Chapter Contents

• Introduction
• Cortical folding
• Ventricular system and extracerebral space
• Germinal matrix
• White matter
• Myelination
• Basal ganglia and thalami
• The future
• Summary
• References

Introduction

Brain maturation involves a complex sequence of morphological, functional and organizational changes. Although these changes are complex they occur in a sequence that is both organized and predictable. Pathological studies have been important in documenting the process of brain maturation but imaging offers the added advantage of being able to study the live fetus or infant. Furthermore, repeated or serial imaging may be performed, thus permitting longitudinal assessment of maturity both in utero and ex utero.

Ultrasound is readily available in the neonatal nursery and has been used extensively to assess the preterm infant brain; however, recently interest in using MRI in this age group has increased. Magnetic resonance imaging (MRI) is a non-invasive multiplanar technique that provides detailed images. Qualitative and quantitative assessment of brain development including myelination can be performed and pathological processes including migration disorders and neonatal intracranial hemorrhage are well demonstrated. Sequential imaging provides the means to study not only normal development but also the response of the brain to injury.

Although MRI is a useful technique in the preterm infant, differences exist from adult imaging and these must be addressed in order to obtain optimal images. The immature brain has higher water content than the adult brain and this is associated with a marked increase in T1 and T2 values. Appropriate changes in the pulse sequences are required in order to produce optimum images. In our experience it has been possible to produce good-quality images using the same sequence parameters between 23weeks and term, although measurements of T2 values have been shown to gradually decrease over this period9 (Fig. 3.1). T1 and T2 shortening occurs more dramatically from term age over the first year of life in association with myelination¹⁹.

The aim of this chapter is to describe the MRI appearances of the brain in preterm infants imaged between 24 weeks’ gestational age (GA) and term (37–42 weeks). MR study of the developing brain is important, not only to illustrate the normal changes that occur but also because it may shed light on the origin of brain lesions causing long-term neurodevelopmental sequelae in the preterm infant. Evaluation of the developing brain using MRI is likely to be of value in the interpretation of isolated images taken later in infancy. MRI has also been shown to produce valuable postmortem data and it is feasible to image the neonatal brain both in and outside of the body after death.

In order to establish the normal variation in a preterm population we have attempted to image every infant born at less than 30 weeks’ gestation at the Hammersmith Hospital. The majority of images presented in this chapter were obtained from this cohort of over 150 preterm infants. Images were obtained using a 1T (Oxford Magnet Technology/Marconi Medical Systems) neonatal MRI system14 situated in the neonatal unit (see Chapter 2). The GA for the infants was calculated from the date of the last menstrual period and confirmed with data from early antenatal ultrasound scans. Parental consent for imaging the infants was obtained in each case and ethical approval for this study was given by the Hammersmith Hospitals Research Ethics Committee.

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Cortical folding

The most obvious changes in the preterm brain between 24 weeks and term are the increase in overall size and the increase in cortical folding. Cortical development occurs from approximately 8 weeks, initially with replication of neurons and glial cells in the periventricular germinal zones. In the mammalian brain the germinal zone consists of a ventricular zone, which forms first, and a more superficial subventricular zone. The former produces mainly neuronal cells and the latter is responsible for mainly glial cell proliferation4 (see Fig. 3.14). Although these layers may be distinguishable histologically, they are indistinguishable on MRI. The ventricular zone is largely exhausted by the end of neuronal migration and residual ventricular zone cells become ependymal cells. The subventricular zone remains and persists into adult life as the subependymal layer. The term germinal matrix is usually used to describe the residual subependymal tissue in the caudothalamic notch, which is easily visible with cranial ultrasound. Using MR images it is possible to see that there is a densely cellular layer, the subependymal layer, lining the entire ventricle although it is most obvious overlying the caudate nucleus. It is not possible to differentiate the ependymal layer on MR images as this is only one cell thick.

The layers of the developing cortex are formed initially by neuronal migration along radial glia. Radial glia not only guide neurons but appear to facilitate the columnar organization of the cortex. The first wave of immature neurons to migrate form the preplate of the developing cortex, which is then split into an inner and outer layer by neurons arriving to form the cortical plate. The inner layer of the preplate is known as the subplate and plays an important role in cortical organization. The outer layer is the subpial marginal zone.

The permanent cortical layers form from the inside out, so that layer six which lies medially is laid down first. The mature cortex consists of six distinct layers in most areas of the brain. Neuronal migration to the cerebral cortex is completed by 20–24 weeks’ gestation in the human brain. Glial cell migration probably continues for at least 1 year post birth. Between 29 weeks’ gestation and term cortical gray matter volume increases from approximately 60ml to approximately 160ml¹⁷. This subsequent increase in cortical gray matter volume is secondary to glial cell migration, neuronal differentiation and organizational changes. Following migration, radial glia proliferate and differentiate into astrocytes and possibly oligodendrocytes within the white matter.

During early gestation the brain is smooth or ‘lissencephalic’ in appearance but as growth proceeds the typical convoluted pattern develops allowing a considerable increase in the surface area of the brain. Normal convolution probably relies on a full complement of neurons within the developing cortical plate. Primary sulci begin as a shallow groove with widely separated side walls and straight ends. The groove then becomes deeper and the side walls become progressively steeper approximating and eventually meeting each other. These secondary sulci may show V-shaped or bifid ends. With continued maturation, the gyri and sulci become complex and side branches develop as seen in the adult brain. Each of the gyri and matching sulci are named according to their site within the brain.

The anatomical development of the major sulci and gyri in the brain has been well documented by Chi et al.⁵ who studied 507 brains obtained from fetuses and infants from 10 to 44 weeks’ gestational age. The gyral development evolves in an ordered fashion up until term.

In pathological series, the first fissure to develop is the interhemispheric fissure, which appears at 8 weeks’ gestation. It starts anteriorly and proceeds posteriorly separating the two cerebral hemispheres by 10 weeks’ gestation. At 14 weeks the Sylvian fissure begins as a shallow depression formed by the progressive indentation of the cortex in the region of the insula. By 19 weeks the Sylvian fissure is deeper and the insula can be identified. At 20 weeks the central sulcus is first seen. The parieto-occipital fissure, which divides the parietal from the occipital lobe, is first seen at 16 weeks and is documented on antenatal ultrasound in all infants by 24 weeks’ gestation. The calcarine sulcus appears at about 16 weeks and joins the parieto-occipital fissure anteriorly. Together they form a Y shape that is easily visible on parasagittal ultrasound scan. The calcarine sulcus is seen on ultrasound in the majority of infants by 24–25 weeks and in all infants by 26–27 weeks. The cingulate sulcus is present in the anterior frontal lobe by 18 weeks’ gestation on ultrasound but may lag behind as in 25% of infants it is not visible until 24–25 weeks. The callosal sulcus separates the cingulate gyrus from the corpus callosum and appears at 14 weeks’ gestation but is not a constant finding on ultrasound until 24 weeks’ gestation. The process of cortical folding is also recognizable on postnatal ultrasound^{15, 27, 30}and may be used as a guide to GA. Murphy et al.²⁴ used ultrasound to study the development of sulci on the lateral and medial surfaces of the brain in preterm infants between 24 weeks and 34 weeks.

Using MRI Martin et al.²² described a four-stage grading system for the structural maturation of the brain surface. In stage 1 there is lissencephaly; in stage 2 the primary gyri are well identified and separated by shallow sulci; in stage 3 the infolding of the brain surface is more pronounced; and in stage 4 the adult pattern with well-developed tertiary gyri and sulci is seen. This system, however, is not detailed enough to be used for assessment of sulcation in a population of premature or extremely premature infants. Systematic study of sulcal and gyral development using MRI has been reported in infants from 30 weeks onwards by Van der Knapp et al.29 and subsequently in infants as immature as 25 weeks’ gestation³. The gyral development score is a scoring system used to describe cortical folding. A score of 1–5 is given for different areas of the brain depending on the depth, width, the relationship to adjacent sulci, and the complexity of sulcation and gyration. Using this scoring system an increase in cortical folding can be seen in each area which correlates well with increasing age (Fig. 3.2).

MRI can be performed as early as 23 weeks’ gestation and at this stage a rim of cortex is demonstrated as high signal intensity compared to the underlying white matter on T1 and low signal intensity on T2 weighted images. In our cohort of infants there was some variation in cortical maturity in infants born at the same gestation (Fig. 3.3 and Fig. 3.4). Delays in cortical folding may have important neurodevelopmental consequences or may just reflect normal individual variation.

Visual analysis of cortical folding is sufficient for identifying major abnormalities or discrepancies in maturation (Fig. 3.11). Occasionally, the evolution of abnormal folding can be detected with serial imaging in the very preterm infant (Fig. 3.12). Visual analysis of images of term-equivalent preterm infants is not sufficient to detect a milder delay or abnormality in cortical folding (Fig. 3.10).

COMPUTERIZED QUANTIFICATION OF CORTICAL FOLDING

In order to study cortical development in more detail we have developed a computerized method for quantifying cortical folding²⁵. We use T2 weighted fast spin echo images as these give optimum contrast between the cortex and underlying white matter. The process involves drawing a cortical contour as a template for each slice of the brain. The program then measures the length and curvature of this cortical contour. A curvature code is produced. The program also allows a measure of cortical density to be obtained and the product of this and the curvature code gives a cortical convolution index. Using this program we have shown an exponential increase in the whole cortical convolution index (measuring all slices through the brain but excluding the cerebellum) from 24 weeks until term (Fig. 3.13).

It has been suggested that gyral development proceeds in a programmed fashion and that there is little effect of illness on this pattern²³. However, this has been questioned by Hüppi¹⁶. At term-equivalent age, preterm infants show less cortical folding than infants born at term (Fig. 3.13) ^{1 2 5} . This is not explained by a smaller brain size as the brain volumes between the two groups are not significantly different (Fig. 3.13). These findings imply that the brain of the preterm infant is developing in a different way ex utero. The differences in cortical development compared with those infants born at term may be associated with the increase in neurocognitive and neurobehavioral disorders seen in ex-preterm children^{7, 28}.

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Ventricular system and extracerebral space

Very preterm infants <26 weeks’ gestation may have a transient mild dilation of the posterior horns of the lateral ventricles, a developmental colpocephaly (Fig. 3.16). The ventricles are smooth in outline but may show some asymmetry. In most cases the left ventricle is larger than the right. The reason for this asymmetry is unclear but has also been noted on fetal MRI12 and on ultrasound. On repeat scan at term-equivalent age the asymmetry may persist or no longer be apparent. In the very preterm infant there is a marked widening of the posterior parietal extracerebral space (Figs 3.5 – Fig. 3.8). This may persist until approximately 36 weeks; it is minimally widened in Fig. 3.9 at 34 weeks, but is only occasionally seen at term-equivalent age. The space has been termed benign external hydrocephalus13 but probably represents a normal development process. This posterior widening gradually disappears and is not usually apparent at term-equivalent age.

At term-equivalent age there may be an increase in the anterior extracerebral space with widening of the anterior interhemispheric fissure (Fig. 3.26) ²⁰. This is often attributed to atrophy of the brain but it may not be secondary to a reduction in brain size (Fig. 3.13) and tends not to persist beyond 1 year of age.

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Germinal matrix

The germinal matrix or subependymal layer is situated at the surface of the lateral ventricles. It consists of a loose stroma and is highly vascularized with irregular endothelial lined vessels. From 10 to 20 weeks’ gestation it is responsible for neuroblast and glioblast production and thereafter glioblast production alone, from the subventricular zone. The matrix includes the transient ventricular zone and the subventricular zone and increases in volume from 13 weeks’ gestation to a maximum at about 26 weeks’ gestation. It then regresses although it persists for longer in the caudothalamic notch and in the roof of the temporal horn. On cranial ultrasound the term ‘germinal matrix’ is usually applied to the tissue seen in the caudothalamic notch. On MRI the germinal matrix may be visualized as a prominent structure at the lateral margin of the lateral ventricles, overlying the caudate (Fig. 3.14) and at the roof of the temporal horns of the lateral ventricles. The subependymal layer also appears to extend as a much thinner layer all around the ventricles. It is characterized by a high signal intensity on T1 weighted images and more obviously as a low signal intensity on T2 weighted images (Fig. 3.14)²⁰.

The germinal matrix can be identified by virtue of its shape and location adjacent to the lateral ventricles as well as its signal characteristics. This appearance of high signal on T1 weighted and low signal on T2 weighted images in the germinal matrix is also described on fetal imaging12 and persists until between 30 and 32 weeks’ gestation, continuing for longer on the T2 weighted images (Fig. 3.15).

Germinal matrix is easier to identify on MRI than on ultrasound. Using MRI it is possible to identify thicker rests of germinal tissue, over the caudate heads and at the roof of the temporal horn of the lateral ventricles. It is also possible to detect the thinner cellular layer that lines the entire ventricular system. On ultrasound the germinal matrix is only really identified over the caudate heads. This is partly because cranial ultrasound is not routinely used in the transverse plane and therefore matrix in the temporal horns cannot be detected. In addition, the subependymal layer elsewhere around the ventricles may to be too thin for detection by ultrasound.

Germinal matrix hemorrhage has similar characteristics to germinal matrix with a short T1 and T2 but is distinguished from normal matrix by its irregular shape, asymmetry and persistence of susceptibility effect (Fig. 3.16) (see Chapter 9). Preterm infants may show small lesions consistent with hemorrhage within the subependymal layer with or without evidence of hemorrhage in more classical sites of matrix over the caudate nuclei (Fig. 3.17). In addition, infants with multiple hemorrhagic lesions may appear to have white matter lesions but in fact the lesions are in the subependymal layer and partial volume effects give the appearance of white matter lesions, particularly superiorly (Fig. 3.17).

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White matter

The high water content of the premature infant brain produces relatively long T1 and T2 times and gives rise to a low signal on T1 weighted images in the white matter. As previously mentioned, provisional data suggest that these values gradually decrease between 24 weeks and term. Term-born infants demonstrate a steady decrease in the brain water content throughout the first 2 years of life.

Within the white matter of the centrum semiovale (CSO) and periventricular area, several well-defined layers of alternating signal intensity are observed in the brain of preterm infants. At 24 and 25 weeks’ gestation four layers can be identified in the CSO. These represent the cortex, subcortical white matter, an intermediate zone representing migrating cells and a periventricular zone representing developing white matter. This periventricular zone lies adjacent to the subependymal layer or germinal matrix (Fig. 3.18).

At a low ventricular level the bands are incomplete but areas are observed around the anterior horns of the lateral ventricles that form the shape of a ‘cap’ (Figs. 3.19 and 3.23) and around the posterior horns of the lateral ventricles forming the shape of an ‘arrowhead’. These ‘caps’ and ‘arrowheads’ are in continuity with the multilayered periventricular appearance described above. Caps have an additional area of low signal intensity on T2 weighted images (high signal intensity on T1 weighted images) (Figs. 3.19 and 3.23).

Arrowheads differ from the caps by their posterior site and characteristic shape. They also do not have alternating layers of long and short T2 within them. Infants born at ≤27 weeks’ gestation may not demonstrate high signal intensity within bands, caps and arrowheads when first imaged but this develops on follow-up imaging with increasing GA20. Histologically, these sites correspond to regions with dense white matter fibers converging from different regions of the brain.

In posterior white matter it is possible to see the developing optic radiation with a cellular layer either side (Fig. 3.19). In summary, layers of high and low signal intensity are found within the unmyelinated white matter of the CSO and periventricular regions. These may be described as ‘bands’ in the CSO and periventricular white matter, ‘caps’ around the anterior horns of the lateral ventricles and ‘arrowheads’ around the posterior horns of the lateral ventricles.

The MRI appearances described are thought to be part of the normal developmental features of the white matter since, as we have seen them on first MRI in over 95% of infants born at less than 30 weeks’ gestation respectively³. The periventricular bands were also demonstrated in another imaging study of preterm infants⁶. In Maalouf et al’s study loss of bands, caps or arrowheads was associated with cerebral pathology such as large hemorrhagic infarction and posthemorrhagic hydrocephalus²⁰. The bands, caps and arrowhead appearances do become less obvious with increasing GA. Child et al.⁶ have described multiple bands consistent with ‘waves’ of migrating cells in the white matter. Whilst we see distinct layers of altering signal intensity within the cerebral hemispheres we have not identified multiple bands of short T1, short T2 consistent with different bands or waves of cells with MRI or on histology. This may be due to inadequate image definition but it is possible that the effect of multiple bands of cells may sometimes be produced by either motion artifact and or partial volume effects.

We have noted that in some infants approaching term the white matter demonstrates a long T1, long T2 component, the so-called diffuse excessive high signal intensity (DEHSI) on T2 weighted images20 (Fig. 3.24). This is probably normal if restricted to the arrowheads and caps but in some infants is more diffuse and extends beyond these areas towards the subcortical white matter. Preliminary studies have shown that DEHSI is associated with the development of abnormal long T2, consistent with glial tissue, in the periventricular white matter at 2 years of age (Fig. 3.25). These later changes could be described as a mild form of periventricular leukomalacia but whilst they may be associated with ventricular dilation the ventricular outline is usually normal. The corpus callosum may be thin. These periventricular and corpus callosal changes are a common finding when ex-preterm children and adolescents are imaged7 but the exact relationship to later neurodevelopmental and neurocognitive deficits remains unclear. It is possible that these relatively focal changes are the visible side of a process that may have effected a much larger amount of developing brain, so-called perinatal teloleukoencephalopathy²¹.

In some ex-preterm infants there is ventricular dilation and widening of the extracerebral space at term, findings that suggest cerebral atrophy²⁰. However, these findings may not be apparent at later follow-up imaging although children born preterm have smaller heads than term-born controls⁷. Serial measurements of brain and ventricular volume may help clarify this relationship, although in our initial studies there is no difference between the brain volume of ex-preterm infants at term-equivalent age and term-born controls (Fig. 3.13).

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Myelination

Myelination of white matter enables the more effective transmission of neural impulses. It can be demonstrated histologically to occur in a systematic fashion beginning with the medial longitudinal fasciculus at the end of the first trimester. It is, however, predominantly a post-term process and continues at least until the end of the second year. On MRI, myelination is associated with a shortening of T1 and T2 and is seen as high signal intensity on T1 weighted sequences and low signal intensity on T2 weighted sequences. In term-born infants, early changes of myelination are best seen on T1 weighted images, particularly on inversion recovery images, in the first 6 months of life and thereafter on T2 weighted images²⁶. However, in our experience of imaging preterm infants, evidence of myelination is observed more easily on fast T2 weighted spin echo rather than on T1 weighted scans perhaps due to the better contrast achieved with this sequence. Myelination appears in the inferior cerebellar peduncles as early as 25 weeks and is followed by the inferior colliculi, posterior brain stem and ventro-lateral nuclei of thalamus. In our cohort we have demonstrated myelin in all these areas in infants using a fast spin echo T2 weighted sequence on first scan (Fig. 3.27).

Between 28 and 35 weeks we have found no evidence for new myelination on MRI^{8, 17}. Chi et al.⁵ also report that there is relatively little new myelination between 29 and 40 weeks’ gestation and this is also our experience⁸. Using MRI myelination becomes evident in the posterior limb of internal capsule (PLIC) and in the corona radiata by 35 weeks. Histological studies demonstrate the onset of myelination in the PLIC to occur between 32 and 36 weeks’ gestation. The preterm infant appears to show myelination within the internal capsule at an earlier post-menstrual age than more mature infants (Fig. 3.28).

The myelin sheath has a high lipid content, which is arranged in alternating layers with protein. The T1 shortening that is observed with the process of myelination probably occurs due to the hydrophilic cholesterol and glycolipid components of the developing myelin sheath²⁶. T2 shortening is reported to occur at the time of tightening of myelin around the axon2 and may correlate best with the development of myelination determined on histological methods.

Myelination is usually only visible in the corpus callosum from 3 months of age. It is difficult to visualize the unmyelinated corpus callosum in the transverse plane in term infants prior to myelination (Fig. 3.10). However, the corpus callosum is clearly visualized on heavily T2 weighted imaging as low signal intensity, prior to myelination (Figs 3.4, 3.6 and 3.10) The reasons for this are unclear, but it may be secondary to tightly packed fibers reducing the water content of the structure and thereby decreasing its T2.

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Basal ganglia and thalami

The basal ganglia and thalami in very preterm infants are characterized by a short T1 and are uniformly high signal intensity on T1 weighted images. On T2 weighted images the thalami are diffusely low signal intensity but the lentiform nucleus may have a more heterogeneous appearance. The ventro-lateral nuclei of the thalamus is clearly identifiable at 25 weeks’ gestation showing as a low signal area on T2 weighted images. This appearance is likely to be due to the increased cellular density of the nuclei and the presence of myelin which can be demonstrated histologically at this age. It is less obviously high signal intensity on T1 weighted images (Fig. 3.29). From 24 weeks until term the basal ganglia and thalami become more isointense on both T1 and T2 weighted images. By 35 weeks’ gestation there is only focal high signal intensity on T1 weighted images within the ventro-lateral nuclei and secondary to early myelination in the posterior part of the posterior limb of the internal capsule. There is additional more diffuse residual high signal intensity in the globus and posterior part of the putamen, inferiorly (see Chapters 4 and 6). On T2 weighted images there is low signal intensity in the ventro-lateral nuclei, which are very clearly seen. There is additional low signal intensity along the lateral border of the lentiform nuclei and in the posterior part of the posterior limb of the internal capsule (Fig. 3.29).

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The future

MRI is still a relatively new technique for imaging the very preterm infant. Any new developments in imaging the preterm infant have to be safe and quick as time is of the essence. Fast diffusion weighted imaging may increase our understanding on the formation of white matter tracts in health and disease¹⁸. Quantification of the brain and its structures will allow us to accurately compare the development of the brain with the development of the child¹⁷. This may produce more accurate neuroimaging correlates for later neurocognitive disorders. Spectroscopy is providing new insights into metabolic processes in response to injury (Chapter 16). Functional imaging is limited in the newborn but may also throw light on the mechanisms involved in normal and abnormal neurological functioning (Chapter 18). The interpretation of images is greatly aided by accurate histological comparisons although it is becoming increasingly difficult to obtain consent for postmortem with retention of the brain.

Summary

• Cell-rich regions such as the cortex and subependymal layer or germinal matrix have a short T1 and short T2.
• Sulcation and gyration of the cortex increases in a predictable way.
• Cortical folding can be quantified and appears to be reduced in preterm infants at term-equivalent age.
• MRI can detect bands of migrating glial cells.
• Germinal matrix involution can be documented.
• White matter structures of caps and bands and arrowheads correspond to normal developmental processes within the white matter of the immature brain.
• Diffusion weighted imaging and magnetic resonance spectroscopy should help to further characterize the developing white and gray matter.

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References

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