
and its axons terminate on the ascending aminergic arousal neurons silencing them during sleep.
A balance between wakefulness and sleep is regulated by the suprachiasmatic nucleus (SCN), the principal
circadian pacemaker of the sleep/wake cycle in the hypothalamus, and is maintained by the stabilizing
influence of orexin. The SCN is capable, in addition to its usual modulating influence on the sleep/wake cycle,
of independently inhibiting the sleep-inducing effect of VLPO neurons.
Carrasco M, Stafstrom CE (2018) How Early Can a Seizure Happen? Pathophysiological Considerations of Extremely
Premature Infant Brain Development. Dev Neurosci. 40(5-6):417-436.
Within the microcolumns neurons become organised in such a way that from a certain stage of develoment,
seizures can be generated there (Carrasco and Stafstrom 2018). Issues are compounded when considering
seizures in premature infants. The clinical and electrographic phenomenology of seizures in extremely preterm
infants reflects the specific pathophysiology of brain development in that age window. Major developmental
events during premature brain development. The gestational age at which a seizure can first occur is
uncertain. Specifically, before 28 w PMA synapse formation is not robust, synchronized activity and neuronal
oscillations have not yet developed, and excitation via glutamate and GABA synaptic activity has not yet
become engaged. At P0–2 and earlier in rodents (corresponding to 24-26w PMA in humans, neurons are
immature and ion channels show activity that is random and spontaneous, derived from voltage-gated calcium
channels. By P1–3 (27-28w PMA), some cells are interconnected via gap junctions (expressing connexins) and
produce local synchronized neural activity in the form of spindle bursts and gamma bursts in the surface EEG.
By P4–10 (28-40w PMA) chemical synapses form, mediated by both glutamate and GABA; GABA is excitatory at
an early stage; synchronised activity gradually propagates in networks of increasing scale (cENOs cortical early
network oscillations peaking around 30w PMA develop into cGDPS cortical giant depolarising potentials peaking
around 35w PMA). After P10 (after term), neurons and circuits are more mature (dark gray): GABA becomes
hyperpolarizing and inhibitory, and neural firing is desynchronized, cGDPs disappear. Hemispheric synchrony
sets on (under brainstem control) around 30w PMA, and becomes stronger by commissural activity after 34w
PMA.
Field potential recording of spindle bursts have a peak amplitude of ∼100 µV and duration of ∼200 ms. Field
potential recording of gamma bursts have a peak amplitude of ∼200 µV and duration of ∼500 ms. Intracellular
recording of cENOs (cortical early network oscillations) have a duration of ∼5 s. Intracellular recording of cGDPs
have a duration of ∼0.5 s.
Around 28w PMA the EEG has a typical tracé discontinu, high amplitude irregular and asynchronous bursts
alternate with flat interburst intervals that become increasingly shorter. Seizures in preterm infants are often
generated in the context of IVH with sequelae and infection, not asphyxia or metabolic disorders. They have
certain characteristics:
- the reported incidence varies (depending on methods of definition and detection) from 5 to around 50 %
below 30-32w PMA;
- focal onset is occipital rather than frontal: limited ability to propagate seizure activity; earlier maturation of
the occipital region ?;
- most seizures are subclinical (>50%): differences from normal movements are subtle; coupling of discharges to
the motor system is immature; there are effects of GABAergic drugs used e.g. for sedation
- seizures are shorter: there is a limited ability to sustain seizure activity.
Late preterm and term infants are especially prone to seizures, contrary to ELBW preterms.
Ion channel development proceeds from first calcium-cannels to later sodium and potassium currents. Once the
latter channels are expressed in the cortical plate, repititive firing becomes possible. Membrane properties
change due to this progression of channel expression and due to transition to chemical synapses. Gradually
more glutamate receptors of the NMDA-type (GluN1 and especially GluN2b) become expressed with a peak
around 37w PMA in white matter and in cortical areas. The Mg++-block at these receptors is present from 26w
PMA, but becomes inceasingly operational in the third trimester, so that in theory magnesium may reduce
excitability ner term. Glutamate receptors expressing AMPA are also overexpressed near term, except for the
GluA2 receptor and this absence may also add to excitability near term.
GABA receptors mediate excitation (mainly trophic actions and not synaptic function), which gradually changes
to inhibition in the third trimester. Around term both patterns of activity coexist. This explains why GABAergic
drugs can cause myoclonic seizures throughout the third trimester. The switch to inhibition is probably related
to expression of chloride-channels like KCC2. This transition is gradual and regionally heterogeneous. Even if
GABA receptors can still be excitatory at term, glutamatergic excitation is considerably stronger.
Although MBP is expressed in thalamus and internal capsule around 20w PMA, cortical expression of MBP (in
mature myelin) gradually increasses after 24w PMA. The largely absent mature myelin contributes to diffiuclt
propagation of seizures in preterm infants.
Slide 86: the medial forebrain bundle
One of the important fiber systems in the function of the reticular formation is the medial forebrain bundle.
The homolog lateral forebrain bundle is the internal capsule.
The medial forebrain bundle is very complex. At the junction of diencephalon and mesencephalon, MFB fibers
are rearranged into a smaller medial and a larger lateral stream.
The medial stream passes through the mesencephalic and rhombencephalic tegmentum close to the raphe
nuclei. It contains descending fibers from hypothalamic centers to the raphe nuclei as well as ascending fibers
from the raphe nuclei to lateral hypothalamus and beyond.
The lateral stream sweeps laterally and caudally and descends through the mesencephalic central tegmental
area. It contains descending fibers from the central amygdaloid nucleus, the bed nucleus of the stria terminalis
and several hypothalamic areas. These descending fibers terminate in a variety of brain stem centers such as
the parabrachial PAG nuclei, the locus coeruleus, the noradrenergic cell groups A1, A2 and A5 and the dorsal
vagal complex.
Most of these projections are reciprocal.
Slide 87: development of human cerebellum: cell production and migration
Bayer SA, Altman J (2004) Atlas of the human central nervous system development. CRC Press.
Doherty D, Millen KJ, Barkovich AJ (2013): Midbrain and hindbrain malformations: advances in clinical dagnosis, imaging,
and genetics. Lancet Neurology 12:381393.
Feess-Higgins A, Larroche J-C (1987) Le Développement du Cerveau Foetal Humain. Atlas Anatomique. Paris: Masson.
Friede RL (1989) Developmenal neuropathology. Springer Verlag.
Guihard-Costa A-M, Larroche J-Cl (1990) Differential growth between the fetal brain and its infratentorial part. Early
Human Development 23:27-40.
Hatten ME, Alder J, Zimmerman K, Heintz N (1997) Genes involved in cerebellar cell specification and differentiation. Curr
Opin Neurobiol 7(1):40-7.
Hochstetter F (1929) Schlußlieferung: Die Entwicklung des Mittel- und Rautenhirns. In: Beträge zur Entwicklungsgeschichte
des menschlichen Gehirns. Wien and Leipzig: Franz Deuticke.
Larroche JC (1977) Developmental pathology of the neonate. Excerpta Medica, Elsevier.
Loeser JD, Lemire RJ, Alvord EC (1972) The development of the folia in the human cerebellar vermis. Anat Rec 173:109-114.
Lemire RJ, Loeser JD, Leech RW, Alvord EC (1975) Normal and abnormal develoment of the human nervous system.
Hagerstown, Harper and Row.
Martinez S, Andreu A, Mecklenburg N, Echevarria D (2013) Cellular and molecular basis of cerebellar development. Frontiers
in Neuroanatomy 7: article 18: 1-9.
Millen KJ, Millonig JH, Wingate RJ, Alder J, Hatten ME. Neurogenetics of the cerebellar system. J Child Neurol. 1999
Sep;14(9):574-81; discussion 581-2.
Murofushi K. [Normal development and dysgenesias of the dentate nucleus and inferior olive (author's transl)]. Acta
Neuropathol. 1974 Apr 30;27(4):317-28.
Nowakowska-Kotas M, Kedzia A, Dudek K (2014) Development of external surfaces of human cerebellar lobes in the fetal
period. Cerebellum; on line 16 may 2014.
Rubenstein JLR, Rakic PR (eds): Comprehensive developmental neuroscience: Cellular migration and formation of neuronal
connections. Komuro Y, Kumada T, Ohno N, Foote KD, Komuro H. Chapter 15: Migration in cerebellum. pp 745-785.
Academic Press 2013.
Ten Donkelaar HJ, Lammens M, Wesseling P, Thijssen HOM, Renier WO (2004) Development and developmental disorders of
the human cerebellum. J Neurol 250: 1025-1036.
Volpe JJ (2009) Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. J Child Neurol
24(9):1085-1104.
Wingate RJ (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11(1):82-8.
From the fifth week of gestation future cerebellar neurons proliferate in the ventricular zone of the alar plate
of rhombomere 1 at the level of the isthmus: from this (sub)ventricular zone Purkinje cells (radially) and
before them deep cerebellar nucleus cells (tangentially) migrate into the primitive cerebellum between 8 and
13 weeks after conception. All these neurons are GABA-ergic. Clustered Purkinje cells form an early layer
around 10 weeks. Their GABA-ergic nature serves to inhibit deep cerebellar and some vestibular nuclei. Other
cortical neurons (basket, stellate, deep cerebellar nuclear interneurons and Golgi cells) develop between week
10 and 23. Basket and stellate cells “loiter’ in the molecular layer by forming a complex 4-stage migration
sequence before arriving near the Purkinje cells.
All glutamatergic cells, including neurons in deep cerebellar nuclei, like the dentate nucleus, are derived
from the rhombic lip, as do Bergman glia precursors. A transient cell mass, the nuclear transitory zone, lies
between the rhombic lip and their final position. Dentate nuclei are formed at stage 23, around 8 weeks after
conception. By the end of the embryonic period (8 weeks of conception) the cerebellum still presents as an
inverted V, with rhombic lips protruding like near horizontal bars in and out of the velum medullare; the
superior cerebellar peduncles have been formed. Choroid plexus has already separated the velum into an
anterior and posterior part around day 47-48 and even before this arachnoid space formation has begun. The
choroid plexus only has lateral projections at this stage. Around w8 the posterior velum opens caudally and
forms the foramen of Magendi (median aperture). This is proceeded by bulging of the velum into the primitive
cisteran magna, referred to as Blake’s pouch. This pouch gradually deflates upon opening of the apertures in
the velum.
From the latter part of the embryonic period until about 15 months after term another cell type migrates from
the dorsal and rostral part of the rhombic lip tangentially along the future cerebellar surface to become the
external granular layer. These glutamatergic neurons proliferate for months at the cerebellar surface; at some
stage they migrate radially down into the cerebellar cortex beneath the Purkinje cells along radial Bergman
glia to become the internal granular layer. This inward migration corresponds to Purkinje cell maturation: the
Purkinje layer is clustered around day 48 to become a monolayer around day 70. The external granular layer is
itself thus a secondary germinal zone, stimulated by sonic hedgehog, a mitogen secreted by developing
Purkinje cells. Mossy fiber contact between 20 and 30 weeks after ovulation parallels presence of the lamina
dissecans beneath the Purkinje cell line. The glycoprotein reelin, secreted by the external granular layer, binds
to receptors on Purkinje cell processes, to reduce adhesion between Purkinje cells and to enable cell clusters
to elongate into long parasagittal stripes.
In the developing midbrain, neurons are generated from the ventricular zone and first migrate radially, with
those on the dorsal side forming the tectum and those on the ventral side forming the substantia nigra, red
nuclei, and cranial motor nerves 3 and 4. Nuclei in pons and medulla (precerebellar nuclei: pontine nucleus,
tegmental pontine reticular formation, external cuneate nucleus and lateral reticular nucleus) are the result of
migration streams rostrally from the lower rhombic lip, referred to with the term corpus pontobulbare (or
anterior extramural stream). Proliferation and migration of these nuclei occurs between weeks 5 and 11. By 15
weeks the inferior olive, developing first and perhaps separate from the inferior rhombic lip, is a C-shaped
nucleus that becomes convoluted under the influence of fiber connections between 15 and 22 weeks. A
posterior extramural stream gives rise to the lateral reticular and external cuneate nuclei.
Congenital malformations of the cerebellum are often interwoven with anomalies of the brainstem or
diencephalon. They emerge between the 7th and 10th gestational week and, together with rhombencephalic
structures, adjacent brain membranes are often affected as well.
Nowakowska-Kotas M, Kedzia A, Dudek K (2014) Development of external surfaces of human cerebellar lobes in the fetal
period. Cerebellum; on line 16 may 2014.
The external cerebellar surface increases mainly at the anterior lobe (before the primary fissure) between 15
and 28 weeks of gestation, at the same time the surface of the flocculonocular lobe is relatively reduced
(Nowakowska-Kotas et al. 2014). At later stages the posterior lobe grows relatively stronger. Mitosis is mainly
very active at the surface, explaining vulnerability to injurious molecules at the cerebellar surface. Spreading
of the EGL is very active in third trimester, such that cerebellar surface increases 40-fold between 24 weeks
and term (Lemire et al. 1975). The relative cerebellum to total brain weight % reverts from a decrease to
increase around 20 weeks (from around 4 % at 20 weeks to 6 % at term)(Guihard-Costa and Larroche 1990). At
the same time, brainstem becomes relatively smaller. Peak cerebellar growth in % is around 6 fetal months, in
grams around term. Where cerebellum is around 5-6 % of brain size around term, it reaches 10 % around 18
months. After term, the EGL dissipates, at the same time parallelled by an increase in molecular layer and IGL
thickness. Increasing axonal input further drives neuronal differentiation of the cortex.
Slide 88: development of human cerebellum: features at the end of the
embryonic period and in second trimester
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
O’Rahilly R, Müller F (2001) Human embryology and teratology. Wiley-Liss, New York.
Scheme representing presence of different structures related to the cerebellum, at the end of the embryonic
period. Neuronal staining of axial sections though the cerebellum at 14 and 26w PMA respectively, on the right.
Slide 89: development of human cerebellum: histology of cerebellar cortex
and evolution of the dentate nucleus
Larroche JC (1977) Developmental pathology of the neonate. Excerpta Medica, Elsevier.
Murofushi K (1974) Normal development and dysgenesias of the dentate nucleus and inferior olive (author's transl). Acta
Neuropathol 27(4):317-28.
Histology of cerebellar cortex and development of the dentate nucleus.
Slide 90: development of human cerebellum: formation of the internal
granular layer
Hatten ME, Alder J, Zimmerman K, Heintz N (1997) Genes involved in cerebellar cell specification and differentiation. Curr
Opin Neurobiol 7(1):40-7.
Lemire RJ, Loeser JD, Leech RW, Alvord EC (1975) Normal and abnormal develoment of the human nervous system.
Hagerstown, Harper and Row.
Nieuwenhuys R, Voogd J, van Huijzen C (2008) The human central nervous system. Fourth revised edition. Springer-Verlag.
Purves D (2001) Neuroscience, 2nd edition. Edited by Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz,
Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams.Sunderland (MA): Sinauer Associates; 2001.
Schilling K, Oberdick J, Rossi F, Baader SL (2008) Besides Purkinje cells and granule neurons: an appraisal of the cell biology
of the interneurons of the cerebellar cortex. Histochem Cell Biol 130(4):601-15.
Vincent Y. Wang & Huda Y. Zoghbi (2001 Genetic regulation of cerebellar development. Nature Reviews Neuroscience 2,
484-491.
Wingate RJ (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11(1):82-8.
http://www.ncbi.nlm.nih.gov/books/NBK10865/
http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_8B.html
Cell types and functions.
Between 20 weeks gestation and term, the salient feature of cerebellar development is expansion of the
external granular layer and formation of the internal granular layer: the external layer reaches a peak
thickness around 25 weeks.
Only after precursors have divided within the EGL (external granular layer), postmitotic granule cells migrate
radially through the cerebellum, bypassing outwardly migrating Purkinje cells and settling in the internal
granule cell layer (IGL). The glutamatergic neurons of the EGL proliferate for months at the cerebellar surface.
The external granular layer is a secondary germinal zone, stimulated by sonic hedgehog, a mitogen secreted by
developing Purkinje cells. Mossy fiber contact between 20 and 30 weeks after ovulation parallels presence of
the lamina dissecans beneath the Purkinje cell line. The glycoprotein reelin, secreted by the external granular
layer, binds to receptors on Purkinje cell processes, to reduce adhesion between Purkinje cells and to enable
cell clusters to elongate into long parasagittal stripes.
Basic circuit. The ultimate destination of the afferent pathways to the cerebellar cortex is the Purkinje cell.
However, the input from the cerebral cortex to the Purkinje cells is indirect. Neurons in the pontine nuclei
receive a projection from the cerebral cortex and then relay the information to the contralateral cerebellar
cortex. The axons from the pontine nuclei and other sources are called mossy fibers because of the appearance
of their synaptic terminals. Mossy fibers synapse on granule cells in the granule cell layer of the cerebellar
cortex. The cerebellar granule cells give rise to specialized axons called parallel fibers that ascend to the
molecular layer, bifurcate there to form T-shaped branches that relay information via excitatory synapses onto
the dendritic spines of the Purkinje cells. Purkinje cells have elaborate dendrites that extend into the
molecular layer, where they branch extensively in a plane at right angles to the trajectory of the parallel fibers
(the foliation axis). In this way, each Purkinje cell is in a position to receive input from a large number of
parallel fibers, and each parallel fiber can contact a very large number of Purkinje cells (on the order of tens
of thousands). The Purkinje cells receive a direct modulatory input on their dendritic shafts from the climbing
fibers, all of which arise in the inferior olive. Each Purkinje cell receives numerous synaptic contacts from a
single climbing fiber.
The Purkinje cells project in turn to deep cerebellar nuclei. They are the only output cells of the cerebellar
cortex. Since the Purkinje cells are GABAergic, the output of the cerebellar cortex is inhibitory. However, the
deep cerebellar nuclei receive excitatory input from the collaterals of the mossy and climbing fibers. Purkinje
cell inhibition of the deep nuclei modulates the level of this excitation. Inputs from local circuit neurons
modulate the inhibitory activity of Purkinje cells and occur on both dendritic shafts and the cell body. The most
powerful of these local inputs are inhibitory complexes of synapses made around the Purkinje cell bodies by
basket cells. Another type of local circuit neuron, the stellate cell, receives input from the parallel fibers and
provides an inhibitory input to the Purkinje cell dendrites. Finally, the molecular layer contains the apical
dendrites of a cell type called Golgi cells; these neurons have their cell bodies in the granular cell layer. The
Golgi cells receive input from the parallel fibers and provide an inhibitory feedback to the granule cells.
This basic circuit is repeated over and over throughout every subdivision of the cerebellum and is the
fundamental functional module of the cerebellum. Modulation of signal flow through these modules provides
the basis for both real-time regulation of movement and the long-term changes in regulation that underlie
motor learning. The flow of signals through this complex circuitry is best described in reference to the Purkinje
cells. The Purkinje cells receive two types of excitatory input from outside of the cerebellum, one directly
from the climbing fibers and the other indirectly via the parallel fibers of the granule cells. The Golgi, stellate,
and basket cells control the flow of information through the cerebellar cortex. For example, the Golgi cells
form an inhibitory feedback that may limit the duration of the granule cell input to the Purkinje cells, whereas
the basket cells provide lateral inhibition that may focus the spatial distribution of Purkinje cell activity. The
Purkinje cells modulate the activity of the deep cerebellar nuclei, which are driven by the direct excitatory
input they receive from the collaterals of the mossy and climbing fibers. The modulation of cerebellar output
also occurs at the level of the Purkinje cells. The Purkinje cell axons are the only nerve fibers to actually leave
the cerebellar cortex and they synapse on deep cerebellar nucleus neurons and on some vestibular neurons,
inhibiting them powerfully. Therefore, the excitatory input that entered the cerebellum with the mossy fiber
was responsible for exciting the deep nucleus neuron and then for exciting granule cells that stimulate Purkinje
cells that "turn off" the deep nucleus neuron. It is critical that the correct amount of inhibition arrives at the
deep cerebellar nucleus in order to produce an appropriate output, inhibiting unwanted activity in the deep
nuclei. According to one model, the climbing fibers relay the message of a motor error to the Purkinje cells.
This message produces long-term reductions in the Purkinje cell responses to mossy-parallel fiber inputs. This
inhibitory effect on the Purkinje cell responses disinhibits the deep cerebellar nuclei. As a result, the output of
the cerebellum to the various sources of upper motor neurons is enhanced, in much the way that this process
occurs in the basal ganglia.
How does the cerebellum contribute to motor learning? This appears to be the result of plasticity of the
synapse between the parallel fiber and the Purkinje cell. At the moment of activation of the Purkinje cell by
the climbing fiber, all of the parallel fiber synapses that were recently active will undergo a process of longterm depression (activation of metabotropic glutamate receptors at the parallel fiber terminal on the Purkinje
cell at the same time they are activating the ionotropic AMPA receptors -> activation of phospholipase C, which
results in creation of IP3 and DAG -> both contribute to formation of protein kinase C (PKC) -> PKC
phosporylates proteins associated with the AMPA (ionotropic glutamate) receptors -> internalization of
phosphorylated AMPA glutamate channels). The synapses that were active around the time of climbing fiber
input will be weakened, so that the next time the specific parallel fiber is active, it will have less of an
excitatory effect on the Purkinje cell. Since our current concept of the climbing fiber function is that they
convey an error signal, the granule cell to Purkinje cell synapses that were active at the time of the error will
be inhibited. Therefore, each synapse can be adjusted during a process of learning to produce the correct
cerebellar output. In the case of motor patterns, this allows for procedural learning, where each time an
action is performed, it becomes somewhat more accurate since the "right synapses" are contributing to the
response.
Slide 91: development of human cerebellum: foramen of Magendi and fourth
ventricle roof
Blake JA (1900) The roof and lateral recess of the fourth ventricle, considered morphologically and embryologically. J Comp
Neurol 10:79-108.
Lafouge A, Gorincourt G, Desbriere R, Quarello E (2012) Prenatal diagnosis of Blake’s pouch cyst following first trimester
observation of enlarged intracranial lucency. Ultrasound Obstet Gynecol 40:479-483.
Nelson MD, Maher K, Gilles FH (2004) A different approach to cysts of the posterior fossa. Pediatr Radiol 34:720-732.
Paladini D, Quarantelli M, Pastore G, Sorrentino M, Sglavo G, Nappi C (2012) Abnormal or delayed development of the
posterior membranous area of the brain: anatomy, ultrasound diagnosis, natural history and outcome of Blake’s pouch cyst
in the fetus. Ultrasound Obstet Gybecol 39:279-287.
Robinson AJ, Goldstein R (2007) The cisterna magna septa. J Ultrasound Med 26;83-95.
Teele RL, Taylor GA (2012) Demonstration of fourth ventricular choroid plexus on neonatal cranial ultrasonography. Pediatr
Radiol 42:620-623.
Growth of vermis is particularly rapid during the third trimester of pregnancy. The early tuberculum cerebelli
consists of a band of tissue in the dorsolateral part of the alar plate that straddles the midline in the shape of
an inverted V. Vermis develops independently of the hemispheres, it is not the result of a process of fusion. The
arms of the V thicken caudally as well as laterally. The rostral, midline part of the V remains relatively small.
Caudally and laterally directed limbs of the tuberculum cerebelli thicken rapidly during the sixth postovulatory
week and on each side give rise to the internal cerebellar bulge; during the seventh week of development, the
rapidly growing cerebellum bulges outwards as the external cerebellar bulges which represent the flocculi, that
are delineated by the posterolateral fissures. During the third month of development, growth of the midline
accelerates and begins to fill the gap between the limbs of the V, thereby forming the vermis, and by the 12th
to 13th weeks growth processes reshape the cerebellum to a transversely oriented bar of tissue overriding the
fourth ventricle. At the 12th week, fissures begin to form transversely to the longitudinal axis of the brain, first
on the vermis and then spreading laterally into the hemispheres. The corpus cerebelli consists of the
spinocerebellum medially, and the pontocerebellum (or neocerebellum) laterally. The tentorial leaflets,
separating the anterior from the posterior fossa, descend to a more caudal and posterior position by excessive
relative forebrain growth until about 24 weeks of gestation. Relative cerebellar growth halts this process after
that moment in time.
By 18 weeks of gestation (at latest around 24 weeks) the fourth ventricle is covered by its unbulging velum with
the foramen of Magendi present since the late embryonic or early fetal period. Around 14 to 16 weeks, some
bulging of the cavity between its two lateral septa is normal. Against the occipital squame, and containing the
occipital sinus, one may on occasion see the falx of the cerebellum between the Blake pouch membranes,
creating a triple membrane aspect during fetal ultrasound. Blake’s pouch cyst is the protruding intra-axial
cavity that develops when the metapore in the caudal portion of the velum medullare is not formed (the
foramen of Magendi is not formed by week 17 to 18 of GA) and neither are the lateral foramina of Luschka
(they are normally formed somewhat later, but before 24 weeks GA). In that case - without hypoplasia of the
vermis - dilatation of the fourth ventricle emerges, itself communicating with Blake’s pouch in the cisterna
magna. Due to some mass effect the vermis may be uplifted and somewhat rotated backwards and the mesial
cerebellar hemispheres may be compressed. When the foramen of Magendi does form, but later than normal,
some distension of the related spaces persists, this is referred to as mega cisterna magna. Normally the
ependymo-pial septa of Blake’s pouch are visible in the large majority of the fetuses in the second trimester.
The membranes span the cisterna magna on both sides of the vermis in a direction perpendicular to the
cerebellar surface. Following opening of the metapore, CSF gradually finds its way through the arachnoid
membranes along these membranes. Because of this fluidification, the space onder the cerebellar hemispheres
is mildly hyperechoic in second trimester. In some infants regression of the dilatation of Blake’s pouch may take
place after 23 weeks gestational age. Dandy-Walker malformation is at the severe end of this spectrum with
vermis hypoplasia added to Blake’s pouch cyst, because the primary abnormality in DWM is in the velum
medullare anterius, where vermis is formed.
Slide 92: development of human cerebellum: foliation
Korsten A, Lequin M, Govaert P (2006) Sonographic maturation of third-trimester cerebellar foliation after birth. Pediatr Res
59(5):695-9.
Loeser JD, Lemire RJ, Alvord EC (1972) The development of the folia in the human cerebellar vermis. Anat Rec 173:109-114.
The cerebellum consists of the lobus anterior, lobus posterior, and lobus flocculonodulus. These lobes can be
subdivided into lobules. Lobes and lobules are separated from each other by fissures. Each lobule is composed
of folds of cerebellar cortex called folia. The lobes, lobules and folia can be followed across the midline from
one side of the cerebellum to the other. The cerebellum is also divided into the vermis in the midline, on both
sides the paravermes, and more lateral the hemispheres.
At the 12th week of development, fissures begin to form transversely to the longitudinal axis of the brain, first
on the vermis and then spreading laterally into the hemispheres. The fissura posterolateralis is the first fissure
to appear around 50 mm CR (12 weeks gestational age). It divides the cerebellum into lobus flocculonodulus
and corpus cerebelli. The second fissure to appear is the fissura prima at 75 mm CR (14 weeks gestational age).
This fissure subdivides the corpus cerebelli into the lobus anterior and lobus posterior. The fissura prima and
the fissura prepyramidalis demarcate the middle lobe, identifiable by 17 weeks. All nine of the vermis lobules
can be identified by the development of the major fissures at approximately 15 weeks of gestation. Later
secondary fissures appear in the vermis and lobus floccunodularis which eventually extend into the
hemispheres and give rise to the adult folia. Shallower fissures subdivide lobus anterior and posterior into a
series of transverse lobules which are given specific names.
The lobus anterior is divided into three lobules: lingula, lobulus centralis, and culmen. The lobus vermis
posterior is divided into five lobules: declive, folium, tuber, pyramis, and uvula. The lobus hemispheri is
divided into five lobules as well: simplex, semilunaris, gracilis, biventralis, and tonsilla. The lobulus
semiluminaris is further subdivided into superior and inferior. The lobules of the vermis are present at 150 mm
CRL (20 weeks postmenstrual age).
The vermis cerebelli begins to develop folia by 13-14 weeks gestational age. Each of the lobules vermis except
the “middle lobe” (declive, folium and tuber vermis) has at least one sulcus by 14 weeks of gestation. The
development of folia continues throughout gestation and is not completed numerically until about two months
after term. At this time the number of folia in vermis is nearly the same as in the adult. The gestational age at
which each of the lobules has attained half of the adult average number of folia varies between 24 and 37
weeks. Even though the largest lobules (culmen, declive and pyramis) are producing more folia per week, it
takes somewhat longer for them to reach the half-way point (28-32 weeks). Smaller lobules (lingula, centralis
and nodulus) reach their half-way point earlier (18-28 weeks). The folium vermis and tuber vermis, part of the
middle lobe, are the last to reach their half-way point (32-36 weeks).
The pattern of folding of the cortex cerebelli is related to the development of the cells within the cortex. The
nodulus which is embryologically the first to develop has a higher cell concentration of the internal layer than
any other lobule at birth but its increase in cell concentration is much slower than the other lobules. The
declive is embryologically the last to develop and shows an opposite pattern of cellularity than the nodulus,
starting later but ending with a higher cell concentration. The other lobules of the lobus centralis develop
between the nodulus and the declive and their cellular postnatal growth apparently reflects a mid-way
development. The definite number of foliae is reached a few months after term birth.
Slide 93: adult human cerebellum: macro-anatomical landmarks
Images adapted from Smith CG, van der Kooy DJ (1985) Basic Neuroanatomy. 3rd Edn. Toronto: Collamore Press.
Macro-anatomical landmarks of the cerebellar surface, with its peduncles.
Slide 94: deep cerebellar nuclei and functional subdivision of cerebellum
Brossard-Racine M, du Plessis AJ, Limperopoulos C (2015) Developmental cerebellar cognitive affective syndrome in expreterm survivors following cerebellar injury. Cerebellum 14(2):151-64.
Limperopoulos C, Chilingaryan G, Sullivan N, Guizard N, Robertson RL, du Plessis AJ (2012) Injury to the premature
cerebellum: outcome is related to remote cortical development. Cereb Cortex 24(3): 728–36.
In 1937 Larsell introduced the nomenclature lobules I-X for the vermis and HI-HX for the hemispheres. Lobulus
HI is usually absent. This scheme emphasizes the transverse continuity of lobules across the vermis and the
hemispheres. Another scheme by Bolk (1906) and elaborated by Voogd (1964 and 1967) emphasized
discontinuity between the two hemispheres and the vermis inferior which are separated completely by the
sulcus paramedianus. They proposed that hemispheres and vermis are distinguished by separate, longitudinally
continuous chains of lobules.
The continuous relationship between the lobes of the vermis and the hemispheres is present in smaller
mammals and during the ontogenesis of larger mammals. However in mature, larger mammals it seems that the
continuity between the lobes of the vermis and the hemispheres is obscured, due to unequal growth of the
subdivisions of the hemispheres and by consequent displacement of the lobules which induce secondary
changes in the lobus posterior.
Observe subdivision of cerebellum in three main parts: spino-, vestibulo- and cerebro-cerebellum. The
cerebellar cortex relays information to four deep nuclei, each with different output.
Cerebellar injury is increasingly recognized as an important complication of very preterm birth. Available data
suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and
adversely affect neurodevelopment (Brossard-Racine et al. 2015). Early life impairment of cerebellar growth
extends far beyond motor impairments and plays a critical, previously underrecognized role in the longterm cognitive, behavioral, and social deficits associated with brain injury among premature infants, which
could be referred to as a developmental form of the cerebellar cognitive affective syndrome of adults.
Expressive language and congitive skills eem to be affect by injury to vermis and hemispheres, also leading to
social impairment. Motor problems can be predicted from injury to the vestibulocerebellum (vermis area) and
autism psectrum disorders may also be part of this sequence. Cerebero-cerebellar diaschizis (cerebral atrophy
on the other side of a large cerebellar lesion) has been reported in preterm infants, but further descriptions
are needed to understand the consequences and importance of it (Limperopoulos et al. 2012).
Slide 95: development of human cerebellum: aspects of foliation in cranial
ultrasound
Korsten A, Lequin M, Govaert P (2006) Sonographic maturation of third-trimester cerebellar foliation after birth. Pediatr Res
59(5):695-9.
Development of foliation in cranial ultrasound. Examples below of measurement of the PA (pons area), HA
(hemisphere area) and MFID (foliation hight at facies superior).
Slide 96: development of choroid plexus
Adeeb N, Deep A, Griessenauer CJ, Mortazavi MM, Watanabe K, Loukas M, Tubbs RS, Cohen-Gadol AA (2013) The intracranial
arachnoid mater : a comprehensive review of its history, anatomy, imaging, and pathology. Childs Nerv Syst.
Jan;29(1):17-33.
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
Ariëns Kappers JA (1958) Structural and functional changes in the telencephalic choroid plexus during brain ontogenesis. In:
Wolstenholme GEW, O’Connor CM (eds) The Cerebrospinal Fluid. Little, Brown, Boston, MA, pp 3–25.
Bartelmez GW, Dekaban AS (1962) The early development of the human brain. Contrib Embryol Carnegie Instn 37:13–32
Bronsteen R, Lee W, Vettraino I, Balasubramaniam M, Comstock C (2006) Isolated choroid plexus separation on second
trimester sonography: natural history and postnatal importance. J Ultrasound Med 25(3): 343-347.
Catala M (1998) Embryonic and fetal development of structures associated with the cerebrospinal fluid in man and other
species. Part I: The ventricular system, meninges and choroid plexuses. Arch Anat Cytol Pathol 46(3):153–169.
Desmond ME, Jacobsen AG (1977) Embryonic brain enlargement requires cerebrospinal fluid pressure. Dev Biol 57:188–198.
Dziegielewska KM, Ek J, Habgood MD, Saunders NR (2001) Development, evolution and ageing: Development of the Choroid
Plexus. Microscopy research and technique 52:5-20.
Galarza M (2002) Evidence of the subcommissural organ in humans and its association with hydrocephalus. Neurosurg Rev
25:205–15.
Gomez DG, DiBenedetto AT, Pavese AM et al. (1982) Development of arachnoid villi and granulations in man. Acta Anat
(Basel) 111:247–58.
Hochstetter F (1939) Über die Entwicklung und Differenzierung der Hüllen des menschlichen Gehirns. Morphol Jahrb 83:359–
494.
Iliff JJ, Wang M, Liao Y et al. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the
clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111.
Kraus I, Jirásek JE (2002) Some observations of the structure of the choroid plexus and its cysts. Prenat Diagn 22:1223–1228.
Kurjak A, Schulman H, Predanic A, Predanic M, Kupesic S, Zalud I (1994) Fetal choroid plexus vascularisation assessed by
color flow ultrasonography. J Ultrasound med 13(11): 841-844.
Møllgård K, Malinowska DH, Saunders NR (1976) Lack of correlation between tight junction morphology and permeability
properties in developing choroid plexus. Nature 264:293–294.
Nakada T, Kwee IL (2018) Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and
Cerebrospinal Fluid Circulation in the Brain. The Neuroscientist 1-12.
Netsky MG, Shuangshoti S (1975) The choroid plexus in health and disease. Bristol: Wright.
O’Rahilly R, Müller F (1986) The meninges in human development. J Neuropathol Exp Neurol 45:588–608.
Paladini D, Quarantelli M, Pastore G, Sorrentina M, Sglavo G, Nappi C (2012) Abnormal or delayed development of the
posterior membranous area of the brain: anatomy, ultrasound diagnosis, natural history and outcome of Blake’s pouch cyst
in the fetus. Ultrasound in Obstetrics and Gynecology 39:279-287.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Robinson AJ, Goldstein R (2007) The cisterna magna septa. J Ultrasound Med 26:83-95.
Rodriguez EM, Oksche A, Montecinos H (2001) Human subcommissural organ, with particular emphasis on its secretory
activity during the fetal life. Microsc Res Tech 52:573–90.
Sakkaa L, Coll G, Chazala J (2011) Anatomy and physiology of cerebrospinal fluid. European Annals of Otorhinolaryngology,
Head and Neck diseases 128, 309—316.
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Donkelaar HJ, Lammens M, Hori A: Clinical Neuroembryology: Development and Developmental Disorders of the Human
Central Nervous System.
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Bottom left: Mid-sagittal scheme of immature brain after closure of the neural tube, showing sites of choroid
plexus formation. The plexus in the IVth ventricle develops first, then in the lateral ventricles, and last in the
third ventricle. According to Netsky and Shuangshoti (1975), the lateral and third ventricular plexuses are
continuous as shown in the drawing. However, in all species so far reported on there is an interval of several
days or more between the first appearance of the lateral ventricular plexuses and the IIIrd ventricular plexus;
their continuity in later stages of development appears to be secondary. III, site of formation of IIIrd ventricle;
IV, site of IVth ventricle.
Growth of choroid plexus may have a role in the extension of the ventricular fluid compartments, by increasing
ventricular surface area and thus promotion of a widespread proliferation of neocortical precursors (Desmond
and Jacobsen 1977, Altman and Bayer 2015). The choroid plexus sits between two barrier systems (blood and
cerebrospinal fluid) and has as primary goal the production and regulation of cerebrospinal fluid (Catala 1998).
Choroid plexus first appears in the roof of the fourth ventricle at stage 18 (day 41), in the lateral ventricles at
stage 19, and in the third ventricle at stage 21 (Ariëns Kappers 1958, Bartelmez and Dekaban 1962). The
primordia appear as simple club-shaped folds protruding into the ventricles, emanating from pial mesenchymal
vascular extensions covered by single ependymal epithelium: these protrusions are later named vela
interposita. The time at which choroid plexus starts to secrete CSF has not been clearly determined, but
carbonic anhydrase (for bicarbonate excretion) is present two weeks after appearance of plexus. It may be that
an early nutritional rôle for plexus is present, but this function is lost during development. In the eight week,
from the choroidal fissure extending out, the lobular character of the plexus gradually changes into an
arrangement of wavy folds; capillaries form single loops under the cuboidal epithelium (Kraus and Jirasek
2002). Bone morphogenetic proteins and tropomyosin are involved in specification of plexus development.
Four stages of lateral ventricular plexus development have been defined (Dziegielewska et al. 2001): stage 1:
7-9 weeks after conception, no glycogen, ill defined blood islets, pseudostratified epithelium; stage 2: 9-17
weeks after conception, abundant glycogen, primari villi, low columnar epithelium, subepithelial capillaries,
very large relative size in relation to ventricle; stage 3: fetal period, moderate glycogen, many primary villi,
cuboidal epithelium, mature capillaries in villous core; stage 4: after 29 weeks: villi with multiple fronds,
disappearing glycogen, cobuoidal or squamous epithelium, relatively small plexus in relation to ventricle size.
The mechanisms involved in formation of a blood-CSF barrier at choroid plexus combine diffusion restraint
(tight junctions between the plexus epithelial cells) and specific exchange. One barrier mechanism unique to
the developing brain transfers specific proteins from blood to cerebrospinal fluid (CSF), via tubulocisternal
endoplasmic reticulum in plexus epithelial cells. This results in a high concentration of proteins in early CSF.
Proteins may function as colloid osmotic agents for ventricle expansion but also as specific carriers and growth
factors. Some proteins are not transferred in but are locally produced, like transthyretin and IGF II. Barrier
mechanisms in the immature brain reflect developmental specialisation rather than immaturity.
Human fetal choroid plexus sometimes contains a large central mass of amorphous material with a few poorly
distinguishable blood vessels, surrounded by a single layer of epithelial cells (Voetmann 1949, Netsky and
Shuangshoti 1975). Its significance is uncertain, but the resemblance with Wharton’s jelly suggests it may have
a mechanical, expanding function. In many fetuses plexus cysts appear (and often regress) in which fluid
accumulates in the mesenchymal space without epithelial lining (unlike colloid cysts). The cysts have irregular
angiomatous capillaries in there walls, unlike the normal capillary loops (Kraus and Jirasek 2002). As an
isolated finding this is within normal development, very often an incidental sonographic finding.
Already at 9 weeks, with transvaginal fetal ultrasound, the plexus can be seen at the level of both lateral
ventricles. Between 9 and 11 weeks, plexus covers most of the surface of the standard transventricular fetal
ultrasound axial section. As pregnancy progresses, the volume ratio between choroid plexus and the ventricles
decreases. As the ventricles develop, the choroid plexus grows to occupy the atrium, covering posterior
thalamus (Timor-Tritsch et al. 2012). The finding of choroid plexus separation by more than 3 mm from the
medial ventricle wall is usually temporary in the second trimester, resolving in most cases within 4 weeks of
the initial diagnosis in the second trimester. Most infants with this finding have no abnormalities (Bronsteen et
al. 2006). During stage 21, the plexuses become vascularized. Choroid plexus vessels are first seen with doppler
ultrasound at 10 to 11 weeks GA.
Slide 97: development of choroid plexus on postnatal ultrasound
Some images to show development of choroid plexus with ultrasound. Notice relative larger size in preterm
infants. The presence of small cysts in choroid plexus is more rule than exception.
Slide 98: ventricle anatomy
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015.
Brouwer MJ, de Vries LS, Groenendaal F, Koopman C, Pistorius LR, Mulder EJH, Benders MJNL (2012) New reference values
for the neonatal cerebral ventricles. Radiology 262; 224-233.
Cardoza JD, Goldstein RB, Filly RA (1988) Exclusion of fetal ventriculomegaly with a single measurement: the width of the
lateral ventricular atrium. Radiology 169: 711-714.
Davies MW, Swaminathan M, Chuang SL, Betheras FR (2000) Reference ranges for the linear dimensions of the intracranial
ventricles in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 82(3): F218-23.
DiPietro MA, Brody BA, Teele RL (1985) The calcar avis: demonstration with cranial US. Radiology 156: 363–364.
Helmke K, Winkler P (1987) Sonographisch ermittelte Normwerte des intrakraniellen Ventrikelsystemes im ersten
Lebensjahr (Ultrasonic measurements of the normal intracerebral ventricular system in the first year of life). Monatsschrift
für Kinderheilkunde 135: 148-152.
Johnson ML, Dunne MG, Mack LA (1980) Evaluation of fetal intracranial anatomy by static and real time ultrasound. Journal
of Clinical Ultrasound 8: 311-318.
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of Disease in Childhood 56: 900-904.
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O’Rahilly R, Müller F (2001) Human embryology and teratology. Wiley-Liss, New York.
Poland RL, Slovis TL, Shankaran S (1986) Normal values for ventricular size as determined by real time sonographic
techniques. Pediatric Radiology 15: 12-14.
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Saliba E, Bertrand P, Gold F, Vaillant MC, Laugier J (1990) Area of lateral ventricles measured on cranial ultrasonography in
preterm infants: reference range. Archives of Disease in Childhood 65: 1029-1032.
Schimmel MS, Hammerman C, Bromiker R, Berger I (2006) Third Ventricle Enlargement Among Newborn Infants With Trisomy
21. Pediatrics 117;928-931.
Shen EY, Huang FY (1989) Sonographic finding of ventricular asymmetry in neonatal brain. Archives of Disease in Childhood
64:730-744.
The lateral ventricles are cavities filled with cerebrospinal fluid. They are inferolaterally bordered by the head
of the caudate nucleus. Their shape resembles a horseshoe curled round the caudate nucleus, thalamus and
cerebral peduncles. The lateral ventricles each consist of a body (corpus), an atrium and three horns. On a
cross section, the corpus shows as a triangle pointing laterally upwards, with a slight convex bulge towards the
vertex. On its floor there is vascular tissue resting on thalamic nuclei, while medially the fornix borders the
ventricular floor. The frontal horn has an elliptical slit-shaped lumen, partly covered by the corpus callosum
and situated laterally to the septum pellucidum. The temporal or sphenoidal horn ends in the ventricular
atrium. Medially the temporal horn is bordered by the pes hippocampi. The occipital horn is not always well
visualized from the anterior fontanel, its dimensions differing from one individual to another. Choroid plexus
projects horizontally in the direction of the occipital lobe. Plexus from the floor of the ventricular corpus
continues into the roof of the temporal horn. Frontal and occipital horns do not contain plexus.
The foramen of Monro is the connecting passage between third ventricle and frontal horn of the right and left
lateral ventricle. In the absence of ventriculomegaly it is not always visible. It can be localized as the place
where third ventricle plexus curves into the lateral ventricle in the foramen’s upper caudal margin.
In fetal life, the ventricle opposite the scanhead clearly shows its lateral wall as an echoic line; at the level of
the corpus of the lateral ventricle, this line parallels the falx; the lateral ventricle width is represented by the
distance between midline and far ventricle wall, identical to the lateral ventricle index after birth (Johnson et
al. 1980: mean width 8 mm at 16 weeks postmenstrual age, 9 at 26, 11 at 33 and 12 at 40 weeks). Atrial width
is constant in third trimester.
Slide 99: ventricle anatomy, fluid production and circulation: classic and
updated views
Adeeb N, Deep A, Griessenauer CJ, Mortazavi MM, Watanabe K, Loukas M, Tubbs RS, Cohen-Gadol AA (2013) The intracranial
arachnoid mater: a comprehensive review of its history, anatomy, imaging, and pathology. Childs Nerv Syst.
Jan;29(1):17-33.
Jiang Q (2019) MRI and glymphatic system. Stroke and Vascular Neurology 4: e000197. doi:10.1136/svn2018-000197
Nakada T, Kwee IL (2018) Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and
Cerebrospinal Fluid Circulation in the Brain. The Neuroscientist 1-12.
Oreskovic D, Rados M, Klarica M (2017) Role of choroid plexus in cerebrospinal fluid hydrodynamics. Neuroscience 354;
69-87.
Raper D, Louveau A, Kipnis J (2016) How Do Meningeal Lymphatic Vessels Drain the CNS ? Trends in Neurosciences,
September Vol. 39, No. 9.
On the left the classical view on water production and circulation in the cranium. It is believed that this only
represents around 80 % of the actual water circulation in the adult. Depending on the site of production, CSF
flows from the lateral ventricles through the foramina of Monro into the third ventricle, from which it passes to
the fourth ventricle through the aqueduct of Sylvius. From the fourth ventricle, the CSF enters the
subarachnoid space and basal cisterns through the paired lateral foramina (of Luschka) to the cerebellopontine
angle and prepontine cistern, and by the median aperture (of Magendi) to the cisterna magna. In the cisterna
magna the CSF has three routes: superiorly to enter the hemispheric subarachnoid space, inferiorly to enter
the spinal subarachnoid space, and anteriorly to enter the cerebellopontine, prepontine cisterns and
premedullary cisterns. To get into the hemispheric subarachnoid space, CSF leaves the basilar cistern through
two routes: ventrally through the interpeduncular and chiasmatic cisterns to enter the subarachnoid space of
the lateral and anterior aspect of the hemispheres, and dorsomedially through the ambient and quadrigeminal
cisterns to enter the subarachnoid space of the medial and posterior aspects of the hemispheres.
The movement of CSF is facilitated by: continuous production of CSF, ciliary action of the ventricular
ependyma, pulsatile CSF movement and the pressure gradient across the arachnoid villi. The pulsatile motion
of CSF is related to the interaction of brain movement, arterial blood flow, and cardiac cycle. During early and
mid systole, blood flow within the brain compresses the ventricles and leads to choroid plexus expansion and
displacement. This, in turn, propels the CSF in a direction towards the spinal subarachnoid space. This caudal
flow occurs first in the spinal canal or at the base of the brain due to expansion of the larger arteries, and
then, as the blood fills the arterioles and capillaries in the brain tissue and choroid plexus, the caudal flow
occurs in the ventricles. During late systole and diastole, the pressure is higher caudally, which propels the CSF
cranially within the ventricles and the subarachnoid space. This allows the CSF to be mixed in the ventricles
and spread in all direction in the subarachnoid space.
The role of choroid plexus in the CSF dynamics is debated (Oreskovic et al. 2017): it does not participate in
regulation of ICP/CSF pressure; plexus liquor production is not the reason for the existence of a pressure
gradient in the CSF system (the gradient disappears in the horizontal position). Although CSF is partially
produced by the plexus, it is also to an important extent formed as a consequence of water filtration between
capillaries and interstitial fluid. Transport of Na+, Cl, and HCO3 ions regulates the net osmotic gradient across
the choroid plexus. Na+ is pumped out of the choroid cells by the Na+/K+ pump and its intracellular
concentration is driven down. The Na+ gradient activated in this way on the plasma-facing membrane
(basolateral membrane) subsequently activates via Na+/Cl- cotransport the transport of Na+ into the cell. Clexchange takes place across the apical and basolateral membranes. The regulation of intracellular pH is
performed by basolateral Na+/H+ antiport and Cl-/HCO3 - pumps. Cl- accumulation on the Cl-/HCO3 exchanger on the basolateral membrane is stimulated by intracellular HCO3 - produced by the hydration of
carbon dioxide, which is catalyzed by carbonic anhydrase. Aquaporin-1 channels, which exist on the apical and
basolateral membrane regulate the water movement across the choroid epithelia.
On the right the glymphatic system is added (Nakada and Kwee 2018). Because of the tight junctions of brain
capillary endothelium, the interstitial fluid system of the brain cannot benefit from the hydrodynamic force of
the systolic pulse of the heart, and interstitial fluid may become “stagnant” without a proper hydrodynamic
alternative. AQP-4 localized to endfeet at the GLE is believed to play the role of ensuring proper water influx
into the intracellular space of astrocytes.The AQP-4 system provides water influx into the peri-capillary
Virchow-Robin space (VRS). Necessary water enters astrocytes through AQP-4 at the glia limitans externa (GLE).
This system promotes appropriate interstitial fluid circulation, including bulk flow through the VRS (interstitial
flow). The mixed CSF and ISF with interstitial metabolic waste flows towards paravenous (or para-arterial
perforator) pathways, and then to the nasal lymphatic system via the basal cisterns. AQP4 water channels in
both arteries and veins play important role in reducing the resistance to CSF movement between paravascular
spaces and the interstitium. In addition to the nasal pathway, true dural lymphatics have been described
around the major sinuses and spinal nerves.
Waste clearance during sleep is the most likely function of the glymphatic system: changes in efficiency of CSF–
ISF exchange between the awake and sleeping brain are caused by expansion and contraction of the
extracellular space, which increases by ~60% during sleep to promote clearance of interstitial wastes such as
amyloid beta; the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic
waste products produced by neural activity in the awake brain. In addition there may be a rôle in lipid
transport:
- transport of small lipophilic molecules,
- paravascular transport of lipids through the glymphatic pathway activates glial calcium signalling; impairment
of the glymphatic circulation, leads to unselective lipid diffusion, intracellular lipid accumulation and
pathological signalling among astrocytes.
Boulton M, Young A, Hay J, Armstrong D, Flessner M, Schwartz M, Johnston M (1996) Drainage of cerebrospinal fluid through
lymphatic pathways and arachnoid villi in sheep: measurement of 125 I- albumin clearance. Neuropathol Appl Neurobiol
22:325-333.
Boulton et al. 1996 studied the effect of pressure on the clearance of tracer from the ventricular system in
sheep. The collection of the radiolabeled tracer from the lymphatic and venous systems was evaluated during a
3-hour low-pressure perfusion and a similar period for evaluating outflow at various pressure levels. On average
an increase in ICP of 10 cm H2O elevated arachnoid villi and lymphatic CSF clearance 2.7 and 3.9 fold
respectively.
Ding Y, Zhang T, Wu G, McBride DW, Xu N, Klebe DW, Zhang Y, Li Q, Tang J, Zhang JH. Astrogliosis inhibition attenuates
hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix
hemorrhage. Exp Neurol. 2019 Oct;320:113003.
Germinal matrix hemorrhage (GMH) results from the rupture of the immature thin-walled blood vessels and
consequent bleeding into the subependymal germinal matrix and possible lateral ventricles. GMH was induced by
stereotaxic collagenase infusion into P7 Sprague-Dawley rats of both sexes. Western blot and immunofluorescence were
used to assess astrogliosis and how astrogliosis affects glymphatic function by measuring Aquaporin-4 expression.
Intracisternal injection of fluorescence tracer was used to measure CSF diffusion throughout the brain, its dispersion in the
paravascular area and CSF drainage into the deep cervical lymph nodes at 28 days after GMH. Both short-term and longterm behavioral tests were used to assess the neurological outcomes. Nissl staining was used to assess the morphological
changes at 28 days after hemorrhage.
GMH elicited astrogliotic scarring and reduced the exchange between CSF and interstitial fluid, as well as CSF
reabsorption through the meningeal lymphatic vessels. This might be associated with redistribution of
Aquaporin-4. Olomoucine limited scar tissue formation and attenuated post-hemorrhagic hydrocephalus. These
findings suggest that the glymphatic system might play a role in CSF reabsorption in neonates following GMH.
Scar tissue formation impairs this CSF clearance route, and therefore astrogliosis inhibition might be a
potential therapeutic strategy for neonatal post-hemorrhagic hydrocephalus.
This sequence of events may explain postnatal onset of striatal arteriopathy (hyperechoic perforator arteries)
following GMH/IVH.
Slide 100: lateral ventricle configuration on ultrasound
Inspection of lateral ventricle size is routinely part of cranial ultrasound. This image shows typical
configurations of the lateral ventricle in coronal sections. Inset: five mechanisms behind dilatation of the
lateral ventricles.
Slide 101: lateral ventricle size
Brouwer MJ, de Vries LS, Groenendaal F, Koopman C, Pistorius LR, Mulder EJH, Benders MJNL (2012) New reference values
for the neonatal cerebral ventricles. Radiology 262; 224-233.
Cardoza JD, Goldstein RB, Filly RA (1988) Exclusion of fetal ventriculomegaly with a single measurement: the width of the
lateral ventricular atrium. Radiology 169: 711-714.
Davies MW, Swaminathan M, Chuang SL, Betheras FR (2000) Reference ranges for the linear dimensions of the intracranial
ventricles in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 82(3): F218-23.
Helmke K, Winkler P (1987) Sonographisch ermittelte Normwerte des intrakraniellen Ventrikelsystemes im ersten
Lebensjahr (Ultrasonic measurements of the normal intracerebral ventricular system in the first year of life). Monatsschrift
für Kinderheilkunde 135: 148-152.
Levene MI (1981) Measurement of the growth of the lateral ventricles in preterm infants with realtime ultrasound. Archives
of Disease in Childhood 56: 900-904.
Perry RNW, Bowman ED, Roy RND, de Crespigny LCH (1985) Ventricular size in newborn infants. Journal of Ultrasound
Medicine 4: 475-477.
Poland RL, Slovis TL, Shankaran S (1986) Normal values for ventricular size as determined by real time sonographic
techniques. Pediatric Radiology 15: 12-14.
Saliba E, Bertrand P, Gold F, Vaillant MC, Laugier J (1990) Area of lateral ventricles measured on cranial ultrasonography in
preterm infants: reference range. Archives of Disease in Childhood 65: 1029-1032.
Shen EY, Huang FY (1989) Sonographic finding of ventricular asymmetry in neonatal brain. Archives of Disease in Childhood
64:730-744.
In healthy neonates the lateral ventricles are often asymmetrical (i.e. the diagonals of the right and left lateral
ventricle differ at least 2 mm in a frontal section at the level of the foramen of Monro). Different types of
asymmetry have been described depending on the place where mild asymmetrical dilatation is most clear
(corpus and/or occipital horn). The left ventricle most often tends to be larger, a predilection that does not
correlate with head presentation at vaginal delivery. There is no significant difference between supine and
upper ventricle in case of lateral head position. Dilatation of the lateral ventricles often begins in the occipital
horns. If they fail to show up this is an argument against dilatation. In case of obvious ventriculomegaly, the
concavity that characterizes the floor of the frontal horn disappears, whereby the normal boomerang shape is
gradually lost. If one can clearly see the whole ventricle in one parasagittal section, including temporal and
occipital horns, ventriculomegaly must be present.
Most prefer to define lateral ventricle width as a function of cranial width (the cella media index). This
produces indices which, under normal circumstances, tend to remain constant during the first months of life.
They are good tools for recognition of hydrocephalus. In term neonates the following data are found:
• On an axial section through the body of the lateral ventricle the ratio [midline to lateral wall of the
ventricle]/[midline to internal table of the skull] varies between 0.25 and 0.35 (0.22–0.33 according to Helmke
and Winkler).
On a frontal section through the head of the caudate nucleus the ratio [laterolateral diameter between the
points of the frontal horns]/[distance between the left and right internal table on that section] averages 0.32
(95% reliability margin 0.23–0.42).
Slightly higher ratios have been found in preterm (0.32–0.36) than term infants (0.25–0.30). Term values are
achieved around 36 weeks gestation. Such a ratio measured behind the foramen of Monro, at the level of the
corpus of the lateral ventricle, tends to be 0.35 at or around term. It has been customary to talk about
ventriculomegaly for values between 0.36 and 0.4 and about hydrocephalus for values above 0.4. The
ventricular diameter can be followed serially on axial sections by measuring the distance between the falx and
the external wall of the body of the opposite ventricle: 97th centile measurements for Levene’s lateral
ventricle index are 10 mm around 26 weeks, 13 mm around 33 weeks and 14 mm around 40 weeks. The
diagonal width of the lateral ventricle in a frontal section rarely exceeds 3 mm at the foramen of Monro. One
speaks of “ballooned” frontal horns when this diagonal measure exceeds 6 mm.
Another method consists of measuring the surface of the body of the lateral ventricle on a cross section behind
the foramen of Monro, through the base of pons (Saliba et al. 1990)
- in preterm infants with a gestational age of 27 to 36 weeks, normal values show a broad range: around birth
the surface varies between 5 and 15 mm2, with an average value of about 8 mm2
more than 15 mm2 during the first week of life and more than 20 mm2 during the first month of life, appear to
exceed the normal range. Any such value must be compared with the child’s head circumference and
subarachnoid space width, to determine whether ventricular dilatation is due to obstruction of liquor flow or to
loss of brain tissue.
Slide 102: third ventricle configuration and size
Bosch i Ara L, Katugampola H, Dattani MT (2021) Congenital hypopituitarism during the neonatal period: epidemiology,
pathogenesis, therapeutic options and outcome. Frontiers in Pediatrics 8; 600962; 1-17.
Helmke K, Winkler P (1987) Sonographisch ermittelte Normwerte des intrakraniellen Ventrikelsystemes im ersten
Lebensjahr. Monatsschrift für Kinderheilkunde 135: 148–152.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
Sarnat HB (2021) Transitory and vestigial structures of the developing human nervous system. Pediatric Neurology 12;
86-101.
Sagittal section: The third ventricle is a slit-shaped rectangular cavity filled with CSF. It is situated in between
the thalami and above the bony sella turcica. On a sagittal section the echogram shows a clearly delineated
echolucent zone of rounded triangular shape. Ventrocranially and slightly laterally, one finds the
interventricular foramen of Monro. Ventrocaudally there is the pointed anterior recess around the chiasma, and
dorsocranially there is the pineal recess. In fact, the anterior recess consists of a supra-optic recess and an
infundibular recess, sonographically inseparable unless high frequency linear probes are in use. Often one can
see the aqueduct emerge in the space between the pineal and anterior recesses. Sometimes one suspects an
indentation of the ventricular floor by the mamillary bodies. Echoic linear choroid plexus is found superiorly.
Ventrally the latter bifurcates and, via the interventricular foramina, it courses on as plexus from right and left
lateral ventricles. The echolucent interpeduncular cistern is visible under the third ventricle. Behind it one can
find the particularly dense bifurcation of the basilar artery and, further dorsally, the echolucent cerebral
peduncles. The anterior wall of the third ventricle, between the interventricular foramina and optic chiasm, is
formed by the mildly echoic lamina terminalis and its commissures. This rostral wall of the third ventricle
contains the anterior commissure at it’s dorsal and the optic chiasm at it’s ventral end. The dorsal lamina
terminalis is the site of the prosencephalic neural crest. There is no convincing description of abnormal
pituitary glands with neonatal cranial ultrasound. Congenital hypopiuitarism is a rare, treatable and often
difficultly diagnosed condition (Bosch i Ara et al. 2021).
Coronal section: In the healthy term infant it is difficult to recognize the third ventricle on frontal sections
because it is narrow and because its lateral walls course parallel to the direction of the sound waves. For this
reason it is better to approach measurement of this ventricle through the lateral fontanels, as in axial view
both thalamic walls appear as bright lines with a dark space in between. On both sides of the ventricle one
suspects (sub)thalamic and ventrocaudally hypothalamic nuclei, both not amenable to discrete sonographic
description. The massa intermedia is a cylindrical echoic structure in the third ventricle, consisting of grey
matter interconnecting the lateral walls. The size of this commissure is variable, and it is absent in a signficant
proportion of the infants.
Axial section: The width of the third ventricle normally averages 2.8 mm and 3.8 mm respectively for age
groups 0–3 and 9–12 months. In the early neonatal period the third ventricle is no wider than 2 mm. When its
anatomic boundaries are clearly distinguishable in the sagittal plane, the ventricle is already dilated.
Slide 103: cisterns
Adeeb N, Deep A, Griessenauer CJ, Mortazavi MM, Watanabe K, Loukas M, Tubbs RS, Cohen-Gadol AA (2013) The intracranial
arachnoid mater: a comprehensive review of its history, anatomy, imaging, and pathology. Childs Nerv Syst 29(1):17-33.
Sarnat HB (2021) Transitory and vestigial structures of the developing human nervous system. Pediatric Neurology 12;
86-101.
Cisterns are accumulations of liquid between brain structures and the skull. Normally they rarely show up on
echograms. Their existence can be suspected because the walls, consisting of leptomeninges and blood vessels,
are strongly echoic. An enlarged cistern looks like an irregularly rimmed cavity and generally indicates a
proximally located obstruction to the circulation of CSF. The cisterna magna and the prepontine cistern
normally show as a cavity. It follows they play an important part when looking for subarachnoid haemorrhage in
a sagittal ultrasound section.
Basal (suprasellar) cistern: comprises the chiasmatic and interpeduncular cisterns.
Cisterna magna (cerebellomedullary cistern): this cistern, located under the echoic vermis above the occipital
bone, is of variable size. If large, it will be viewed as an accumulation of liquid in the posterior fossa, around
the cerebellum. In this cistern are found the postero-inferior cerebellar artery, cranial nerves IX–XII and the
cerebellar tonsils.
Pontine cistern: is an hypoechoic zone ventrally above the pons, in front of the cerebral peduncles, under and
behind the anterior recess of the third ventricle. The particularly echodense zone with arterial pulsations in
this cistern corresponds with the bifurcation of the basilar artery. It ends in the interpeduncular cistern
Quadrigeminal cistern: is an echofree area (1-3 mm wide) behind an echoic line between the plexus of the
third ventricle and the vermis. A cyst of the quadrigeminal cistern thus lies behind this ventricle. This cistern
contains the posterior cerebral and posterior choroidal arteries, the IVth cranial nerve and the great vein of
Galen. There is a direct lateral communication with the retrothalamic cistern behind the pulvinar. The
thickness of the echoic zone overlying the colliculi (normally no more than 3 mm) often increases in case of
subarachnoid haemorrhage.
Ambient cistern: constitutes the lateral connection between the prepontine and interpeduncular cisterns in
front, and the quadrigeminal cistern behind. In this cistern we find the posterior cerebral artery, superior
cerebellar artery, mesencephalic vein, cranial nerve IV and the optic tract. On a frontal section through
hippocampus the ambient cistern shows as the vertical part of a C, encircling the brainstem on both sides. The
upward curve of the C corresponds to the hippocampal fissure and the plexus of the temporal horn, whereas
the lower curve corresponds with the tentorium. This echoic curve is 1–3 mm wide in preterm infants around 26
weeks postconceptional age.
Chiasmatic cistern: This is a pentagonal echodense zone around the optic chiasm. Its angles correspond to the
arteries of the circle of Willis: in front the anterior cerebral arteries; laterally, the carotid siphon with the
origin of the middle cerebral arteries; and at the back, the posterior cerebral arteries. Sideways the cistern
ends, together with the middle cerebral artery, in the lateral cistern which fills out the Sylvian fossa.
Slide 104: Liliequist membrane in the basal cisterns
A complex arachnoid thickening has been described by Liliequist and therefore carries his name. It may be
involved in both the genesis and (endoscopic) treatment of suparasellar arachnoid cysts.
Adeeb N, Deep A, Griessenauer CJ, Mortazavi MM, Watanabe K, Loukas M, Tubbs RS, Cohen-Gadol AA (2013) The intracranial
arachnoid mater : a comprehensive review of its history, anatomy, imaging, and pathology. Childs Nerv Syst.
Jan;29(1):17-33.
Dias DA, Castro FL, Yared JH, Lucas Júnior A, Ferreira Filho LA, Ferreira NF (2014) Liliequist membrane: radiological
evaluation, clinical and therapeutic implications. Radiol Bras 47(3):182-5.
Liliequist B (1956) The anatomy of the subarachnoid cisterns. Acta Radiol 46:61–71
Mortazavi MM, Quadri SA, Khan MA, Gustin A, Suriya SS, Hassanzadeh T, Fahimdanesh KM, Adl FH, Fard SA, Taqi MA,
Armstrong I, Martin BA, Tubbs RS (2018) Subarachnoid Trabeculae: A Comprehensive Review of Their Embryology, Histology,
Morphology, and Surgical Significance. World Neurosurg 11:279-290.
Mortazavi MM, Rizq F, Harmon O, Adeeb N, Gorjian M, Hose N, Modammadirad E, Taghavi P, Rocque BG, Tubbs RS (2015)
Anatomical variations and neurosurgical significance of Liliequist's membrane. Childs Nerv Syst 31(1):15-28.
Based on the various descriptions, Liliequist membrane (LM) has been divided into three types:
- type A: the LM is composed of two leaflets, the diencephalic leaf (DL) and mesencephalic leaf (ML) that
originate at the dorsum sellae
- type B: LM appears as one leaf anteriorly and two leaflets posteriorly, with the LM arising as single membrane
and then splitting into DL and ML
- type C: LM appears as a single (diencephalic) membrane.
The description by Liliequist was of a single membrane with forward convexity, extending from the dorsum
sellae to the anterior edge of mammillary bodies (type C). This well-developed membrane stretches like a
curtain from one mesial temporal surface to the other. Thus, a full description of the type C LM would be of a
single, non-fenestrated membrane that arises inferiorly from the basilar arachnoid membrane covering the
dorsum sellae and the posterior clinoid processes, curves anteriorly, and attaches superiorly to the pia of the
hypothalamus just anterior the mammillary bodies (premammillary), posterior to the infundibulum. Laterally, it
attaches to the pia of the mesial surface of the temporal uncus. This lateral extension (at the carotidinterpeduncular wall) is perforated by the oculomotor nerve and the posterior communicating artery.
Slide 105: cavum veli interpositi and cavum Vergae
There are two midline cavities in addition to the cavum septi pellucidi. Both can draw the attention (by
unexpected large size) of both fetal and neonatal ultrasound specialists, and some cavities need follow-up and
even surgical treatment when they exert pressure. The cavum of Verga and the cavum of the velum
interpositum have to be differentiated from an aneurysm of the great vein of Galen: both are subcallosal and
have no doppler flow in them; vein of Galen malformation is more subplenial and with doppler flow.
The cavité du septum lucidum or cavum septi pellucidi and cavum Vergae were described by Tenchini in 1880,
who noted that its incidence in preterm neonates was 100%. Unlike the ventricular system, the space between
the two vertical leaves of the septa is not lined by ependyma. The septum pellucidum in the late second and
third trimesters and in postnatal infants is a fused pair of thin glial membranes containing no neurons or axonal
pathways. In early development, however, the septum is a true structure with cellular progenitors neuronal and
glial lineage, formed in the ventromedial quadrant of the early prosencephalon. A thick septum can be well
demonstrated in normal fetuses in the early second trimester of gestation. Septal neuroblasts do not develop
functional importance even in the fetal and preterm neonatal brain, the cells undergo apoptosis and disappear.
The cavum arises as a pocket between the walls of the infolded primordial hippocampus, bridged by the
developing corpus callosum. Beginning at about 15 weeks GA, the human septum begins to regress or diminish
in size with loss of its neuronal progenitors but preservation of maturing astrocytes, until it evolves into a pair
of thin glial membranes with a space between them, the cavum. The septum persists until the early postnatal
period when the cavum decreases in width and the paired membranes of the vestigial septum fuse into a single
midline structure in later infancy and childhood. The cavum is uniformly present in normal fetal brain of less
than 36 weeks' gestation but by term only 1/3 infants still exhibit a cavum. A minority of adult brains may show
persistence of a thin cavum septi pellucidi. In fetal hydrocephalus due to aqueduct stenosis, fourth ventricular
obstruction, or other causes, the septum becomes stretched and may rupture from physical forces and no
longer be evident in neuroimaging prenatally or postnatally. Alternatively, fetal ventriculomegaly from
obstructive hydrocephalus may compress the two leaves of the septum pellucidum against each other,
obliterating the cavum. Agenesis of the corpus callosum is another condition in which the septum pellucidum
and its cavum may appear absent by imaging. The septum is truly absent in some malformations involving
principally midline cerebral structures, such as alobar holoprosencephaly and septo-optic pituitary dysplasia.
Rarely only partial agenesis of the septum but with cavum is demonstrated.
The cavum Vergae is a caudal extension of the cavum septi pellucidi, lying behind an arbitrary vertical plane
formed by the columns of the fornix. The cavum vergae is continuous with the cavum septi pellucidi and is
similarly lined by glial processes, not ependyma. It appears later in fetal life than the cavum septi pellucidi and
usually is obliterated by six months gestation. Cavum Vergae can be demonstrated by perinatal imaging but is
not as constant as the cavum septi pellucidi.
Dandy WE (1931) Congenital cerebral cysts of the cavum septi pellucidi (fifth ventricle) and cavum Vergae (sixth ventricle).
Diagnosis and treatment. Arch Neurol Psychiatry 25: 44-66. Farruggia S, Babcock DS (1981) The cavum septi pellucidi: its
appearance and incidence with cranial ultrasonography in infancy. Radiology 139:147–150.
Gebarski SS, Gebarski KS, Bowerman RA, Silver TM (1984) Agenesis of the corpus callosum: sonographic features. Radiology
151:443–448.
Madonick MJ, Gilbert S, Stern WZ (1964) Partial agenesis of septum pellucidum with cave of septum pellucidum. Arch
Neurol. 1964;11:324e329.
Mott SH, Bodensteiner JB, Allan WC (1992) The cavum septi pellucidi in term and preterm newborn infants. J Child Neurol
7:35–38.
O’Rahilly R, Müller F (2006) The Embryonic Human Brain. An Atlas of Developmental Stages, third ed. Wiley-Liss, Hoboken,
NJ.
O’Rahilly R, Müller F (2008) Significant features in the early prenatal development of the human brain. Ann Anat 190:
105-118.
Sarnat HB (2021) Transitory and vestigial structures of the developing human nervous system. Pediatric Neurology 12;
86-101.
Shaw C-M, Alvord EC (1969) Cava septi pellucidi et Vergae: their normal and pathological states. Brain 92:213–224.
The cavum Vergae (Verga’s ventricle) is the caudal part of the cavum developed within the septal leaflets,
posterior to the columnae fornicis.
The cavum veli interpositi is often a virtual space with the internal cerebral vein in its lateral wall. When
dilated, the internal cerebral vein remains a marker in its lateral wall, as opposed to an arachnoid cyst in the
cisterna quadrigemina, which lies under the internal cerebral vein.
Birnbaum R, Barzilay R, Brusilov M, Wolman I, Malinger G. The normal cavum veli interpositi at 14-17 weeks: threedimensional and Doppler transvaginal neurosonographic study. Ultrasound Obstet Gynecol. 2020 Aug 15.
In a retrospective analysis of 89 3DUS volumes, acquired from the median view of the brain of normal fetuses
between 14-17 weeks, by transvaginal US:
1) interhemispheric fluid collections of various sizes were found in only 54.4% (49/90) of the fetuses (mean
length = 5.5 mm, range 3-7.8 mm)
2) color flow images were obtained in 32/49 of the fetuses: in 100% of these, the internal cerebral vein
separates the "cystic" fluid collection from the hyperechoic tela choroidea.
The midline "cyst-like" structure seen during early second trimester, is present in only half of normal fetuses in
various random sizes. Its distinct location on top of the internal cerebral veins, shows its true origin, a
physiologic transient cavum veli interpositi.
Slide 106: calcar avis
DiPietro MA, Brody BA, Teele RL (1985) The calcar avis: demonstration with cranial US. Radiology 156: 363–364.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
The calcar avis (ergot de Morand, ergot d’oiseau) is a piece of cortex and subcortical white matter underneath
to the incurved calcarine fissure at its merger with the sulcus parieto-occipitalis. The calcarine fissure is
formed around the 16th postconceptional week. Between the 32nd and the 40th week it stretches, thus shifting
a piece of cortex and white matter into the occipital horn. The calcar avis will be more or less prominent
dependent upon the depth of the gyri. An echogram through the posterior fontanel clearly shows this structure.
Distinction should be made with haemorrhage in the occipital horn, in that case showing as dense reflections
from the lower margin of the occipital horn rather than its lateral and superior wall. The use of Doppler
imaging to illustrate the absence of vessels in a clot can be helpful to make this distinction, especially if
viewed from the posterior fontanel.
Slide 107-109
This text is adapted from Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb Clin-Neurol
171:245-289.
The brain at 10 w GA, 8 w postovulatory, stage 23, CRL 27-31 mm.
At the end of the embryonic period, the cortical plate (first appearing in the insular area lateral to the lateral
ganglionic eminence at stage 21) has begun development from the alar telencephalic neuroepithelium, and is
now covering nearly the entire neopallium as a sheet much thinner than neuroepithelium. It has a dual origin: a
primitive plexiform cortex (forming primary plexiform layer with Cajal-Retzius cells and subplate from stage
20, day 50), with the mammalian neocortex (layers II to VI) intercalating between them. The cortical plate
develops with a lateral to dorsal and a central to frontal gradient.
Choroid plexus develops in concert with the cortical plate. The indented area of the insula is visible in the
basal centre of the curved hemispheres. The diencephalon is separated by mesenchyme from the
telencephalon and is still partially uncovered. Olfactory structures and the optic commissure have formed in
stage 20 around day 51. The basal ganglia and amygaloid nuclei are present in the form of their definitive
nuclei.
Dorsal thalamus is covering about half the diencephalic third ventricle surface. In addition to fourth ventricle
neuroepithelium, the rhombic lips have become an active cerebellar neuroepithelial production site, first
forming floccular cortex, inferior olive and pontine grey nuclei. Early reciprocal connections between thalamus
and cortex are present in the lateral prosencephalic fasciculus (predecessor of the internal capsule which has
just formed). Pioneering thalamic axons reach the occipital area.
The corticospinal tract has reached the pyramidal decussation.
Intrinsic brain vessels have already appeared at the moment telencephalic hemispheres appear around day 32
(stage 14). Arteries forming the mature circle of Willis are present, MCA and ACA branches overlie the insular
cleavage. The superior sagittal sinus has appeared. At the rostral neuropore (closed at stage 11, day 24) the
massa commissuralis is growing.
The brain at 24w PMA.
The second trimester, the fetal period before viable preterm age, is characterised by maturation of the cortical
plate and development of white matter tracts. Cortical layering is already different between different regional
types of cortex. Asymmetric progenitor division permits production of postmitotic migrating neurons, of
subventricular zone precursors and of glial cells.
At the end of the second trimester, around viable age, myelin is still absent in cerebrum and cerebellum, but it
is present in the ventral spinal quadrant, in cuneate fascicle and spinal motor efferent fibers. The neopallial
mantle has been separated for weeks into transient layers between neuroepithelium (ventricular and
subventricular zone) and the cortical plate.
Subplate has been and continues to be an important organisor for structuring the cortical plate under the
influence of thalamic afferents. The stratified transitional fields reflect different cortical neuronal precursors
on their way to the cortex, and these fields grow especially between weeks 14 to 18 of gestation.
Matrix neuroepithelium is very prominent between the caudothalamic grooves and the dorsal temporal horn.
The fourth ventricle neuroepithelium and external granular layer are actively producing cerebellar cells.
Commissural white matter tracts have shaped the corpus callosum and underneath it the cavum septi pellucidi.
Early primary gyri are present (parieto-occipital, calcarine and later central) and opercularisation has started
caudally, forming the lateral fissure. The calcarine sulcus separates the lingula from the cuneus, for upper and
lower visual field processing respectively.
Thalamic and striatal nuclei are formed, although GABAergic neurons will migrate into thalamus from the
corpus gangliothalamicum throughout the third trimester.
The brain at 37w PMA.
By this stage sublobulation, the result of secondary gryration, is active and will continue after term birth.
Between 24 and 31 weeks primary sulci and gyri develop as a consequence of gradual intercalation of migrating
cells from the subventricular zone into the cortical plate. Primary sulci develop orderly, their appearance at
postmortem exam precedes detection with imaging for at least two weeks.
By 37 w the corticospinal tract and the rest of cerebral white matter is still mostly unmyelinated, but myelin is
present in the superior cerebellar peduncle, the rubrospinal tract and inferior olive. Corticospinal tract
myelination mainly proceeds in the first 4 months after term birth, except for an early core of myelinated
fibers in the posterior limb of the internal capsule that is already present before term birth. Cerebral white
matter myelination is purely postnatal.
Germinal matrix disappears from telencephalon around term except for frontal subventricular neuroepithelium
that continues to produces GABAergic neurons for several months.
Slide 110: the brain surface at 32w and at term with important landmarks
from Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
Slide 111: “standard” sectional planes
The use of standard planes is nothing but a logical anatomical approach, there is no proof of its validity,
neither in clinical use nor in research.
It is a method for saving images available for retrospective interpretation (serial comparison, medicolegal
issues) and for prospective studies with some necessary standardisation of imaging.
Additional sections and movies focusing on lesions are as important as the standard sections.
There are 5 standard coronal planes and 4 parasagittal planes per hemisphere. With the sagittal plane this adds
up to 14 standard sections through the anterior fontanelle.
Slide 112: anterior coronal plane through olfactory sulci
The anterior (rostral) coronal plane 1.
In this section focus is on the presence and presentation of the interhemispheric fissure and on the presence
and depth of the olfactory sulci. These sulci increaese in depth from rostral to caudal and often the standard
image is taken at the far anterior end of the corpus callosum (the genu) with the tips of the frontal horn just
visible. A slightly more posterior section may be needed to measure the maximum depth of the sulcus
olfactorius. Notice how the anterior end of the lateral fissure splits into a ramus ascendens and ramus
horizontalis.
Slide 113: anterior coronal plane through olfactory sulci: congenital
anomalies
Leboucq N, Menjot de Champfleur N, Menjot de Champfleur S, Bonafe A (2013) The olfactory system. Diagnostic and
Interventional imaging 94: 985-991.
Guimiot F, Marcorelles P, Aboura A, Bonyhay G, Patrier S, Menez F, Drouin-Garraud V, Icowick V, Eurin D, Garel C, Moirot H,
Verspyck E, Saugier-Veber P, Attie-Bitach T, Picone O, Oury JF, Verloes A, Delezoide AL, Laquerrière A. Giant diencephalic
harmartoma and related anomalies: a newly recognized entity distinct from the Pallister-Hall syndrome. Am J Med Genet A.
2009 Jun;149A(6):1108-15.
Top right: an early sulcus olfactorius and the frontal transitonal field of migrating cells and axons at 26w PMA.
Above: a scheme of the olfactory structures.
Congenital anomalies observed in the anterior coronal plane. Observe the major efferent olfactory pathways to
temporal pole and amygdala. Sulcus olfactorius is bordered medially by the gyrus rectus and laterally by the
medial orbital gyrus.
Very exceptionally hemimegalencephaly may be recognized in a neonatal ultrasound scan. Perfectly
symmetrical scanning may not permit to have the interhemispheric fissure exactly sagittal due to a shift toward
the smaller (normal) hemisphere.
Arhinencephaly is also rare, but one can depict this indirectly by noticeing absence of the olfactory sulci. The
image shows a list of disease entities with arhinencephaly.
The bottom right image (courtesy of Neelam Gupta, Southampton) is from a neonate with cardiac problems and
a large brain, in which the frontal mesial gyri inderdigitated, creating a sinuous fissure. This distortion of the
interhemispheric fissure is also reported in other conditions as listed.
Slide 114: coronal plane around the foramen of Monro
The coronal plane 2 @ foramen of Monro.
This section is important for describing absence of the septal leaflets and especially for the detection of lesions
in germinal matrix. The (perfectly symmetrical) coronal section is chosen only a fraction of distance in front of
the rostral end of the tela choroidea. Tela choroidea is hyperechoic choroid plexus in the roof of the third
ventricle (in the midline) and it curves laterally into the lateral ventricles in the foramina of Monro. In more
mature newborns this section also depicts the closed anterior end of the lateral fissure with presence of frontal
and temporal operculum. A far anterior mesial temporal sulcus is the sulcus rhinalis, just rostral to the sulcus
collateralis that appears in more posterior sections. During doppler imaging this section may display both
carotid arteries.
Slide 115: coronal plane around the foramen of Monro: anterior commissure
and sulcus rhinalis
Especially in ELBW infants and with a high frequency probe, it is possible (not always) to depict the anterior
commissure. This commissure interconnects temporal areas and the amygdala. In axial sections the anterior
commissure appears as a hypoechoic band traversing the area perforata anterior with hyperechoic dots of the
Virchow-Robin spaces around perforator arteries.
Sulcus rhinalis (initially called fissura rhinalis as it is the first groove formed on the cerebral surface between
olfactory cortex and neocortex) is similar in location to sulcus collateralis, but it lies more rostral and a little
bit more inferior, below the uncus.
Slide 116: coronal plane around the foramen of Monro: septal area
The septal area is important for CUS because agenesis of the septal leaflets and absence of the cavum septi
pellucidi is not exceptional and is often a surprise finding with clinical consequences. Although it is possible to
depict the septal gray nuclei in some infants where the ventricles are open and the cavum is present, the
description of other related structures is disappointing. The columnae fornicis hang under these septal nuclei.
Slide 117: coronal plane around the foramen of Monro: lesions in germinal
matrix
The presence of hyperechoic or cystic structures in the lateral wall of the frontal horn, rostral to tela
choroidea, is abnormal. GMH (germinal matrix haemorrhage) and germinolysis (of non-haemorrhagic nature)
are both very common findings in neonatal CUS. Germinal matrix is hardly visible as it is very midly
hyperechoic when one uses high frequency probes, but it is most often only recognized by the presence of
lesions in it. GMH can present both in front of and behind the foramen of Monro, but the most common location
for GMH is around it. Although germinolysis is often present from birth it can also develop in the late neonatal
period when it is often mistaken for GMH. Hyperechoic germinolysis is best seen in parasagittal sections when a
soft homogeneous area of hyperechoic change extends along the caudate head in front of the caudothalamic
groove.
Slide 118: coronal plane around the foramen of Monro: preferential sites of
GMH
Nakamura Y, Okudera T, Fukuda S, Hashimoto T (1990) Germinal matrix hemorrhage of venous origin in preterm neonates.
Human Pathology 21, 1059-1062.
Nakamura Y, Okudera T, Hashimoto T (1991) Microvasculature in germinal matrix layer : its relationship to germinal matrix
hemorrhage. Modern Pathology 4, 475-480.
AnstromJA, Brown WR, Moody DM, Thore CR, Challa VR, Block SM (2004) Subependymal veins in premature neonates:
implications for hemorrhage. Pediatr Neurol 30; 46-53.
The location of GMH, depends on the nearby presence of collector veins. It is distension of venules that is the
most likely cause of GMH. Notice the common occurrence of GMH in the roof of the temporal horn and
especially around the caudothalamic groove.
Slide 119: coronal plane around the foramen of Monro: striatum and its
boundaries
Although a prominent and important structure, in normal brains CUS hardly shows the presence of putamen. In
asphyxia putamen may stand out due to cell death in it and due to relatively dark appearance of the internal
capsule between thalamus and putamen. In preterm infants one may see putamen in a parasagittal section
lateral to thalamus, because putamen is relatively more echoic in VLBW infants.
Slide 120: coronal plane through thalamus
The coronal plane 3 @ thalamus.
This section has ventrolateral thalami, not standing out but faintly visible by discrete hyperechoic change
between mediodorsal thalamus and putamen with PLIC on the lateral side. This section also holds coronal
representations of at least two frontal sulci and a clear vision of the insular cortex covered by the inward
extension of the lateral fissure. The interpedoncular cistern is a hyperechoic dot in the middle of the rostral
mesencephalon. In cerebellum vermis and the superior facies of the cerebellar hemispheres appear
hyperechoic due to ultrasound reflections in the folia.
Slide 121: coronal plane through thalamus: stria terminalis with terminal vein
During doppler insonation the terminal vein can often be directly demonstrated in this section. It lies in stria
terminalis, between caudate head laterally and upper thalamus medially. The terminal vein flows upward and
rostral into the internal cerebral vein, which flows downward and caudal.
Slide 122: coronal plane through thalamus: central core, tracts in isthmus
cerebri
Schmahmann JD, Pandya DN (2006) Fiber pathways of the brain. oxford University press.
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
The isthmus cerebri is a bilateral passage of tracts between the pallium and the cerebral central core. It
extends from the lateral ventricle outer angle to the superior insular cortex. Some important cortico-cortical
association tracts are depicted on the right. The left image is based on a a section of fiber pathways in a
primate brain, with primate tracts projected on the coronal sonogram. Observe the Muratoff bundle and
fasciculus fronto-occipitalis just lateral to the ventricle, the fasciculus longitudinalis superior just superior to
it.
Slide 123: coronal plane through thalamus: network injury in pulvinar
Slightly more caudal (posterior) sections through thalamus mainly contain pulvinar, a large posterior thalamic
nucleus between pretectum and midthalamus.
Posterior thalamic region: Pul Pulvinar complex, including lateralis posterior and nucleus intergeniculatus.
PUL is the largest association nucleus, occupying the posterior dorsal thalamus (the cushion of thalamus).
Phylogenetic develoment of this region is explosive. PUL receives inputs especially from many diverse areas of
the major sensory systems and projects to the all of the association areas of cortex in the parietal, occipital
and temporal lobes. It shares these connections with associative parts of striatum. It also receives sensory
information from components of the visual system, the medial geniculate nucleus, and the cerebellum. PUL
and MD nucleus form a continuum of cortical associative connection. Intergeniculate nucleus receives (in a
visuotopic map) superior collicular and occipital cortical afferents and sends efferents to (peri)visual cortex
and temporal cortex. This means that pulvinar is part of an extra-geniculocortical visual pathway, implicated in
blindsight.
One of the primary outputs of pulvinar is to the secondary visual areas (18 and 19). There is evidence that this
secondary pathway conveys information only about stimulus position and is not involved in pattern recognition.
This contributes to visual perception and eye movements, probably related to visual attention at a new image
or sound. Which explains why lesions in pulvinar may cause neglect. Posterior thalamus also seems to be
fundamentally involved in our control of upright body posture. Pathologic processes associated with posterior
thalamic haemorrhage in adults may provoke contraversive pushing in combination with additional neurologic
symptoms (Pusher Syndrome). Even if lesions in the posterior region are apparently silent they can affect
superior functions involving visual and language modalities and are related to hallucination experiences in
patients.
Network injury to pulvinar.
Connected nuclei - like pulvinar - may secondarily suffer from cell injury with restriction of water diffusion in
the acute phase, referred to as network injury (1,3,4,7-9). Acute callosal changes reflect network injury to
connected tracts, similar to distant injury in the corticospinal tract (2,9). Part of callosal highlighting in acute
DWI may be related to seizure activity. Crossed cerebellar atrophy (diaschizis) related to supratentorial stroke
has recently been demonstrated in children (6). Within affected nuclei, like pulvinar, restriction of diffusion is
probably in affected neurons, but may be also in tracts passing by. The fact that diffusion is abnormal suggests
that pulvinar cells die in a necrotic or hybrid mode, not with pure apoptosis.
1. Govaert P et al. (2008) Network injury to pulvinar with neonatal arterial ischemic stroke. Neuroimage 39:1850-7.
2. Righini A, Doneda C, Parazzini C, Arrigoni F, Matta U, Triulzi F (2010) Diffusion tensor imaging of early changes in corpus
callosum after acute cerebral hemisphere lesions in newborns. Neuroradiology 52:1025-35.
3. Wintermark P and Warfield SK (2012) New insights in perinatal arterial ischemic stroke by assessing brain perfusion.
Transl Stroke Res 3:255-62.
4. Dudink J, Counsell SJ, Lequin MH, Govaert PP (2012) DTI reveals network injury in perinatal stroke. Arch Dis Child Fetal
Neonatal Ed 97:F362-4.
5. De Vis JB, Petersen ET, Kersbergen KJ, Alderliesten T, de Vries LS, van Bel F, Groenendaal F, Lemmers PM, Hendrikse J,
Benders MJ (2013) Evaluation of perinatal arterial ischemic stroke using noninvasive arterial spin labeling perfusion MRI.
Pediatr Res 74:307-13.
6. Mah S, deVeber G, Wei XC, Liapounova N, Kirton A (2013) Cerebellar atrophy in childhood arterial ischemic stroke: acute
diffusion MRI biomarkers. Stroke 44:2468-74.
7. Okabe T, Aida N, Niwa T, Nozawa K, Shibasaki J, Osaka H (2014) Early magnetic resonance detection of cortical necrosis
and acute network injury associated with neonatal and infantile cerebral infarction. Pediatr Radiol 44:597-604.
8. Kline-Fath BM, Horn PS, Yuan W, Merhar S, Venkatesan C, Thomas CW, Schapiro MB (2018) Conventional MRI scan and DTI
imaging show more severe brain injury in neonates with hypoxic-ischemic encephalopathy and seizures. Early Hum Dev.
122:8-14.
9. Srivastava R, Rajapakse T, Carlson HL, Kess J, Wei XC, Kirton A (2019) Diffusion imaging of cerebral disaschisis in neonatal
arterial ischemic stroke. Pediatric Neurology 100; 49-54.
Slide 124: coronal plane through thalamus: network injury versus primary
injury
Top image is from a term infant with hypertonia from birth, the first day scan shows well delineated old
primary thalamic injury with fossilized and therefore very bright neuronal cadavers in ventrolateral thalamus.
The bottom image is from a preterm infant of 34w PMA with extensive subcortical white matter injury and
secondary network injury to pulvinar. Observe the difference in hyperechoic location (more posterior) and the
curved anterior margin of pulvinar network injury.
Slide 125: coronal plane through thalamus: PLIC stands out hypoechoic in
acute total asphyxia
PLIC (posterior limb of the internal capsule) stands out as a dark (echopoor) line between hyperechoic injured
thalamus and striatum. The cell poor PLIC may be oedematous at postmortem but this does not increase echoic
reflections. This four column aspect in coronal CUS sections is typical of acute total asphyxia around birth. It is
less common in the cooling era than before. The images on the right are spectacular because all the injured
areas turned into haemorrhagic necrosis in the acute stage.
Slide 126: coronal plane through the atria
The coronal plane 4 @ atrial level.
This section cuts perirolandic white matter in addition to choroid plexus. It is the only section where an overall
impression of pathological flaring can be caught in one image.
Slide 127: coronal plane through the atria: the optic radiation
In this coronal plane the optic radiations are very often clearly visible in preterm infants. Certainly between 28
and 34 weeks, the period where different grades of leukomalacia are observed, the optic radiation is present
as two almost symmetrical elliptoid hyperechoic areas between the lateral fissure and the upper third of the
atrium. It is relatively reassuring when the optic radiations stand out amidst less echoic white matter
(especially superior to the optic radiation).
Slide 128: coronal plane through the atria: flaring to cystic leukomalacia
Typical examples of the location and nature of characteristic leukomalacia. The infant below shows progression
from heterogeneous (coarse) flaring (present from day 1) to focal cystic leukomalacia. Notice absent
visualisation of the optic radiation. Injured sites extend to the sulcus parieto-occipitalis and not beyond,
sparing occipital periventricular white matter.
Slide 129: coronal plane through the atria: normal and abnormal flaring
Three examples (top coronal and bottom parasagittal CUS) of, from left to right, normal white matter, mild
homogeneous flaring and heterogeneous pathological flaring. Notice absence of the optic radiation with
pathological flaring.
Slide 130: coronal plane through the atria: choroid plexus haemorrhage
Two different types of plexus haemorrhage. On the left bilateral subtle haemorrhagic change of the glomus
choroideum, difficult to recognize with CUS (unusual swelling attracts attention). On the right unilateral plexus
haemorrhage (only minimal change on the other side) presenting with low grade fever in a term infant.
Slide 131: coronal plane posterior to the atria: the parietal lobe
The coronal plane 5 @ post-atrial level.
In this plane the parietal lobe is clearly delineated by the ramus supramarginalis sulci cinguli above and the
sulcus-parieto-occipitalis below. Notice how limited the visualisation of the occipital lobe is from the anterior
fontanel.
Slide 132: coronal plane posterior to the atria: focal parietal lesions
Top: sulcus intraparietalis behind the sulcus postcentralis.
Bottom: two different focal parietal lesions, one haemorrhagic, the other arterial embolic stroke.
Slide 133: coronal plane posterior to the atria: sulcus calcarinus
Sulcus calcarinus and sulcus parieto-occipitalis form a special pattern in the coronal plane (incomplete
spectacles). At the merger of these two sulci the calcar avis bulges into the mesial ventricle wall behind the
atrium. The example below shows striking exaggeration of the visibility of the calcar avis by the presence of
mesial occipital subdural haematoma, not due to sinus thrombosis. Images on the right are through the
posterior fontanel.
Slide 134: midsagittal plane
The midsagittal plane 6.
It is almost always possible to depict, in the sagittal plane, the vermis, the pons and the entire corpus callosum
with midline cavities under it. Splenium can be least well delineated. Often one of the sulci cinguli and the
parieto-occipital and calcarine sulci are also in view.
Slide 135: midsagittal plane: vermis
Compare normal aspect of vermis (left) with 4 different pathological conditions. Although the distance from
the anterior fontanel precludes high resolution images, on many occasions an abnormal midline in the fossa
posterior is the first hint to an important hindbrain/cerebellum problem. When a large haematoma forms in
cerebellum the upper margin of what appears to be midline vermis can be elevated but still sharp, this is in
contrast to the irregular aspect of the upper margin of vermis superior in case of central tentorial tear with
local subdural haematoma outside of the cerebellum. Relative size of fourth ventricle and cisterna magna are
important for the detection of (ponto)cerebellar hypoplasia. The fourth ventricle is positioned slightly caudal
to the most protruding part of the basis pontis in normal infants and the ventricle is an undeep triangle with
the fastigium at the top.
Slide 136: midsagittal plane: cavities, fornix and internal cerebral vein
The midline cavities and their related internal cerebral veins are important regional structures in the sagittal
plane.
Slide 137: parasagittal plane through the caudothalamic groove
Parasagittal plane 7 through the caudothalamic notch.
Between the midasagittal plane and a typical parasagittal section through the gangliothalamic notch, a section
just lateral to the midline best shows eventual matrix injury at the rear end of the caudate head, just in front
of the notch. Observe the prominent sulcus rostralis superior in front of and below the genu corporis callosi.
Slide 138: parasagittal plane through the caudothalamic groove: sulcus
cinguli comparative anatomy
The juxtasagittal plane through the caudothalamic notch often depicts sulcus cinguli in its full length.
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Ebeling U, Steinmetz H, Huang Y, Kahn T (1989) Topography and identification of the inferior precentral sulcus in MR
imaging. AJR 10: 937-942.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Liu Y, Yu Q, Cheng L, Chen J, Gao J, Kiu Y, Lin X, Wang X, Hou Z (2022) The parcellation of cingulate cortex in neonatal
period based on resting-state functional MRI. Cerebral Cortex may 1-11.
Paturet G (1964) Traité d’anatomie humaine. Tome IV: Système nerveux. Masson & co, Paris.
Paus T, Tomaiuolo F, Otky N, MacDonald D, Petrides M, Atlas J, Morris R, Evans AC (1996) Human cingulate and paracingulate
sulci: pattern, variability, asymmetry and probabilistic map. Cerebral Cortex 6: 207-214.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24
Slagle TA, Oliphant M, Gross SJ (1989) Cingulate sulcus development in preterm infants. Pediatric Research 26: 598–602.
Spasojevic G, Stojanovic Z, Suscevic D, Malobabic S, Vujnovic S (2010) Morphological variations of the limbic-lobar border
cortex on the inner side of the human brain hemisphere. Periodicum Biologorum 112: 89-95.
Testu L, Latarjet A (1948) Traité d'anatomie humaine. Doin, Paris.
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
Also called the callosomarginal or supracallosal sulcus (Huxley 1861), the sulcus cinguli begins below the
rostrum of the corpus callosum, in the subcallosal region, before it sweeps around the genu running more or
less parallel to the corpus callosum. Phylogenetically in primates, sulcus cinguli separates from the sulcus
calcarinus compared to other mammals.
The sulcus cinguli, in its anterior part, separates the mesial frontal gyrus above from the cingulate gyrus
below. In front of the precallosal part, two inconstant vertical sulci run parallel to sulcus cinguli. The sulcus
rostralis (superior) of Eberstaller (1884, emerging just before 30w GA) courses front to back around the rostrum
of the corpus callosum, originating near the “carrefour olfactif “ of Broca, and ends closely behind the frontal
pole. It is independent and roughly parallel to the anterior cingulate sulcus and is very frequently accompanied
by the inferior shallower rostral sulcus, also named the accessory rostral sulcus. In about 1/3 the superior
rostral sulcus is connected to sulcus cinguli. Below the genu corporis callosi and below the initial point of
sulcus cinguli, a short vertical sulcus arcuatus may separate the mesial frontal lobe from the subcallosal area.
In a small number of brains (around 1/20) an intralimbic sulcus divides gyrus cinguli in two ascending parts in
front of the genu corporis callosi.
Posteriorly sulcus cinguli ends with a very constant ascending (supra)marginal ramus in the parietal lobe,
separating precuneus from the paracentral lobule. The marginal ramus has a characteristic relationship to the
central sulcus, ending about 1 cm (in adults) posterior to it, and it is often festonnated. A posterior connection
between sulcus cinguli (at the ascension of the ramus supramarginalis, from a near constant ramus posterior)
and sulcus subparietalis (developing after 26w gestation) occurs in about 1/3 brains. A constant branch, sulcus
paracentralis, ascends from the sulcus cinguli in front of the mesial end of the sulcus centralis: between this
branch and the ramus supramarginalis the sulcus cinguli contains the lobulus paracentralis.
The cingulate sulcus starts to be visible at postmortem in some fetuses just before 20 weeks, in some preterms
first indications of it appear only around 24 weeks. It is a continuous groove around 29weeks (if not
interrupted) and ramifies after 32w PMA.
A maturational delay but not an alteration in shape (compared to the normal detailed description from a
discontinuous sulcus around 26w, to continuity by 30w and branching in the following 4 weeks) was documented
by postnatal sonographic study of the developing cingular groove following unilateral medullary venous
infarction in preterm infants with GA below 32w (Slagle et al. 1989).
Using functional MRI (fMRI) with resting state sequences in term newborn infants, a parcellation of cingulate
cortex has been proposed that is a prelude to adult parcellation Liu et al. 2022). Anterior cingulate cortex is
part of the salient and of the default mode network (prefrontal, related to emotional control), the middle
cingulate cortex is anchored in motor control (parietal) and the posterior cingulate cortex functions in the
default mode network. Limbic fibers have indeed been demonstrated in fornix and gyrus cinguli with structural
MRI (DTI) from around 19 w PMA.
Slide 139: parasagittal plane through the caudothalamic groove: sulcus
cinguli variation in anatomy
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Ebeling U, Steinmetz H, Huang Y, Kahn T (1989) Topography and identification of the inferior precentral sulcus in MR
imaging. AJR 10: 937-942.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Paus T, Tomaiuolo F, Otky N, MacDonald D, Petrides M, Atlas J, Morris R, Evans AC (1996) Human cingulate and paracingulate
sulci: pattern, variability, asymmetry and probabilistic map. Cerebral Cortex 6: 207-214.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
The cingulate sulcus is duplicated in about one third of hemispheres, mainly in its anterior segment, the
“double” groove being referred to as sulcus paracinguli, situated either above or below sulcus cinguli itself.
Doubling of the anterior cingulate sulcus occurs twice as frequently in the left versus right hemisphere, its
incidence is slightly over half on the left and around 1/3 on the right. This may be related to Brodmann area
32, for vocalisation.
Up to three interruptions are frequently (40%) noted along the course of sulcus cinguli. These interruptions lead
to invaginations of the mesial frontal gyrus into the cingulate gyrus, corresponding to the “plis de passage
fronto-limbiques” of Broca, annectant gyri of Cunningham. An unbranched sulcus cinguli is not most common
(around 1/3 brains). Frontolimbic annectant gyri often correspond to upward frontolimbic ramifications (from 2
to 8 ramification in the adult brain).
Meng Y, Li G, Wang L, Lin W, GilmorJH, Shen D (2016) Discovering Cortical Folding Patterns in Neonatal Cortical Surfaces
Using Large-Scale Dataset. Med Image Comput Comput Assist Interv. 9900: 10–18.
A method is proposed for discovering the major patterns of cortical folding in a large dataset of neonatal brain
MR images (N = 677). Cortical folding is characterized by the distribution of sulcal pits, which are the locally
deepest points in cortical sulci. Because deep sulcal pits are genetically related, relatively consistent across
individuals, and stable during brain development, they are suitable for characterizing cortical folding.
Similarities between sulcal pit distributions of any two subjects are measured from spatial, geometrical and
topological points of view; these measurements are adaptively fused using a similarity network fusion
technique, to preserve their common and catch their complementary information. Finally, leveraging the fused
similarity measurements, a hierarchical affinity propagation algorithm is used to group similar sulcal folding
patterns together. The proposed method has been applied to 677 neonatal brains in the central sulcus, superior
temporal sulcus, and cingulate sulcus. In cingulate sulcus, four folding patterns are recognized.
Slide 140: parasagittal plane through the caudothalamic groove: germinolysis
and vessels near the groove
Some aspects of normal CUS anatomy around the caudothalamic notch, inclusing vessels. Observe the typical
location of hyperechoic germinolysis (often of postnatal onset in preterm infants) in the notch in front of the
anterior end of the tela choroidea. Observe (left) the hypo-echoic character of the normal corpus callosum in
VLBW preterms.
Slide 141: parasagittal plane through the caudothalamic groove: sulcus
parieto-occipitalis
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres.
The section near the midline often displays sulcus parieto-occipitalis and sulcus calcarinus, including calcar avis
as one moves around a bit. Gyrus cunei is a prominent annectant gyrus that often comes to the surface.
Sulcus parieto-occipitalis.
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
First analyzed by Gratiolet (1854), the parieto-occipital sulcus is deep, constant and characteristic of the
primate brain. Situated principally on the posterior mesial aspect of the hemisphere, it extends downward
from the dorsal margin of the hemisphere forward to the caudal aspect of the splenium where it joins the stem
of the calcarine fissure from which it is frequently separated by the cuneolimbic gyrus (gyrus cunei) connecting
the apex of the cuneus to the isthmus. It shows a number of folds connecting the cuneus to the precuneus in its
depths. The parieto-occipital sulcus continues as the deep external incisure on the lateral aspect of the
hemisphere for a short distance. Close to the dorsal margin this sulcus may form a branch, the sulcus limitans
precunei which connects in 25% of the cases with the intraparietal sulcus. A line connecting the parietooccipital incisure to the preoccipital notch draws the arbitrary boundary on the lateral surface separating the
occipital lobe from the temporal and parietal lobes. Sulcus parieto-occipitalis develops in synchrony but
separate from the calcarine sulcus, its precursor in lower mammals is the postsplenial sulcus.
Sulcus calcarinus.
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
The calcarine sulcus extends anteriorly and stops at the most posterior extent of the collateral sulcus, where
the isthmus of the cingulate gyrus extends into the parahippocampal gyrus. The cuneus is connected to the
posterior aspect of the adjacent cingulate gyrus by the deeply situated gyrus cunei (cuneolimbic annectant
gyrus, Ecker). At the occipital pole, the sulcus calcarine bifurcates as vertical retrocalcarine sulcus behind
which is the gyrus descendens of Ecker (1869). The latter may sometimes be located on the lateral aspect of
the hemisphere, or bounded posteriorly by an occipital polar sulcus limiting the striate area.
The calcarine sulcus arises behind and just below the splenium of the corpus callosum and proceeds backward
toward the occipital pole where it usually ends in this bifurcation, but it may encroach, most frequently by its
superior ramus, on the lateral aspect of the hemisphere. Sulcus calcarinus is divided into two segments at the
point of its junction with the parieto-occipital sulcus. The first, cephalad to this junction, taking part in
formation of calcar avis (ergot de Morand), is the anterior calcarine sulcus (the calcarine stem) and the other caudal - division is the posterior calcarine sulcus, developing separately later than the anterior part. Both
parieto-occipital and calcarine sulcus start to visualise around 16 weeks and by 27 weeks cuneus and subjacent
gyrus lingualis are clearly demarcated. It is unusual for the calcarine sulcus to be absent after 22w of
gestation. The parieto-occipital sulcus develops separately from the calcarine stem and even when they are
aligned at the surface (rarely), an annectant gyrus cunei is always present between cuneus and limbic gyrus.
The course and form of the posterior calcarine sulcus is variable, but it is usually just in front of the medial
end of the transverse sinus. One or two submerged gyri, the anterior and the posterior cuneolingual folds of
Déjerine, may be found within the posterior calcarine segment. The early sulcal pits from which the calcarine
sulcus develops are between these later annectant gyri. So in the early fetal period of development it is usual
for the middle calcarine sulcus to be visible and separated from the vertical posterior part by the cuneolingual
annectant gyri in development. Exceptionally, one of these anastomotic folds may become superficial and
permanently interrupt the calcarine sulcus (around 1/20 brains). The upper and the lower lips of the posterior
calcarine sulcus and the lower lip only of the anterior calcarine correspond to the striate cortex (area 17). A
limiting (parallel) calcarine sulcus can be present both above and below the sulcus calcarinus.
Slide 142: parasagittal plane through the ganglio-thalamic egg
Parasagittal plane 8 through the ganglio-thalamic egg.
Thalamus and basal ganglia are important targets of perinatal brain injury. Careful analysis with CUS in
parasagittal view is therefore important. Observe the limited grey-scale nuance between nuclei in the normal
brain.
Slide 143: parasagittal plane through the ganglio-thalamic egg: the internal
capsule and myelination
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
In late pregnancy the corticospinal tract myelinates, starting first in the postcentral gyrus. There are no studies
of myelin content with ultrasound. MR T1 hypersignal and T2 hyposignal can show (and to some degree
quantify) myelination of tracts. Because of the presence of several projection tracts, recognition of lesions and
their influence on the internal capsule is part of routine CUS. Observe position of fibers for face, arm trunk and
leg in the posterior limb of the internal capsule.
Slide 144: comparison of deep grey matter with postmortem descriptions
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
An important distance lies between detailed neuro-anatomy and findings in CUS; although disencourageing at
first impression, as you progress into this tutorial, it will become clear that knowledge of this part of the brain
is essential for any one with an interest in the newborn brain.
Slide 145: a schematic impression of the large thalamic nuclei and
surrounding structures
Altman J, Bayer SA (2015) Development of the human neocortex: a review and interpretation of the histological record. A
Free eBook from the Laboratory of Developmental Neurobiology, Inc. www.neurondevelopment.org © 2015, The Laboratory
of Developmental Neurobiology, Inc. Ocala, FL 34481, USA
Between the internal capsule and the ventricle cavity (with choroid plexus), thalamic nuclei orderly present in
this parasagittal section: thalamic reticular nucleus TRN, ventral anterior nucleus VA, ventral lateral nucleus
VL, ventral posterior nucleus VP, pulvinar.
The caudothalamic notch between head of caudate and thalamus is the place where neuroepithelium still has
large pockets in preterm infants: germinal matrix.
Slide 146: thalamic functional regions on CUS scans at 24w PMA
adapted from Nieuwenhuys R, Voogd J, van Huijzenz C (2008) The human central nervous system. Fourth edition.
Except for the central nuclei and the geniculate nuclei, four major thalamic regions can be located with CUS
(scans of a 25w PMA preterm infant in the first days of life).
Slide 147: parasagittal plane through the ganglio-thalamic egg: objective
comparison of grey values along the same TGC-band
As long as structures in thalamus and basal ganglia are in the same TGC band (time gain compensation),
relative estimation of echogenicity is reliable.
Slide 148: parasagittal plane through the ganglio-thalamic egg: hippocampal
structures
Although hippocampal neurons are a hit in asphyxia and kernicterus for instance, there are no publications of
selective neuronal hippocampal injury relying on CUS. The hippocampal anatomy is presented in detail for
evaluation of MRI scans and gross lesions (focal infarction and haemorrhage) in and around the temporal lobe
on CUS. Hippocampus has a central rôle in memory registration, storage and retrieval.
Slide 149: parasagittal plane through the ganglio-thalamic egg: hippocampal
neurogenesis throughout life
Building brains: an Introduction to neural development, first edition (2011) Price D, Jarman A, Mason J, Kind P. John Wiley &
sons.
Some further views of hippocampal anatomy and a reference to the understanding that hippocampal
neurogenesis extends throughout life. Around the lateral ventricles some subventricular zone progenitors
remain active throughout life; best known progenitor production in mature brain is in olfactory bulb and in
hippocampus. To maintain the capacity of building new memories, neurogenesis remains necessary: granule
neuron precursors, derived from stem cells in dentate gyrus (DG), take on new connections based on
experience. They activate long-term potentiation in CA3 neurons along the mossy fiber pathway.
Slide 150: development of hippocampus
Bajic D, Ewald U, Raininko R (2010) Hippocampal development at gestation weeks 23 to 36. An ultrasound study
of preterm neonates. Neuroradiology 52; 489-494.
Basma J, Guley N, Michael Ii L, et al. (2020) The Evolutionary Development of the Brain As It Pertains to
Neurosurgery. Cureus 12(1): e6748.
Humphrey T (1967) The development of the human hippocampal fissure. J Anat 101(Pt 4):655-76.
Kier EL, Kim JH, Fulbright RK, Bronen RA (1997) Embryology of the Human Fetal Hippocampus: MR Imaging,
Anatomy, and Histology. AJNR Am J Neuroradiol 18:525–532.
Lemire RJ, Loeser JD, Leech RW, Alvord EC (1975) Normal and Abnormal Development of the Human Nervous
System. Hagerstown, Md: Harper & Row; 260–265
According to Humphrey, before the 10th week of development, the dentate gyrus and cornu ammonis are thin
rudimentary structures positioned successively along the posterolateral aspect of the diencephalon. At the 10week stage, a broad shallow hippocampal sulcus is present along the posterolateral aspect of the
diencephalon. This shallow hippocampal sulcus appears when the telencephalic wall of the primordial dentate
gyrus becomes thicker than that of the cornu ammonis. When first identified, the primordial hippocampal
sulcus lies opposite the dentate gyrus. At 10 to 11 weeks, the dentate gyrus increases in thickness, and the
sulcus is deeper and shifts toward the junction of the cornu ammonis and dentate gyrus.
At 12 to 14 weeks, the increasing thickness of the dentate gyrus causes it to rotate toward the cornu ammonis,
and the hippocampal sulcus becomes progressively deeper and more sharply defined. As the sulcus deepens it
becomes oriented more toward the junction of the cornu ammonis with the subicular region. When the dentate
gyrus and cornu ammonis approach each other, a diffuse zone of scattered cells appears deep to the sulcus. In
the human fetus, this diffuse zone is a well-defined triangular area by 13 to 14 weeks and lies between the
definitive molecular stratum of the dentate gyrus and the molecular stratum of the cornu ammonis. The growth
of the dentate gyrus and cornu ammonis causes the medial wall of the hemisphere to bulge into the lateral
ventricle. At 15 to 16 weeks, the hippocampal sulcus is best developed in the temporal portion of the
hippocampal formation. The sulcus both deepens and widens as the dentate gyrus enlarges and then narrows as
its two walls come in contact. Fusion is apparently rapid, for no signs of it were found at 15.5 weeks and
definite manifestations occur at 18.5 weeks and later. Both pia mater and blood vessels may be included
between the walls of the hippocampal fissure as they fuse. The leptomeninges are resorbed, for traces of them
are rare at 30 weeks. A shallow but distinct superficial fissure then remains on the surface. Superficially the
indentation made by this fissure (following infolding of the dentate gyrus) may be situated between the
dentate gyrus and the entorhinal cortex as early as 20.5 weeks.
By 18 to 21 weeks, the relationship of the hippocampal sulcus to the surrounding structures is similar to that of
the adult brain. The relationship of the hippocampal sulcus to the granular layer of the dentate gyrus remains
constant while its position with reference to theother parts of the limbic system changes with development.
Anteriorly, a deep sulcus is still present. More caudally, where the dentate gyrus is infolded to a greater
degree, the deep part of the sulcus is closed. Its walls are fused and a there is a remaining shallow indentation
between the dentate gyrus and the presubiculum, and later between the dentate gyrus and the adjacent
entorhinal cortex. Both pia mater and blood vessels may be included between the walls of the hippocampal
sulcus as they fuse. At times, a residual cavity of the hippocampal sulcus may remain. The end result of the
infolding is that the linear arrangement of the components of the hippocampus is changed so that the external
surfaces of the dentate gyrus and subiculum end up in contact around an obliterated hippocampal sulcus. The
amount of infolding varies along the length of the hippocampus. The infolding or “rolling in” of the
hippocampal formation increases in mammals in proportion to the increase of the neocortical cerebral
hemisphere. This is associated with a concomitant decrease in the size of the rhinencephalon. In primates, the
infolding is greater than in carnivores. The infolding is most pronounced in the dolphin, which has a huge
cerebral hemisphere associated with a relatively reduced hippocampus.
In the fetus of 30 weeks and in the adult human brain, the superficial groove that constitutes the hippocampal
fissure is oriented toward the junction of the presubiculum and the entorhinal cortex. In the 30-week fetus, in
the newborn infant and in the adult human brain, in typical sections the hippocampal fissure is situated
between the entorhinal cortex and the granular layer of the sulcoproximal limb of the gyrus dentatus. Gyrus
dentatus growth, added to that of the cornu ammonis, causes the medial wall of the hemisphere to bulge into
the lateral ventricle. Because this ventricular prominence is aligned with the hippocampal fisure, it has been
classified as a total fisure.
Kier EL, Kim JH, Fulbright RK, Bronen RA (1997) Embryology of the Human Fetal Hippocampus: MR Imaging,
Anatomy, and Histology. AJNR Am J Neuroradiol 18:525–532.
-
13 to 14 weeks’ gestation, widely open hippocampal sulcus (hippocampal fissure)
-
15 to 16 weeks: the dentate gyrus and cornu ammonis are infolding; hippocampal sulcus remains open;
parahippocampal gyrus is growing and more medially positioned; CA1, CA2, and CA3 fields of the cornu
ammonis are arranged linearly; dentate gyrus has a narrow U shape
-
18 to 20 weeks: dentate gyrus and cornu ammonis have folded into the temporal lobe; hippocampus and
subiculum approximate each other across a narrow hippocampal sulcus; CA1–3 fields form an arc and the CA4
field has increased in size within the widened arch of the dentate gyrus
Gyrus dentatus growth, added to that of the cornu ammonis, causes the medial wall of the hemisphere to bulge
into the lateral ventricle. Because this ventricular prominence is aligned with the hippocampal fisure, it has
been classified as a total fissure.
Basma J, Guley N, Michael Ii L, et al. (2020) The Evolutionary Development of the Brain As It Pertains to Neurosurgery.
Cureus 12(1): e6748.
Early in fetal development, the dentate gyrus (D), cornu ammonis (C), subiculum (S), and parahippocampal
gyrus (P) are arranged serially along the medial wall and floor of the temporal horn (T). As a result of the
marked expansion of the neocortex and unequal growth of the various components of the hippocampus, there
is gradual infolding of the components into a progressively smaller temporal horn. The infolding occurs around
the hippocampal sulcus that first forms between the dentate gyrus and cornu ammonis. The hippocampal sulcus
shifts later to a location between the dentate gyrus and subiculum, and eventually becomes obliterated.
Slide 151: infolding of hippocampus
Bajic D, Ewald U, Raininko R (2010) Hippocampal development at gestation weeks 23 to 36. An ultrasound study
of preterm neonates. Neuroradiology 52; 489-494.
The infolding or “rolling in” of the hippocampal formation increases in mammals in proportion to the increase
of the neocortical cerebral hemisphere. This is associated with a concomitant decrease in the size of the
rhinencephalon. In primates, the infolding is greater than in carnivores. The infolding is most pronounced in
the dolphin, which has a huge cerebral hemisphere associated with a relatively reduced hippocampus.
Hippocampal development begins at gestation week (GW) 8. During the development, the dentate gyrus and
the cornu ammonis fold around the hippocampal sulcus in the temporal lobe. This process is called
hippocampal inversion. The fully inverted hippocampus has an oval form in coronal brain slices, with the longer
axis horizontal. It is preceded by a round or pyramidal form, signs of incomplete hippocampal inversion (IHI). In
coronal section around the level of the third ventricle, the ratio between the horizontal and vertical diameters
of the hippocampal body can be calculated, ending in three categories: ≤1=IHI; ≥1.5=complete inversion; if the
ratio is between 1 and 1.5, additional criteria such as the enlargement of the temporal horn and the
orientation of the collateral sulcus can be used to diagnose IHI. A clear difference exists between IHI in
preterm infants examined before PMA 25 w and those examined at PMA 25 or later: up to PMA 24, about 50 %
have IHI. The IHI frequency at PMA 29–36 w (14%) approached the IHI frequency (19%) published in children and
adults. Unilateral IHI is usually situated in the left both in preterm neonates and in children and adults, but
bilateral IHI is more common among VLBW preterms.
Slide 152: parasagittal plane through the ganglio-thalamic egg: uncus and
hippocampus
Observe the appearance of uncus and hippocampus in parasagittal CUS sections through the ganglio-thalamic
egg. Quite often the temporal horn of the lateral ventricle extends mesially near the uncus; uncal recessus.
The uncus resembles a snakes open mouth pointing posteriorly: the lower part of this structure may be the
onset of stria terminalis, main efferent of the amygdala; alternatively it represents gyri digitati externi.
Slide 153: parasagittal plane through the ganglio-thalamic egg: uncus and
hippocampus, and tracts from them
Goren CC, Sarty M, Wu PY (1975) Visual following and pattern discrimination of face-like stimuli by newborn infants.
Pediatrics 56; 544-549.
adapted from Netter FH (1986) The CIBA Collection of Medical Illustrations. Vol. 1. Nervous System. Part I: Anatomy and
Physiology. West Caldwell, NJ: CIBA Pharmaceutical
Schultz R (2005) Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int
J Devl Neuroscience 23; 125-141.
Efferent tracts from amygdala and hippocampus.
Although knowledge of the functional status of the amygdala in the newborn is scarce, there are indications
that it already plays a role at birth in early facial recognition. As early as 36w PMA a preference for face-like
patterns is documented (Goren et al. 1975).
Autism is marked by a triad of deficits, including impairment in reciprocal social interaction, delay in early
language and communication, and restrictive, repetitive and stereotyped behavior. Many studies have
documented the difficulties persons with an autism spectrum disorder have accurately perceiving facial
identity and facial expressions. A heuristic model suggests an early developmental failure in autism involving
the amygdala, with a cascading influence on the development of cortical areas that mediate social perception
in the visual domain, specifically the fusiform ‘‘face area’’ of the base of the temporal lobe (the area lateral to
a sulcus that splits the midpart of the fusiform gyrus) that specialises in identification of faces based on “low
spatial frequency” information (gestalt analysis). Visual perceptual areas of the ventral temporal pathway (e.g.
the area for recognition of facial expression the sulcus temporalis superior) are also involved in important ways
in representations of the semantic attributes of people, social knowledge and social cognition. Social
perception and social cognition are postulated as linked during development such that growth in social
perceptual skills during childhood provides a scaffold for developments of ocial skills. It is argued that the
development of face perception and social cognitive skills are supported by the amygdala–fusiform system, and
that deficits in this network are instrumental in causing autism. Functional neuroimaging detected
hypoactivation of the fusiform face area FFA in autism. Three possible factors moderate the degree of FFA
engagement: (1) the degree of attention applied to the stimulus while performing a perceptual task; (2)
chronic levels of abnormal attention to faces appear to lead to reduced perceptual skill and hypoactivation of
the FFA in autism; (3) the FFA appears to encode social knowledge, such that tasks not involving faces, but
requiring social judgments strongly activate the FFA. This amygdal to fusiform cortex setting appears to be an
example of a broader principle of brain organization whereby those cortices involved in perception are also
engaged in long term storage of information related to those perceptual properties which points to the deep
relationship between perceptual and conceptual processes.
Slide 154: parasagittal plane through the insula of Reil
Parasagittal plane 9 through the insula of Reil.
The sulci in and around the insula and the sulcus circularis insulae define the regional insular anatomy.
Slide 155: parasagittal plane through the insula of Reil: superficial branches
of the lateral fissure
The insular lobe and its cortex, claustrum and underlying striatum are outgrown by frontal and temporal lobes.
These lobes cover the insula (opercularisation) and the fissure remaining at the meeting of these operculae is
the lateral fissure. This fissure extends below these opercula in a complex manner, along the limen insulae to
the lateral margin of the substantia perforata anterior.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Paturet G (1964) Traité d’anatomie humaine. Tome IV: Système nerveux. Masson & co, Paris.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
The lateral fissure, first described by Bartholin in 1641 and in more detail by Sylvius in 1652, is a major and
constant landmark on the cerebral convexity. It extends from the lateral border of the anterior perforated
substance and passes over the limen insulae in a posteriorly concave path. By definition lateral fissure
ramifications all cut an opercular margin, develop during primary gyration and are in front of the precentral
sulcus.
The deep portion of the lateral fissure is divided into sphenoidal and operculoinsular compartments. The
sphenoidal compartment lies proximal to the limen area behind the sphenoidal ridge, and the operculo-insular
compartment is positioned deep to the superficial portion of the lateral fissure. This compartment is formed by
two narrow clefts: opercular and insular. The opercular cleft is situated between the opposing lips of the
frontoparietal operculum above and the temporal operculum below. The insular cleft, situated between the
insula and the medial surface of the opercula, has two limbs: the superior limb of the insular cleft is located
between the insula and the medial surface of the frontoparietal operculum; the inferior limb is situated
between the insula and the medial surface of the temporal operculum.
The superficial portion of the lateral fissure is composed of a stem and several rami. This stem begins at the
anterior clinoid process, extends laterally behind the sphenoid ridge, and ends at the convexity by dividing into
an anterior horizontal, anterior ascending and posterior branch. The anterior branches are almost obligatory
present, are of similar length and they have a divergent course, delimiting a triangular space whose apex faces
the lateral fissure. These rami start end in the fissure separately (forming a U or V together) or with a common
trunk (one third of cases). They divide the inferior frontal gyrus, from rostral to caudal, into the partes
orbitalis, triangularis and opercularis frontalis. The anterior horizontal ramus separates the partes orbitalis and
triangularis; the anterior ascending ramus separates the partes triangularis and opercularis. The pars
triangularis is usually situated above the anterior gyrus brevis insulae. Ramus ascendens is positioned above the
tip of the temporal lobe. The pars triangularis and opercularis form Broca’s speech area.
The posterior and largest part of the lateral fissure (between parietal and temporal operculum) usually
bifurcates at its end in about 70% of the cases forming a long ascending and a short descending part. The latter
is the posterior transverse temporal sulcus more frequently found on the right (70% of cases). This sulcus,
which shows an anterior inferior oblique course, should not be confused with the transverse supratemporal
sulcus, seen on the first temporal gyrus separating the posterior border of Heschl’s gyri from the planum
temporale. The cortical regions adjacent to the lateral fissure are the frontal, parietal and temporal opercula,
covering the insular lobe. The posterior branch extends backward and upward from the region of the pterion to
its termination in the inferior parietal lobule, where the supramarginal gyrus wraps around its posterior end.
This gyrus is located above the posterior insular triangle. The lateral fissure guides the MCA and its branches to
the cerebral surface and frontal lobe. This posterior part of the lateral fissure tends to be longer and without
ascension on the left, probably due to location of speech.
In the weeks before viability between 20 and 24 weeks PMA the triangular shape of the insular fossa is clearly
established. Most often the anterior wall of this triangle is subdivided into a short straight superior part (grown
in by the pars triangularis in the frontal operculum) and round lower orbital part. Opercularisation is strong
along the posterior (horizontal) branch of the lateral fissure and the temporal operculum slightly overlaps the
centro-parietal operculum as the horizontal part of the lateral fissure is covered. The anterior insula remains
uncovered until late in fetal life and even early after term birth. The extensions of the lateral fissure between
the frontal and orbital opercula become the ramus ascendens and ramus horizontalis of the lateral fissure. In
some brains these two fissures are replaced by one anterior oblique fissure. They become more prominent
when maturation approaches 30 weeks PMA. The vertical ramus ascendens is usually deep and slightly
anteriorly oriented, the anterior horizontal ramus sits around the latero-basal convexity margin, most often
visible on the lateral convexity and always lateral to the external olfactory sulcus. Two smaller orbital limbs of
the lateral fissure may develop even later, medial to this external olfactory sulcus. The lateral one of these
limbs is in contact with the gyrus transversus insulae.
Bottom left an example of advanced right versus left sulcal development.
Mallela AN, Deng H, Brisbin AK, Bush A, Goldschmidt E (2020) Sylvian fissure development is linked to differential genetic
expression in the prefolded brain. Scientific Reports, Nature Research, 10; 14489.
A digital human fetal brain atlas was developed using previously obtained MRI imaging of 81 healthy fetuses
between gestational ages 21 and 38 weeks, comparing growth of the frontotemporal opercula with the insular
cortex and studying the transcriptome of the developing cortices for both regions. Spatiotemporal mapping of
the lateral hemispheric surface showed the highest rate of organized growth in regions bordering the Sylvian
fissure of the frontal, parietal and temporal lobes. Volumetric changes are first observed in the posterior
aspect of the fissure moving anteriorly to the frontal lobe and laterally in the direction of the temporal pole.
The insular region, delineated by the limiting insular gyri, expands to a much lesser degree. The Sylvian fissure
forms by the relative overgrowth of the frontal and temporal lobes over the insula, corresponding to domains
of highly expressed transcription factors involved in neuroepithelial cell differentiation. Genes overexpressed
in the opercula are a.o.: SOCS7, NTF3, IRX2, DOCK7, ATX3, GREM1. The insula develops from the pallialsubpallial border and contains genes from both (PAX6 and Gsh2).
Slide 156: planes through the insula of Reil: nomenclature of insular anatomy
Lateral view of the insula, showing three short gyri, an accessory gyrus and two long gyri.
Afif A, Bouvier R, Buenerd A, Trouillas J, Mertens P (2007) Development of the human fetal insular cortex: study of the
gyration from 13 to 28 gestational weeks. Brain Struct Funct 212: 335-346.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
O’Rahilly R, Müller F (2006) The Embryonic Human Brain. An Atlas of Developmental Stages, third ed. Wiley-Liss, Hoboken,
NJ.
O’Rahilly R, Müller F (2008) Significant features in the early prenatal development of the human brain. Ann Anat 190:
105-118.
Paturet G (1964) Traité d’anatomie humaine. Tome IV: Système nerveux. Masson & co, Paris.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24.
ğ
Ribas EC, Ya murlu K, de Oliveira E, Ribas GC, Rhoton Jr A (2017) Microsurgical anatomy of the central core of the brain. J
Neurosurg December 22.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
Tanriover N, Rhoton AL, Kawashima M, Ulm AJ, Yasuda A (2004) Microsurgical anatomy of the insula and the sylvian fissure. J
Neurosurg 100: 891-922.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
Testut L, Latarjet A (1948) Traité d’anatomie Humaine, Vol. 2. Paris: Doin.
The insula of Reil is the smallest cerebral lobe nested in the depth of the lateral fissure. It is triangular with
an antero-inferior pole (apex or dome) in front of the limen insulae. The insula of Reil is covered by
frontoparietal and temporal opercula. Limen insulae is a slightly raised, arched ridge located at the junction of
the sphenoidal and operculoinsular compartments of the lateral fissure and extends from the temporal pole to
the orbital surface of the frontal lobe. It overlies the uncinate fasciculus. The point of entrance of the most
lateral lenticulostriate perforator artery is considered to be the lateral limit of the anterior perforated
substance near the limen. A shallow recess devoid of perforator arteries, referred to as the “limen recess,”
exists between the medial border of the limen insulae and the point of entrance of the most lateral perforator,
which originates either from the M1 segment prior to bifurcation, or from the inferior (posterior) or superior
(anterior) trunk. The central artery of the insula is identical to the central cerebral (cortical) artery.
The main (posterior) branch of the lateral fissure parallels and covers the insula near the sulcus limitans
inferior/posterior. The pars triangularis of the frontal operculum nearly always covers the anterior gyrus brevis
insulae. The inferior limiting sulcus is located medial to the superior temporal sulcus.
The insula is surrounded by the circular (limiting) sulcus of the insula (sulcus circularis insulae of Reil). This
sulcus has three parts: anterior, superior, and inferior. The anterior limiting sulcus rises upward and forward,
deep to the pars orbitalis of the frontal operculum. The superior limiting sulcus is oriented horizontally. It
extends beneath the frontoparietal operculum from the anterosuperior edge of the insula to the posterior end
of the inferior limiting sulcus. Beneath the temporal operculum at the lower edge of the insula lies the inferior
limiting sulcus, which can in fact be subdivided into a posterior (slightly more ascending) and inferior part. The
longest limiting sulcus is the superior; the shortest, the anterior.
The insula contains several vertically directed gyri, usually three short gyri (gyri breves insulae), anterior,
middle and posterior, and one or two long gyri (gyri longi insulae), anterior and posterior, separated by the
central sulcus of the insula (sulcus centralis insulae) which courses almost parallel to the central (Rolandic)
sulcus of the hemisphere (it extends around the opercular lip in about 1/5 brains and thus both sulci centrales
may rarely be connected). The three short gyri converge to the pole of the insula, and are joined to the orbital
part of the inferior frontal gyrus by a short annectant gyrus, the transverse insular gyrus of Eberstaller. A less
constant gyrus accessorius may exist above the transverse insular gyrus, between anterior gyrus brevis and
anterior limiting sulcus.
Of the gyri breves, the middle one is usually smallest, surrounded anteriorly by the sulcus insularis anterior,
and posteriorly by the sulcus precentralis insulae (most often a triangular depression more than a sulcus, but in
fetal life it may me relatively prominent compared to the sulcus centralis insulae). The highest point of the
insula, the apex or pole, is usually on the inferior part of the middle gyrus brevis. The sulcus postcentralis
insulae starts from the superior limiting sulcus (at 1/3 its length in front of its posterior angle), ends at some
distance from the insular pole and divides the posterior insula in two gyri longi. These communicate with the
polar/limbic temporal area, whereas the anterior insula communicates upward with the corresponding parts of
the frontal operculum (e.g. gyrus brevis posterior insulae with gyrus precentralis cerebri, gyrus longus anterior
insulae with gyrus postcentralis cerebri, gyrus longus posterior insulae with supramarginal gyrus).
Slide 157: parasagittal plane through the insula of Reil: functional anatomy of
the insula
The limen insulae and the site of the MCA bifurcation is located medial to the temporal operculum; the site of
the main branching of the MCA trunks is located medial to the frontal operculum. Some gross functional
subdivisions of the insula are shown bottom left, with respective afferents.
Slide 158: the insula of Reil: nomenclature and function
Evrard HC (2019) The Organization of the Primate Insular Cortex. Front Neuroanat 13:43.
The insular interface substantiates emotional embodiment and has the potential to have a key role in the
interoceptive shaping of cognitive processes, including perceptual awareness. A model in macaque primates
proposes that interoceptive afferents representing the physiological status of all body organs are first being
received in the granular dorsal fundus of the insula or “primary interoceptive cortex,” then processed through
a series of dysgranular poly-modal “insular stripes,” and finally integrated in anterior agranular areas that
serve as sensory platform for visceral functions and as an output stage for efferent autonomic regulation. One
of the agranular areas hosts the specialized von Economo and Fork neurons, which could provide evolutionary
advantage for the role of the anterior insula in the autonomic and emotional binding inherent to subjective
awareness.
The agranular areas anterior to the limen, posterior to area 13 and adjacent to the anterior end of the
claustrum, are considered part of the insula, both in humans and monkeys. In humans, this region, which
contains von Economo and Fork neurons, is encased by the folding surrounding the insula, including the
anterior peri-insular sulcus.
The regional functional anatomy displayed here goes for primates as far as these are comparable to humans.
Especially the anterior part of the insula needs further study in humans.
González-Arnay E, González-Gómez M, Meyer G (2017) A Radial Glia Fascicle Leads Principal Neurons from the
Pallial-Subpallial Boundary into the Developing Human Insula. Front Neuroanat 11:111.
The human insular lobe displays three main cytoarchitectonic divisions. These comprise a rostro-ventral
agranular area, an intermediate dysgranular area, and a dorso-caudal granular area. The insular cortex is
unique in that it develops far away from the ventricular zone (VZ), with most of its principal neurons deriving
from the subventricular zone (SVZ) of the pallial-subpallial boundary (PSB). In human embryos (Carnegie stage
16/17), the rostro-ventral insula is the first cortical region to develop; its Tbr1+ neurons migrate from the PSB
along the lateral cortical stream. From 10 gestational weeks (GW) onward, lateral ventricle, ganglionic
eminences, and PSB grow forming a C-shaped curvature. The SVZ of the PSB gives rise to a distinct radial glia
fiber fascicle (RGF), which courses lateral to the putamen in the external capsule, as part of the early lateral
cortical stream. In the RGF, four components can be established: PF, descending from the prefrontal PSB to the
anterior insula; FP, descending from the fronto-parietal PSB toward the intermediate insula; PT, coursing from
the PSB near the parieto-temporal junction to the posterior insula, and T, ascending from the temporal PSB and
merging with components FP and PT. The RGF fans out at different dorso-ventral and rostro-caudal levels of the
insula, with descending fibers predominating over ascending ones. The RGF guides migrating principal neurons
toward the future agranular, dysgranular, and granular insular areas, which show an adult-like definition at 32
GW. Despite the narrow subplate, and the absence of an intermediate zone except in the caudal insula, most
insular subdivisions develop into a 6-layered isocortex. The small size of the initial PSB sector may, however,
determine the limited surface expansion of the insula, which is in contrast to the exuberant growth of the
opercula deriving from the adjacent frontal-parietal and temporal VZ/SVZ.
Allman JM, Watson KK, Tetreault NA, Hakeem AY (2005) Intuition and autism: a possible role for Von Economo
neurons. Trends Cogn Sci 9(8):367-73.
Allman JM, Tetreault NA, Hakeem AY, Manaye KF, Semendeferi K, Erwin JM, Park S, Goubert V, Hof PR (2010)
The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans. Brain Struct
Funct 214(5-6):495-517.
Von Economo neurons (VENs) are a recently evolved cell type which may be involved in the fast intuitive
assessment of complex situations. As such, they could be part of the circuitry supporting human social
networks. The VENs relay an output of fronto-insular and anterior cingulate cortex to the parts of frontal and
temporal cortex associated with theory-of-mind, where fast intuitions are melded with slower, deliberative.
VENs and associated circuitry enable us to reduce complex dimensions of decision-making into a single
dimension that facilitates the rapid execution of decisions. VENs may be dysfunctional in autism spectrum
disorders
Slide 159: parasagittal plane through the insula of Reil: underlying tracts and
inlying vessels
Some ultrasound landmarks of insula and lateral fissure. Observe pars triangularis between ramus ascendens
and horizontalis of the lateral fissure. The latter almost covers the sulcus circularis postero-inferior but
extends caudal to it. Fasciculus uncinatus and fasciculus fronto-occipitalis inferior take part in the external
capsule under the insular cortex.
Slide 160: parasagittal plane through the insula of Reil: development of
insular sulci
Afif A, Bouvier R, Buenerd A, Trouillas J, Mertens P (2007) Development of the human fetal insular cortex: study of the
gyration from 13 to 28 gestational weeks. Brain Struct Funct 212: 335-346.
Govaert P, Swarte R, De Vos A, Lequin M (2004) Sonographic appearance of the (ab)normal insula of Reil. Dev Med Child
Neurol 46: 610-616.
Five stages can be discerned of insular gyral and sulcal development.
The macro-anatomy of the insula becomes definitive between 24 and 34w gestation, at a variable pace. In the
region of the future frontal and temporal lobe the Sylvian depression is the first sign of insular development at
the end of the embryonic period. The circular outline of this depression elongates into the upward (vertical)
and posterior direction, when at the same time the surrounding mantle is slightly raised above the early insula
in the third (fetal) month. In the weeks before viability between 20 and 24 weeks the triangular shape of the
Sylvian fossa is clearly established and the insular dome starts to rise above its future circular (limiting) sulcus.
central sulci
13-17w GA
18-19 w GA
stage 1: appearance of
the inferior part of the
central cerebral sulcus
20-22 w GA
stage 2: development of
the pericentral lateral
regions and beginning of
opercularization
insular sulci
stage 1: appearance of the first sulcus = the inferior peri-insular
sulcus, around 15 w GA; MCA and M2 branches visible in the early
vallecula
stage 2: insular area more conspicuous by elevation of surrounding
tissue; postero-inferior but also superior peri-insular sulci are
shallow but visible; the superior part of the anterior peri-insular
sulcus becomes visible; opercularization has not yet begun; anterior
and posterior insular regions are separated by a fine groove that will
become the central sulcus of the insula; the central cerebral sulcus
becomes identifiable, especially the inferior part; both central sulci
are better identified on the right; anastomosis between the MCA and
ACA can be observed especially on the peri-Rolandic convexity
stage 3: (pre) central sulci and opercularization of the insula;
progressive development of the temporal and parietal opercula
earlier than the frontal opercula, earlier on the right; the inferior
part of the anterior peri-insular sulcus is identifiable; the lower
extremity of the central cerebral sulcus is localized 1–2 mm anterior
to the superior extremity of the central insular sulcus; it is possible
to identify the early precentral sulci (insular and cerebral) by the
20th w GA, and postcentral sulci (insular and cerebral) by the 22nd
w; diameter of MCA and its branches M2 and M3 have increased, in
particular the vessels which correspond to the central sulci; the
central cerebral artery arises from the central insular artery (most
often collateral of the superior division of the MCA)
24-26w GA
stage 3: development of
parietal and temporal
cortices and covering of
the postcentral insular
region
27-28w GA
stage 4: maturation of
the central cerebral
regions
stage 4: covering of the posterior insula, with only partial covering
of the anterior tip of the anterior insula and the anterior peri-insular
sulcus; the upper end of the sulcus centralis insulae separates the
superior peri-insular sulcus into two anterior thirds and one
posterior third; the post-central insular sulcus can be seen; the
distal branches of the MCA and their anastomoses are more easily
identifiable
stage 5: closure of the lateral fissure; it is already closed with
complete coverage of the insula by the opercula (except
orbitofrontal parts, especially on the left); the shape of the insula
becomes the definitive trapezoid form; the central insular sulcus is
deeper than the surrounding later sulci
Slide 161: parasagittal plane through the insula of Reil: doppler findings of
insular arteries
The limen insulae is near the arterial spring. The central artery of the insula is the same as the central cerebral
(cortical) artery. The lateral fissure parallels and covers the insula near the sulcus limitans inferior and
posterior.
Using Doppler, most high-end current ultrasound machines will allow to visualize the vessels emerging from the
limen insulae. Insular arteries (MCA branches passing through): red parts are ascending M2 branches, blue are
descending M3 branches.
Slide 162: parasagittal plane through the insula of Reil: coronal sections
through rostral and caudal insula
Coronal sections indicated on this scheme, through rostral and caudal insula, demonstrating the recumbent Y of
the lateral fissure as it spreads over the insula, the solitary line of the same fissure posterior to the insula.
Preterm infant of GA 32w scanned at 34w PMA. At 34 weeks the gross subdivisions of the insula are often
visible.
Slide 163: parasagittal plane through the insula of Reil: pars anterior and
posterior of the insula
Pars anterior and posterior of the insula clearly separated by the sulcus centralis insulae in these preterm
infants of 36w PMA. Gyrus accessorius is probably visible in the rostral insula.
Slide 164: parasagittal plane through frontal and pericentral cortex
Parasagittal plane 10 through frontal and pericentral cortex.
Three ascending (vertical) sulci separate the rostral cerebrum (frontal lobe) from the rest of the cerebrum.
The sulcus precentralis is almost always interrupted and presents with an inferior and superior sulcus
precentralis. The sulcus centralis is most often undivided. The sulcus postcentralis is often undivided in the
section that CUS presents.
Slide 165: parasagittal plane through frontal and pericentral cortex: sulcus
centralis
Afif A, Trouillas J, Mertens P (2014) Development of the sensorimotor cortex in the human fetus: a morphological
description. Surg Radiol Anat 37: 153-160.
Chi JG, Dooling EC, Gilles FH (1977) Gyral development of the human brain. Annals of Neurology 1: 86-93.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
De Vareilles E, Sun Z, Benders M, Fischer C, Leroy F, de Vries L, Groenendaal F, Rivière D, Dubois J, Mangin J-F () A
longitudinal study of the evolution of the central sulcus’ shape in preterm infants using manifold learning.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Ecker 1869: https://digi.ub.uni-heidelberg.de/diglit/ecker1869/0007
Gajawelli N, Deoni SCL, Ramsy N, Dean DC 3rd, O'Muircheartaigh J, Nelson MD, Lepore N, Coulon O (2021) Developmental
changes of the central sulcus morphology in young children. Brain Struct Funct 226(6):1841-1853.
Hopkins WD, Meguerditchian A, Coulon O, Bogart S, Mangin JF, Sherwood CC, Grabowski MW, Bennett AJ, Pierre PJ, Fears S,
Woods R, Hof PR, Vauclair J. Evolution of the central sulcus morphology in primates. Brain Behav Evol.
2014;84(1):19-30.
Kappers A, Huber C, Crosby E (1967) The Comparative Anatomy of the Nervous System of Vertebrates, including Man. Hafner
publishing company, New York.
Naidich TP, Grant JL, Altman N, Zimmerman RA, Birchansky SB. Braffman B, Daniel JL (1994) The developing cerebral
surface. Neuroimaging Clinics of North America 2: 201-24
Paturet G (1964) Traité d’anatomie humaine. Tome IV: Système nerveux. Masson & co, Paris.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24
Schweizer R, Helms G, Frahm J (2014) Revisiting a historic human brain with magnetic resonance imaging the first
description of a divided sulcus centralis. Frontiers in Neuroanatomy 8: art 35: 1-8.
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
Wagner, R (1860). “Über die typischen Verschiedenheiten der Windungen der Hemisphären und über die Lehre vom
Hirngewicht, mit besondrer Rücksicht auf die Hirnbildung intelligenter Männer”, in Vorstudien zu Einer Wissenschaftlichen
Morphologie und Physiologie des Menschlichen Gehirns als Seeleorgan. Göttingen, verlag der Dieterischschen Bucchandlung.
The central groove is the middle of the ascending sulci halfway between frontal and occipital pole of the
cerebrum. Described by Vicq d’Azyr in 1796 and by Rolando in 1831, the central sulcus thus separates the
frontal from the parietal lobe. Detailed descriptions of adult central groove morphology are present in
Eberstaller 1890, Cunningham 1892, Retzius 1896. The sulcus centralis can be divided in three parts. The
superior part is a rostroconvex arch, followed by a sharp posterior convex middle part, itself followed by a
faint rostroconvex third arch in the direction of the lateral fissure. In between these arches two knees have
been described. The cortex located below the genu superior represents the middle portion of the precentral
gyrus innervating the arm and this portion faces the sulcus frontalis superior anteriorly.
The direction of the sulcus centralis is in general a rostroconvex but sinuous structure slightly oblique from
inferior and anterior to superior and posterior. In about 3 adults in 5 the sulcus centralis cuts the upper
hemisphere border (with an acute angle to the frontal pole of around 70 °) and ends on the mesial surface with
a posteriorly oriented hook (“le crochet rolandique”), which never joins the ramus supramarginalis sulci
cinguli. If the sulcus centralis oversteps the hemisphere border this usually occurs in the last month of
pregnancy. The sulcus centralis lies within the lobulus paracentralis, itself bordered in front by the paracentral
sulcus (a branch arising from the sulcus cinguli) and caudally the ramus supramarginals sulci cinguli itself. In
1/5 of the remaining brains each the sulcus centralis just reaches the convexity top without posterior bend, or
falls short of the convexity top with a posterior hook similar to the instances where it reaches the mesial
cerebrum.
In about 4/5 the lower end of the sulcus centralis is separated from the lateral fissure by an inferior
frontoparietal annectant gyrus (the subcentral gyrus). Both anterior and posterior to the central groove this
subcentral gyrus is bordered by either the sulcus subcentralis anterior or posterior, both small upward branches
of the lateral fissure. In the remaining 1/5 the sulcus centralis is connected indirectly to the lateral fissure by
an intervening inferior transverse sulcus (Eberstaller)(now referred to as sulcus subcentralis anterior, a very
common appearance in the last two months of pregnancy). In late pregnancy the postcentral gyrus is often
slightly elevated above the precentral gyrus and the sulcus centralis moves slightly caudal (away from the
coronal suture) due to relative faster growth of the frontal lobe.
Anastomoses with the subcentral, precentral and postcentral sulci are fairly frequent, occurring in about 50%
of cases.
In the depth of the sulcus centralis rostrocaudal annectant gyri (Cunningham 1892) between pre- and
postcentral gyri are always present (pli fronto-pariétales by Broca). Two in particular are important: a “pli
frontoparietal moyen” at the hand knob and a “pli frontoparietal inférieur” at the lower end of the sulcus
centralis (see above). The “pli fronto-pariétal moyen” is visible in nearly all ultrasound scans after 30 weeks GA
as an interruption of the central groove at its base in outward parasagittal sections. If the central groove is
divided (interrupted) it is at this site, likely due to relative elevation of this annectant gyrus, prevalence
around 1/300 brains (figures in Sernoff 1887 and Kappers 1967). The exceptional nature of this phenomenon of
interruption of the sulcus centralis is in contrast with the almost constant existence of an interrupted sulcus
precentralis.
Development: According to Chi et al. 1977 and reviewed by Afif et al. 2014 the first appearance at postmortem
is in the 19th or 20th week of gestation (PMA), the sulcus being rarely visible at or before 17 weeks. It is
usually a distinct line by 23 weeks. The right sulcus is in general one week earlier to appear than the left. For
comparison the precentral sulcus usually appears around 24 weeks and the postcentral sulcus at 25 weeks. The
central groove is first identifiable in its inferior part and it develops independently from the central insular
sulcus. At early stages, the projection from the inferior extremity of the central sulcus is located anterior to
that of the superior extremity of the central insular sulcus. Development of the central groove is inherent to
gradual sensorimotor cortex development: stage 1: appearance at 18–19 gestational weeks of the inferior part
of the central cerebral sulcus; stage 2: development of the pericentral lateral regions and beginning of
opercularization at 20–22 w; stage 3: development of parietal and temporal cortices and covering of the
postcentral insular region at 24–26 w; finally stage 4: maturation of the central cerebral regions at 27–28 w.
The lower portion of the central groove develops first as a linear depression, separated in some fetuses or
preterm infants (not in all) initially from the superior part of the groove initially appearing as a sulcal pit
(depression). Very soon after formation the lower part of the groove merges with the upper part transforming
in the mean time into a single groove. It is still possible in some infants to observe separation of these two
parts at 25w PMA. This bipartite development is also seen in primates but not in lower apes. The central groove
is probably the homologue of two subprimate sulci, the sulcus coronalis and the sulcus ansatus.
A bimodal type of sulcus centralis is most ommon in MRI studies of children 12-16 months of age (Gajawelli et
al. 2021): this reflects the two deep parts with the primitive hand knob in between them. The bimodal shape is
more common on the left than on the right; some children have a unimodal shape (no strong annectant gyrus),
others a trimodal shape in the sulcus centralis. Results also reveal the presence of a rightward depth
asymmetry at 12 months of age at a location related to orofacial movements. That asymmetry disappears
gradually, mostly between 12 and 24 months, which could be related to the development of language skills.
Slide 166: parasagittal plane through frontal and pericentral cortex: sulcus
centralis development in imaging
Development of sulcus centralis on in vivo images.
In axial T2 brain MRI figures you can observe the gradual appearance and development of central sulcus, absent
in a 27w infant born from twin gestation (twins are about 2 w "behind the schedule"), deep and narrow in 29w
infant, becoming more complex at 32w. Precentral suclus is shallow and wide and postcentral sulcus starts
forming in 29w infant, both becoming more developed at 30w and 32w.
Using a high frequency linear probe (anterior fontanel, parasaggital views) one can study gyration with cerebral
ultrasound. Observe how a broad linear speckle track develops into one bright line that becomes tortuous after
30 weeks. In the 27w scan you can see faint appearances of the pre- and postcentral sulci around the central
sulcus.
Observe the nearly constant presence in CUS of the “pli fronto-pariétal moyen” (middle annectant gyrus) under
the centre part of the sulcus centralis, aligned with sulcus frontalis superior. At higher (towards the surface)
sections the sulcus is most often continuous, but at lower sections (near the base or pit of the sulcus, the sulcal
line is often interrupted).
Slide 167: parasagittal plane through frontal and pericentral cortex: divided
sulcus centralis
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
De Bisschop B, Camfferman F, van Hengel-Jacobs M, Delanghe G, Vanderhasselt T, Govaert P (2019) Abnormal primary
gyration in relation to deep brain injury in preterm infants. Acta Paediatr. 2019 Sep 4.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Sockholm: PA Norstedt 1-167.
Schweizer R, Helms G, Frahm J (2014) Revisiting a historic human brain with magnetic resonance imaging the first
description of a divided sulcus centralis. Frontiers in Neuroanatomy 8: art 35: 1-8.
Wagner, R (1860). “Über die typischen Verschiedenheiten der Windungen der Hemisphären und über die Lehre vom
Hirngewicht, mit besondrer Rücksicht auf die Hirnbildung intelligenter Männer”, in Vorstudien zu Einer Wissenschaftlichen
Morphologie und Physiologie des Menschlichen Gehirns als Seeleorgan. Göttingen, verlag der Dieterischschen Bucchandlung.
The existence of a divided sulcus centralis in man (around 1/300 adult brains according to Heschl 1877) may be
independent of its dual homologous origin.
The figure presented here is by Sernoff 1889, used in Cunningham DJ (1892) Contribution to the surface anatomy of the
cerebral hemispheres. The fissure of Rolando. pp 161-192.
In some fetuses, near the end of the fifth or in the early sixt month, the first appearance of the sulcus centralis
is a fissure along the later midportion of the mature sulcus. This fissure then rests halfway between the insular
upper margin and the convexity top. In most fetuses, however, the lower two thirds form from a large early
shallow fissure (r1), later followed by a deep pit or depression for the upper third. This deeper depression near
the convexity (r2) joins the lower larger fissure soon after appearance. This joining occurs by the appearance
of a furrow on top of the elevated intervening part between r1 and r2. The superior genu develops at this
junction.
Part of the sulcus centralis is less deep in almost all brains because of the presence of an annectant gyrus at
the level of the genu superior. When this annectant gyrus reaches the surface, it divides (completely
interrupts) the sulcus centralis, usually at the level of the superior frontal sulcus. The original description of
divided central groove was in an adult by Wagner in 1860 (top left)(reviewed in Schweizer et al. 2014). It is not
uncommon in man (around 1/300 adult brains according to Heschl 1877, more often males are affected).
Images of a divided central groove in perinatal postmortem studies were later provided by Cunningham in 1892,
Retzius in 1896 and Sernoff in 1877. Such descriptions are absent from human medical literature throughout
the twentieth century. The annectant gyri between frontal and parietal lobe were described by Broca earlier,
under the terms "pli frontoparietal supérieur, moyen et inférieur". The superior annectant gyrus lies at the
mesial surface in front of the ramus supramarginalis of the sulcus cinguli.
Slide 168: parasagittal plane through frontal and pericentral cortex: sulcus
centralis tortuosity and venous infarction
It is an unanswered question whether the definitive form of sulcus centralis (or sulci precentales or
postcentrales) is influenced (altered) by deep lesions such as venous infarction in relation to GMH. The top
example suggest straigthening and poor ramification associated with large terminal vein infarction on that side.
This is not the case in the example below, with residual left porencephaly.
slide 169: parasagittal plane through frontal and pericentral cortex: frontal
sulci
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Ebeling U, Steinmetz H, Huang Y, Kahn T (1989) Topography and identification of the inferior precentral sulcus in MR
imaging. Am J Neuroradiol 10: 937-942.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Keller SS, Highley JR, Garcia-Finana M, Sluming V, Rezaie R, Roberts N (2007) Sulcal variability, stereological measurement
and asymmetry of Broca’s area on MR images. J. Anat 211, pp534–555. (score)
Paturet G (1964) Traité d’anatomie humaine. Tome IV: Système nerveux. Masson & co, Paris.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
Ribas G (2010) The cerebral sulci and gyri. Neurosurg Focus 28(2): 1-24
Tamraz JC, Comair YG (2006) Brain cortical mantle and white matter core. Ch 3, pp 51-116. In Atlas of regional anatomy of
the brain using MRI. Springer Verlag.
ten Donkelaar HJ, Tzourio-Mazoyer N and Mai JK (2018) Toward a Common Terminology for the Gyri and Sulci of the Human
Cerebral Cortex. Front. Neuroanat. 12:93.
The horizontal gyri of the frontal lobe have been numbered from 1 to 3, starting in F1 above the sulcus
frontalis superior, through F2 between sulcus frontalis superior and inferior, F3 between the lateral fissure and
the sulcus frontalis inferior Broca’s convolution). F2 is connected along the rostral pole with the orbitofrontal
cortex between sulcus olfactorius and sulcus orbitalis externus. F3 is connected to the orbitofrontal cortex
lateral to the sulcus orbitalis lateralis and to the olfactory cortex behind the cruciform sulcus of Hervé
(transverse orbital sulcus).
The sulcus precentralis.
In the majority this sulcus is interrupted, either in an inferior and superior part, or in three parts. There is
(mirror) similarity between the appearance of the frontal complex of sulcus precentralis inferior with sulcus
frontalis inferior and the similar parietal complex of sulcus postcentralis inferior with sulcus intraparietalis.
Both parasagittal sulci end in a bifurcation: the frontomarginal sulcus anteriorly for the sulcus frontalis inferior,
the sulcus occipitalis transversus posteriorly for the sulcus intraparietalis. The parasagittal (horizontal) sulcus
frontalis superior (sulcus f1) is connected to the vertical sulcus precentralis superior in a similar way as the
parasagittal sulcus frontalis inferior (sulcus f3) connects to the vertical sulcus precentralis inferior, although
the connection of the former is often more intimate than of the latter.
Broca’s lateralized expressive speech area is located between the sulcus precentralis inferior and the ramus
ascendens of the lateral fissure, with the pars triangularis included.
The sulcus precentralis inferior and frontalis inferior appear around 25 w GA, not much later followed by the
sulcus precentralis superior and frontalis superior; some variation is present but these four sulci should be
visible at postmortem before 28w PMA. Although these sulci may appear complex and branched later on, they
are simple lines at first, as in primates and lower monkeys. Before these lines are formed there are first sulcal
pits with annectant primitive connections between them.
The sulcus precentralis inferior.
The sulcus precentralis inferior is composed of a vertical and a horizontal part from which it may be rarely
separated by an annectant gyrus that reaches the surface.
The vertical part runs parallel to the sulcus centralis in front of the lower third of the gyrus precentralis
inferior and may have a slightly oblique rostral course on ascending. The sulcus precentralis inferior usually
does not connect to the lateral fissure directly, but it may be indirectly connected via the sulcus diagonalis in
front or the sulcus subcentralis anterior (inferior transverse sulcus) in the back, in about one in five instances
each. Typically therefore, the sulcus precentralis inferior is the vertical groove between ramus ascendens of
the lateral fissure and the sulcus centralis. Variants (less than 25 %) depend on the presence of a sulcus
diagonalis and/or on the absence of the ramus ascendens. The sulcus precentralis inferior can be bifid towards
the lateral fissure. The sulcus subcentralis anterior ascends from the lateral fissure obliquely up and forward,
underlining the gyrus subcentralis, which connects the gyrus pre- and postcentralis with each other (“pli
fronto-pariétal inférieur de Broca”). A large sulcus subcentralis anterior may mimick a sulcus precentralis
inferior.
The horizontal part of the sulcus precentralis inferior sits on top of the vertical part, together appearing like a
T. The posterior branch of this horizontal part (sometimes called dorsal branch) ascends in the precentral gyrus
behind the lower part of the sulcus precentralis superior. If disconnected, this posterior branch may be
described as sulcus precentralis medius (below). The anterior branch of the horizontal part is often longer and
runs forward and ascends in the middle frontal gyrus until about the posterior end of the sulcus frontalis
medius (see below). This anterior branch is often connected (at least superficially) from above to the sulcus
frontalis inferior that continues below it a rostral course over the pars triangularis.
The vertical part of the sulcus precentralis inferior appears around 25 weeks of gestation. Around 34w of
gestation the both are still separated in about one fetus in two, which suggests that the connections develop
later because ultimately in most brains there is some connection between sulcus frontalis inferior and sulcus
precentralis inferior (either with vertical or horizontal part).
There is a volume asymmetry of the pars opercularis of the frontal operculum, significantly related to the
asymmetrical presence of the diagonal sulcus which is more common on the left and expands the Broca area
when present. There is no significant volume asymmetry of the pars triangularis. There is a significant leftward
volume asymmetry of the planum temporale, in itself associated with a straight posterior part of the lateral
fissure (not ascending).
The sulcus diagonalis.
The sulcus diagonalis (Eberstaller) lies in front of the sulcus precentralis inferior and ascends while shifting
posteriorly. It often connects to the lateral fissure and may superiorly connect to the sulcus precentralis
inferior or sulcus frontalis inferior. An unusually long sulcus diagonalis may also mimick the sulcus precentralis
inferior. The sulcus diagonalis arises from the horizontal part of the lateral fissure behind its ramus ascendens.
A sulcus diagonalis is present in less than half of the brains and when present it is more often seen on the left
where it increases the cortical gray matter volume of the pars opercularis of the inferior frontal gyrus. The
morphology of this sulcus does not constitute a uniform appearance, as it occasionally merges with the anterior
ascending ramus of the Sylvian fissure or extends from the inferior precentral sulcus or inferior frontal sulcus.
Four connections of the diagonal sulcus are recognized: (a) with the ascending horizontal ramus of the lateral
fissure; (b) with the inferior precentral sulcus; (c) with the inferior frontal sulcus; (d) no connection with
surrounding sulci. On occasion a sulcus diagonalis can be detected with CUS in a newborn infant near term.
The sulcus precentralis superior.
This most often complete sulcus runs parallel to the sulcus centralis in front of the upper half of the gyrus
precentralis. It does not reach the convexity (superciliary margin) but ends below it in a short transverse
sulcus, the sulcus precentralis marginalis. The lower part ends between both branches of the horizontal part of
the sulcus precentralis inferior and appears first. Usually the sulcus frontalis superior is connected to its
middle. A surfacing annectant gyrus may on occasion interrupt the sulcus precentralis inferior either above or
below this connection. A cruciform connection can also exist, with a short secondary branch from the junction
into the gyrus precentralis.
The sulcus precentralis medius.
This inconstant sulcus starts behind the inferior precentral sulcus at its upper end and ends in front of the
superior precentral sulcus at its lower end. It may be described as a separated posterior part of the horizontal
branch of the sulcus precentralis inferior, although in other variants it is more connected to the superior
precentral sulcus. In some infants (about 1/10) the sulcus precentralis medius connects both sulcus precentralis
inferior and superior with each other, so that an intact sulcus precentralis appears as one line parallel to the
sulcus centralis. A similar phenomenon, formation of a complete sulcus postcentralis, occurs much more often
behind (in about 7/10) than in front of the sulcus centralis. The sulcus precentralis medius can also descend
towards the lateral fissure behind the sulcus precentralis inferior.
The sulcus frontalis inferior (f3).
The posterior end of this sulcus usually lies below the horizontal part of the sulcus precentralis inferior. It
follows a parasagittal course immediately over the ramus ascendens of the lateral fissure and ends in a
bifurcation: the lower end of this bifurcation descends into the pars triangularis. When the inferior frontal
sulcus is continuous it ordinarily terminates at approximately the midportion of the pars triangularis. In front of
this bifurcation, the sulcus radiatus (also called pretriangular sulcus) is a vertical sulcus, different from the
sulcus frontalis inferior, with an upward extension that may connect to the sulcus frontalis medius or inferior;
the sulcus radiatus is visible from around 30 weeks GA, present in about 1/2. Even more rostral descends the
lateral part of the frontomarginal sulcus, the appearance of which may even precede the appearance of the
sulcus frontalis inferior. Both anterior vertical sulci should not be considered part of the sulcus frontalis
inferior. The sulcus frontalis inferior is continuous in about half, in the remainder it is subdivided into two
parts, anterior and posterior. There are several types of connections between the posterior inferior frontal
sulcus and the ventral (or horizontal) segment of the inferior precentral sulcus: (1) a true connection; (2) a
superficial connection on the surface, with a submerged bridge of cortex interrupting it; (3) no connection.
Typically two pits are the first indication of the appearance of this sulcus, around 26 weeks.
The sulcus frontalis superior (f1).
This sulcus runs rostrally from the middle part of the sulcus precentralis inferior and ascends slightly toward
the superciliary margin. A series of several small sulci parallel to it may further separate the mesial from the
lateral (convexity) part of the gyrus frontalis superior. These align with the sulcus precentralis marginalis. Such
sulci are only seen in humans (not even in primates), and if somehow continuous they can be referred to as
sulcus frontalis mesialis.
The sulcus frontalis superior is continuous in about 1/2 and interrupted in two or more pieces in the others. If
interrupted the subsequent short sulci are such arranged that the caudal end of one lies more lateral (below)
the rostral end of the sulcus posterior to it. There is less often a connection to the sulcus frontomarginalis than
is the case for the sulcus frontalis medius. Size of gyrus frontalis superior and medius are inversely related.
The sulcus frontalis medius (f2).
This sulcus is much more variable than the sulcus frontalis inferior and superior, although variation is
impressive. It divides the gyrus frontalis medius in two parts. Its posterior end forms a bifurcation about
halfway in the frontal lobe (starting at the level of the anterior end of the horizontal part of the sulcus
precentralis inferior). Its anterior end is also a bifurcation, the lower end of which is the horizontal branch of
the sulcus frontomarginalis. The sulcus frontalis medius is rarely continuous and may even be interrupted in up
to five pieces. It can be visible at 26 weeks, usually rather at 30w GA.
The sulcus frontomarginalis.
The anterior (sagittal) part of this sulcus cuts the anterior cerebral pole in two, thus separating the lower
orbital part from the upper prefrontal part. It runs down on the convexity into the vertical part of the sulcus
frontomarginalis, described above as a vertical sulcus in front of the sulcus radiatus. The horizontal anterior
part is most often connected to the sulcus frontalis medius.
The sulcus frontalis mesialis.
An interrupted sulcus, parallel to the sulcus frontalis superior may be present at the convexity margin. This
sulcus separates gyrus frontalis superior on the lateral convexity from the medial frontal gyrus on the mesial
convexity, above the sulcus cinguli.
Sulci orbito-frontales.
On the orbital side of the frontal lobe, some relatively constant sulci subdivide the orbitofrontal surface. Gyrus
rectus aligns with the interhemispheric fissure and is bordered by the straight linear sulcus olfactorius. The
olfactory sulcus originates at the anterior border of the anterior perforated substance in two rami, of which
the longer lateral branch may anastomose with the lateral fissure or, less frequently, with the arcuate orbital
sulcus. It courses from back to front roughly parallel to the anterior interhemispheric fissure. The olfactory
gyrus is separated by the sulcus rostralis inferior from the rest of the frontal lobe on the mesial convexity, and
is a part of the longitudinal arciform region corresponding to the orbital portion of the superior frontal
convolution. A complicated cruciform groove (shaped H, X or K)(also called transverse orbital sulcus) subdivides
the core of the orbitofrontal cortex into anterior, medial, lateral and posterior orbital gyri. This transverse
cruciform complex is convex to the frontal pole. The posterior orbital gyrus is connected to the transverse
insular gyrus and often has the shape of a crescent “french hat”. An inconstant lateral olfactory sulcus borders
these orbital gyri near the lateral convexity, it limits the orbitofrontal lobe from the lateral aspect of the
inferior frontal gyrus. A transverse rostral sulcus separates the gyrus rectus from the subcallosal gyrus, in about
60% of cases (Beccari).
Slide 170: parasagittal plane through frontal and pericentral cortex: frontal,
parietal and temporal primary sulci in a 3D scheme
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Retzius G (1896) Das Menshenhirn: Studien in der Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167.
A complete image of all primary sulci of the convexity on a 3D model, representing a near term brain according
to Cunningham and Retzius. Small template with primary sulci bottom left.
Slide 171: parasagittal plane through frontal and pericentral cortex: typical
primary sulci
To describe typical sulci is different than recognizing them in any individual brain. Some important primary
sulci are indicated on this image from a term infant by “Retzius G (1896) Das Menshenhirn: Studien in der
Makroskopischen Morphologie. Stockholm: PA Norstedt 1-167”. Time of first appearance at postmortem
inspection indicated in the legend.
Slide 172: parasagittal plane through frontal and pericentral cortex: typical
term (38w) aspect in ELBW infant (GA 24w5d)
Typical term sulcal pattern in an ELBW preterm infant born at 24w PMA. The possibility of studying the
anatomy of frontal and pericentral sulci with CUS is surprisingly strong.
Slide 173: parasagittal plane through frontal and pericentral cortex: frontal
sulci variation
Further study of the primary sulci fo the frontal lobe. Legend with preceding anatomical drawings (pcm is
sulcus precentralis medius). Observe the deep end of the sulcus frontalis medius in the top row, middle image.
Middle row: descent of sulcus frontomarginalis from the sulcus frontalis medius. Clearly the primary sulci
present with great variation, but often the basic anatomy can be well studied around 30-34w PMA. Notice deep
sulcal pit of the sulcus frontalis medius in coronal section.
Slide 174: parasagittal plane through frontal and pericentral cortex: sulcus
intraparietalis
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Zlatkina V, Petrides M (2014) Morphological patterns of the intraparietal sulcus and the anterior intermediate parietal sulcus
of Jensen in the human brain. Proc Biol Sci. 281(1797).
Schematic of the parietal sulci of interest on the lateral surface of the human brain. Distinct parts of the
intraparietal sulcal cortex contribute to sensorimotor integration and to processing of attention in visual space.
A detailed examination of the morphological relations of the different segments of the complex intraparietal
sulcal region, which is a prerequisite for detailed structure-to-function studies, is not evident. The IPS is
divided into two branches: a ramus anterior and posterior, often separated by an annectant submerged gyrus.
The sulcus of Jensen emerges between the anterior and posterior rami of the IPS, and its ventral end is
positioned between the first and second caudal branches of the superior temporal sulcus. In a small number of
brains, the sulcus of Jensen may merge superficially with the first branch of the superior temporal sulcus.
In parasagittal CUS sections one can often see the onset (ramus anterior) of the intraparietal sulcus at the
middle of the postcentral sulcus, pointing caudal. in Coronal section the vertical position of the sulcus
intraparietalis makes it easy to separate from the pericentral sulci.
The transverse parietal sulcus (Brissaud) may subdivide the superior parietal lobule (SPL) into anterior and
posterior portions, when it extends from the mesial side to the superolateral aspect of the cerebrum in the
direction of the intraparietal sulcus. The SPL includes the preparietal and the superior parietal area, each with
subdivisions.
Slide 175: parasagittal plane through frontal and pericentral cortex: sulcus
temporalis superior
Becker Y, Phelipon R, Sein J, Renaud L, Meguerditchian A (2021) Planum temporale grey matter volume asymmetries in
newborn monkeys (Papio anubis). Brain Structure and Function, may 2021.
Brodmann K (1909) Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des
Zellenbaues. Transl. by L.J. Garey in English (1999) Brodmann’s Localisation in the Cerebral Cortex. Leipzig, Barth, London:
Imperial College Press.
Chau AMT, Stewart F, Gragnaniello C (2014). Sulcal and gyral anatomy of the basal occipital-temporal lobe. Surgical
Radiological Anatomy, 36, 959-965.
Cunningham DJ (1892) Contribution to the surface anatomy of the cerebral hemispheres. The praecentral and other sulci in
the external surface of the frontal lobe. pp 244-302.
Eberstaller O (1890) Das Stirnhirn. Urban & Schwarzenberg, Wien und Leipzig.
Geschwind N, Levitsky W (1968) Human brain: left-right asymmetries in temporal speech region. Science, N.Y., 161,
186-187.
Hanke J (1997). Sulcal pattern of the anterior parahippocampal gyrus in the human adult. Anatomischer Anzeiger 179,
335-339.
Heschl RL (1878) Über die vordere quere Schläfenwindung des menschlichen Grosshirns. Braumuller, Vienna.
Heschl R (1877) Tiefen-windungen des menschlichen Grosshirns und die Überbrückung der Zentralfurche. Wien. Med.
Wochenzeitschr. 41: 987-988.
Holl M (1908) Die Insel des Menschen und Affenhirns in ihren Beziehung zum Schlafenlappen. Sitz Berl Akad Wissensch Wien
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asymmetry: an in utero neuroimaging study. Cerebral cortex 21: 1076-1083.
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Lobus temporalis is formed by the superior, middle and inferior temporal gyri, classically numbered T1, T2, and
T3, separated by the superior and inferior temporal sulci (sulcus temporalis superior and inferior, also
numbered t1 and t2). The temporopolar cortex is heterogenous, transition between isocortex laterally and
paleocortex medial and dorsal. On the upper surface of the superior temporal gyrus the planum polare, the
transverse gyri (gyrus temporalis transversus anterior and posterior of Heschl) and the planum temporale form
the temporal operculum. A late appearing and small rostral transverse sulcus may cut the temporal pole in
front of the rostral end of sulcus temporalis superior; a vertical temporopolar gyrus lies lateral to it in front of
the horizontal (sagittal) large temporal gyri and sulci. The superior temporal sulcus limits the superior
temporal gyrus inferiorly.
Sulcus temporalis superior (t1) is a constant and phylogenetically old sulcus (evolved from the postsylvian
sulcus), the middle part of which separates Brodmann areas 21 and 22. It stems from the parallel sulcus of
lower mammals and monkeys, and ends in the angular gyrus. The superior temporal sulcus so described is
complex: it consists of the anterior temporal sulcus (related to the area temporalis polaris), the inferior
parallel sulcus (related to areas 21 and 22), a portion of the superior parallel sulcus and the angular sulcus
(related to area 39). The rostral end of the sulcus temporalis superior, phylogenetically the anterior temporal
sulcus, never extends into the temporal tip. This explains the apparent spreading of the superior temporal
gyrus over the temporal pole. The angular sulcus is a compensatory sulcus produced by the expansion of the
cortex forming area 39. That portion of the parallel sulcus which borders areas 21 and 22 is homologous with
the postsylvian sulcus of lower forms. The upper portion of the sulcus temporalis superior arches over the
upper end of the lateral fissure in many human brains and is named the superior parallel sulcus (ramus
ascendens of the sulcus temporalis superior). Below the angular sulcus the anterior occipital sulcus with its
sulcus annectans is recognised as a very definite entity bounding the pre-occipital area in front of the sulcus
lunatus. This constellation with a sulcus lunatus further posterior to it can be seen in some humans.
Sulcus temporalis superior in adults is a deep sulcus extending from near the inferior border of the insula,
parallel to the opercular surface of the superior temporal gyrus. It is rarely interrupted (32% of cases) divided
into anterior and posterior parts. The posterior part penetrates into the inferior parietal lobule and usually
divides into three rami within the angular gyrus (see above).
Its most consistent interruption point is at the level of the central sulcus where a large annectant gyrus reaches
the surface and connects the transverse gyri of Heschl along the superior temporal gyrus with the middle
temporal gyrus. This interruption is found in slightly less than 1/3 adult brains. At this level there is an
inconstant sulcus acousticus which ascends towards the lateral fissure, limiting the anterior extent of Heschl
gyri (see below). Retzius described three additional less common annectant gyri in the depth of the sulcus
temporalis superior.
Brodmann’s Area 21 or the middle temporal area is situated approximately in the middle temporal gyrus,
although its borders do not precisely follow the sulci that demarcate the gyrus; it also blends gradually,
especially anteriorly and posteriorly, with the neighbouring areas. Area 22 or the superior temporal area,
together with the cortex of the transverse gyri of Heschl, forms a homogeneous structural region: it encroaches
on the posterior two-thirds of the superior temporal gyrus. Anteriorly it reaches approximately the level of the
central sulcus where it climbs partly onto the medial surface of the superior temporal gyrus; posteriorly it just
attains the level of the vertical terminal branch of the lateral fissure and gradually blends with the
supramarginal area.
The sulcus temporalis superior is usually seen at postmortem around 24 weeks of gestation, clearly present by
26w. The earliest stretch becomes the large middle and posterior part of the definite sulcus. The anterior part
and the ascending branch develops later after 30w, as does the sulcus temporalis medius which apperas around
28 tot 30w.
There are early left-right asymmetries in sulcus temporalis superior: already at 26w the right sulcus temporalis
superior is more prominent and later on deeper than the left; on the other hand the left lateral fissure tends to
be longer and there is a higher frequency of a left sulcus diagonalis. The left planum temporale (and temporal
lobe) tends to be larger than the right from early on. This asymmetry is suggested to be language-related. But
the fact that this asymmetry (in grey matter volume around the posterior lateral fissure and in surface of the
planum temporale) is present in primates suggests that the asymmetry may be related to a core cognitive
process that guides limb gestures and/or language depending on the species (Geschwind and Levistky 1968,
Becker et al. 2021). The absence of right predominant deeper sulcus temporalis superior may correlatie
positively with higher language production (not comprehesnion) skills (Bartha-Doering et al. 2023). In 4/5 of
human brains the right superior temporal sulcus is deeper than the left.
Slide 176: parasagittal plane through frontal and pericentral cortex: sulcus
temporalis superior and relations
An ultrasound study of sulci of the temporal lobe in an ELBW infant of GA 24w, but scanned at 38w PMA.
Observe gyrus fusiformis and sulcus collateralis. Sulcus rhinalis is under the uncus more rostral than sulcus
collateralis.
Slide 177: the auditory system ending in primary auditory cortex of the
temporal lobe
An overview of the auditory system, summarized from standard anatomy works. The core cortical organisation
is in areas 41 and 42 on the surface of the temporal lobe, between planum polare and planum temporale,
further processing is in the auditory belt on the superior temporal gyrus.
Slide 178: parasagittal plane through frontal and pericentral cortex: motor
and sensory areas (with Broadmann numbers)
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des
Zellenbaues. Transl. by L.J. Garey in English (1999) Brodmann’s Localisation in the Cerebral Cortex. Leipzig, Barth, London:
Imperial College Press.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, White LE (2012) Neuroscience. Fifth edition. Sinauer
associates.
Zilles K (2018) Brodmann: a pioneer of human brain mapping-his impact on concepts of cortical organization. Brain: a
journal of neurology, 141(11).
A simplified view on some Brodmann cytoarchitectonic areas visible in the CUS window. Based on variations in
the thickness, cell density and other histological features of the six neocortical laminae, the human brain can
be divided into some 50 cytoarchitectonic areas, typically those recognized by the neuroanatomist Korbinian
Brodmann around 1909. Against a rudimentary Brodmann area map, the major connections for language
function are demonstrated. Injury to the cortex in related areas and/or to underlying tracts may impair
language development.
Slide 179: parasagittal plane through frontal and pericentral cortex: language
areas related to the MCA
Language problems following neonatal stroke.
1. Vargha-Khadem F, O'Gorman AM, Watters GV (1985) Aphasia and handedness in relation to hemispheric side, age at
injury and severity of cerebral lesion during childhood. Brain 108:677-96.
2. Wulfeck BB, Trauner DA, Tallal PA (1991) Neurologic, cognitive, and linguistic features of infants after early stroke.
Pediatr Neurol 7:266-9.
3. Fair DA, Brown TT, Petersen SE, Schlaggar BL (2006) fMRI reveals novel functional neuroanatomy in a child with perinatal
stroke. Neurology 67:2246-9.
4. Carlson HL, Sugden C, Brooks BL, Kirton A (2019) Functional connectivity of language networks after perinatal stroke.
Neuroimage: Clinical 23 (101861).
5. Lee J, Croen LA, Lindan C, Nash KB, Yoshida CK, Ferriero DM, Barkovich AJ, Wu YW (2005) Predictors of outcome in
perinatal arterial stroke: a population-based study. Ann Neurol. Aug;58(2):303-8.
6. Ricci D, Mercuri E, Barnett A et al. (2008) Cognitive outcome at early school age in term-born children with perinatally
acquired middle cerebral artery territory infarction. Stroke 39 (2): 403–410.
7. Raja Beharelle A, Dick AS, Josse G et al. (2010) Left hemisphere regions are critical for language in the face of early left
focal brain injury. Brain 133 (Pt. 6): 1707–1716.
8. Tillema JM, Byars AW, Jacola LM et al. (2008) Cortical reorganization of language functioning following perinatal left
MCA stroke. Brain Lang 105: 99–111.
9. Northam GB, Adler S, Eschmann KCJ, Chong WK, Cowan FM, Baldeweg T (2018) Developmental conduction aphasia after
neonatal stroke. Ann Neurol 83 (4): 664–675.
Persistent dysphasia develops with left-sided lesions, expressive more than receptive; not all left hemiplegics
have a language deficit [1]. Language delay already presents in the earliest communicative efforts (babbling)
[2].
Cortical language areas may differ transiently from normal in perinatal posterior truncal MCA stroke [3]. Using
resting state functional MRI in children aged 6-19 years, with a seed-based analysis (no task paradigm)
connectivity was compared between right inferior frontal gyrus and other language-related anatomical areas
(superior temporal and inferior parietal) in typically developing children versus children with unilateral
neonatal arterial cortical or venous periventricular stroke [4]. Left hemisphere strokes still left normal
connectivity in the right hemisphere but had a reductive effect on intra- and inter-hemispheric connectivity for
arterial strokes only. Following right hemispheric stroke findings were similar to normal children. Asymmetry of
connectiviy in these language networks was not yet found in the controls of this childhood cohort, suggesting
that left language lateralisation occurs in early adulthood. The study suggests that crowding contralateral to
the lesioned hemisphere for language tasks is not prominent, but that deficits may relate more to intra- and
inter-hemispheric connectivity. In other words the areas dedicated to language take over but not at expected
speed and bihemispheral communication level ?
Typically preterm venous white matter lesions seem to spare language functional connectivity compared with
term cortical infarction. The findings go along with knowledge that language deficits occur in both left and
right large artery stroke.
The relation between size and involvement of language areas was also studied by Lee et al. [5]. The
multilingual context in a family may have a negative impact on verbal IQ [6].
Although orobuccal motor aspects of language are most often organised in the left Broca area (pars triangularis
of the frontal lobe), both left and right neonatal stroke may have an impact on language. The discussion of how
this develops continues [7]. Left stroke may effect in both ipsilateral as well as contralateral activation of
language areas on fMRI [8].
Subtle language problems (speech repitition impairment) seem to occur most in case of left strokes where
language representation remained in the affected left hemisphere [9]. Language outcomes have been
compared to controls with DTI and fMRI in 30 children aged 7-18 years after neonatal stroke at term (21 on the
left). Left dorsal language stream injury was associated with selective speech repetition impairment for
nonwords and sentences. The majority of children with this type of impairment had retained left hemisphere
language representation. Right hemisphere dominance was correlated with minimal or absent repetition
deficits. It seems that early dorsal language stream injury can result in specific and long-lasting problems with
speech repetition that are similar to the syndrome of conduction aphasia of adults.
Of 40 infants with perinatal stroke, 36 were observed over 12 months [5]. Abnormal outcomes included CP
(58%), epilepsy (39%), language delay (25%), and behavioral abnormalities (22%). A delayed presentation (with
postneonatal neurological signs) was not unexpectedly associated with increased risk for CP (relative risk [RR
2.2 (1.2-4.2)].
Radiological predictors of CP included:
-
large stroke size (RR, 2.0; 95% CI, 1.2-3.2)
injury to Broca's area (RR, 2.5; 95% CI, 1.3-5.0)
injury to internal capsule (RR, 2.2; 95% CI, 1.1-4.4)
injury to Wernicke's area (RR, 2.0; 95% CI, 1.1-3.8) or
injury to basal ganglia (RR, 1.9; 95% CI, 1.1-3.3).
Language delay was common and results from either injury to the primary language areas (Broca and Wernicke)
or to the connecting subcortical long white matter tracts. When primary motor cortex is affected purely,
paresis follows. Spastic CP only follows when associated connections from premotor or sensory areas to the
brainstem motor centres are also involved.
Slide 180: ultrasound sections other than from the anterior fontanel
Routine scans are often only done from the anterior fontanelle. There are no good reasons for not scanning
routinely via the mastoid and other fontanels. Often in unstable preterm infants scanning via both mastoid
fontanels is planned on two different days to avoid repositioning of the infant.
Slide 181: axial sections above the ear: basal cistern and structures
Axial sections from the temporosquamosal suture area depict the pedunculus cerebri and tuber cinereum. The
movie on the right also shows the optic tract.
Slide 182: axial sections above the ear: brainstem
The recognition of fine structure of brainstem is difficult on MRI and all but impossible on CUS.
Top: sagittal section through brainstem and cerebellar vermis, compared with a sagittal scan of an infant of 27
weeks gestation, taken though the anterior fontanel with an 8.5 MHz scanhead.
Far right: sagittal 7.5 MHz ultrasound section of the area, taken through the posterior fontanel near the neck of
an infant with cleidocranial dysplasia (posterior fontanel extending to the foramen magnum).
Bottom: Temporo-squamosal sections (parallel to the cantho-meatal line): the echopoor mesencephalon looks
like a butterfly; the cerebral peduncles and tectal lamina are surrounded by hyperechoic cisterns and parts of
the tentorium. Bright reflections in the posterior part of the brainstem coincide with the walls of the
aqueduct. In the basal cisterns the arteries of the circle of Willis show as short, pulsating lines. Term MRI
sections for comparison.
Slide 183: levels and angles of section through the mastoid fontanel
Dudink J, Steggerda S, Horsch S; eurUS.brain group (2020) State-of-the-art neonatal cerebral ultrasound: technique and
reporting. Pediatr Res 87(Suppl 1):3-12.
Scanning through the mastoid fontanel is easy with both convex and high frequency linear probes. Scans can be
made in coronal as well as axial planes.
Slide 184: mastoid sections at 24 w GA
Fumagalli M, Parodi A, Ramenghi L, Limperopoulos C, Steggerda S; eurUS.brain group (2020) Ultrasound of acquired
posterior fossa abnormalities in the newborn. Pediatr Res 87(Suppl 1):25-36.
An example of mastoid sections of the cerebellum in an ELBW infant.
Slide 185: mastoid sections: posthaemorrhagic ventricular dilatation
Mastoid sections in posthaemorrhagic hydrocephalus. All ventricles can be inspected with CUS and treatment is
almost always based on the evolution of CUS scans, not on MRI.
Slide 186: mastoid section: lesions
Four different examples of common disease entities well recognized in mastoid views: pericerebellar
haematoma, temporal lobe cerebral cortical necrosis, clot in fourth ventricle with aqueduct patency, clot in
temporal horn.
Slide 187: mastoid section: subtle lesions
Even relatively subtle lesions can be picked up via the mastoid fontanel: a periventricular small cyst,
cerebellar haemorrhage, hyperechoic change of dentate nucleus in asphyxia, partial transverse sinus
thrombosis.
Slide 188: mastoid section: early transverse sinus thrombosis (sludging)
With high frequency linear probes impressive dynamic views can be made of flow in transverse and sigmoid
sinus, to the extent that sludging and partial thrombosis can be readily diagnosed. This may influence
positioning of the head (avoid jugular vein obstruction by extreme head rotation) and fluid management.
Slide 189: mastoid and nuchal section: large cisterna magna
Scanning via the nuchal view (through foramen magnum) is not infant friendly but inspection of cisterna magna
may necessitate this technique.
Slide 190: posterior fontanel and mastoid section: patent SSS above
occipital subdural haematoma
Example, in a term infant, of scanning from the anterior and posterior fontanel as well as from the mastoid
one, to document occipital subdural haematoma with patency of the nearby sinus.
Slide 191: linear 2D measurements for estimation of brain growth
Plenty of measurements (linear) have been reported and used in CUS. Best known of course are ventricle
diameters at specific places e.g. roof to floor distance of the lateral ventricle at the foramen of Monro, axial
width of the third ventricle and interhemispheric width. For many reasons (mainly the absence of a 3D volume
of high resolution in almost all machines and with almost all clinicians) it is not easy to publish useful and
reproducible measures. The roof to floor index is an example of a well recognized tool in management of
ventricular dilatation. Transverse cerebellar diameter at the mastoid fontanel is also used in clinical care. More
work can be done in this field.
Slide 192: the major cerebral arteries and the circle of Willis
Images adapted from Smith CG, van der Kooy DJ (1985) Basic neuro-anatomy. Third edition. DC Heath and Compagny.
Content in:
- Henri M. Vander Eecken, with permission: Normal cerebral arterial anatomy. In 'The anastomoses between the
leptomeningeal arteries of the brain’. Gent University Hospital.C.C. Thomas, Springfield-Illinois, 1959, an injection study of
40 adult brains.
- Govaert P. (2009) Sonographic stroke templates. Semin Fetal Neonatal Med 14:284-98.
The major cerebral arteries that form the circle of Willis in a parasagittal view and in antero-inferior view.
Slide 193: the major cerebral arteries and some details of the circle of Willis
Some details added about the anatomy of the circle of Willis, with the anterior choroidal artery exposed.
The a. choroidea anterior (AChA) sometimes originates from the MCA at its very origin. It other instances it
emerges from the terminal part of the ICA itself. In some an absolute distinction between the a. chorioidea
anterior and the aa. striatae laterales is impossible. From its origin on the MCA, and less frequently on the ICA
or even on the PCoA, it is pressed by the leptomeninges against the medial portion of the anterior perforate
substance. It then runs lateralward and posteriorly to reach the curvature of the optic tract, continuing
underneath it to the corpora geniculata, where it divides into (a) a branch entering, on the lateral side, the
telediencephalic fissure of Bichat—this is the anterior choroid artery proper—and (b) a much thinner branch
continuing to the lamina quadrigemina. It gives off the following side branches during its course :
Laterally : some fine branches supplying the uncus hippocampi, the anterior part of the lower side of the gyrus
hippocampus, the gyrus dentatus, the amygdaloid nucleus, the curvature of the tail of the nucleus caudatus.
Medially: a series of fine branches, supplying, from before backwards the optic tract, the lower part of the crus
posterius and the portio retrolenticularis (radiatio optica), the internal capsules, and the inner and
intermediary segment of the pars pallida nuclei lentiformis (the lower part of the genu capsulae is usually
supplied by one or two fine branches directly originating from the ICA).
The end branches can also be subdivided into one lateral and several median branches: the median terminal
branches supply the middle third of the crus cerebri, the upper part of the substantia nigra and of the nucleus
ruber, the lateral part of the subthalamic nucleus and, usually, a superficial part of the ventrolateral thalamic
nucleus. The lateral terminal branch enters the lateral part of the telediencephalic fissure to end in the
choroid plexus of the cornua, temporale and occipitale.
Slide 194: development of brain arteries
Development of brain arteries according to Padget.
Embryonic arteries.
• The internal carotid, basilar and vertebral arteries are formed during the first three embryonic vascular
stages of Padget in the branchial period (approximately 4–12 mm). When pharyngeal arches form during the
fourth and fifth weeks of development, each arch receives its own cranial nerve and artery. These arteries, the
aortic arches, arise from the aortic sac, the most distal part of the truncus arteriosus. The third aortic arch
forms the common carotid artery and the first part of the internal carotid artery. The remainder of the internal
carotid artery is formed by the cranial portion of the dorsal aorta. Six pairs of aortic arches are formed,
coursing around the five branchial arches by the 32nd day. In the postbranchial phase, the vascular apparatus is
replaced by the adult arterial system during a period that lasts about 18 days.
• Phases of arterial development are listed according to Padget 1948, revisited by Gillilan 1975 and Raybaud
2010. A realistic painting by Blechschmidt 1963 is added in the next image for comparison with the Gillilan
sketches.
Dimmick SJ, Faulder KC (2009) Normal variants of the cerebral circulation at multidetector CT angiography. Radiographics
Jul-Aug;29(4):1027-43.
Gregg L, Gailloud P (2017) The Role of the Primitive Lateral Basilovertebral Anastomosis of Padget in Variations of the
Vertebrobasilar Arterial System. The Anatomical Record 300:2025–2038.
Gillilan LA (1975) Anatomy and embryology of the arterial system of the brain stem and cerebellum. Chapter 2 in Vinken PJ,
Bruyn GW (Eds) Handbook of Clinical Neurology, pp 24-44.
Kathuria S, Gregg L, Chn J, Gandhi D (2011) Normal arterial cerebral development and variations. Seminars in Ultrasound
CT MRI 32:242-251.
Macchi V, Porzionato D, Guidolin D, Parenti A, De Caro R (2005) Morphogenesis of the posterior inferior cerebellar artery
with three-dimensional reconstruction of the late embryonic vertebrobasilar system. Surg Radiol Anat 27:56-60.
Marin-Padilla M (2012) The human brain intracerebral microvascular system: development and structure. Frontiers in
Neuroanatomy.
Padget DH (1948) The development of the cranial arteries in the human embryo. Contrib Embryol 212(32): 205-271.
Raybaud C (2010) Normal and abnormal embryology and development of the intracranial vascular system. Neurosurg Clin N
Am 21: 399-426.
ten Donkelaar HJ (2011). Clinical Neuroanatomy Brain Circuitry and Its Disorders. Ch 2: Vascularization of the Brain and
Spinal Cord. Springer Verlag.
Vasovic L, Jovanovic ID, Ugrenovic SZ, Andjelkovic ZP (2008) Normal subtypes of the posterior part of the cerebral arterial
circle in human fetuses. Surgical Neurology 70:287-294.
Arterial macrovasculature.
The development of the cranial vasculature can be divided into 4 stages. During stage 1 (weeks 2-4), the open
neural plate is fed by diffusion from the amniotic fluid. In stage 2 (week 4) the closed neural tube is enveloped
by a dense network of developing connective tissue called the meninx primitiva, which contains a primitive
vascular plexus irrigated from primitive dorsal aorta and cardinal veins during weeks. In stage 3, the primary
brain vesicles differentiate and a portion of the meninx primitiva invaginates into the neural tube, depositing
the primitive choroid plexus and developing vasculature that evolve into choroidal arteries. By stage 4, the
neural tube is too thick to be supplied by diffusion alone and intrinsic capillaries develop from the vessels of
the meninx primitiva to supplement perfusion. The internal carotid, basilar, and vertebral arteries are formed
during the first three embryonic vascular stages in the branchial period (approximately 4–12 mm). In the
postbranchial stage, the vascular apparatus is replaced by the adult arterial system during a period that lasts
about 18 days. Six pairs of aortic arches are formed, coursing around the five branchial arches by the 32nd day.
The internal carotid artery (ICA) originates from the dorsal aorta and the third aortic arch at the 4- to 5-mm
embryonic stage. The ICA receives contributions from the upper intersegmental and presegmental arteries,
connecting the longitudinal neural artery (LNA) on the ventral side of the hindbrain and forming carotid–
vertebrobasilar (trigeminal, otic, hypoglossal, and proatlantal intersegmental) anastomoses. The proatlantal
intersegmental artery (PIA) supplies the caudal part of the LNAs until this embryonic stage, when the
developing vertebral arteries (VAs) take over this function. The basilar artery (BA) becomes evident in the 7- to
12-mm stage through the union of the LNAs. The caudal end of every LNA reaches the cervical region and
anastomoses with the primitive VAs ascending from the longitudinal anastomotic vessels of cervical
intersegmental arteries, branches of the dorsal aorta. At the 11.5-mm stage (34 days), the BA and VA are
completely formed.
At approximately 15- to 17-mm crown rump length, the superior (SCA) and anterior inferior cerebellar arteries
(AICA) become prominent. The establishment of a primitive trigeminal artery (PTA) is related to the
development of the trigeminal ganglion. The PTA has regressed at the 45-mm stage because of the subsequent
development of the posterior cerebral artery (PCA) which takes over blood supply to the BA. The persistence of
the PTA in adults is fixed in the 11- to 14-mm embryonic stage (41–43 days).
The carotido–vertebrobasilar anastomoses are patent for a period of 7 to 10 days. It is thought that no rigid
genetic program exists but that the dynamic needs of the developing brain continually reshape the vessels.
Failure to do so may result in persistent primitive carotido-basilar arteries, the most common of which is the
PTA (observed in 1-2 angiograms/1000). The PTA leaves the cavernous part of the ICA and courses either
medially or laterally of the abducens nerve to the basilar artery, usually between the origins of SCA and AICA.
Its presence can change the caliber and presence of other arteries of the circle of Willis substantially, especialy
the PCA (Saltzman types I-III) (Vasovic et al. 2012). PTA has been associated with PHACE syndrome, Kippel-Feil
syndrome, aplasia of the inferior vermis and a rudimentary right arm (ref. in Vasovic et al 2008).
Two precommunicating segments of the PCAs (P1) and two posterior communicating arteries (PCoAs) are
interconnected on both sides into the posterior part of the circle of Willis. P1 is responsible for the blood
supply of globus pallidus, lateral wall of the third ventricle, mammillary bodies, pretectal area,
interpeduncular fossa, cerebral peduncle, and the posterior part of mesencephalon. PCoA branches supply the
anterior part of thalamus, part of subthalamus and hypothalamus, the oculomotor nerve, and the posterior
limb of the internal capsule. Following development of the basilar artery there is period of transition in fetal
development where carotid contribution via the PCoA gradually decreases (or not). This transition period has
been studied by Vasovic et al. 2008. in 172 brains of human fetuses (injected and microdissected) from the
13th to the 24th week. al. 2012).
According to diameter values of vascular components, 6 basic types and many subtypes are present: bilateral
transitory (18.6%, P1 and PCoA equal size), fetal (9.3%, PCoA larger), and adult (33.1%, P1 larger) types, as well
bilateral asymmetric types (fetal transitory in 5.8%, adult-transitory in 14.5%, and adult-fetal in 18.6% of
cases). Dominant configuration of the posterior part is thus not yet present in the period from the fourth to the
sixth gestational month, but caliber differentiation starts in that period. In fact the formation of the PCA is
complex, as the vessel is built up by a caudal branch from the carotid artery and the common trunk of
mesencephalic, diencephalic, and posterior choroidal arteries, a further proximal portion of the primitive
posterior choroidal artery and one of its branches, and a new vessel developing against the mesial occipital
ventricle wall.
The posterior inferior cerebellar artery (PICA) shows the most variable course among the cerebellar arteries,
mainly at the level of the lateral medullary segment (Macchi et al. 2005, studying transverse serial sections of
two human embryos of 22.5 and 23 mm crownrump length). The cerebellar primordium is vascularized by the
metencephalic plexus that will form BA and SCAs. Due to the development of the pontine flexure the rhomboid
lips approach and the cerebellum comes into contact with the myelencephalon; thus the myelencephalic plexus
represents an acquired source of vascularization for the approaching cerebellum. The VAs and BA, SCAs, AICAs,
and primitive lateral vertebrobasilar anastomoses are well recognizable. The PICA is not yet defined due to the
persistence of a plexus of thin vessels at the lateral aspect of the myelencephalon, indicating that its origin
and course are established at the end of the embryonic period, in relation to growth of the neocerebellum. The
high origin of the PICA from the basilar artery could be ascribed to its development from a rostral collateral of
the plexus. The possible patterns of the PICA reflect the variable retention of the primitive lateral
vertebrobasilar anastomosis in the trunk of the definitive PICA.
Slide 195: embryonic arteries
Blechschmidt E (1963) Der menschliche embryo. Friedrich-Karl Schattauer-Verlag, Stuttgart. Plate 27.
Padget DH (1948) The development of the cranial arteries in the human embryo. Contrib Embryol 212(32): 205-271.
Two different drawings of the embryonic arterial situation, with the normal transient carotido-basilar
anastomoses in the Padget scheme.
Slide 196: arterial developmental tree
Gillilan LA (1975) Anatomy and embryology of the arterial system of the brain stem and cerebellum. Chapter 2 in Vinken PJ,
Bruyn GW (Eds) Handbook of Clinical Neurology, pp 24-44.
Menshawi K, Mohr JP, Gutierrez J (2015) A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood
Supply). Journal of Stroke 2015;17(2):144-158.
Padget DH (1948) The development of the cranial arteries in the human embryo. Contrib Embryol 212(32): 205-271.
Raybaud C (2010) Normal and abnormal embryology and development of the intracranial vascular system. Neurosurg Clin N
Am 21: 399-426.
The arterial tree of the brain as it develops.
• The brain arterial system is built upon the flow from two carotid arteries and one basilar artery.
• The internal carotid artery (ICA) originates from the dorsal aorta and the third aortic arch at the 4- to 5-mm
embryonic stage. The ICA receives contributions from the upper intersegmental and presegmental arteries,
connecting the longitudinal neural artery (LNA) on the ventral side of the hindbrain and forming carotid–
vertebrobasilar (trigeminal, otic, hypoglossal, and proatlantal intersegmental) anastomoses. The proatlantal
intersegmental artery (PIA) supplies the caudal part of the LNAs until this embryonic stage, when the
developing vertebral arteries (VAs) take over this function.
• The basilar artery (BA) becomes evident in the 7- to 12-mm stage through the union of the LNAs. The caudal
end of every LNA reaches the cervical region and anastomoses with the primitive VAs ascending from the
longitudinal anastomotic vessels of cervical intersegmental arteries, branches of the dorsal aorta. At the 11.5mm stage (34 days), the BA and VA are completely formed. At approximately 15- to 17-mm crown rump length,
the superior (SCA) and anterior inferior cerebellar arteries (AICA) become prominent. At the 11.5-mm stage (34
days), the BA and VA are completely formed.
• At approximately 15- to 17-mm crown rump length, the superior (SCA) and anterior inferior cerebellar
arteries (AICA) become prominent.The internal carotid arteries (ICA) appear during the 3 mm embryonic stage
(24 days) from the combination of the 3rd branchial arch arteries and the distal segments of the paired dorsal
aortae. At 4 mm stage (28 days), the ICA branches off into the anterior and the posterior division. The anterior
division initially supplies the optic and olfactory regions through primitive arteries. Later the anterior division
of the ICA will give rise to the anterior cerebral artery (ACA), the middle cerebral artery (MCA), and the
anterior choroidal artery (AChA), while the posterior division will produce the posterior cerebral artery (PCA)
and the posterior choroidal artery. At this stage the superior cerebellar artery, a branch of the future basilar
artery (BA), is the only blood source to the primitive cerebellum. At the 4-5-mm embryonic stage, the
hindbrain is supplied by two parallel longitudinal neural arteries. These obtain their blood supply from carotidvertebrobasilar anastomoses: trigeminal artery (TA), otic artery (OA), hypoglossal artery (HA) and proatlantal
artery (ProA). The BA forms during the 5-8 mm stage from the consolidation of the neural arteries. The lifespan
of the TA, OA, and the HA is of approximately a week, and when the posterior communicating artery (PCoA)
develops and connects with the distal BA, the three pre-segmental arteries regress. Unlike the TA, OA, and the
HA, the ProA persist until the VA are fully developed, and in fact, a segment of the ProA gets incorporated into
the V3 segment of the VA and distal portions of the suboccipital artery. At 7 to 12 mm stage, the VA forms from
transverse anastomoses between cervical intersegmental arteries, beginning with the ProA and proceeding
downward to the 6th intersegmental artery, which eventually becomes the origin of adult VA from the
subclavian artery. At 35 days, the development of the MCA is first identified as small buds originating proximal
to the ACA on the anterior division of the primitive ICA. Although the MCA is still plexiform, it becomes the
major blood source for the cerebral hemispheres. At the16-18 mm stage, the MCA becomes prominent as the
plexuses fuse into a single artery and branches pierce the cerebral hemisphere. At the 18-mm stage, the stem
of the ACA gives rise to the olfactory artery. The ACA then continues growing medially towards the contralateral
ACA, eventually leading to the formation of the ACoA at the 21-24 mm embryological stage. The posterior
aspect of the circle of Willis is formed at earlier stages, when the fetal PCA turns into PCoA, the adult PCA
connects with the BA as branches from the fetal PCA fuse medially to form the distal end of the BA, and the
PChA incorporates into the adult PCA. Consequently, the full development of the ACA and the ACoA mark the
shaping of the circle of Willis in the 6-7 weeks embryo.
Slide 197: MCA functional anatomy
Blechschmidt E (1963) Der menschliche embryo. Friedrich-Karl Schattauer-Verlag, Stuttgart. Plate 27.
Blumenfeld H (2010) Neuroanatomy through Clinical Cases, Second Edition. Sinauer Associates.
Crelin ES (1969) Anatomy of the newborn. Lea and Febiger.
Dimmick SJ, Faulder KC (2009) Normal variants of the cerebral circulation at multidetector CT angiography. Radiographics
29(4):1027-43.
Gielecki J, Zurada A, Kozlowska H, Nowak D, Loukas M (2009) Morphometric and volumetric analysis of the middle cerebral
artery in human fetuses. Acta Neurobiol Exp 69; 129-137.
Gillilan LA (1975) Anatomy and embryology of the arterial system of the brain stem and cerebellum. Chapter 2 in Vinken PJ,
Bruyn GW (Eds) Handbook of Clinical Neurology, pp 24-44.
Kase CS (1988) Middle cerebral artery syndromes. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Clinical Handbook of
Neurology: Vascular Disease. Amsterdam, The Netherlands: Elsevier Science 353-370.
Komiyama M, Nakajima H, Nishikawa M, Yasui T (1998) Middle cerebral artery variations: duplicated and accessory arteries.
AJNR Am J Neuroradiol 19; 45-49.
Krayenbühl HA, Yasargil MG (1968) Cerebral angiography, ed. 2. JB Lippincott Co.
Marinkovic S, Gibo H, Filipovic B, Dulejic V, Piscevic I. Microanatomy of the subependymal arteries of the lateral ventricle.
Surg Neurol 2005;63(5):451-8.
Michotey P, Moscow NP, Salamon G (1974) Anatomy of the cortical branches of the middle cerebral artery. in Newton TH,
Potts DG (eds) Radiology of the Skull and Brain. Saint Louis: Mosby. pp 1442-1478.
Netter FH (1986) The CIBA Collection of Medical Illustrations. Vol. 1. Nervous System. Part I: Anatomy and Physiology. West
Caldwell, NJ: CIBA Pharmaceutical.
Nieuwenhuys R, Voogd J, van Huijzen C (2008) The human central nervous system. Fourth revised edition. Springer-Verlag.
Padget DH (1948) The development of the cranial arteries in the human embryo. Contrib Embryol 212(32): 205-271.
Rhoton AL (2007) The cerebrum. Neurosurgery 61[SHC Suppl 1]:SHC-37–SHC-119.
Ring BA (1974) Normal middle cerebral artery. Michotey P, Moscow NP, Salamon G (1974) Anatomy of the cortical branches of
the middle cerebral artery. in Newton TH, Potts DG (eds) Radiology of the Skull and Brain. Saint Louis: Mosby. pp
1442-1478.
ten Donkelaar HJ (2011) Clinical neuroanatomy. Brain circuitry and its disorders. Springer.
Vander Eecken HM (1959) Normal cerebral arterial anatomy. In: The anastomoses between the leptomeningeal arteries of
the brain. Charles C Thomas, Springfield Illinois.
Functional anatomy of the MCA: overview.
The MCA is the largest of the three cerebral arteries, it develops as a side branch from the primitive internal
carotid artery distal to the origin of the anterior choroidal artery, in the 7 to 12 mm embryo. The MCA arises at
the division of the internal carotid artery, just lateral to the optic chiasm and it courses from this point forward
and laterally, underneath the anterior perforate space. The M1 segment begins at the origin of the MCA,
extends laterally within the depths of the sylvian fissure and terminates at the site of a 90-degree turn, the
genu, located at the junction of the sphenoidal and operculoinsular compartments of the sylvian fissure. MCA
usually bifurcates where the truncus anterior is as described above, and the rest of the vessel is referred to as
tuncus posterior (or inferior). Sometimes it trifurcates, with the middle part of the fork containing precentral
and central arteries. M1 is subdivided into a prebifurcation and postbifurcation part. The prebifurcation
segment is composed of a single main trunk that extends from the origin to the bifurcation. The postbifurcation
trunks of the M1 segment run in a nearly parallel course, diverging only minimally before reaching the limen
insulae. The M2 segment includes the trunks that lie on and supply the insula. This segment begins at the genu
where the MCA trunks passes around the limen insulae and terminates at the circular sulcus of the insula. The
M3 segment begins at the circular sulcus of the insula and ends at the surface of the sylvian fissure. The
branches forming the M3 segment closely adhere to and course over the surface of the frontal, parietal, and
temporal opercula to reach the superficial part of the sylvian fissure. The M4 segment is composed of the
branches to the lateral convexity. The M4 begins at the surface of the sylvian fissure and extends over the
cortical surface of the cerebrum. The more anterior branches turn sharply upward or downward after leaving
the sylvian fissure. The intermediate branches follow a gradual posterior incline away from the fissure, and the
posterior branches pass backward in nearly the same direction as the long axis of the fissure.
M1 perfusion area: medial parts of striatum including anterior commissure and ventral striatum, genu capsulae
internae in its lower part, anterior pallidum internum; lateral parts of striatum (aa putamino-capsulo-caudate)
including lateral and dorsal caudate head and corpus, crus anterius lateral part, entire putamen except for a
ventral posterior portion, pallidum externum; thalamus is perfused from anterior choroidal, posterior
communicating and posterior cerebral artery
M2-4 perfusion area: entire convex cortical and immediate subcortical area except for a margin of 1-2 cm perfused
by either anterior or posterior cerebral artery pial branches; insular gyri and lateral orbital gyri
As the MCA reaches the lateral fissure, it describes a wide curve with its convexity facing forward and lateral.
In this arc it crosses the gyrus transitivus frontotemporalis and the anterior and lower part of the island of Reil.
Then its posterior major trunk courses in an oblique postero-superior direction, crossing the lower part of the
sulcus centralis insulae and the lobulus insulae posterior. It reaches the sulcus insulae posterior, the lower part
of which it traverses in an infero-superior direction. Leaving this sulcus it reaches the end of the lateral
cerebral fissure, where it ends as the a. angularis. During this course the middle cerebral artery gives off a
series of deep and superficial side branches.
The deep branches are the a. choroidea anterior (although this vessel stems from the internal carotid artery in
most cases and not from the MCA) and the aa. striatae laterales.
The superficial leptomeningeal arteries are the a. temporopolaris, the a. temporalis anterior and medius, a
truncus anterior or ascendens (from which arise: a. orbitofrontalis, a. precentralis, a. centralis and a.
parietalis anterior), the a. temporalis posterior, the a. parietalis posterior. Sometimes the prefrontal and
precentral arteries have a common initial part, the ascending frontal or operculofrontal candelabra.
Around 3 % of persons have an accessory MCA, sometimes referred to as axoid artery; it represents a very large
Heubner’s artery with its origin in the ACA. Stroke in this vessel may lead to striato-capsular infarction. Other
rare anomalies are the presence of duplicate MCAs originating from the ICA, or absence of the MCA.
The a. parietalis posterior usually arises as the last side branch from the upper side of the truncus occipitalis of
the MCA or as an upper side branch of the angular artery. It is far more superficial and less hidden in sulci than
the other arteries described, and finally divides itself over the gyrus supramarginalis, the middle third of the
lobulus parietalis inferior and the lower part of the lobulus parietalis superior. The terminal branch of the
truncus posterior, after the last side branches have been given off, is the very thin a. angularis. There is often
a gentle hump in the artery as it leaves the lateral fissure over the transverse gyrus of Heschl. It supplies the
gyrus angularis and the lower part of the inferior portion of the superior and inferior lobuli parietales. A branch
to the occipital lobe is inversely related in size to the posterior temporal artery, and can be referred to as a.
temporo-occipitalis.
In adults, the larger arteries (diameter exceeding 1 mm) are often the operculofrontal candelabra, the
posterior parietal and posterior temporal arteries, and the angular artery.
The a. choroidea anterior sometimes originates from the MCA at its very origin. It other instances it emerges
from the terminal part of the ICA itself. In some an absolute distinction between the a. chorioidea anterior and
the aa. striatae laterales is impossible. From its origin on the MCA, and less frequently on the ICA or even on
the PCoA, it is pressed by the leptomeninges against the medial portion of the anterior perforate substance. It
then runs lateralward and posteriorly to reach the curvature of the optic tract, continuing underneath it to the
corpora geniculata, where it divides into (a) a branch entering, on the lateral side, the telediencephalic fissure
of Bichat—this is the anterior choroid artery proper—and (b) a much thinner branch continuing to the lamina
quadrigemina. It gives off the following side branches during its course :
Laterally : some fine branches supplying the uncus hippocampi, the anterior part of the lower side of the gyrus
hippocampus, the gyrus dentatus, the amygdaloid nucleus, the curvature of the tail of the nucleus caudatus.
Medially: a series of fine branches, supplying, from before backwards the optic tract, the lower part of the crus
posterius and the portio retrolenticularis (radiatio optica), the internal capsules, and the inner and
intermediary segment of the pars pallida nuclei lentiformis (the lower part of the genu capsulae is usually
supplied by one or two fine branches directly originating from the ICA).
The end branches can also be subdivided into one lateral and several median branches: the median terminal
branches supply the middle third of the crus cerebri, the upper part of the substantia nigra and of the nucleus
ruber, the lateral part of the subthalamic nucleus and, usually, a superficial part of the ventrolateral thalamic
nucleus. The lateral terminal branch enters the lateral part of the telediencephalic fissure to end in the
choroid plexus of the cornua, temporale and occipitale.
Specific MCA branches (proximal and anterior)
The aa. striatae laterales are always found as 7-9 extremely fine branches arising from the first one and a half
centimeters of the MCA after the division of the internal carotid artery. Some perforators may originate as far
lateral as the first parts of an M2 segment. The horizontal M1 part of the MCA is bordered mesial and superior
by the optic tract, it courses under the substantia perforata anterior and it is bordered laterally by the caudal
end of the lateral olfactory stria. Usually each branch subdivides into two finer vessels before entering the
anterior substantia perforata in a direction perpendicular to the brain surface (immediate bifurcation). It has
been customary to make a distinction between the more numerous median and the less numerous lateral
vessels. The former, or the aa. pallidae externae supply the lateral segment of the pars pallida nuclei
lentiformis. The latter, or the aa. putamino-capsulo-caudatae supply the putamen, the upper part of the
internal capsule, the corpus nuclei caudati and the upper part of the caput nuclei caudati. There are no
anastomoses between them, except for small distal ones at their terminal irrigation areas near the ventricle.
When lateral perforators take their origin in inte M2 segment, occlusion may lead to combined prefrontal and
lateral striatal stroke.
The a. orbitofrontalis arises 1/3 times as a completely individualized side branch of the MCA. In 2/3 cases it
originates at the division of the truncus ascendens. After having ramified in the insular sulci, the a.
orbitofrontalis supplies the middle two-thirds of the middle frontal gyrus, the pars orbitalis and the pars
triangularis of the inferior frontal gyrus and the lateral part of the orbital gyri, namely the orbitalis portion of
the inferior orbital gyrus and the lateral half of the orbitalis portion of the middle frontal gyrus. The
orbitofrontal artery lies in front of and below the ramus ascendens of the lateral fissure, contrary to the
ascending operculofrontal candelabra that emerges behind the ramus ascendens. It courses laterally, anteriorly
and superiorly from its origin. The size of the orbitofrontal artery is inversely related to an orbitofrontal artery
that is derived from the ACA.
Just lateral to the aa. striatae laterales there is another inconstant side branch of the MCA, the a. temporalis
polaris. It supplies the anterior pole of the gyri temporales and the anterior gyrus fusiformis. The vessel
courses to the temporal pole in anterp-lateral direction, but a recurrent branch running posteriorly for a short
while in the lateral fissure, is often called the anterior temporal artery.
In most cases the a. temporalis anterior originates at about 1 cm. before the point of origin of the truncus
ascendens. In some it emerges at the same level as an individualized a. orbitofrontalis and in one case just
distal to the origin of the a. orbitofrontalis. This artery courses stepwise in an antero-posterior direction and
supplies the anterior half of the anterior third part of the gyri temporales and about the anterior eighth part of
the gyrus fusiformis. As stated above, the part of this area at the pole of the temporal lobe is often supplied by
an inconstant direct branch, the a. temporalis polaris.
From the upper side of the MCA, at about the level of the anterior pole of the insula, a truncus ascendens
arises. It is the common stem of origin for four arteries, being, from the front to the back, the a.
orbitofrontalis, the a. praecentralis, the a. centralis, the a. parietalis anterior. A"complete" truncus ascendens
as such is found in less than half. In the majority one or two of the four above mentioned arteries arise
separately and directly from the MCA. In rare cases the a. centralis and a. parietalis posterior arise together
directly. It is exceptional to find four completely independent arteries: there exists nearly always a truncus
from which four, three or at least two arteries originate. The four arteries arising from it successively run in
the insular sulci. They also give off small side branches for the blood supply of the insula. At the upper border
of the insula they fall deeply into the sulcus circumferentialis, and then resume their course and arise a second
time at a right angle from the bottom of the upper part of the lateral cerebral fissure.
The a. orbitofrontalis arises 1/3 times as a completely individualized side branch of the MCA. In 2/3 cases it
originates at the division of the truncus ascendens. After having ramified in the insular sulci, the a.
orbitofrontalis supplies the middle two-thirds of the middle frontal gyrus, the pars orbitalis and the pars
triangularis of the inferior frontal gyrus and the lateral part of the orbital gyri, namely the orbitalis portion of
the inferior orbital gyrus and the lateral half of the orbitalis portion of the middle frontal gyrus. The
orbitofrontal artery lies in front of and below the ramus ascendens of the lateral fissure and the pars
triangularis, contrary to the ascending operculofrontal candelabra that emerges in or behind the ramus
ascendens. The orbitofrontal a. courses laterally, anteriorly and superiorly from its origin. The size of the
orbitofrontal artery is inversely related to an orbitofrontal artery that is derived from the ACA.
The operculofrontal candelabra group of arteries arises from its initial position over the limen insulae and
provides prefrontal and precentral arteries, immediately in front of the central artery. The term candelabrum
suggests it is often a multifurcation of 3 to 8 branches.
The aa. prefrontales supplies the prefrontal area of the convexity. The a. praecentralis forms part of a more or
less complete truncus ascendens. It emerges from the lateral cerebral fissure on the pars opercularis of the
inferior frontal gyrus to disappear into the depth in the lower end of the sulcus praecentralis through which it
ran further. It very often divides into two branches in the depth of this sulcus. In some instances (1/4) the
thinnest branch enters the sulcus centralis in the lower quarter, where it is found beside the a. centralis with
which it collaborates in the blood supply of the lower part of the lips of the sulcus centralis. The a.
praecentralis, as either a single or double vessel, supplies the pars opercularis of the inferior frontal gyrus and
the lower three-quarters of the area comprising the sulcus praecentralis, i.e. the anterior slope of the
praecentral gyrus and the foot of the middle frontal gyrus (the premotor area).
The a. centralis arises in 3/4 from the truncus ascendens. In some this truncus initially provides a common
stem for the a. praecentralis and the a. centralis. It is uncommon but possible that the central and anterior
parietal arteries arise from the tuncus posterior of the MCA or from a single common branch in case of MCA
trifurcation. The artery in question enters the lower end of the sulcus centralis, where, in about half of the
cases, it divides into two. The normal area of supply of the a. centralis comprises the lower three quarters of
both banks of the gyrus praecentralis and of the gyrus postcentralis. It is custom to refer to the artery buried in
the lower part of the central sulcus as the central artery, the other providers for the pericentral area are then
called accessory arteries. If if there is only one central artery in the area of the lateral fissure it often
bifurcates more distally.
The a. parietalis anterior pivots on the truncus anterior and posterior. It can originate from the truncus
anterior either directly or as a branch from the central artery, but it can also be a branch from the truncus
posterior of the MCA, often than in common with the posterior parietal artery.
Specific MCA branches (posterior)
A clear distinction must be made between an anterior group of side branches of the MCA — those dealt with up
to now, under the name of truncus anterior — and a posterior (occipital) group, consisting of the a. temporalis
posterior, the a. parietalis posterior and the a. angularis. After having given off the first group, the MCA
practically always courses quite far posteriorly before it gives off the second group. There is therefore a long
stretch of the MCA between the far removed side branches of the anterior and the posterior groups which may
be occluded by a thrombus or an embolus to cause a stroke in the region of the posterior group. In some the
truncus ascendens is notably wider than the truncus posterior; in others on the contrary, the truncus posterior
is the widest. In most instances the a. parietalis anterior splits off very soon, at the moment it reaches the
sulcus postcentralis or slightly higher in this sulcus. The anterior of the two main branches of the a. parietalis
anterior runs upwards in the sulcus postcentralis, while the posterior branch, over the anterior part of the
lobulus parietalis inferior, reaches the sulcus intraparietalis, into which it drains. The a. parietalis anterior
supplies the posterior part of the lower two thirds of the gyrus postcentralis, the antero-superior part of the
lobulus parietalis inferior, the lower half of the anterior part of the lobulus parietalis, superior. After having
given off the above described arteries more or less united in a truncus ascendens, the caliber of the MCA is
considerably reduced.
This a. temporalis posterior usually arises from the truncus posterior very far posteriorly, at about 0.5 cm.
before the point where the truncus emerges from the end of the lateral cerebral fissure. Exceptionally it arises
from the MCA at a very rostral site, just next to the origin of the a. temporalis anterior, i.e. still in the region
of the gyrus transitivus fronto temporalis. Here a very long artery begins, which, parallel to the middle
cerebral artery and later next to its ramus occipitalis, passes through the greater part of the lateral or Sylvian
fissure on the convexity of the hemisphere. This anatomical arrangement is of importance since it provides an
explanation for different types of embolic stroke in the truncus posterior. This artery supplies the posterior
third or posterior half of the gyri temporales, superior and medius, as also the upper quarter of the posterior
part of the gyrus temporalis inferior. The supply areas of the a. temporalis anterior and posterior vary, the size
of one being inversely related to the other. Some of the larger branches of the anterior temporal artery that
perfuse the middle part of the temporal lobe, have been called middle temporal arteries.
The a. parietalis posterior usually arises as the last side branch from the upper side of the truncus occipitalis
of the MCA or as an upper side branch of the angular artery. It is less hidden in sulci than the other arteries
described, and finally divides over the gyrus supramarginalis, the middle third of the lobulus parietalis inferior
and the lower part of the lobulus parietalis superior.
The terminal branch of the truncus occipitalis, after the last side branches have been given off, is the a.
angularis. There is often a gentle hump in the artery as it leaves the lateral fissure over the transverse gyrus of
Heschl. It supplies the gyrus angularis and the lower part of the inferior portion of the superior and inferior
lobuli parietales. A branch to the occipital lobe is inversely related in size to the posterior temporal artery, and
can be referred to as a. temporo-occipitalis.
Occlusion of the individual cortical branches of the MCA, depending on the area supplied, may cause the
following deficits in adults: motor weakness caused by involvement of the corticospinal tract in the central
gyrus; sucking and grasping reflex caused by involvement of the premotor area; motor aphasia resulting from
involvement of the posteroinferior surface of the frontal cortex of the dominant hemisphere; changes in
mentation and personality caused by involvement of the pre-frontal area; visual field defects caused by a
disturbance of the geniculocalcarine tract in the temporal, parietal, and occipital lobes; impairment of
discriminative sensations and neglect of space and body parts resulting from involvement of the parietal lobes;
finger agnosia, right-left disorientation, acalculia, and agraphia (Gerstmann’s syndrome) caused by
involvement of the area between the parietal and occipital lobes of the dominant hemisphere; or a receptive
aphasia caused by disturbance of the dominant temporoparietal area.
Slide 198: ACA, PCA and perforator arteries in cerebral deep grey matter
ACA developmental and functional anatomy.
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of Neurology: Vascular Disease. Amsterdam, The Netherlands: Elsevier Science; 339-351.
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cortical branches of the anterior cerebral artery. in Newton TH, Potts DG (eds) Radiology of the Skull and Brain. Saint Louis:
Mosby. pp 1391-1420.
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Med 35(2):129-36.
Sawada T, Kazui S (1995) Anterior cerebral artery. pp 235-246 In Bogousslavsky J, Caplan LR (eds) Stroke syndromes.
Cambridge University Press.
Vander Eecken HM (1959) Normal cerebral arterial anatomy. In: The anastomoses between the leptomeningeal arteries of
the brain. Charles C Thomas, Springfield Illinois.
The anterior cerebral artery (ACA) develops from the initial rostral olfactory end branch of the primitive ICA
distal to the origin of the anterior choroidal artery, in the 7 to 12 mm embryo. It rapidly becomes larger and
evolves into the end branch of the ICA in the 16-18 mm embryo. The initial olfactory artery reduces in size and
becomes a branch of the remaining Heubner’s artery. The ACA crosses the substantia perforata anterior, and
courses almost horizontally above the chiasma opticum and below the olfactory stria to reach the
interhemispheric fissure. Just anterior to the optic chiasm it is connected with the opposite ACA by the a.
communicans anterior. Gross asymmetry between both ACAs is not uncommon. There is even the possibility of
three ACAs or of a single ACA (azygos artery) that provides both frontal lobes. Then it turns upwards in the
direction of the genu corporis callosi, to continue over the corpus callosum and terminates near the splenium.
The typical course is with an initial anterior convex, then subcallosal posterior convex and finally another
anterior convex part around the genu. It releases a series of branches: the aa. striatae mediales, the a.
orbitalis (or frontobasilaris), the a. frontopolaris, the a. calloso-marginalis (which itself gives rise to the a.
frontalis interna anterior, the a. frontalis interna media, the a. frontalis interna posterior), the a. paracentralis
and the a. praecunealis (also called arteria parietalis interna with a superior and inferior branch). These
branches perfuse the entire frontal and most of the parietal lobe at the mesial surface, and over the convexity
the perfusion area of the ACA gradually grows from the central area to the frontal pole. It ends as a.
pericallosa, the latter part of which is called a. pericallosa posterior. The a. pericallosa gives a series of small
side branches along its concave side.
The numerical nomenclature for ACA: A1 before the ACoA, A2 the ascending branches between the frontal lobes
and A3 the distal cortical branches.
The A1 side branches are the aa. striatae mediales, three or four very thin branches perforating directly the
substantia perforata. One of them has a wider caliber: the a. recurrens of Heubner, which supplies an
important area. In many instances it arises from the ACA at higher level than the a. communicans anterior (A2
segment), in a few cases at the same level and in most proximal or lower than the ACoA. This recurrent artery
runs in a lateral and dorsal direction initially following A1, gives off a fine branch for the tuber olfactorium and
finally penetrates into the lateral part of the anterior substantia perforata, to irrigate (with it smaller
companions) the anterior hypothalamus, the septum pellucidum, the medial anterior commissure, the fornix
and the anterior inferior striatum (caudate and putamen) with some anterior limb of the internal capsule
included. Heubner’s artery is usually a single vessel with 4 to 6 final branches.
The anterior communicating artery ACoA is relatively constant, althoug dupli- and even triplication exists. It
can be wide or hypoplastic. A single median artery of the corpus callosum arises from the ACoA to perfuse the
genu, septal area and columnae fornicis (also called subcallosal artery).
The first of the side branches of the convex sides, the a. orbitalis (artère orbitaire de Duret, frontobasilar or
orbitofrontal artery) begins just beyond the ACoA, most often as a separate stem, in sommon in common with
the a. frontopolaris. It curves in a forward and downward direction, along the lower frontal lobe margin and
after a meandering course reaches the orbital side of the frontal lobe. It supplies the facies interhemispherica
of the frontal lobe under the sulcus subfrontalis, the portio orbitalis of the superior frontal gyrus (gyrus rectus
and portio medialis of the gyrus orbitalis medius), and also the gyrus olfactorius (tuber, tractus and bulbus
olfactorii).
The a. frontopolaris (artère frontale interne et antérieure of Duret, artère préfrontale of Foix and Hillemand)
begins on the convex side of the subcallosal ACA at about half a centimeter below the genu corporis callosi. Its
stem is most often single, but can be in common with the orbital or anterior internal frontal artery. From its
origin the a. frontopolaris curves slightly downwards, follows a short part of the pars inferior of the sulcus
cinguli, enters the sulcus rostralis inferior (also calles sulcus subfrontalis) and divides itself over the anterior
portion of the superior frontal gyrus, both laterally and medially. It therefore supplies the anterior part of the
superior frontal gyrus.
The a. callosomarginalis is by far the most important side branch of the anterior cerebral artery. It usually
arises in the region of the genu corporis callosum, crosses the gyrus cinguli and soon reaches the sulcus cinguli,
through which it passes for its whole length. During this course it gives off successively: the a. frontalis interna
anterior, the a. frontalis interna media, the a. frontalis interna posterior and often the a. paracentralis.
The a. frontalis interna anterior begins almost at the level of the genu corporis callosi. It often originates in a
common stem with the a. frontalis interna media, the a. frontalis interna posterior and the a. paracentralis,
either from the pericallosal or callosmarginal artery. The a. frontalis interna anterior has a short ascending
course and irrigates the anteromedial portion (on the convexity and interhemispheric) of the superior frontal
gyrus.
The a. frontalis interna media originates near the beginning of the corpus callosum. In a minority of cases it is
a completely independent branch from the a. calloso-marginalis, most often it has a common stem with
neighbour branches. It divides over the posteromedial part (convexa and interhemispheric) of the superior
frontal gyrus.
The a. frontalis interna posterior originates about 1 cm. after the preceding artery, either as a single artery or
in union initially with adjacent branches. The a. frontalis interna posterior supplies the posterior part of the
superior frontal gyrus, both convex and interhemispheric. This is the artery of the supplementary motor area.
The a. paracentralis often branches off from the a. callosomarginalis via a common stem with the aa. frontales
internae; it can also originate from the a. pericallosa via a common stem with the a. praecunealis. Whatever
its origin, it ascends from the sulcus cinguli or sulcus corporis callosi to reach the paracentral lobule in the
sulcus paracentralis or in the ramus supramarginalis sulci cinguli. It supplies the paracentral lobule, as also the
adjoining superior parts of the pre- and postcentral gyrus.
The a. praecunealis (parietalis interna superior) arises from the a. pericallosa, end branch of the ACA
continuing in the sulcus corporis callosi after it has given off the a. callosomarginalis. Beyond the origin of the
a. praecunealis the ACA continues as a. pericallosa posterior. Along their convex sides the a. pericallosa and a.
pericallosa posterior give off some small branches for the gyrus cinguli, which is, however, mainly irrigated by
side branches of the aa. frontopolaris, callosomarginalis and praecunealis. Usually the a. praecunealis derives
separately from the a. pericallosa at a point between the anterior four fifths and the posterior fifth part of the
corpus callosum. It may originate from the arterial system of the controlateral hemisphere. In other cases the
a. praecunealis stems from a common stem with the a. paracentralis. From its origin the a. praecunealis has an
oblique postero-superior course, over the posterior arc of the gyrus cinguli, to reach the precuneus. It irrigates
the anterior precuneus and also the supero-posterior part of the superior parietal lobulus.
An anteromedial group of short perforator arteries arises from A1 and AcoA and supplies the lamina terminalis,
anterior hypothalamus, including the preoptic and suprachiasmatic regions, the genu of the corpus callosum,
the septum pellucidum, the anterior pillars of the fornix and part of the anterior commissure. Numerous fine
side branches in varying numbers, penetrating the corpus callosum, arise from the concave side of the ACA and
its terminal branch, the a. pericallosa, which itself continues as an a. pericallosa posterior. Some of them also
supply the septum pellucidum, the pars medialis of the commissura anterior and the pars libera of the
columnae fornicis. All but splenium is usually perfused by the ACA, explaining several disconnection syndromes
in adults when the ACA area is infarcted.
The end branch, the a. pericallosa posterior, continues the course of the a. pericallosa in the sulcus corporis
callosi and supplies the upper two-thirds of the splenium corporis callosi. In rare cases a single a. pericallosa
media arises from the anterior communicating artery and bifurcates terminally into two aa. pericallosae
posteriores.
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The posterior cerebral artery is the end branch of the basilar artery, from the division of the latter. It has a
more prolonged and complexer origin than MCA and ACA, the latter are both early branches of the anterior
division of the ICA. In fact the formation of the PCA is complex as the vessel is built up by a caudal branch from
the carotid artery and the common trunk of mesencephalic, diencephalic and posterior choroidal arteries, a
further proximal portion of the primitive posterior choroidal artery and one of its branches, and a new vessel
developing against the mesial occipital ventricle wall [Moffat 1957]. It runs over the stem of the oculomotor
nerve, which separates it from the more caudal superior cerebellar artery. Then it takes a horizontal course
(peduncular cisternal segment) towards the side of the crus cerebri, which it follows in a wide arc with its
convexity on the lateral side (ambient cisternal segment), crossing it in an infero-superior direction until it
reaches the lateral mesencephalic sulcus. Here it turns in an outward and posterior direction to follow the
posterior part of the inner border of the hippocampal gyrus (quadrigeminal cisternal segment, underneath the
basilar vein of Rostenhal, the arteries approach each other here after having loosely encircled the
mesencephalon), and then it divides into two post-cisternal cortical branches, one following the parietooccipital and the other the calcarine sulcus. During this course around the brain stem and over the inferior and
medial parts of the temporal and occipital lobes the PCA gives off branches schematically subdivided into two
groups, from either the cisternal (crural) or the cortical part. The PCA is the artery related to visual functions
in broad terms.
The branches of the cisternal part are usually deep penetrating vessels (perforating or choroidal). There are
the arteriolae retromammilares which are divided in an anteromedial and a posteromedial group. The anterior
group supplies the median-posterior part of the mammillary bodies; to them also belong the aa. perforantes
thalami (posteriores, in contrast to the anterior perforating thalamic, also called tuberothalamic or polar
thalamic arteries from the PCoA) which penetrate into the substantia perforata intercruralis, to vascularize the
median anterior part of the thalamus, the superior part of the nucleus ruber, the median part of the
subthalamic nucleus, the posterior part of the hypothalamus and the superior part of the brachia conjunctiva.
The posterior group supplies the middle part of the crus cerebri after perforating the substantia perforata
posterior, subdivided into interpeduncular (reticular formation, oculomotor and trochlear nuclei, pretectum)
and peduncular (corticospinal and corticobulbar tract, su. nigra, nu. ruber) perforators.
The a. quadrigemina arises close to the origin of the PCA, just medial to the point where the posterior
communicating artery joins the latter. It forms a pericrural arc (it is a circumflex mesencephalic branch of the
PCA), situated between the PCA on the anterior and the superior cerebellar artery on the posterior side. In the
transverse sulcus of the lamina quadrigemina it gives off a branch for the superior colliculus and another for
the inferior colliculus. Further, during its course it gives off branches to the anterolateral side of the crus
cerebri and to the medial geniculate. The quadrigeminal artery sometimes arises from the superior cerebellar
artery (SCA). In some cases it is duplicated. It is exceptionally possible for a similar circumferential artery to
perfuse the upper vermis (Seraslan et al. 2009), which is in typical cases done by the rostral branch of the SCA.
The aa. choroideae posteriores are usually double and originate separately or via a common stem. They also
curve around the crus cerebri. There are anastomoses between these two types of posterior choroidal artery.
The a. choroidea posterior medialis (artère choroidienne postérieure et moyenne of Duret) after having
reached the upper side of the mesencephalon, takes an anterior and superior course towards the lateral side of
the pineal body, to which it gives off small branches; it diminishes in size in the choroid plexus of the third
ventricle, coursing next to the internal cerebral vein. It irrigates mediodorsal thalamus and the superior part of
nucleus anterior thalami. The medial posterior choroidal artery initially usually follows the PCA at its inner
(medial) side. The second, the a. chorioidea posterior lateralis (artère choroidienne postérieure et latérale of
Duret) gives two end branches, both arising lateral to the main stem of the PCA. One follows the median part
of the upper side of the thalamus, the supero-median part of which it irrigates. The other reaches choroid
plexus of the lateral ventricle opposite the lateral part of the pulvinar. It also vascularizes the posterior part of
the caudate. During their ascending course the posterior choroidal arteries give off some small branches
entering the medial part of pulvinar. The posterior choroidal arteries arch around and delineate the posterior
pulvinar.
The aa. thalamogeniculatae arise beyond the point where the posterior communicating artery joins the
posterior cerebral artery, in the ambient cisternal part. They are usually 5 or 6 very thin branches penetrating
into the posterior and lateral side of the thalamus. They supply corpus geniculatum mediale, median and
posterior part of the corpus geniculatum laterale, lower half of the nucleus ventrolateralis thalami and lateral
pulvinar.The geniculate nuclei are perfused by thalamogeniculate, posterior lateral choroidal and anterior
choroidal artery branches.
Hippocampal arteries arise from the PCA trunk or from the lateral choroidal arteries near their origin. One to
four branches on each side usually form anastomoses with rake-like appearance, the connections running in the
sulcus hippocampi.
A meningeal artery derived from the peduncular segment of the PCA supplies the central parts of the tentorial
leaflets.
The post-cisternal (cortical) branches are as follows. The a. temporalis anterior originates from the part of the
PCA that runs in an antero-posterior direction through the lateral mesencephalic sulcus, opposite the origin of
the thalamogeniculate arteries. In many cases it has a specific, separate origin; in a minority it arises in
common with the posterior temporal artery. From its origin the anterior temporal artery describes an arc with
its convexity on the posterior side, and it continues over the anterior part of the gyrus parahippocampalis to
reach the sulcus collateralis, in which it runs further in a postero-anterior direction. It vascularizes the anterior
part of the parahippocampal gyrus, the fusiform gyrus (the anterior part of which belongs to the area of the
anterior temporal artery, branch of the MCA), and a small inferior and anterior part of the inferior temporal
gyrus.
In about 1/4 cases the a. temporalis posterior arises together with the preceding artery from the PCA. In most
however, its origin is situated more posteriorly, some 2 cm behind that of the anterior temporal artery,
opposite the splenium. From its origin the posterior temporal artery crosses the middle part of the
parahippocampal gyrus horizontally to reach the collateral sulcus, where it divides into an anterior and a
posterior branch, which together vascularize and nourish the posterior two-thirds of the parahippocampal and
fusiform gyri, and also the lower three-quarters of the occipital lateral gyri and the posterior part of the
inferior temporal gyrus. In most the posterior temporal artery is by far the more important as regards the
extent of the area of vascularization. In 1/4 the two temporal arteries are about of the same caliber, and their
area of supply is about equally important. Only in a few cases is the anterior temporal artery the more
important one, also providing an a. temporalis polaris.
Rami splenii (posterior pericallosal artery) are described as direct side branches of the concave side of the
posterior cerebral artery in about 1/2. In the rest similar pericallosal arteries come from the parieto-occipital
or from the posterior lateral choroidal artery. They run in a medial and upward direction, to vascularize the
lower part of the splenium of the corpus callosum and the adjacent parts of its radiation.
After having given off these small branches, the PCA disappears into the depth of the descending part of the
calcarine sulcus, and further on, at the curve of this sulcus bifurcates into its two end branches : the a.
parieto-occipitalis and the a. calcarina.
The a. parieto-occipitalis usually arises from a bifurcation some 2 cm beyond the origin of the posterior
temporal artery, in the proximal part of the sulcus calcarinus. It follows the sulcus parieto-occipitalis and
vascularizes the superior part of the cuneus (variably contributing to irrigation of the primary visual striate
cortex), the posterior fifth of the precuneus, the posterior half of the lower fifth of the superior parietal lobule
and the superior occipital gyri.
The a. calcarina originates as a second end branch from the terminal bifrucation of the PCA. It is usually
completely independent. Exceptionally it shares a common origin with the posterior temporal artery. It
traverses the posterior part of the calcarine sulcus and supplies the inferior half of the cuneus and the superior
and posterior part of the lingual gyrus. The localization of the border between the irrigation of the areas of the
two end branches of the posterior cerebral artery may show considerable individual variations at the level of
the cuneus.
The Posterior Communicating Artery (PCoA).
The PCoAusually arises from the last part of the ICA; sometimes also just behind the division of the latter, from
the MCA. It runs in a posterior and somewhat superior direction, beneath the optic tract and above the
oculomotor nerve, and joins the PCA at about 1 cm. distance from the division of the basilar artery. The
differences in caliber observed for this artery have been discussed with the circle of Willis. Five to six small
arteries arise from the PCoA, participating in the vascularization of the floor of the third ventricle and of the
supero-anterior part of the medial thalamic nuclei (called tuberothalamic, anterior perforating thalamic or
premammillary artery). In adults with ongoing internal carotid artery stenosis (e.g. by atheromatosis) the
caliber of the PCoA plays a rôle in the risk of border zone hypoperfusion: small or absent PCoA increase the risk
of watershed infarction [Schomer et al. 1994].
Slide 199: brainstem and cerebellar arteries
adapted from Smith CG, van der Kooy DJ (1985) Basic neuro-anatomy. Third edition. DC Heath and Compagny.
Different views of the main arteries to cerebellum and brainstem.
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Vertebro-basilar arterial developmental anatomy.
The internal carotid arteries (ICA) appear during the 3 mm embryonic stage (24 days), its anterior division
produces rise ACA, MCA and AChA, while the posterior division generates PCA and posterior choroidal artery. At
such early stage the superior cerebellar artery (SCA), a branch of the future basilar artery (BA), is the only
blood source to the primitive cerebellum. Occipital lobe and brain stem growth is the initial stimulus for the
formation of the posterior circulation, first with the BA and later with the vertebral arteries (VA). Prior to the
formation of the VA, the posterior circulation is supplied by a series of anastomoses linking the carotid
circulation to the longitudinal neural arteries (LNA), the latter locally formed from a primordial hindbrain
channel [1-8]. All the cranial members of the segmental series, as far back as the first cervical, contribute by
anastomosis to the formation of the longitudinal neural arteries. The paired LNAs are formed by the meeting
of a cranial branch from the internal carotids and a caudal vessel formed by the anastomosis of segmental
arteries. At the 4-5-mm embryonic stage, the hindbrain is thus supplied by two parallel LNAs. These arteries
obtain their blood supply from carotido-vertebro-basilar anastomoses including from caudal to rostral, the
proatlantal (ProA), hypoglossal, primitive trigeminal and posterior communicating artery (caudal division of the
embryonic internal carotid artery). The posterior communicating artery generally persists, and the ProA
participates in the formation of the cranial segments of the VA as it establishes continuity between the basilar
artery and the cervical VA, which explains the role of the ProA in the formation of several variants of the distal
VA and PICA.
The basilar artery is formed at the 5-8 mm stage by the fusion of the LNAs cranially and by the junction of the
anterior radicular branches of the proatlantal arteries caudally. De Vriese (1905)[5], in her study of the rabbit
embryo, has given a description of the formation of the basilar artery from the paired longitudinal neurals,
which form strong transverse anastomoses and as the segment of the right or the left tract between two
successive anastomoses disappears, so the basilar artery is made up of successive segments taken irregularly
from the right or left tracts. The primitive (and transient) lateral basilovertebral anastomosis PLBA, also
formed from the primordial hindbrain channel, courses parallel to the LNA and is connected to the posterior
radicular branch of the ProA and to the lateral branches of the LNA, some of which will later become proximal
segments of cerebellar arteries. The branching pattern of the ProA follows the typical distribution of an
intersegmental artery. In particular, the spinal division of the ProA provides ventral and dorsal branches,
respectively, coursing along the anterior and posterior roots of the first cervical nerve. The ventral branch is a
prominent anterior radiculomedullary artery which supplies the developing basilar circulation to respectively
form the caudal portion of the basilar artery (ascending) and the anterior spinal artery (descending). The
dorsal branch divides into the artery of the restiform body which establishes connections with the PICA
(ascending), while a descending one corresponds to the origin of the ipsilateral posterior spinal artery chain.
The PLBA is the cranial continuation of the ascending ramus of the dorsal radicular branch of the ProA, which
regresses at the adult stage into the artery of the restiform body. The PLBA and its adult derivatives may thus
be seen as a hypertrophied posterior spinal arterial system developed as an adaptation to the expansion of the
dorsal metencephalon into the cerebellum, the same way the ASA grows into a larger basilar artery to match
the development of the anterior metencephalon into the pons. The capacity of blood flow to make a channel
for itself by coalescing segments of many different vessels was recognized for vertebrate animals by His in
1880 [6]. At 7 to 12 mm stage, the vertebral artery forms from transverse anastomoses between cervical
intersegmental arteries, beginning with the ProA and proceeding downward to the 6th intersegmental artery,
which eventually forms the origin of adult VA from the subclavian artery. At the time of the establishment of
the longitudinal neural arteries, the carotid flow passes backward under the anterior hindbrain. The supply of a
large part of the brain by the vertebral flow is an acquirement of higher vertebrates. De Vriese could trace in
sheep embryos a progressive change in the direction of tapering of the basilar artery of such a nature as to
indicate that this vessel at first acted as a branch of the carotids but later as a part of the vertebral system.
The subclavian artery has a greater current than its companions, due to its supply of the limb-bud. Because of
its success in maintaining itself, the distal territory of its more cranial segments ultimately captures the
vertebral artery as a branch, a natural sequel of its closer connection with the main arterial stream than the
internal carotid artery.
The posterior aspect of the circle of Willis is formed, when the fetal PCA turns into PCoA, the adult PCA
connects with the BA as branches from the fetal PCA fuse medially to form the distal end of the BA, and the
PChA incorporates into the adult PCA. At the 11.5-mm stage (34 days), the BA and VA are completely formed. At
approximately 15- to 17-mm crown rump length, the superior (SCA) and anterior inferior cerebellar arteries
(AICA) become prominent. At the 11.5-mm stage (34 days), the BA and VA are completely formed. At
approximately 15- to 17-mm crown rump length, the superior (SCA) and anterior inferior cerebellar arteries
(AICA) become prominent. The posterior inferior cerebellar artery (PICA) is not yet defined at that stage due to
the persistence of a plexus of thin vessels at the lateral aspect of the myelencephalon, indicating that its origin
and course are established at the end of the embryonic period, in relation to growth of the neocerebellum
[7,8]. PICA shows the most variable course among the cerebellar arteries, mainly at the level of the lateral
medullary segment. The cerebellar primordium is vascularized by the metencephalic plexus that will form BA
and SCAs. Due to the development of the pontine flexure the rhombic lips approach and the cerebellum comes
into contact with the myelencephalon; thus the myelencephalic plexus represents an acquired source of
vascularization for the approaching cerebellum. The high origin of the PICA from the basilar artery could be
ascribed to its development from a rostral collateral of the myelencephalic plexus. The possible patterns of the
PICA reflect variable retention of the primitive lateral vertebrobasilar anastomosis in the trunk of the definitive
PICA.
The adult cerebellar arterial anatomy can be numerically classified, similar to the segmental anatomy of
cerebral arteries [9-13]. This has importance in neurosurgical settings. SCA leaves the basilar artery most often
underneath the oculomotor nerve, as a single trunk in about 8/10. It may be derived from the PCA. SCA turns
around the superior cerebellar peduncle in the pontomesencephalic sulcus and divides in a medial and a lateral
trunk, for (para)vermian and superior heimspheric perfusion respectively. From the cerebellomesencephalic
fissure (s3 segment) it sends precerebellar branches to the dentate nucleus and to 2/3 of deep cerebellar white
matter, just in front of the tentorial margin. AICA is single in 3/4 and has a close relation to the middle
cerebellar peduncle. It perfuses lateral pons and flocculus as well as v4 choroid plexus via the foramina of
Luschka. It ends in cortical branches in the horizontal cerebellar fissure, with a rostral (upward) and a caudal
(downward) branch. AICA is the artery perfusing most of the petrosal surface (anterior surface) of the
cerebellum, also providing the labyrinthine artery. The PICA is the most tortuous of the cerebellar arteries
originating 8/10 from the vertebral artery. It is related to the inferior olive (infratonsillar loop) and inferior
cerebellar peduncle. It turns around the tonsil in a sharp dorsal and caudal angle in the telovelomedullary
segment p4. Its cortical branches perfuse some part of the petrosal (medial branch to inferior vermis) and most
of the occipital surface (lateral branch to hemispheres and tonsil). There are common anastomoses between
these pial cerebellar arteries, less so for deep cerebellar perforating arteries. Deep cerebellar white matter
may be an area of watershed perfusion, possibly site of border zone (junctional) infarcts.
Slide 200: arteries of the medulla oblongata and spinal cord
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segment of the vertebral artery: a direct anatomic study. Rom J Morphol Embryol 54(3): 513-518.
6. Netter F (2013) The Netter collection of medical illustrations. Nervous system, part II: Spinal cord and peripheral motor
and sensory systems. Vol 7, second edition.Saunders, an imprint of Elsevier Inc.
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segment of the vertebral artery: a direct anatomic study. Rom J Morphol Embryol 54(3): 513-518.
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Surg 23(10):581-91.
Brainstem arteries (1-5).
The first branch of each subclavian artery is the vertebral artery (VA) that courses upward and backward
during its first segment (V1) until it enters the transverse foramina of the sixth or fifth cervical vertebra. In its
second segment (V2) it courses within the intravertebral foramina. The third segment (V3) passes posteriorly
behind the articular process of the atlas; it lies in a groove on the upper surface of the posterior arch of the
atlas, before piercing the dura mater to enter the foramen magnum. The intracranial portion (V4) ends at or
near the medullopontine junction, where the two VAs form the basilar artery. Usually the left vertebral artery
is largest and longest (around 6/10), in the remaining the arteries are of equal size or the right is bigger.
Absence of one vertebral artery is rare. The cervical portion of the vertebral arteries gives rise to many
muscular and spinal radicular branches. The spinal branches pass through the intervertebral foramina and enter
the spinal canal to supply the cervical portion of the spinal cord and the periosteum and bodies of the cervical
vertebra. A small anterior and larger posterior meningeal artery originate from the distal extracranial segments
(V2, V3). The intracranial vertebral arteries give off posterior and anterior spinal arteries, penetrating arteries
to the medulla and the large posterior inferior cerebellar arteries (PICAs). There are two spinal branches
forming the anterior spinal artery (ASA) in around 8/10, one from each vertebral artery. In some a double
anterior spinal artery exists.
The basilar artery courses rostrally in a groove closely applied to the anterior surface of the pons, in the
prepontine cistern behind the clivus. The distal segment enters the interpeduncular cistern, where it is often
separated from the basal surface of the brainstem. The distal portion ends at the pontomesencephalic
junction, just after passing between the two oculomotor nerves, by dividing into the two posterior cerebral
arteries. The basilar artery is often curved and tortuous and may deviate from the midline. The main branches
of the artery are the anterior inferior (AICA) and superior (SCA) cerebellar arteries, paramedian arteries that
penetrate directly into the pons, and short circumferential arteries that course around the pons and give off
lateral basal and lateral tegmental penetrating arteries.
Primary vascularization of the pyramid at the level of the medulla oblongata is via many small branches of the
ASA. Arterial supply to the olive varies by location: its anterior aspect is primarily irrigated by the ASA. The
shorter straight branches supply the medial part of the pyramid and do not reach the anterolateral sulcus;
longer branches usually reach the anterolateral sulcus and perforate the anterior surface of the olive and upper
medullary segment, some reach the foramen cecum. The ASA branches from both sides form a single ASA at the
level of C-2 or C-3 in 2/3 of the population, above which the pyramid is supplied only by rami of the ASA. The
upper portion of the posterior aspect of the olive is supplied by the vertebral artery, the AICA and the basilar
artery; and the middle and lower portions of the posterior aspect are fed by the vertebral artery and PICA.
Around the foramen caecum all above mentioned arteries supply branches, mainly from the basilar artery, but
the predominant supply of the posterior olive is from the vertebral artery. An anastomotic net connects the
small arteries in this area, which may account for the rare incidence of medullary infarction in the olive.
There are specific intracranial vertebrobasilar artery syndromes in adults and older children [1,4], described
here for the sake of completeness.
Lateral Medullary Syndrome.
Most often, patients with proximal intracranial vertebral artery occlusive disease present with features of the lateral
medullary syndrome. The findings are understood best by reviewing the structures in the lateral medullary tegmentum that
are specifically involved.
1. Nucleus and descending spinal tract of V. Sharp jabs of pain in the ipsilateral eye and face, and numbness of the face;
decreased pinprick and temperature sensations on the ipsilateral face.
2. Vestibular nuclei and their connections. Feelings of dizziness or instability of the environment may be present;
nystagmus.
3. Spinothalamic tract. Decreased pinprick and temperature sensation in the contralateral limbs and body.
4. Inferior cerebellar peduncle. Veering toward the side of the lesion and clumsiness of the ipsilateral limbs; hypotonia of
the ipsilateral arm.
5. Autonomic nervous system nuclei and tracts. Interruption of descending sympathetic axons that traverse the lateral
medulla in the lateral reticular formation causes an ipsilateral Horner syndrome.
6. Nucleus ambiguus. Hoarseness and dysphagia.
7. At times, there is also ipsilateral facial weakness, perhaps related to ischaemia of the caudal part of the seventh nerve
nucleus, just rostral to the nucleus ambiguus, or involvement of corticobulbar fibers going toward the seventh nerve
nucleus.
8. Abnormal respiratory control, especially in bilateral lateral medullary lesions.
Medial Medullary Syndrome.
Occlusion of one ASA is characterized by a hemiparesis that affects the contralateral arm and leg attributable to ischaemia
of the medullary pyramid, and ipsilateral weakness of the tongue and contralateral loss of position sense explained by
involvement of the hypoglossal nerve and the medial lemniscus. Bilateral medial medullary infarction can extend caudally
into the rostral spinal cord, causing a syndrome of quadriparesis difficult to separate from basilar artery occlusion with
pontine infarction.Basilar artery occlusion (proximal and middle).The major territory of supply of the basilar artery is the
basis pontis. The tegmentum of the pons has a rich collateral supply of blood vessels. The SCAs at the distal end of the
basilar artery provide much supply to the pontine and midbrain tegmentum. Occlusion of the basilar artery often causes
ischaemia in the pontine base bilaterally, sometimes extending into the medial tegmentum on one or both sides. The most
important neurologic signs and symptoms that accompany basilar artery occlusion are:
1. Limb paralysis. Limb paralysis is usually bilateral but often asymmetric.
2. Bulbar or pseudobulbar paralysis. Infarction affects cranial motor nuclei, causing paralysis of the face, palate, pharynx,
neck, or tongue on one or both sides, which causes dysarthria, dysphonia, hoarseness, dysphagia, and tongue weakness
(“pseudobulbar” because it involves the descending pathways controlling the bulbar nuclei rather than the nuclei
themselves). Exaggerated jaw and facial reflexes, increased gag reflex and emotional incontinence with excessive
laughing and/or crying can exist. The limb and bulbar paralysis may be so severe that the patient cannot communicate
verbally or by gesture (locked-in syndrome).
3. Eye movement abnormalities. The sixth-nerve nuclei, medial longitudinal fasciculi (MLFs), and pontine lateral gaze
centers are located in the paramedian pontine tegmentum, and are vulnerable to ischaemia in this region. Lesions of
the sixth nerve or nucleus cause paralysis of abduction of the eye. A MLF lesion (internuclear ophtalmoplegia) results in
loss of adduction of the ipsilateral eye on gaze directed to the opposite side and nystagmus of the contralateral
abducting eye. Lesions may affect the paramedian pontine reticular formation (PPRF), the so-called pontine lateral
gaze cente, resulting in an ipsilateral conjugate-gaze paresis. A unilateral lesion can affect both the PPRF and the MLF
on the same side, resulting in the one-and-a-half syndrome because only one half of gaze (scoring 1 for gaze to each
side) is preserved. Nystagmus: the vestibular nuclei and their connections are also often affected, causing vertical and
horizontal nystagmus. Other eye signs: ptosis, small pupils, and ocular skewing.
4. Coma, when the reticular formation is affected bilaterally in the medial pontine tegmentum.
Top of the basilar syndrome.
Emboli small enough to pass through the vertebral arteries seldom lodge in the proximal basilar artery, a vessel larger than
each intracranial vertebral artery, but reach the distal basilar artery or its terminal branches. The distal basilar artery
supplies midbrain and diencephalon through small vessels that pierce the posterior perforated substance. The findings in
patients with top-of-the-basilar embolism include (in addition to thalamic and cerebellar stroke signs):
1. Pupillary abnormalities. The lesion often interrupts the afferent reflex arc by interfering with fibers going toward the
Edinger-Westphal nucleus. The third-nerve nucleus can also be involved, as well as the rostral descending sympathetic
system. The pupils are usually abnormal and can be small, midposition, or dilated, depending on the level and extent of the
lesion. Decreased pupillary reactivity and eccentricity or an oval shape of the pupil is also found.
2. Eye movement abnormalities. Paralysis of upward or downward gaze is common. The eyes may also be skewed and
deviated at rest, most often downward and inward. Hyperconvergence, retractory nystagmus, and pseudo–VI-nerve paresis
are other oculomotor abnormalities noted.
3. Decreased alertness from bilateral paramedian rostral brainstem dysfunction.
4. Memory loss. Patients are unable to form new memories and may not be able to recall events just preceding their stroke.
Spinal cord arteries (6-10).
The spinal cord is supplied by multiple radiculomedullary arteries (RMAs), which feed the anterior spinal (ASA)
and two posterior spinal arteries (PSA). These radicular arteries stem from spinal segmental branches of the
large cervical and thoracoabdominal arteries (vertebral, costovertebral, subclavian, aorta …). From the spinal
arteries, traversing the intervertebral foramina, many radicular arteries pass medially to supply the anterior
and posterior nerve roots. Only some of the larger arteries reach the dura mater, where they give off small
meningeal branches and then divide into ascending and descending branches to contribute to the spinal
arteries. The anterior RMA’s are usually larger than the posterior ones, because they provide perfusion of about
2/3 of the cord substance.
The anterior spinal artery, most often branching off each fourth (intracranial) segment of the vertebral artery
distal to the origin of PICA, lies within the midline pia along the entire length of the cord. Six to ten anterior
RMAs contribute to it throughout its length. Blood from the ASA is distributed to the anterior two thirds of the
substance of the spinal cord via central (or sulcocommissural) branches and paramedian penetrating branches.
The cervical and first two thoracic segments of the cord are supplied by radiculomedullary arteries from the
subclavian artery. Variability is common, and the branches may arise from either the right or the left (often
alternately) to join the ASA at an angle. Not uncommonly, one anterior radiculomedullary branch arises from
the vertebral artery and accompanies the C3 nerve root, one branch arises from one of the branches of the
costocervical trunk (often the deep cervical artery) and accompanies the C6 root, and one branch arises from
the superior intercostal artery and accompanies the C8 root. The midthoracic region of the spinal cord (T3 to
T7) usually receives only one radiculomedullary artery, which accompanies the T4 or T5 nerve root, and this
artery can be referred to as von Haller’s artery (Colman et al. 2015). Between 8 and 9/10 have at least 1 ASA
contributor between T3 and T7; if no some may have one at an immediately adjacent level (T2 or T8). The
most frequent origin of upper thoracic anterior RMAs is left T5, only left T9 and left T8 are more common. A
significant upper thoracic anterior RMA distinct from the artery of Adamkiewicz appears to be a constant
anatomic feature, which undermines the classic concept of an arterial watershed zone in the thoracic region
(Gailloud 2013). The thoracolumbosacral part of the spinal cord (T8 to the conus medullaris) derives its main
arterial supply from the almost constant (9/10) left intercostal or lumbar artery of Adamkiewicz (most
between T9 and L2). In the 15% of cases in which the Adamkiewicz artery reaches the cord between T5 and T8,
the lower cord is supplemented by a radiculomedullary artery of the conus medullaris. The artery of
Adamkiewicz has a large anterior and a smaller posterior branch. On reaching the anterior aspect of the spinal
cord, the anterior branch ascends a short distance and then makes a hairpin turn to give off a small ascending
branch and a larger descending branch to the level of the conus medullaris, where it forms an anastomotic
circle with the terminal branches of the two posterior spinal arteries.
At the anterior commissure of the cord the sulcocommissural branches of the ASA turn alternately right and left
to supply the corresponding halves of the cord, except in the lumbar enlargement, where the left and right
branches arise from a common trunk. Their perfusion is thus from central to peripheral and highest vascular
density is in grey matter. The terminal branches ascend and descend within the cord, supplying overlapping
territories. Branches from each central artery overlap with those from adjacent arteries. The central arteries
supply the anterior commissure and adjacent white matter of the anterior columns, anterior horns, bases of
the posterior horns, Clarke’s columns, corticospinal tracts, spinothalamic tracts, anterior parts of the gracile
and cuneate fasciculi, and the region around the central canal.
The posterior spinal arteries are paired arteries coursing on the posterolateral aspects of the entire length of
the spinal cord, although they may become discontinuous at times. They originate from the intracranial
corresponding vertebral artery, and receive 10 to 23 posterior radiculomedullary arteries. The PSAs distribute
blood to the posterior third of their respective sides of the cord. In the cervicothoracic region, the PSA receives
one, sometimes two, tributaries at each segment. Between the T4 and T8 levels, there are usually two or three
posterior radiculomedullary branches, while in the thoracolumbar region, there are several feeders, one of
which may be the posterior radicular branch of the artery of Adamkiewicz. The PSA branches perfuse the
posterior cord from peripheral to central.
Pial Arterial Plexus. Small pial branches arise from the spinal arteries and ramify and interconnect on the
surface of the cord to form a pial plexus. Penetrating branches of the plexus are radially oriented to supply the
outer part of the substance of the cord; they follow the posterior median sulcus and the posterior intermedian
sulcus to reach the anterior and posterior horns. The peripheral pial branches supply outer portions of the
posterior horns, most of the posterior columns, and the outer portion of the white matter of the periphery of
the spinal cord. There is some degree of overlap in the distribution of the peripheral and central arteries at the
capillary level, but they do not anastomose at the arterial level, and hence both types are end arteries.
Slide 201: cerebral veins
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Ono M, Rhoton AL Jr, Peace D, Rodriguez RJ (1984) Microsurgical anatomy of the deep venous system of the brain.
Neurosurgery 15:621-57.
Netter FH (1986) The CIBA Collection of Medical Illustrations. Vol. 1. Nervous System. Part I: Anatomy and Physiology. West
Caldwell, NJ: CIBA Pharmaceutical
Padget DH(1956) The cranial venous system in man in reference to development, adult configuration, and relation to the
arteries. Am J Anat 98: 307-55.
Sargent, P . " Some Points on the Anatomy of the Intracranial Sinuses," Journ. Anat. and Physiol., 1911, 46, 69.
Stein RL, Rosenbaum AE (1974). In: Newton TH, Potts DG, eds. Radiology of the Skull and Brain, vol 2, book 3. St Louis:
Mosby. Book 3: Normal deep cerebral venous system: 1904-1928.
Streeter GL(1915) The development of the venous sinuses of the dura mater in the human embryo. Am J Anat 18:145-178.
Wolf BS, Huang YP (1963) The insula and deep middle cerebral venous drainage system: normal anatomy and angiography.
Am J Roentgenol Radium Ther Nucl Med 90:472-89.
An overview of the brain venous system and its confluences.
straight sinus: great cerebral vein, inferior sagittal sinus and common inferior vermis and declive vein
great cerebral vein
internal cerebral veins (precursor=superior choroid vein)(bow outward at pineal level), join below the splenium; enters the
velum interpositum just behind the foramen of Monro and has its entire course in subarachnoid space (not subependymal)
medial subependymal veins
- septal vein (anterior ventricular or internal frontal vein) (runs along septal leaflets and lateral to columna fornicis to
superior part of the foramen of Monro; enters internal cerebral vein near entrance of thalamostriate and anterior thalamic
vein; may enter internal cerebral vein at some distance behind foramen of Monro; frequently duplicated in a superior and
inferior septal vein, each receiving tributaries within the septal leaflet
- frontal pole medullary veins converging from anterolateral to medial at the septal point (anterior end of septum
pellucidum)
- veins of the anterior corpus callosum
- posterior septal veins (direct medial veins, roof veins of the lateral ventricle atrium), run along lower surface of corpus
callosum
frontoparietal medullary veins
short veins from body of corpus callosum
- medial atrial (internal parieto-occipital) vein (stem on surface of the pulvinar is called posterior paraventricular or
common atrial vein, especially if fused with the lateral atrial vein); usually has an anterior, middle (vertical) and posterior
branch; the latter runs above calcar avis and if unique is called the vein of the occipital horn; ends in the great cerebral
vein in around 1/5 brains
deep posterior parietal and occipital medullary veins
vein of the posterior horn
atrial choroid plexus
some branches from hippocampus
- thalamic veins (are not subependymal)
anterior thalamic vein, originates in anterior and inferior thalamus to ascend toward the internal cerebral
or septal vein, near the foramen of Monro
superior thalamic vein, originates in central superior thalamus towards the mesial upper part of thalamus
and runs posteriorly lateral and inferior to the internal cerebral vein before entering it
lateral subependymal veins
- terminal (thalamostriate, although no thalamic tributaries) vein; starts at anterior atrium and lies in stria terminalis,
arches around anterior tubercle of thalamus at foramen of Monro; joins septal vein and anterior thalamic vein at venous
angle to form the internal cerebral vein
transstriate anastomoses to basal vein
anterior caudate veins (anterior terminal veins) form parallel arcs crossing from out and above to in and below
along the caudate surface; a large vein in the floor of the frontal horn is called the anterior inferior caudate vein;
transverse caudate veins drain white matter above the body of the lateral ventricle
frontoparietal medullary veins
may form longitudinal caudate vein at external angle of the ventricle
frontoparietal medullary veins
superior striate veins, caudate veins, veins from anterior limb of the internal capsule
rarely one large anterior caudate vein may largely replace the thalamostriate vein and is than
called retrothalamostriate vein (with absent or hypoplastic TSV)(other name =
thalamocaudate vein)
may be replaced by thalamocaudate vein (= direct lateral vein, surface thalamic vein), ends in mid part
of the ICV (convex summit of ICV) posterior to foramen of Monro; this vein runs almost in a
coronal plane and is present in about 4 % of all brains
frontoparietal medullary veins
- superior choroidal vein, runs anteriorly between fornix and thalamostriate vein toward the venous confluens
anastomoses to inferior choroidal veins
- middle choroidal venules
- common atrial vein, formed on the surface of pulvinar
medial atrial vein
occipital medullary veins
lateral atrial vein (external vein of the atrium); may also drain directly in to the basal vein; is found in
3/4 brains
parieto-occipital medullary veins
posterior temporal medullary veins
- posterior ventricular vein
- superior vein of the vermis
- posterior mesencephalic vein
posterior pericallosal vein(s)
posterior corpus and splenium veins
quadrate lobe veins
posterior cingulate veins
basal veins (precursor=ventral diencephalic vein)
- first (striate) segment
deep middle cerebral vein
some superfical middle cerebral veins
insular veins (may exceptionally drain not through basal vein but through uncal vein or cortical
veins)
posterior insular vein
central insular vein
precentral insular vein
anterior insular vein
anterior cerebral vein (pericallosal vein)(single or bilateral) from genu to anterior perforated substance
inferior striate veins (emerge in the anterior perforated substance; may form short trunks there before
forming the starting point of the basal vein)
fan of veins in lateral view
anterocentral group of some longer veins originate in anterior putamen
olfactory vein (from olfactory bulb to anterior perforated substance)
posterior fronto-orbital veins
- second (peduncular) segment
(inter)peduncular vein; may be joined by posterior communicating vein; communicate with anterior
pontomesencephalic vein in the interpeduncular fossa to end in the superior petrosal sinus
anteroinferior thalamic veins, medial branches from third ventricle wall
midbrain veins
inferior ventricular vein (from outer ventricle wall along the roof of the temporal horn, anteriorly to end with a sharp medial turn - in the basal vein at the level of the lateral geniculate, behind the
uncus); runs medial or lateral to the caudate tail; may drain areas along the atrium as well
inferior choroidal vein (runs from posterior part of temporal horn forward to the inferior
ventricle vein or ends directly in the basal vein)
temporal roof and medullary veins
lateral atrial vein
parieto-occipital medullary veins
posterior temporal medullary veins
hippocampal veins may drain into inferior ventricular vein in stead of directly into basal vein
hippocampal transverse veins (subependymal and pial) and longitudinal collecting vein along the dentate
gyrus (together the hippocampal venous formation)
inferior choroidal vein (joins the stem of the inferior ventricular vein)
- third (posterior mesencephalic) segment
lateral mesencephalic vein (may drain upward over the medial geniculate into the basal vein, or
downward into the petrosal vein)
posterior (inferolateral and posterior thalamus; thalamogeniculate veins) and inferior (inferomedial
thalamus) thalamic veins; may also drain into the posterior mesencephalic vein
great anterior (precerebellar) cerebellar vein
posterior ventricular vein
small medial inferior temporal and occipital cortical veins
- posterior pericallosal vein, single midline vessel originating behind the splenium
splenium veins
quadrate lobe veins
- internal occipital vein
calcarine veins
- great anterior (precerebellar) cerebellar vein
superior hemispheric cerebellar veins
- superior cerebellar vein = fusion of precentral cerebellar vein and superior vermian vein
- posterior mesencephalic vein
transverse sinus
tentorial sinus
superior petrosal sinus
mastoid emissary veins
vein of Labbé
Slide 202: deep cerebral veins in superolateral 3D view; venous systems from
embryological point of view
Aueboonyawat T, Pereira V, Krings T, Toulgoat F, Chiewvit P, Lasjaunias P (2008) Patterns of the Cranial Venous System from
the Comparative Anatomy in Vertebrates. Part III. The Ventricular System and Comparative Anatomy of the Venous Outlet of
Spinal Cord and Its Homology with the Five Brain Vesicles. Interventional Neuroradiology 14: 125-136.
Two schemes:
- the deep venous system (ventricular veins)
- a subdivision of brain veins into dorsal, ventrolateral and ventricular veins.
Slide 203: veins of the posterior fossa
Veins of the posterior fossa are grouped in three systems: petrosal, galenic and tentorial, according to their
main direction of drainage.
Slide 204: ultrasound examples of cerebellar veins
Some doppler examples of veins of the posterior fossa. The petrosal vein runs down in front of the flocculus,
the precentral cerebellar vein runs up from vermis to GCV or ICV. Bottom right is a cerebellar vein draining up
to the straight sinus. To recognize a vein one needs: knowledge of its anatomy, an idea of the direction of flow
and a continuous doppler signal to prove its venous character. Notice that some pulsatility is often present in
the larger brain veins, including those in the deep venous system.
Slide 205: motor symptoms due to parasagittal injury near the central area in
SSS thrombosis
Parasagittal cerebral injury related to superior sagittal sinus thrombosis may lead to sensorimotor symptoms
(presentation with seizures or permanent motor deficit). Observe the presence of the large anastomosing veins
of Labbé and Trolard, often saving brain tissue when sinus thrombosis occurs. The main variations in the large
anastomosing veins are depicted in a simple scheme. Thrombotic occlusion of branches of the vein of Labbé is
one mechanism behind temporal lobe convexity haematoma.
Slide 206: pericentral circulatory loop from MCA and central artery to
terminal and internal cerebral vein
adaptation of an image from Nieuwenhuys R, Voogd J, van Huijzenz C (1988) The human central nervous system. Third
revised edition. Springer-Verlag.
An important vascular loop in the rolandic area: internal carotid artery to MCA to pial artery to thalamostriate
vein to internal cerebral vein to great cerebral vein.
Slide 207: flow visualisation depends on sampling frequency (prf)(spectral
doppler)
For the study of veins with CUS doppler one continuously changes the sampling frequency: at high prf (pulse
repitition frequency) the sampling permits visualisation of high velocities (limiting aliasing in these arteries), at
low prf the low velocities are coloured in the image. Lower prf modus creates more chaotic images due to
blooming artefacts (the vessel appears much large than it is). This adaptation of prf is necessary to depict the
entity at hand: presence of the large veins and their patency or presence of (ab)normal smaller vessels (like in
a DVA or near a GMH).
Notice that central flow in transverse sinus is slower than flow near the vessel wall. This observation agrees
with images of slow flow (sludging prior to thrombosis) at the transverse sinus angle in ELBW infants.
Slide 208: large vessels with high velocity are depicted with a convex low
frequency probe
Large vessels with high velocity are depicted with a convex low frequency probe using spectral doppler.
Slide 209: small vessels with low velocity are depicted with a linear high
frequency probe (low prf)
Small vessels with low velocity are depicted with a linear high frequency probe (spectral doppler, low prf).
Slide 210: doppler images of PCoA and PCA perforators to thalamus (angio
mode spectral doppler)
A collage of doppler images of PCoA and PCA perforators to thalamus (spectral doppler in agnio mode by
reducing speckle information from the parenchyma).
Slide 211: doppler images of ACA and MCA perforators (angio mode spectral
doppler)
A collage of doppler images of ACA and MCA perforators (angio mode spectral doppler).
Slide 212: power doppler impression of the deep arterial perforators and
medullary vessels
A doppler study at low prf of the vessel-poor area lateral and superior to the lateral ventricle ventricle. The
presence of relatively large deep medullary veins does not permit to show the watershed aspect of the area.
Slide 213: stenosis and flow velocity change in the great cerebral vein
Insonation from the posterior fontanel of physiological stenosis of the great cerebral vein.
1. Streeter, L. "The Development of the Venous Sinuses of the Dura Mater in the Human Embryo," Amer. Journ. Anat.,
1918,18, 145-178.
2. Browder J, Kaplan HA, Krieger AJ (1976) Anatomical features of the straight sinus and its tributaries. J Neurosrug 44;
55-61.
3. Okudera T, Huang YP, Ohta T, Yokota A, Nakamura Y, Maehara F (1994) Development of posterior fossa dural sinuses,
emissary veins, and jugular bulb: morphological and radiologic study. AJNR Am J Neuroradiol 15(10):1871-83.
4. Kedzia W, Kedzia E, Kedzia A, Derkowski W (2017) Anatomy of the falcine sinus during the prenatal period. Surg Radiol
Anat 39; 753-758.
Formation of the straight sinus and falx sinus.
Much in the same way the superior sagittal sinus froms from a mesh of midline vessels of the primary forebrain
plexus, the sinus rectus forms in the area between falx and tentorium cerebelli, connecting the newly formed
great vein of Galen with the torcular at the venous confluens area [1,3].
As the superior sagittal sinus becomes established, caudalward it is usually continuous with the ventral main
channel of the right anterior plexus (or tentorial plexus as it is better called in the late stages), which
eventually forms part of the right transverse sinus. The straight sinus is formed in the ventral part of the
sagittal plexus and its caudal adjustment is essentially like that of the superior sagittal sinus. It may drain
chiefly toward the right or left plexus or equally toward both. From a high and straight early fetal position, the
straight sinus is flattened and displaced downward by enlarging cerebral hemispheres. Several intrafalcine
veins connect the primitive axis of internal cerebral vein, great cerebral vein and straight sinus below, with the
superior sagittal sinus (SSS) above. If such vein persists after birth it is called a persistent falcine sinus. Around
term the straight sinus typically drains into the left limb of the SSS.
The straight sinus not uncommonly (1/5) has a duplicated segment (anterior, middle or posterior part)[2]. This
duplication never covers the whole extent of the sinus. Most duplications are anterior. In the anterior part, just
after its origin from the great cerebral vein of Galen, the straight sinus may have a dilated part (a bulb or pool,
after a junctional narrowing). Tributaries are from falx and tentorium. It is normal for some veins in the falx to
form a plexus near the superior sagittal sinus. In many brains this plexus extends in the falx to reach the
straight sinus. When a larger vein in the posterior falx remains, the term falx sinus can be used [4]. Dilated falx
veins occur with vein of Galen malformation, with distal straight sinus obstruction as in torcular thrombosis, or
with congenital hypoplasia of the superior sagittal sinus.
Slide 214: stenosis and flow velocity change in the great cerebral vein
1. Dagain A, Vignes JR, Dulou R, Dutertre G, Delmas JM, Guerin J, Liguoro D (2008) Junction between the great cerebral
vein and straight sinus: an anatomical, immunohistochemical, and ultrastructural study on 25 human brain cadaveric
sections. Clinical Anatomy 21; 389-397.
2. Ghali, WM, Rafla MFM, Ekladious EY, Ibrahim KA (1989) A study of the junction between the straight sinus and the great
cerebral vein. J Anatomy 164; 49-54.
The transition of great cerebral vein to straight sinus.
The straight sinus develops from the formation of the great cerebral vein and the inferior sagittal sinus. A
transition zone between the great cerebral vein may have haemodynamic functions, and this has been studied
in postmortem specimens [review in 1] but not in the newborn brain in vivo.
Three different anatomic aspects have been observed:
- type 1: a junction with elevation in the floor of the transition and a posterior thickening (14 cases)
- type 2: a junction with an outgrowth on the floor like a cornice (gutter)(7 cases)
- type 3: a junction with an intraluminal nodule.
Microscopic study of type 1 and 2 junctions showed a positive coloration to orceine due to the presence of
elastic fibers. Immunohistochemistry revealed the presence of smooth muscular actin and S 100 protein of
nervous fibers. In ultrastructural study (E.M.), a morphological progression of the endothelium is observed:
endothelium in the great cerebral vein is spindle shaped, is rounded in the transition and polygonal in the
straight sinus. The venous orifice of the great cerebral vein into the straight sinus has the characteristics of a
true ‘‘sphincter.’’ Its function in the regulation of the cerebral blood flow needs further exploration.
Arachnoid protrusions into the junction have been reported but are not standard. The transition area may be a
bulge with a cavity under it, sort of an arachnoid vesicle [2]. Since there is a confluence of two venous systems
(inferior sagittal sinus and great cerebral vein), the orifice of the straight sinus is prone to flow turbulence
(vortices). This is certainly likely because the great cerebral vein enters the straight sinus at an acute angle (60
to 90 °) and an immediate narrowing at the orifice is present in most brains. This narrowing induces heigher
velocities and may pull the floor of the orifice into the lumen. The transition zone with its elevations in the
lumen may serve to protect against turbulence in the dead zone that appears when flow from the inferior
sagittal sinus meets flow from the great cerebral vein at an acute angle.
The flow velocities at this junctional area can be studied with high frequency ultrasound from the posterior
fontanel.
Slide 215: basilar artery ghosting
An example of a doppler artefact: athough MRI (cooled term infant with bad start but no brain damage)
demonstrated the presence of a single normal basilar artery, CUS doppler study from the anterior fontanel with
a convex probe repeatedly presented two copies of this vessel. Axial insonation or in some cases study with a
linear high frequency probe, can also document the normal anatomy without the artefact.
Slide 216: ICA thrombosis
The doppler signal of the carotid arteries always reaches a probe in the anterior fontanel. Top left are normal
images, bottom left a right ICA thrombosis as an incidental finding in a preterm infant. Right three different
post-ECMO term infants, with three different right carotid artery residuals: top total occlusion, middle normal
patency, bottom stenosis with both upward flow in the right ICA and flow via the left ICA along the ACoA to the
right MCA.
Slide 217: sequence from carotid injury to medial striate perforator stroke to
GMH to venous infarction
An unusual sequence well documented with CUS. Right carotid artery thrombosis leading to or associated with
ipsilateral GMH and venous infarction, in a preterm infant with neck traction during vaginal breech delivery.
Notice downward flow in both A1 segments of the ACA in axial view.
Slide 218: thalamic arterial stroke types
1.Lazorthes G (1961). Vascularisation et circulations cérébrales. Masson, Paris.
2.Plets C, De Reuck J, Vander Eecken H, Van den Bergh R (1970) The vascularization of the human thalamus. Acta Neurol
Belg 70:687–770.
3.Bogousslavsky J, Regli F, Uske A (1988) Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 38:837–
848.
4.Ghika J, Bogousslavsky J (1995) Abnormal movements. pp 91-101. In Bogousslavsky J, Caplan LR (eds) Stroke syndromes.
Cambridge University Press.
5.Barth A, Bogousslavsky J, Caplan LR (1995) Thalamic infarcts and hemorrhages. pp 276-283. In Bogousslavsky J, Caplan LR
(eds) Stroke syndromes. Cambridge University Press.
6.Percheron G (1976) les artères du thalamus humain II. Artères et territoires thalamiques paramédians de l’artère basilaire
communicante. Rev Neurol (Paris) 132:309–324.
7.Percheron G (1977) les artères du thalamus humain. les artères choroïdiennes. Rev Neurol (Paris) 133:533–545, 547–558.
8.Schmahmann JD (2003) Vascular syndromes of the thalamus. Stroke 34:2264–2278. Carrera E, Michel P, Bogousslavsky J
(2004) Anteromedian, central and posterolateral infarcts of the thalamus. Three variants. Stroke 35:2826–2831.
9.ten Donkelaar HJ (2011) Clinical neuroanatomy. Brain circuitry and its disorders. Springer.
10.Gupta N, Pandey S (2018) Post-thalamic stroke movement disorders. Eur. Neurology 79; 303-314.
Intrinsic arteries to thalamus: thalamus is vascularized by perforating branches of the posterior communicating
artery, thalamoperforating and thalamogeniculate branches as well as the posterior choroidal arteries. These
perforating branches supply the following structures (with summary of clinical findings in adults in case of
stroke)[1-10]:
a. Seven to ten perforating branches arise from the posterior communicating artery. The largest branch is the
premammillary artery (anterior thalamoperforating or tuberothalamic artery). These perforating branches
vascularize the anterior or tuberothalamic territory: the posterior part of the optic chiasm, the optic tract, the
posterior part of the hypothalamus with the mammillary body, and the anterior nucleus, the polar part of the
ventral anterior nucleus and the reticular nucleus of the thalamus. Polar (tuberothalamic) artery syndrome:
apathy, amnesia (inability to make new memories).
b. The thalamoperforating branches (or posteromedial central arteries) arise from the P1 segment and
penetrate the posterior perforated substance. They supply the paramedian territory: the medial nuclei, the
intralaminar nuclei, part of the dorsomedial nucleus, the posteromedial part of the lateral nuclei and the
ventromedial pulvinar of the thalamus. Thalamic-subthalamic syndrome (perforator aa.): hypersomnolence
(arousal problems), disturbed vertical gaze, amnesia, disorientation, abnormal movements like asterixis,
tremor or dystonia.
c. The thalamogeniculate branches usually arise from the distal P2 segment of the PCA. They supply the
inferolateral territory: the major part of the lateral side of the caudal thalamus including the rostrolateral part
of the pulvinar, the posterior parts of the lateral nuclei and lateral dorsal nucleus, and the ventral posterior
and ventral lateral nuclei. Lateral thalamic syndrome (thalamogeniculate aa.): pure hemisensory stroke, hemisensorimotor stroke, abnormal movements with hemisyndrome (thalamic syndrome, dystonia like the thalamic
hand).
d. The posterior choroidal artery usually has one or two medial and one to six lateral branches. The medial
branch supplies the medial geniculate body and the posterior parts of the medial nucleus and the pulvinar of
the thalamus. Posterior choroidal aa. syndrome: visual field defects, milde hemisyndromes, visual
hallucinations, dystonic movements, amnesia.
Recognition of these thalamic specific arterial stroke entities is only beginning in the neonatal literature.
Slide 219: left thalamic stroke near perforator from PCA P1, doppler profiles
Typical left PCA P1 perforator stroke in a preterm infant, most likely paradoxal embolism from an umbilical
venous catheter. Below a normal typical image of the fork of perforators stemming from P1. If one vessel
bifurcates and is thrombosed, this may lead to bilateral thalamic stroke (Percheron a. stroke).
Slide 220: various perforator strokes
Collection of perforator strokes; the bottom ones with decreased or absent flow in the vessel affected.
Slide 221: postnatally acquired striatal arteriopathy following GMH/IVH
Acquired striatal arteriopathy of the preterm infant following GMH/IVH. Initially perforator arteries are not
visible, but some of them become hyperechoic, possibly as a result of glymphatic clearing of waste from the
matrix lesion. Notice in the bottom right image that an inferior striate vein is not hyperechoic whereas some
arteries are.
Slide 222: lenticulostriate arteriopathy
Examples and grading scheme of lenticulostriate vasculopathy. The name is not entirely appropriate as some
infants also have hyperechoic change in thalamic arteries. “Vasculopathy” in itself may even be incorrect in
some infants as the hyperechoic change may stem from the Virchow-Robin space and not from the artery itself
and as far as we know veins are not affected.
Slide 223: medullary veins and venous infarction
Schematic presentation of the medullary veins involved in GMH/IVH and subsequent venous infarction. Notice
in the top right high resolution linear doppler image the palmate and candelabra convergence areas as
described in the adult.
Okudera T, Huang YP, Fukusumi A, Nakamura Y, Hatazawa J, Uemura K (1999) Micro-angiographical studies of the medullary
venous system of the cerebral hemisphere. Neuropathology 19:93-111.
Slide 224: porencephaly develops independent of affected vein in GMH and
venous infarction
A study of development of porencephaly in venous infarction: the focus of porus formation is independent
(more medial) of the collector vein involved in the infarct.
Slide 225: anatomy of deep veins is relevant to onset of GMH in the
caudothalamic groove
The variation of deep venous anatomy is relevant to the mechanistic pathogenesis of venous infarction. Bottom
left: acute change in direction of flow from posterior caudate vein to terminal vein. Top right: GMH on the side
of a direct lateral vein. Bottom right: it is not uncommon to see clear asymmetry in drainage af atrial white
matter; in this infant upward drainage in the terminal vein is typical, whereas drainage of the lateral atrium
downward to the basal vein is atypical. The latter may be protective because such vein does not cross a
substantial collection of fragile matrix.
Slide 226: reduced arterial flow in cortex adjacent to medullary venous
infarction (spasm ?)
On the side of GMH/IVH, and in the top example even preceding venous infarction, the medullary vessels (most
likely small pial arteries) may have reduced flow velocity and appear absent. This suggests some mechanism
originating from GMH to redirect flow at the pial level above it.
Slide 227: large IVH without complete compression of ipsilateral terminal and
posterior caudate veins
Large GMH and IVH (or plexus bleeding) with displacement of but not obstruction of the ipsilateral posterior
caudate collector vein.
Slide 228: pial veins can be more prominent overlying a periventricular
venous infarct
Above some venous infarcts (where flow downward is impeded) an increased flow upward in the direction of
pial veins can be documented with high resolution doppler.
Slide 229: primary in utero thrombosis of the internal cerebral vein
(dysfibrinogenaemia) and posthaemorrhagic hydrocephalus
Tajdar M, Orlando C, Casini A, Herpol M, De Bisschop B, Govaert P, Neerman-Arbez M, Jochmans K(2018) Heterozygous FGA
p.Asp473Ter (fibrinogen Nieuwegein) presenting as antepartum cerebral thrombosis. Thromb Res 163:185-189.
Initial occlusion and later reopening of the right ICV in a newborn with presumably antepartum onset of IVH
associated with dysfibrinogenaemia.
Slide 230: internal cerebral vein thrombosis ?
Even with experience and serial focused scanning it remains difficult to make certain that an internal cerebral
vein is fully obstructed: gradual reappearance of both vessels is very suggestive.
Slide 231: screening for transverse/sigmoid sinus patency from the anterior
fontanel
In ELBW/VLBW infants and in sick term infants it is feasible and perhaps advocated to routinely scan for the
presence of flow in the transverse/sigmoid sinus, from the anterior fontanel. Observe the influence of neck
rotation on sigmoid flow in the images below.
Effects of neck rotation on venous flow.
Watson GH (1974) Effect of head rotation on jugular vein blood flow. Arch Dis Child 49; 237-239.
Cowan F, Thoresen M (1985) Changes in superior sagittal sinus blood velocities due to postural alterations and pressure on
the head of the newborn infant. Pediatrics. 75(6):1038-47.
By compression of the jugular veins in the lower neck, a drop in flow velocities in the superior sagittal sinus
can be registered in many neonates and children; asymmetrical findings are compatible with the above
reported asymmetrical adult transverse and sigmoid sinus anatomy [1,2]. Occlusion is at midjugular level due
to tissue around the sternocleidomastoid muscle. Partial occlusion progresses from occurrence at 45° rotation
to full occlusion at 90°.
A pulsed Doppler bidirectional ultrasound system was used to measure alterations in the blood velocities in the
superior sagittal sinus of the healthy term newborn infant in response to unilateral and bilateral jugular venous
occlusion [2]. These maneuvers were performed with the baby lying in different positions: supine, prone, and
on the side (both left and right), the neck flexed or extended, and with the head in the midline or turned 90
degrees to the side (both left and right). Turning the head effectively occludes the jugular vein on the side to
which the head is turned and occluding the other jugular vein does not force blood through this functional
obstruction. Alterations in velocities were frequently profound although they varied considerably from baby to
baby. Extending the neck reduced the severity of the effects of jugular venous occlusion in most of the babies.
Escape along non-jugular veins thus seems common and variable.
Excessive rotation occludes the jugular vein on the side to which the face is rotated, it is therefore logical
(although difficult to prove) to avoid excessive neck rotation especially in very low birthweight infants with
fluid restriction and/or venous congestion.
Slide 232: patent sinus near an extra-axial haematoma
It is probably good practice to check the patency of sinus near an extra-axial (subdural) or lobar parenchymal
haematoma.
Slide 233: VLBW transverse sinus thrombosis
Especially ELBW infants, ventilated with higher than normal thoracic pressures and often undergoing head to
neck manipulations, are vulnerable to transverse/sigmoid sinus thrombosis. Slow flow and thrombus formation
are often first seen in the centre of the transverse sinus.
Slide 234: Willis’ cords
Mall, FP (1905) On the development of the blood-vessels of the brain in the human embryo. Am J Anat 4:1–18.
Markowski MJ (1922) Entwicklung der Sinus durae matris und der Hirnrenen des Menschen, in Bulletin International de
L’Acad mie Polonaise des Sciences et des Lettres: Classe Des Sciences Meth matiques et Naturelles S rei B: Sciences
Naturelles. Cracovie: Imprimerie de l’Université.
Padget DH (1956) The cranial venous system in man in reference to development, adult configuration, and relation to the
arteries. Am J Anat 98:307–355.
Sharifi M, Kunicki J, Krajewski P, Ciszek B (2004) Endoscopic anatomy of the chordae willisii in the superior sagittal sinus. J
Neurosurg 101:832–835.
Streeter GL (1915) The development of the venous sinuses of the dura mater in the human embryo. Am J Anat 18:145–178.
Chordae Willisii are structures located in the lumen of the superior sagittal sinus (SSS). It is thought that they
act as flow-improving structures within the sinuses. Twenty-five SSSs obtained from fresh human cadavers
during autopsies were flushed with tap water to remove clots (Sharifi et al. 2004). Bridging veins emptying into
the sinus were ligated, and continuous flow of a saline solution through the sinus in a physiological direction
was achieved. Rigid endoscopes of different diameters (2.7–4.5 mm) and optic (0 and 30 ̊) were inserted into
the sinus. After endoscopic photography, the sinuses were opened and the chordae willisii were dissected
Chordae Willisii were observed in all examined specimens. Three different types of the cords were found:
lamellar, trabecular, and valvelike. The most common type was the valvelike (mixed) one, which comprised
45.1% of all cords. The chordae willisii were most commonly observed in the parietooccipital region.
As described by Padget and Markowski, in its distal portion, the anterior dural plexus forms two channels called
“marginal sinuses.” These paired vessels then unite to form a single channel.The intraluminal structures of the
dural sinuses most probably originate from the cells of the primitive veins of the epidural space, which fuse to
different extents into venous sinuses during fetal development. The chordae Willisii were regarded as
functional structures by early anatomists, some of whom termed them “valves.” Others asserted that the
endothelial projections should be regarded as internal extensions of the wall of the sagittal sinus. Finally,
others acknowledged the function of the chordae in preventing blood reflux into the interior of the cerebral
veins. Networks of chordae may act as flow-improving and velocity-regulating structures and may protect the
sinus from outside compression.
Against flow directions of pial veins draining into the SSS create an unfavorable physiological angle at the vein
orifices. Because of this unfavorable angle, the majority of the vein orifices in the sinus are half covered by
valvelike chordae to prevent backflow of blood into the veins. This is one of the most characteristic
physiological functions of the valve-like chordae Willisii in the sinus and explains their shape and location. The
cords, especially the longitudinal type, protect the sinus wall from compression, thus preventing turbulent
nonphysiological blood flow.
Slide 235: Willis’ cords in a newborn infant
Crelin ES (1969) Anatomy of the newborn. An atlas. Lea and Febiger.
Typical presentation of Willis’ cords in a newborn.
Slide 236: a Willis’ cord is not a thrombus
Willis’ cords should not be mistaken for intraluminal thrombus. They are remnants of the fusion of veins that
results in formation of the superior sagittal sinus.
é
é
é
Kehrli P (1999) Le sinus sagittal supérieur. Etude embryologique, histologique et anatomique, vol 1. Thèse de Doctorat de
l’Université Louis Pasteur.
Kopuz C, Aydin ME, Kale A, Demir MT, Corumlu U, Kaya AH (2010) The termination of superior sagittal sinus and drainage
patterns of the lateral, occipital at confluens sinuum in newborns: clinical and embryological implications. Surg Radiol
Anat. 32(9):827.
Padget DH (1956) The cranial venous system in man in reference to development, adult configuration, and relation to the
arteries. Am J Anat 98: 307-55.
Streeter GL (1915) The development of the venous sinuses of the dura mater in the human embryo. Amer. J Anat. 18:
145-178.
Streeter GL (1918) The developmental alterations in the vascular system of the brain of the human embryo. Carnegie Inst.
Wash. Pub. 271, Contrib. to Embryol., 8: 5-38.
https://embryology.med.unsw.edu.au/embryology/index.php/Paper__The_development_of_the_venous_sinuses_of_the_dura_mater_in_the_human_embryo
Superior sagittal sinus formation.
A subdivision of the anterior plexus extends forward to the midline as the plexus sagittalis, being interposed as
a venous curtain between the hemispheres. From its median and dorsal channels develops a unique longitudinal
channel, the superior sagittal sinus. The superior sagittal sinus is formed first in its anterior portions by the
selection and enlargement of the most favorable vein with a corresponding disappearance of the others, in the
posterior part there is later on coalescence of adjacent veins. As the hemispheres extend backward the sinus
correspondingly elongates. The sagittal plexus very early exhibits a tendency to drain more to one side of the
head than to the other, very often toward the right side. The straight sinus is formed in the ventral part of the
sagittal plexus and its caudal adjustment is essentially like that of the superior sagittal sinus. In the fetal
period the transverse sinus bends backward until it comes to lie at an angle of 90° with the internal jugular
vein. As the sinus becomes more definitely established the tentorial plexus becomes smaller as it undergoes
traction by its changing environment. The confluens sinuum is usually plexiform in character and represents the
last trace of the embryonic tentorial plexus. Fetal torcular thrombosis no doubt relates to the complicated
mode of development of this venous crossing. The complex fusion of primitive vessels in the midline leaves
intraluminal septae, also called Willis’ cords.
Slide 237: transverse sinus patency or thrombosis near temporal lobe
haematoma
Two instances of temporal lobe haematoma in term infants, one with and the other without adjacent
transverse sinus thrombosis. Laceration of veins near the temporal pole and thrombus formation of veins
draining into the transverse sinus are two candidate mechanisms for lobar temporal haematoma n the absence
of haemostatic problems.
Slide 238: SSS and straight sinus thrombosis with extensive collateral
escape and congestion plus necrosis in white matter
Extensive doppler study of a preterm infant with extensive haemorrhagic leukomalacia most likely consequent
to combined superior sagittal and straight sinus thrombosis.
Slide 239: plexus anomalies
Lysyy O, Puzhevsky A, Strauss S (2012) Choroid plexus papilloma in an infant: ultrasound diagnosis. Eur J Pediatr 171, 1717–
1718.
Some diseases of choroid plexus and associated vascular findings.
Slide 240: antenatal diagnosis of vein of Galen malformation confirmed with
first day ultrasound
Characteristic images of Vein of Galen Malformation with turbulent flow in the venous sac, feeding arteries
with high flow velocity and a large but patent straight sinus.
Slide 241: characteristic neonatal doppler findings of rare vascular
anomalies: dural AVM, sinus pericranii and choroidal AVM
Raets M, Dudink J, Raybaud C, Ramenghi L, Lequin M, Govaert P (2015) Brain vein disorders in newborn infants. Dev Med
Child Neurol 57:229-40.
Some typical examples of rare neonatal intracranial vascular anomalies.
Slide 242: cavernoma
Morrison L, Akers A. Cerebral Cavernous Malformation, Familial. [updated 2016 Aug 4]. In: Adam MP, Ardinger HH, Pagon RA,
Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of
Washington, Seattle; 1993–2020. PMID: 20301470.
Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G (1994) The
natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422–32.
Two cavernoma examples in the neonate, one by courtesy of Eva Valverde, La Paz, Madrid. This slow flow
vascular anomaly has no large vessels near it.
Some cavernomas are familial (genetic).
Slide 243: arterial aneurysm
An exceptional example of arterial aneurysm presenting in the late neonatal period, resembling retino-subdural
haematoma due to non-accidental injury.
Slide 244: focal vascular dysplasia with adjacent cortical anomalies
Byrd SE, Abramowicz JS, Kent P, Kimura RE, Elias D, Heydeman PT (2012) Fetal MR imaging of posterior intracranial dural
sinus thrombosis: a report of three cases with variable outcomes Pediatr Radiol 42:536–543.
An example of focal vascular dysplasia with adjacent cortical dysplasia, resembling the published description of
Byrd et al. 2012.
Slide 245: frontal paracingular developmental venous anomaly (DVA)
Typical example of DVA in the cingulate area. Some DVAs present with seizures and altered diffusion weighted
MRI findings (Geraldo et al. 2020).
Developmental venous anomaly.
Cakirer S (2003) De novo formation of a cavernous malformation of the brain in the presence of a developmental venous
anomaly. Clin Radiol 58(3):251-6.
Chang CL, Chiu NC (2010) Developmental venous anomaly found by cranial US in a neonate. Pediatr Radiol 40(3):374.
Geraldo AF, Messina SS, Tortora D, Parodi A, Malova M, Morana G, Gandolfo C, D'Amico A, Herkert E, Govaert P, Ramenghi
LA, Rossi A, Severino M (2020) Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up.
AJNR Am J Neuroradiol 41(12):2370-2376.
Horsch S, Govaert P, Cowan FM, Benders MJ, Groenendaal F, Lequin MH, Saliou G, de Vries LS (2014) Developmental venous
anomaly in the newborn brain. Neuroradiology 56(7):579-88.
Oran I, Kiroglu Y, Yurt A, Ozer FD, Acar F, Dalbasti T (2009) Developmental venous anomaly (DVA) with arterial component: a
rare cause of intracranial haemorrhage. Neuroradiology 51(1):25-32.
Riel-Romero RM, Mattingly M (2005) Developmental venous anomaly in association with neuromigrational anomalies. Pediatr
Neurol 32(1):53-5.
San Millan Ruiz D, Gailloud P (2010) Cerebral developmental venous anomalies. Childs Nerv Syst 26(10):1395-406.
Truwit CL (1992) Venous angioma of the brain: history, significance, and imaging findings. AJR Am J Roentgenol
159(6):1299-307.
A cerebral developmental venous anomaly (DVA) is considered a “variant” of venous drainage, with an
incidence in adult autopsies of 2.6% (Truwit 1992, San Millan Ruiz and Gailloud 2010). Characteristic is an
umbrella-like convergence of multiple venules that merge into a dilated collector vein, which drains either
superficially into a cortical vein or sinus or into the subependymal deep venous system, or in a minority of
cases into both. Until recent little was known about neonatal DVA appearances on MRI and even less about the
findings on cUS/Doppler ultrasound (Horsch et al. 2014). While the ultrasound appearance - dilated slow flow
collector vein surrounded by increased echogenicity - is striking in some cases, it is subtle in others and only
detected retrospectively, once the diagnosis is made with MRI. DVA can be mistaken for (haemorrhagic)
parenchymal infarction when positioned adjacent to the lateral ventricle. The absence of breakdown into a
porencephalic cyst excludes infarction. Doppler ultrasound can help to recognize a DVA by depicting blood flow
in the collector vein, typically localized in the centre of the hyperechogenicity (Chang and Chiu 2010).
“Arterialized” DVAs have somewhat larger than normal arteries within them (San Millan Ruiz and Gailloud 2010,
Oran et al. 2009) and flow in them may be pulsatile. It is uncertain how increased arterial flow into some DVAs
relates to possible haemorrhagic transformation and how DVA relates to cavernous haemangioma (Cakirer
2003). An association with disorders of neuroblast migration has been observed (Riel-Romero and Mattingly
2005). Serial imaging during early infancy has learnt that imaging findings of DVA vary over time. This
challenges the idea that DVAs are a stable variation of venous angioarchitecture.
Recent review of a large cohort by Geraldo et al. 2020.
Slide 246: perfusion indices and vascular reactivity
Some general background ideas about perfusion measurement. Because reliable estimation of vessel diameters
is (not yet) possible with CUS, actual flow volume estimation is not possible. There have been studies that
correlate volume flow with flow velocities, but this limitation is still important to realise. More insight has
recently emerged from NIRS monitoring (El-Dib M, Soul JS (2019) Monitoring and management of brain
hemodynamics and oxygenation. Ch 14 in de Vries LS, Glass HC (Eds) Handbook of clinical neurology vol 62; pp
295-314).
Slide 247: arterial flow velocity indices
Camfferman FA, de Goederen R, Govaert P, Dudink J, van Bel F, Pellicer A, Cools F; eurUS.brain group. Diagnostic and
predictive value of Doppler ultrasound for evaluation of the brain circulation in preterm infants: a systematic review.
Pediatr Res. 2020 Mar;87(Suppl 1):50-58.
Frank van Bel (1996) The use of cerebral blood flow velocity waveform characteristics in neonatology. in Govaert, P., De
Vries, L. (1996) An atlas of neonatal brain sonography. McKeith Press, London en Cambridge University Press, Cambridge, UK
as Clinics in Developmental Medicine, nrs 141/142., ISBN 1 898683 09 3
Arterial flow indices ofen used in literature studies. In general the routine measurement of indices has been
popular for suspecting PDA, but there is no longer a strong clinical drive to measure flow velocities, neither for
PDA, nor for asphyxia and hydrocephalus.
Slide 248: gates on arteries: caliber of the vessel matters
Ecury-Goossen GM, Raets MM, Camfferman FA, Vos RH, van Rosmalen J, Reiss IK, Govaert P, Dudink J. Resistive indices of
cerebral arteries in very preterm infants: values throughout stay in the neonatal intensive care unit and impact of patent
ductus arteriosus. Pediatr Radiol. 2016 Aug;46(9):1291-300.
Observe how gates on arteries of different caliber provide indices with decreasing velocity as the diameter
decreases, but also decreasing RI with smaller size.
Slide 249: significant PDA: clinical relevance only when steal is important
Typical ductal steal repercussion on the indices of the pericallosal artery. Observe that increased pulsatility is
not transmitted to the internal cerebral vein. Pulsatility in the internal cerebral vein is certainly not (always)
due to large ductal steal.
Slide 250: decreasing resistance index in term birth asphxyia: poor
correlation with lesion pattern
Following intrapartum asphyxia, luxury perfusion of onset several hours after the insult, is well documented.
Its prognostic value is limited because prediction with MR imaging is very detailed and because severe injury to
deep grey matter sparing subcortex may not be associated with luxury perfusion as measured in the large
arteries.
Slide 251: luxury perfusion in term birth asphyxia: high velocities in deep
veins and normal arterial RI
Luxury perfusion in term birth apshyxia may be transmitted to the deep venous system, and in this example
velocities in the deep vein were clearly to high whereas RI in the MCA was not low.
Slide 252: near term, NIFHydrops due to chronic anemia: arterial pattern in
deep veins, normalisation after 1 week
An example of striking changes in perfusion following chronic fetal anaemia. This striking early deep venous
pulsatility may be due to retrograde effect of high cardiac pressures along the venous system, but a forward
contribution of chronic hyperactive circulation may also play a rôle. It took several days for this pattern to
normalise, suggesting that chronic perfusion alterations may change the arterial muscular characteristics.
Slide 253: term, heart failure, PPHN and NO, major inotropic use, not on
oscillator, not on ECMO: unexplained rate observation in a deep vein
Very sick term infants are worth scanning more in depth, including doppler characteristics. In this infant on
high doses of inotropes, the ICV had repeatly double heart rate pulsation frequencies around 380 bpm in the
ICV and not in the arteries. This has not been described, but hypothethically this may have been heart beat
resonance in a vein stiffened by inotropes ?
Slide 254-261
Routine of cranial ultrasound:
practical routine: overview
practical routine: quality score and limitations for qood quality scanning
practical routine: a good quality scan takes planning and time
practical routine: probes and sequence
practical routine: probes, symmetry and window
practical routine: sweeps and frames, image quality
progression of image quality in recent decades
image quality difference between probes and presets.
Slide 262-275
Physics of ultrasound and artefacts:
information in the image
ultrasound physics: the wave and impedance
ultrasound physics: scanhead, speckle, scatterers
ultrasound physics: resolution and texture
ultrasound physics: postprocessing and velocities
ultrasound physics: adaptive beam forming
image artifacts
tangential section artifacts
gyral core bruising due to contusion, different from tangential artefacts
optimising scan settings
optimising scan settings: zonal gain (TGC or time gain compensation)
speckle and resolution
sonographic quantification of the optic radiation
(ab)normal cortex to subcortex grey to white matter differentiation
Slide 276: ultrasound energy and doppler: limitations of use
Safety issues of cranial ultrasound.
Slide 277: cranial ultrasound: reference list
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