The bilateral cerebral vesicles that will form the cerebral hemispheres first appear at about 35 days of gestation as outpouchings of the telencephalon from the regions of the foramina of Monro. At the time of these outpouchings, the walls of the vesicles are uniformly thin and are connected in the midline by the lamina terminalis, a midline area derived from the roof plate that has shrunken due to apoptosis. The lamina terminalis does not grow as development proceeds; however, the cerebral vesicles exhibit marked expansion laterally, rostrally, ventrally, and caudally. As the vesicles expand, cellular layers develop within their walls, forming the germinal matrices from which the cells that form the cerebrum will eventually develop. The germinal matrices are initially composed only of a single region of proliferating cells (the ventricular zone
), but as development proceeds, a more peripheral subventricular germinal zone
develops, separated from the ventricular zone by a periventricular fiber-rich zone. These germinal zones are divided based upon their location, the type of neurons generated, and the ultimate destination of the neurons: (a) medial ganglionic eminence (located near the developing third ventricle, GABAergic neurons generated, including cortical interneurons, hippocampal interneurons, and globus pallidus interneurons); (b) lateral ganglionic eminence (located near the developing third ventricle, GABAergic neurons generated, mainly striatal projection neurons and olfactory interneurons, also some thalamic interneurons); (c) preoptic area (located near the
bottom of the developing third ventricle, GABAergic neurons generated, including cells to the preoptic area, amygdala, posterior globus pallidus, and cortex); (d) dorsal neocortical germinal zone (located in walls of developing lateral ventricles, glutamatergic neurons destined for the neocortex) (1
). Neurons migrate from these germinal zones through the developing hemispheres to form the cerebral cortex, initially in an incomplete form that is often called the preplate
. As the neurons migrate, they develop axonal connections with other cortical and subcortical (subplate) neurons. The axons form a prospective zone of white matter that is called the intermediate zone
because it is in the region intermediate between the ventricular zone and the developing cortex. In addition to afferent and efferent axons, the intermediate zone contains migrating neurons and oligodendrocyte progenitor cells (8
). Between the preplate and the intermediate zone is a transient area of loosely packed and loosely organized neurons that form temporary neuronal circuits, particularly with the thalamus (9
); this zone is known as the subplate
. The subplate is largest at the 30th postconceptional week (10
). At that time, it is about four times thicker than the cortex, occupying up to 45% of the telencephalon, and is easily seen on fetal MRI as an area of T1 hypointensity and T2 hyperintensity between the intermediate zone and cortex (10
). It gradually disappears after the 30th gestational week, as definitive cortical connections are established (10
) but remains functional, in part, possibly for as much as the first half of the first postnatal year (10
). Details of the development of the hemispheres are described in more detail in Chapter 5
. For the purposes of the discussion to follow, it is sufficient to understand that the occipital pole begins to develop at about the 43rd gestational day and the temporal pole at approximately the 50th gestational day. During the early weeks of gestation, the surfaces of the cerebral hemispheres are smooth. The fetal sulci appear in an orderly sequence; the phylogenetically older sulci appear first, and the more recently acquired sulci appear later. The principal sulci and gyri form the characteristic pattern of the human cortex that can be identified in the full-term infant (Table 2-1
). The primitive sylvian fissure, the earliest fetal sulcus, is usually present when the fetus is imaged in the fourth gestational month. The next sulci to appear are the calcarine, parieto-occipital, and cingulate sulci during the fifth month (by 20-22 weeks); the Rolandic (central), interparietal, and superior temporal sulci that appear toward the end of the sixth month (by 25 weeks); and the precentral, postcentral, superior frontal, and middle temporal sulci that appear during the seventh gestational month (24-28 weeks) (13
) (Fig. 2-1
and Table 2-1
). In the medial temporal lobe, the hippocampal sulci are variable and often asymmetrical; asymmetry is also often seen in the formation of the collateral sulcus (14
). Because sulcal formation occurs so late in gestation, imaging studies of premature infants show sulci that are shallow and few in number. It is, therefore, important to know the postconceptional age of a child before assessing the sulcal pattern
. Otherwise, a false diagnosis of lissencephaly may be made. In addition, as will be discussed in more detail later in the chapter, sulcation, myelination, and corpus callosum development are often delayed in prematurely born neonates compared to fetuses of the same postconceptual age
van der Knaap et al. (20
) have devised a method by which gyral development can be divided into five stages: (a) before 32 weeks, (b) 33 to 34 weeks, (c) 35 to 37 weeks, (d) 38 to 41 weeks, and (e) beyond 41 weeks. The gyral maturity is determined by measurements of the width of the gyri and depth of the sulci. The stage of gyral development is then assigned based upon the degree of gyral maturity in seven different regions of the brain. Battin et al. (21
) and Ruoss et al. (22
) have also developed systems of assessing sulcal development based on ratios of the width and depth of the sulci and gyri. Gyral development proceeds most rapidly in the area of the sensorimotor and visual pathways. These are also the areas in which myelination occurs earliest ((23
) and following section), in which glucose uptake increases earliest (24
), in which relative cerebral perfusion increases earliest (25
), in which cortical microstructure matures most rapidly (26
), and in which brain chemistry matures most rapidly (27
). Gyral development takes place most slowly in the frontobasal, frontopolar, and anterior temporal regions, which are also the slowest regions to myelinate and to mature metabolically (24
). It is important to evaluate the sulcal pattern of neonates and infants, as abnormal sulcation predicts abnormal functional development (28
Table 2-1 Chronology of Sulcation of the Brain (15,16,17,18,19)
Age of Sulcation
Secondary cingulate sulci
Secondary occipital sulci
Superior frontal sulcus
Inferior frontal sulcus
Superior temporal sulcus (posterior part)
Superior temporal sulcus (anterior part)
Inferior temporal sulcus
In general, the earlier numbers are from pathology studies and the later ones from radiology studies. Imaging numbers (later numbers) indicate when the sulcus is seen in more than 75% of studies.
Imaging of the Preterm Brain (Premature Infant and Fetus)
As mentioned earlier, the imaging modality being used determines which features of brain development can be evaluated. If the anterior fontanelle is large enough, ultrasound shows development of the gyri and sulci nearly as well as CT and MR but does not give information
about brain myelination. CT allows fairly good information about sulcal development but gives a poor assessment of myelin development and it exposes the baby to ionizing radiation; it is not recommended for brain imaging in the fetus, neonate, or infant unless other methods are unavailable
. MR allows excellent assessment of myelination, sulcation, and chemical maturation and is the imaging technique of choice for evaluation of normal development in the neonate and infant.
Figure 2-1 Schematic demonstrating normal development of the fetal brain. During the early weeks of gestation, the cerebral hemispheres are smooth. The earliest fetal sulcus is the sylvian fissure, which first appears during the fifth gestational month. By about 27 weeks, the Rolandic, interparietal, and superior temporal sulci have appeared. Secondary and tertiary sulci develop during the last 2 months of gestation. Because of the different appearance of the brain in premature infants as compared with term infants, it is important to know the gestational age of a child at the time of delivery before assessing the structure of the brain.
Figure 2-2 MR images of a fetus at 16 postconceptional weeks. A. Sagittal SSFSE image shows the small size of the cerebellar vermis (large black arrow) and the corpus callosum (small black arrow) at this age compared with the quadrigeminal plate (large white arrow). B. Axial SSFSE image shows the relatively small size of the cerebellum (white arrows) at this age compared with the pons (black arrow).
Fetal MR imaging has been successfully utilized in a large number of centers for the past two decades (12
). Studies have shown that the cerebral cortex and deep gray structures are relatively large before 20 weeks (Fig. 2-2
) but that the cerebellum and cerebral white matter grow disproportionately during the last 20 weeks (36
). Improvements in coil technology (particularly the use of multiarray-phased array coils), improved pulse sequences, and development of higher-field strength MRIs have allowed progressive improvement in the quality of the images. Studies (19
) indicate that brain development follows a similar progression of sulcation in fetuses as in prematurely born infants; sulci are increasingly identified with increasing postconceptional age. However, it appears that sulcal development occurs earlier in utero than ex utero. In other words, sulci are seen slightly earlier in fetuses still in the uterus than in neonates of similar postconceptional ages that have been born prematurely
). This may result from the fact that the subarachnoid spaces are considerably bigger in fetuses than in newborns of the same postconceptual age (40
), allowing the sulci to be more easily seen. The reasons for this are not yet clear, nor are the precise differences in timing. Studies also show that the cerebrum and its components grow largely proportionally. For example, the volume of cortical gray matter, basal ganglia volumes, and ventricular volume parallel that of supratentorial volume, while supratentorial white matter volume grows more rapidly than overall supratentorial volume (41
Prior to 20 weeks
of gestation, the cerebral mantle is quite thin and the ventricles are relatively large (Fig. 2-2
). Supratentorially, the T2 hypointensity of the germinal matrices lining the walls of the lateral ventricles is thicker than that of the cortex at 16 weeks (Fig. 2-2D
); it is roughly equivalent in thickness to the cerebral white matter layer. The germinal matrix is thickest at the region of the caudate heads and should not be mistaken for a germinal matrix hemorrhage at this location. The more central ventricular zone and adjacent subventricular zone cannot be distinguished by in vivo imaging. Between the germinal zones and the cortex, MR also shows a layer of intermediate signal intensity, separated from the more peripheral cerebral cortex and more
central germinal matrix (Fig. 2-2C-E
). Although previously believed to represent migrating glial cells, this layer has recently been identified as the intermediate zone
or the developing fetal white matter (11
). Projection and commissural axons are present, as are some late migrating neurons and many migrating astrocyte and oligodendrocyte precursors (42
). Immediately peripheral to the intermediate zone and deep to the cerebral cortex is a region of T1 hypointensity/T2 hyperintensity (Fig. 2-2F
), known as the subplate
, a region composed of loosely spaced neurons where thalamocortical afferent axons, basal forebrain cholinergic afferent axons, and callosal and ipsilateral corticocortical axons accumulate for a variable period before entering the cortical plate to establish definitive thalamocortical and corticocortical synapses (10
). These zones are most prominent in younger fetuses (<20 gestational weeks). Before 20 weeks, the sylvian fissures are
extremely shallow and no operculization can be identified. The basal ganglia can be identified and are intermediate in signal between the darker cortex and germinal zone and the lighter white matter (Fig. 2-2D
). The cerebellum remains quite small at this age, barely bigger than the pons on axial images and smaller than the mesencephalic tectum on the midline sagittal image (Fig. 2-2A and B
Figure 2-2 (Continued) C. Axial image at the level of the diencephalon shows a very small fourth ventricle (black arrow) between developing thalami and developing temporal horns. D-F. Axial images at the level of the basal ganglia (D) and above show the large hypointense germinal zones of the ganglionic eminences (black arrows in D) and in the walls of the frontal horns and trigones at all levels. Note the thin layer of hyperintense white matter (the white w in F) at this age between the hypointense germinal zones and cortex.
Figure 2-3 Fetal MR at 20 postconceptional weeks. A-D. Axial images show that the germinal zones (low-intensity rims around the ventricles, small black arrows) and lateral ventricles (V) are rather large at this age. The intermediate zones (large white arrows) are best seen at higher levels (C and D). E. Coronal image nicely shows the germinal zone (very low intensity, small white arrows), intermediate zone (intermediate intensity, large white arrow), subplate (higher intensity, large black arrow), and cerebral cortex (similar low intensity to germinal zone, small black arrows).
Fetal MR at 23 postconceptional weeks. A.
Sagittal SSFSE image shows a thin corpus callosum (black arrows
) and an enlarging cerebellar vermis (compare with Fig. 2-2A
At 20 (Fig. 2-3) to 24 (Fig. 2-4) weeks
of gestation, the cerebrum has grown considerably (especially the white matter; Fig. 2-3B-D
), but it remains essentially agyric with the exception of the wide, vertically oriented sylvian fissures. The size of the brain is very small and the cerebral cortex is extremely thin, so thin imaging sections (≤3 mm) must be used for optimal evaluation. MR images show the cortex to be very hyperintense with respect to the underlying white matter on T1-weighted images and very hypointense compared to white matter on T2-weighted images (Figs. 2-3
). The germinal matrix has not yet involuted and can still be seen as a stripe in the walls of the lateral ventricles that is isointense to the gray matter of the cortex on T1- and T2-weighted images (Fig. 2-2
) and very hypointense on echo-planar T2 imaging; it is, however, thinner than in younger fetuses (18-20 weeks) and becomes thinner and discontinuous with further maturation (Fig. 2-4
). At this age (23-24 weeks), the germinal matrices remain large and conspicuous as areas of relative
hyperintensity between the cerebral cortex and the white matter on T2-weighted imaging studies (12
), but they seem to begin to disappear rapidly after 25 weeks. The lateral ventricles and the cisterns around the brain stem and cerebellum are visible and more prominent at this age than in the mature infant; they are relatively smaller at 23 to 24 weeks (Fig. 2-4
) than at 18 to 20 weeks (Fig. 2-3
). When imaging at 3T, the third and fourth ventricles are easily visualized at this age unless a lot of motion artifact is present; if difficulty is encountered, waiting a few minutes for the fetus to calm down usually results in good images. The globi pallidi typically appear hyperintense on T1-weighted images starting at about 20 weeks. This likely represents premyelination changes, such as the appearance of proteolipid protein in oligodendrocyte processes (47
Axial T2 FSE images through the cerebrum. Note the complete absence of myelination in the white matter at this age and the smaller germinal zones compared with the 20-week fetus illustrated in Figure 2-3
. Note also that the subplate and intermediate zones, although still visible, are less conspicuous at this age than at 20 weeks.
Between 24 and 30 weeks
, the cerebral cortex shows development of shallow Rolandic (central), calcarine, pericallosal/callosomarginal, interparietal, and superior temporal sulci (Figs. 2-5
); in some patients, the precentral, postcentral, superior frontal, and middle temporal sulci may be visualized. The subplate is still seen in the subcortical white matter as a layer of T1 hypointensity/T2 hyperintensity; it becomes difficult to see on imaging in the posterior frontal and
parietal lobes at about 28 weeks but remains visible in less mature areas such as the anterior frontal and temporal lobes for some time thereafter (12
). Myelination is seen in some brain stem structures during this period, including the median longitudinal fasciculus (MLF; bright at 25 weeks on T1-weighted images, dark at 29 weeks on T2-weighted images), the lateral lemnisci (bright at 26 weeks on T1-weighted images, dark at 28 weeks on T2-weighted images), the medial lemnisci (bright at 27 weeks on T1-weighted images, dark at 30 weeks on T2-weighted images), and the superior and inferior cerebellar peduncles (bright at 28 weeks on T1-weighted images, dark at 29 weeks on T2-weighted images) (48
). The basal ganglia and thalami are better seen at this age on MR imaging and have intensity similar to the cerebral cortex on both T1-and T2-weighted images, although not as hyperintense on T1-weighted images or as hypointense on T2-weighted images (Fig. 2-5I-L
). The ventrolateral nucleus of the thalamus becomes hypointense compared with the remainder of the thalamus on T2-weighted images by about 25 weeks and hyperintense on T1-weighted images by 27 to 28 weeks, mostly due to its high cellularity and, possibly, to early myelination. The lateral ventricles, particularly the trigones and occipital horns, are less prominent at this age than at 22 to 23 weeks, probably secondary to both growth of the cerebral white matter and development of the calcarine sulci.
Figure 2-5 MR of 28-week fetus (A-D) and of 28-week postconceptional age prematurely born neonate (E-H). A-D are FSE, E-H are SE T1 MR images, and I-L are SE T2 images. Note that sulcation is more advanced in the fetus than in the prematurely born neonate of a similar gestational age. By this age, gyri and sulci other than the sylvian fissure become detectable. The development of shallow Rolandic (central), calcarine, pericallosal/callosomarginal, interparietal, and superior temporal sulci can be visualized. In addition, the germinal matrix is less prominent. The basal ganglia and thalami are better seen at this age and have intensity similar to the cerebral cortex on both T1- and T2-weighted images, although not as hyperintense on T1-weighted images or as hypointense on T2-weighted images. The lateral ventricles, particularly the trigones and occipital horns, are less prominent at this age than at 22 to 23 weeks, probably secondary to both growth of the cerebral white matter and development of the calcarine sulci.
Figure 2-5 (Continued)
Figure 2-6 MR of normal 31-week fetus (images A-D) and a 31-week postconceptional age premature infant (images E-H are T1 weighted and I-L are T2 weighted). Note that there is not much difference in brain development between the postnatal and prenatal images. More sulci have developed by this age, although they are still rather shallow. The myelinated dorsal brain stem is contrasted by the unmyelinated ventral pons (E and I) and the thalami and globi pallidi are contrasted by the completely unmyelinated internal capsule (F, G, J, and K). The germinal matrix has involuted considerably, but some gray matter signal remains present along the lateral walls of the lateral ventricles, most prominently seen at the tips of the frontal horns (arrows in C, G, and K); this can persist until the end of the 44th gestational week. The cisterns in the occipital region remain prominent (C, G, and H). The signal intensity of the entire cerebral cortex is uniform at this age on both T1- and T2-weighted images. Foci of gray matter intensity are seen just anterior to the tips of the frontal horns of the lateral ventricles (arrows in C), representing foci of residual germinal matrix. Hyperintensity on T1-weighted images and hypointensity on T2-weighted images is present in the dorsal brain stem, superior and inferior cerebellar peduncles, far lateral putamen, and ventrolateral thalamic nucleus. The cerebral white matter still appears completely unmyelinated.
Figure 2-6 (Continued)
By 31 to 32 weeks
, an increased number of gyri and shallow sulci become visible in the cerebral cortex of prematurely born neonates (Fig. 2-6
). The sylvian fissures retain their immature appearance, although some development of the opercula can be detected. The cisterns around the brain stem and cerebellum remain large at this age, and the cerebrospinal fluid (CSF) spaces in the occipital region and in the interhemispheric fissure remain prominent, although the interhemispheric fissure is more variable in size. The cavum septi pellucidi and cavum vergae are prominent and will remain so throughout the first 40 postconceptual weeks (29
). The dorsal brain stem (relatively hyperintense on T1-weighted images and hypointense on T2-weighted images) is contrasted by the unmyelinated ventral pons (Fig. 2-6E and I
). The thalami and globi pallidi are contrasted by the unmyelinated (relatively hypointense on T1-weighted images and hyperintense on T2-weighted images) internal capsule (Fig. 2-6F and J
). The signal intensity of the entire cerebral cortex is uniform at this age on both T1- and T2-weighted images. The subplate is poorly seen on T1-weighted images and is best identified in the anterior temporal lobes on T2-weighted images. The germinal matrix has involuted to a large degree. However, some curvilinear T2 hypointensity is seen extending along the lateral walls of the frontal horns of the lateral ventricles to the medial tip of the frontal lobes and into the olfactory sulci at this age (Fig. 2-6G and K
); previously thought to be regions of residual germinal matrix (49
), these areas turn out to be migrating GABAergic neurons that are present until about 6 postnatal months (50
). The dorsal brain stem and superior and inferior cerebellar peduncles remain bright on T1-weighted images, but the middle cerebellar peduncles remain unmyelinated, isointense to the cerebral white matter. T2-weighted MR shows hypointensity in the dorsal brain stem (predominantly due to the MLF, medial and lateral lemnisci), superior and inferior cerebellar peduncles, nuclei of the inferior colliculi, far lateral putamen, and ventrolateral thalamic nucleus (51
) (Fig. 2-6
). The white matter of the centrum semiovale still appears completely unmyelinated.
Figure 2-7 Normal 34/35 week premature infant. Images A-F are T1 MR images, and G-L are T2 MR images. More sulci are forming, as can be seen along the interhemispheric fissure and over the convexities. Sulcal development varies considerably at this age. The sylvian fissures have markedly diminished in prominence due to opercular development. Notice that the dorsal brain stem and globi pallidi have increased in signal intensity on the axial T1-weighted MR (A-F). The posterior limb of the internal capsule remains completely unmyelinated at this age. On T2-weighted images, the brain stem nuclei, the periphery of the cerebellar dentate nuclei, and the cerebellar vermis are relatively hypointense structures in the posterior fossa (G and H). The subthalamic nuclei (arrows in I) have become hypointense.
At 34 to 36 weeks
, the cerebral cortex has further thickened and more sulci have developed. Little change occurs in the signal intensity of the white matter between 32 and 36 postconceptional weeks (51
). On T1-weighted MR, the posterior limb of the internal capsule remains hypointense as compared to the lentiform nucleus (Fig. 2-7C and D
); some patients will show a small dot of hyperintensity in the posterior aspect of the posterior limb at 39 weeks (48
). On T2-weighted images, the posterior limb of the internal capsule remains entirely hyperintense compared with surrounding structures (Fig. 2-7J
). The sylvian fissures and, to a lesser extent, the CSF spaces in the posterior parietal area remain prominent (Fig. 2-7C-E
, J, and K). Considerable variation in brain maturity can be seen at this age, some infants having a gyral pattern that resembles a term infant and others still appearing quite immature (29
Figure 2-7 (Continued)
By 38 to 40 weeks
, the brain has a nearly normal adult sulcal pattern (Fig. 2-8
); the sulci are largely formed but are not as deep as they will become in the next several weeks. On T1-weighted MR studies, the dorsal brain stem, posterior portion of the posterior limb of the internal capsule, and the central portion of the corona radiata (the corticospinal tracts) are hyperintense compared to the rest of the brain. On T2-weighted images, the dorsal brain stem is hypointense and, at 39 to 40 weeks, a characteristic spot of hypointensity is present in the posterior limb of the internal capsule, lateral to the hypointense lateral thalamic nuclei. There are few differences between the CT images of a newborn term infant and those of older infants. The frontal white matter and parieto-occipital white matter remain relatively low in attenuation compared to the gray matter (Fig. 2-8A-E
). This probably results from the known high water content of the newborn brain, related to the lack of myelination. The MR appearance of the newborn brain, on the other hand, is considerably different from that in older children, as discussed in the following section. The sylvian fissures may remain prominent in the immediate newborn period; the occipital CSF spaces may also remain somewhat large for several months. The cavum vergae and cavum septi pellucidi are usually present at birth; they disappear rapidly in the first few months after birth as the septal leaves fuse from back to front.
The cisterna magna and basilar cisterns are relatively large throughout infancy, as the cerebellum continues to grow considerably (compared to the cerebrum) during the first postnatal year. This enlargement is quite apparent on MR scans but less so on CT where only the axial plane is available and beam hardening artifact frequently obscures details in the basilar cistern area.
Figure 2-8 CT/MR of normal 38- to 40-week infant. A-E. With the exception of increased lucency of the frontal and temporoparietooccipital white matter, the CT scan of this infant resembles any normal infant during the first year of life. The sulcal pattern is nearly mature. A cavum septi pellucidi is frequently prominent at this age.