Myelination and Retarded Myelination

4.1 Myelination

It was Flechsig (1920) who originally put forward the view that the degree of myelination of the CNS might be correlated with functional capacity. In his theory he stated that myelination started in projection path- ways before association pathways, in peripheral nerves before central pathways, and in sensory areas before motor ones. Although he modified his theory slightly in response to his critics, he continued to maintain that fibers always myelinated in the same order: first the afferent (sensory), then the efferent (motor), then the association fibers.

The histological study of fetal development has confirmed that myelination proceeds systematically and, in nerve pathways with several neurons, in the order of conduction of the impulse. The first signs of myelination appear in the column of Burdach at the gestational age (GA) of 16 weeks, becoming stronger from the 24th week onward. The column of Goll starts to myelinate at 23 weeks of gestation. Cerebellar tracts start to myelinate at about 20 weeks of gestation, and the amount of myelin at birth is considerable. Pyra- midal tracts start to myelinate at 36 weeks at the level of the pons, but at birth the amount of myelin is still small. In other tracts, for example, the rubrospinal tracts, the pattern of the pyramidal tract is followed.

In a term neonate at a GA of 40 weeks myelin stains reveal myelin in the medulla oblongata, in the central parts of the cerebellar white matter, in the cerebellar peduncles and the vermis, in the medial lemniscus and fasciculus medialis longitudinalis in the pons and mesencephalon, in the posterior limb of the internal capsule, spreading into the globus pallidus and thala- mus and, in the thalamocortical connections in the centrum semiovale, upwards to the parasagittal parts of the postcentral gyrus and backwards into the optic radiation. Paul Flechsig’s lithographs (1920) demon- strate this myelination pattern beautifully (Fig. 4.1).

Several authors, including Keene and Hewer (1931) and Yakovlev and Lecours (1967), have published dia- grams of the progress of myelination (Fig. 4.2).

MRI is unique in making it possible to visualize the progress of myelination in vivo in astonishing detail.

It is now possible to describe the state of myelination in preterm and term neonates in detail and to follow this process through up to full maturation.

In the preterm child with a GA of less than 30 weeks the following structures show myelination:

cerebellar vermis, inferior cerebellar peduncles, vesti- bular nuclei, superior cerebellar peduncles and their decussation, dentate nucleus, medial longitudinal fas- ciculus, medial geniculate bodies, subthalamic nuclei, inferior olivary nuclei and ventrolateral nuclei of thalamus. Myelin can also be seen in the fasciculus gracilis and cuneatus and in their nuclei (Counsell et al. 2002; Sie et al. 1997).

In the period between 30 and 36 weeks of gestation the quantity of myelin in the aforementioned struc- tures increases, but from weeks 30–36 of gestation no myelin is seen in any new sites on MRI. This is not in agreement with histological descriptions of the myelin process. Reasons for this are the lower sensi- tivity of MRI to small quantities of myelin, also the reason for a time-lag in myelination timetables be- tween histology and MRI, and the higher spatial res- olution of histological methods. At a GA of 36 weeks evidence of the presence of myelin appears on T

- weighted images in the posterior limb of the internal capsules (with higher intensity in the area of the cor- ticospinal tracts) and in the tracts from and to the precentral and postcentral gyri in the corona radiata.

In the period between 37 and 42 weeks of gestation myelination of these tracts also becomes visible on T

-weighted images. At this time myelination is visi- ble in the tegmentum pontis but not in the basis pon- tis. Myelin now also appears in the lateral geniculate bodies and in the optic tracts, chiasm, and nerves. The myelin density in the basal ganglia and corticospinal tracts increases, and myelin shows up in the optic ra- diation.

During the 1st month after birth, myelination pro- gresses rapidly. It becomes more prominent in the ar- eas mentioned above. The pattern of myelin presence in the cerebellum changes (see below). On T

-weight- ed MR images myelin becomes visible in the rest of the striatum and caudate nucleus. Myelin in the optic pathways becomes more prominent, and myelin is al- so present in cortical layers of the primary motor and sensory cortex and in the hippocampus and parahip- pocampal gyrus. With increasing myelination in the occipital and parietal lobes, the splenium of the cor- pus callosum starts to myelinate. From the 3rd or 4th month onward myelination proceeds in the frontal direction, and from the 4th to 5th month onward, also in the temporal direction. The anterior limb of the internal capsule shows myelination from the 3rd to 4th month onward, proceeding in the 5th month to-

Myelination and Retarded Myelination

Chapter 4

wards the genu of the corpus callosum. At 6 months myelination starts to spread in the frontal lobes, and on the T

-weighted images the pattern of myelination is seen to be more or less complete at about 8 months.

The corpus callosum reflects the myelination of the parts it connects. T

-weighted images show myelin in the splenium at 3 months and in the genu at about 6 months of age; T

-weighted images show this 4–6 weeks later.

It should be clear that we are describing ’apparent’

myelination, i.e. myelination as it appears on T

- or T

-weighted images, which is dependent on pulse se- quences and field strength. The apparent progress in myelination on T

-weighted images lags behind that seen on T

-weighted images. Because of this, myelina-

tion can be followed for much longer on T

-weighted than on T

-weighted images. On T

-weighted images myelination does not reach the arcuate fibers in the frontal and temporal areas before the 12th–14th and 14th–18th months, respectively.

Myelination is not an all-or-none process. Myeli- nated white matter gradually replaces the unmyeli- nated white matter. In T

-weighted series unmyelinat- ed white matter has higher signal intensity than gray matter. With ongoing myelination, white matter becomes darker, and eventually it can no longer be differentiated from gray matter. This transition or

’cross-over’ period is reached in the parietal and occipital areas between 8 and 10 months after birth.

After this period myelinated white matter has lower

Fig. 4.1. Lithograph in left upper row is reproduced from work of Paul Flechsig (1920), who used refined histological techniques to depict ongoing myelination in the brain.

Progress of myelination of a young

infant is presented here. Note that

myelin (dark in the image) is already

circling around the temporal horn to

reach the hippocampus and parahip-

pocampal gyrus. Also note myelina-

tion of the auditory pathway in the

superior temporal gyrus. The two

T

-weighted coronal MR images show

the same features in vivo. Myelination

in this case is somewhat further

advanced than on the lithograph,

already spreading towards the

parietal U fibers

signal intensity than gray matter on T

-weighted images in this region. The frontal and temporal lobes show this cross-over at 12–14 and 14–18 months, respectively. T

-weighted images show the same re- versal in signal as the T

-weighted images, but in the reverse direction. Unmyelinated white matter has a lower signal than gray matter, whereas myelinated white matter has a higher signal. Because of the pref- erential T

-shortening effect of myelin, which exceeds the T

-shortening effect, the signal reversal on T

- weighted images occurs weeks to months before it occurs on the T

-weighted images. This implies that there is a phase, for the cerebral hemispheric white matter mainly in the second half of the 1st year of life, in which white matter structures have a higher signal than gray matter on both T

- and T

-weighted images.

4.2 MRI Pulse Sequences

T

-weighted spin echo (SE) or inversion recovery (IR) and T

-weighted SE sequences are complementary. In the first 6 months of life, T

-weighted images show to better advantage which areas contain myelin, while T

-weighted SE images, with the proper pulse se- quence, differentiate partially myelinated from non- myelinated and completely myelinated white matter more adequately. In MRI, pulse sequences should be chosen so that the contrast/noise ratio is as high as possible and the differences between tissues are max- imal. It is, therefore, useful to consider the T

and T

values of gray matter and of unmyelinated and myeli- nated white matter in order to make an adequate choice. Holland et al. (1987) found that at a field strength of 0.35 T, T

of white matter is 1615±120 ms

4.2 MRI Pulse Sequences 39 Fig. 4.2. Classic diagram of progression of

myelination as conceived by Yakovlev and

Lecours. Most of the structures mentioned

can also be made visible on MRI. Appearance

of myelination on MR images is 1 or 2 weeks

behind this schedule with conventional MR

techniques. From Yakovlev and Lecours

(1967), with permission

(mean±standard deviation) at birth, 1150±60 ms at 6 months and 580±50 ms at 1 year; T

of white matter is 91±6 ms at birth, 64±6 ms at 6 months, 57±5 ms at 1 year and 53±3 ms at 3 years. For gray matter the corresponding T

measurements are 1590±60 ms at birth, 1300±70 ms at 6 months and 890±75 ms at 1 year, and the corresponding T

measurements 88±8 ms at birth, 67±7 ms at 6 months, 69±3 ms at 1 year and 62±3 ms at 3 years. The changes observed with increasing age can be explained by a decreasing water content and increasing myelin content. Protons in the myelin membrane are less mobile, water con- tent is lower, and T

and T

are, therefore, shorter in myelinated areas.

A long TR, long TE sequence is advantageous to allow full benefit of the T

differences between gray matter, unmyelinated white matter and myelinated white matter and to minimize T

effects, which coun- teract the T

effects. We use a 3000/120 SE series, which shows unmyelinated white matter with high signal intensity, gray matter and partially myelinated white matter with intermediate signal intensity, and myelinated areas with low signal intensity. In our SE 3000/120 series, the transition or ’isointense’ pattern between gray and white matter is reached in the pari- etal and occipital lobes in normal children by the age of 6–9 months.With a different pulse sequence, for in- stance SE 2000/80, this transition phase may be 7–12 months. Because of the heavier T

-weighting in our series, the T

-decay trajectories traverse each other at a somewhat steeper angle and the transition period is, therefore, more clearly marked and of shorter duration.

Fast or turbo spin echo (FSE or TSE) sequences are time-saving procedures and are frequently used in imaging of neonates and infants, but they have impor- tant disadvantages. Instead of one ’projection’ or line in the k-space (the virtual spatial frequency space from where the image is reconstructed by Fourier transformation), FSE sequences generate multiple spin echoes from a single RF excitation, which are close enough together (echo spacing in the order of 15 ms) to provide multiple ’projections’ or lines in the k-space. Imaging time is shortened by a factor of the number of echoes collected in the train. SEs are, therefore, acquired at slightly different TEs, which will affect the resulting image. The repetition of refo- cusing 180° pulses improves local magnetic homo- geneity, thus diminishing magnetic susceptibility ef- fects. On FSE and TSE images hemorrhages and calci- fications will consequently be less conspicuous. Be- cause of the short time interval between refocusing pulses, the apparent T

of adipose tissue becomes longer and the fat signal will be less suppressed than on conventional T

-weighted SE images. Fat will, therefore, appear bright on heavily T

-weighted FSE images. Other factors influence FSE images. The mag-

netization transfer component present in multislice conventional SE images is increased in FSE and influ- enced by the number of slices. From this it will be clear that MR images made with FSE sequences can- not be compared with conventional SE images. The influence of the FSE techniques on the estimation of the progress of myelination is probably negligible, but the influence on the depiction of disease conditions should be considered, especially when the abnormal- ities are subtle. In examination of neonates it is im- possible to be sure in advance whether abnormalities will be found.

T

-weighted SE or IR series are of great importance for following the spurt of myelination during the first 6°months after birth. They demonstrate the progres- sion of myelination beautifully, but they are less reli- able than T

-weighted images for assessing the quan- tity of myelin deposited. The difference in T

between gray matter and unmyelinated white matter at birth gives the unmyelinated white matter a darker appear- ance than the cortex. With ongoing myelination the white matter will become brighter than the cortex.

Between these structures, again, a cross-over or con- trast inversion takes place. In T

-weighted images, however, this is a less striking event than in T

- weighted images. In premature neonates the unmyeli- nated white matter appears much darker than the rim of cortical gray matter. Even at 40°weeks of GA this difference is still present, although less marked. After that, the unmyelinated white matter rapidly changes its signal and becomes almost isointense with gray matter. The white matter structures in which myelin is advancing stand out as very bright and attract most attention in the assessment of myelination age. A comparison of T

- and T

-weighted images makes it clear that the T

-weighted images are more sensitive indicators of the presence of myelin, even when it is present only in small amounts. Partially myelinated structures, which are isointense or even still mildly hyperintense relative to gray matter on T

-weighted images, are already white on T

-weighted images. The reason for the higher myelin sensitivity of T

- than of T

-weighted images can be found in a number of fac- tors at the molecular level. The special structure of the myelin membrane with a lipid : protein ratio of 70 : 30 (dry weight) and a cholesterol content of 30%

is important. The construction of lipid layers separat- ed by a 40-molecule thick layer of water, into which the hydrophilic phosphate polar groups of lipids and the cholesterol hydroxyls project, creates a unique lipid–water interfacial interaction seven times as in- tense as that at a typical protein–lipid interface. There is a field-dependent cross-relaxation between protons of myelin water and protons of myelin lipid, a phe- nomenon known as magnetization transfer. The ap- parent effect of these conditions is a shortening of T

induced by myelin, which is more pronounced than

would be expected to result from deposition of mem- branous structures alone.

Fluid-attenuated inversion recovery (FLAIR) im- ages use a combination of an IR pulse with an inver- sion time chosen to suppress the water signal, fol- lowed by a heavily T

-weighted FSE. Because the water signal is suppressed, abnormalities will stand out clearly. FLAIR pulses are not very useful in the estimation of progress of myelination. The difference between gray, unmyelinated and myelinated white matter is much less on FLAIR images than on conven- tional T

- and T

-weighted images. It is probably the suppression of the water signal in the water-rich envi- ronment of the neonatal brain that is responsible for this diminished contrast, since the disappearance of

’free’ water in the brain of neonates and its replace- ment by myelinated structures play a major part in the maturation process.

4.3 Diffusion-weighted Imaging and Diffusion Tensor Imaging

Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) use the microscopic movement of water molecules and the relative loss of phase of protons caused by this movement in different brain structures as a means of image contrast. Parameters that are frequently used are the apparent diffusion co- efficient (ADC) of tissues and the relative anisotropy of brain structures, usually expressed as fractional anisotropy (FA).

The relative anisotropy is practically zero in gray matter in term-born neonates and in adults: diffusion in gray matter is isotropic. However, at a GA of 26 weeks cortical anisotropy is not zero, because at that time the cortical cyto-architecture is dominated by radial glial fibers and radially oriented apical den- drites of the pyramidal cells. This structure is dis- rupted in time by the addition of basal dendrites and thalamocortical efferents.

White matter ADC and FA depend on stage of mat- uration. During the early development of the brain ADC values are high, and they subsequently fall. This is because of the initial high water content and the subsequent overall decrease in water content together with the development of more densely packed struc- tures with a high density of membranes that hinder free water movement. FA is initially low and increases rapidly. The increase in FA can be observed even in the premyelination state. The increase in FA during early development is not only the result of the pro- gressing myelination; other contributing factors are the number of microtubule-associated proteins in ax- ons, axon caliber changes, and a significant increase in the number of glia. More densely packed structures have higher FA. Both ADC and FA can be displayed in

images. In contrast with ADC maps, FA images show excellent gray–white matter contrast. In clinical practice, estimation of ADC and FA of different brain structures makes it possible to quantitate the progress of brain maturation, including myelination, and to visualize the formation of white matter tracts.

In addition, DWI offers anisotropic diffusion maps that can be displayed separately for each diffusion gradient direction or as an averaged ADC map, the so-called trace map.

Measurements of ADC are available for different ages from the fetal period to adult age. ADC values decrease in between these points in time and develop- ment, from 1.50–1.95 × 10

mm

/s for white matter in the fetal brain to about 0.87–0.95 × 10

mm

/s in the mature brain. Maturity in this respect is reached at the age of approximately 2 years. For the basal ganglia the corresponding data are, respectively, 1.56 × 10

mm

/s and 0.79 × 10

mm

/s. More detailed data are available for term neonates (see Table 4.1). ADC and FA values are different for different brain structures, depending on their structure and stage of develop- ment.

ADC values decrease with ongoing maturation and FA values rise. This process is exponential. The de- crease in ADC and increase in FA are fast in the first 3–6 months, followed by a slower further decrease and increase, respectively. White matter anisotropy increases over the next 6 months, leveling in the 2nd year of life. The numbers in Table 4.1 are only guide- lines.ADC and FA values reported from different cen- ters can differ substantially. Data given here are in the same order of magnitude as those reported by Neill et al. (1998).

Detailed measurements of diffusion tensor charac- teristics related to brain maturation have been taken and have shown regional differences running parallel to the progress of myelination as seen on convention- al MR images (Mukherjee et al. 2002). Unfortunately,

4.3 Diffusion-weighted Imaging and Diffusion Tensor Imaging 41 Table 4.1. Apparent diffusion coefficient (ADC) ( ×10

mm

/s) and fractional anisotropy (FA) (10

) in term neonates

Region ADC FA

Frontal white matter 1.62–1.73 190–210 Posterior limb internal capsule 1.06–1.01 410–500

Occipital cortex 1.15–1.20 150–180

Occipital white matter 1.58–1.69 330–370 Corpus callosum

Genu 1.22–1.37

Splenium 1.17–1.32

Thalamus 1.23–1.08

Mesencephalon (tegmentum) 0.99–1.09 420–480

Pons, anterior 1.13–1.27

Pons, posterior 0.94–1.06

the reported values refer to ’eigenvalues’ of the diffu- sion tensor and are not directly comparable to ADC and FA values.

4.4 Magnetization Transfer

With magnetization transfer (MT) quantitative infor- mation about the condition of brain tissue can be ob- tained by estimating MT ratios (MTRs), either voxel based and displayed as maps, or measured globally and displayed as MTR histograms. It has been shown that MTR changes in infants correlate with changes in the degree of myelination (Van Buchem et al. 2001).

MTR can be used to quantitate the progress of myeli- nation and monitor the regional development. MTR values (%) show an increase over time (Rademacher et al. 1999) (Table 4.2).

Gray matter structures also show an increase in MTR over time; these changes, however, are much less impressive (Rademacher et al. 1999).

It is possible to use MTR whole-brain histograms to monitor the progress of brain maturation. This will possibly develop into a method that will allow easy es- timation of retarded maturation and be a good tool for individual follow-up studies (Van Buchem et al.

2001).

4.5 Myelination: Timetables

In daily practice it is useful to have a timetable of nor- mal progress of myelination at hand. Even with a con- siderable variation, it is evidently possible to provide a time scale for normal development and to assess re- liably significant delay in myelination. There are sev- eral approaches to making a timetable and each one has its own advantages and disadvantages. The meth- ods can be subdivided in nonquantitative (visual in- spection), semi-quantitative (ratios) and quantitative (absolute values).

Timetables can be based upon the visual inspection of changes on T

- and T

-weighted images. T

-weight- ed images are very useful in the first 6 months of life, as discussed above, whereas T

- weighted images pro- vide more useful information after 6 months. Combi- nation of T

and T

data has distinct advantages, espe- cially in cases with delayed or distorted myelination.

At term birth, T

-weighted images show evidence of myelination in the medulla spinalis, cerebellar white matter, dorsal part of the pons, mesencephalon, posterior limb of the internal capsula (in particular the area of the corticospinal tracts), and the postcen- tral parasagittal areas, as a continuation of the long ascending spinocortical tracts. The optic radiation becomes myelinated soon after birth. The splenium of the corpus callosum is myelinated in the 3rd month, the truncus in the 4th and 5th month, and the genu in the 5th and 6th months. In the 3rd and 4th months myelination spreads to the anterior limb of the inter- nal capsule. From the parietal parasagittal area, myelination starts to spread in anterior and posterior directions. After this stage further distinction on T

- weighted images becomes difficult.

Additional T

-weighted images can be used to re- fine the assessment of myelination. Myelination of the central parts of the brain can be distinguished from the hemispheric white matter, making it possible to compose a timetable based on signal intensities with five steps of progression (see Tables 4.3, 4.4).

Some markers are useful in daily practice. On long TR, long TE SE images, the splenium of the corpus callosum has a low signal by 6 months of age, the genu at 8 months of age. The cross-over in the occipital lobe, when gray and white matter have a uniform and indistinguishable intermediate signal intensity (are isointense), occurs at about 7–9 months. At about 9 months the ‘adult’ contrast between gray and white matter starts to emerge in the occipital lobes. The an- terior limb of the internal capsule is myelinated on the heavily T

-weighted sequence at 8–11 months. At 12 months the frontal white matter starts to myeli-

Table 4.2. Magnetization transfer ratio (%) during develop- ment

Projection fibers (pyramidal tracts) At 1 month 23–25 % At 3 months 25–27 % At 6 months 31–33 % At 20 months 34–37 % Association fibers At 1 month 19–21 % At 3 months 22–25 % At 6 months 28–30 % At 20 months 29–33 % Commissural fibers At 1 month 23–24 % At 3 months 24–25 % At 6 months 29–33 % At 20 months 34–37 %

Table 4.3. Signal intensity of central white matter relative to white matter on long TR SE images

Short TE Long TE

Stage Age MWM MWM

I 1st month ↑ =/ ↓

II 2nd months =/ ↓ ↓/↓↓

III 3rd–6th months ↓ ↓↓

IV 7th–9th month ↓ ↓↓

V >9th month ↓ ↓↓

↑↑ hyperintense,↑ slightly hyperintense,= isointense,↓ slight-

ly hypointense, ↓↓ hypointense, SE spin echo, MWM myelinat-

ed white matter, TE echo time

nate; it should be nearly complete at 14 months of age.

The temporal lobe is the last to myelinate; this occurs between 14 and 18 months of age. The U-fibers of the cerebral hemispheric white matter become fully myelinated between 18 and 24 months.

Use of marker sites can be helpful, especially for re- search purposes, to provide the necessary detail and quantitation. An approach defining specific targets for myelination, and scoring in a large population the time of onset and completion of myelination of such targets, leads to normal values with definition of nor- mal variation.

In a semi-quantitative way the progress of myeli- nation can be assessed by calculating a ratio between the averaged signal intensity of a chosen region of in- terest and dividing that by the averaged signal inten- sity of a fully myelinated structure. For this purpose the posterior limb of the internal capsule is often cho- sen, because myelination is complete at that structure at a GA of 44 weeks. A ratio so obtained is indepen- dent of type of equipment and field strength. In myelin disorders that also affect the posterior limb of the internal capsule, of course, this does not apply.

The head of the caudate nucleus has also been used as a reference.

Some groups have used this more refined method of marker sites in combination with estimation of time of contrast cross-over between structures and used this approach to look at the detailed progress of myelination in the cerebellum and brain stem in the first months of life. Martin et al. (1990) took as target areas the cerebellar hemispheres, dentate nucleus, nucleus ruber, middle cerebellar peduncle, corpus medullare cerebelli, pontine tegmentum, basis pontis, medial lemniscus, and corticospinal tracts. They de- fined five stages of progress of cerebellar myelination, depending on the relative signal intensities of these regions. Landmarks of these studies used for time es- timates were again the gradually darker appearance of myelinated areas on T

-weighted images, the fur- ther extension of myelination towards the subcortical structures, and inversion of contrast between struc- tures. An example of the first marker is the gradual

darkening of the rim around the dentate nucleus in the first weeks of life; of the second marker, the exten- sion of myelin into the cerebellar folia; and of the third marker, the cross-over in signal intensities be- tween the corticospinal tracts and the substantia ni- gra. When automatic scaling is used, which is usually the case on MR systems, it proves difficult to identify the five stages as described by these authors. Usually, however, three stages of maturation can be distin- guished in the posterior fossa. The structures in- volved in the recognition of these three stages on T

- weighted transverse images are: the basis pontis, the tegmentum pontis, the middle cerebellar peduncle, the dentate nucleus, the peridentate white matter, the corpus medullare cerebelli, and the white matter ex- tending into the cerebellar folia (Fig. 4.3). In stage 1 (<1 month after term) the basis pontis is not myeli- nated, there is some myelin in the tegmentum of the pons and in the middle cerebellar peduncles, and the nucleus dentatus has a high signal intensity and is surrounded by a rim of lower signal intensity, fol- lowed by a high signal of the cerebellar white matter.

In stage 2 (>1 months, <3–4 months) myelination starts to appear in the basis pontis; the tegmentum is still darker, however, and the dentate nucleus starts to appear darker. In stage 3 (>3–4 months), tegmentum and basis pontis are now approximately as dark as each other; the dentate nucleus and the cerebellar white matter appear completely dark and isointense with the middle cerebellar peduncle. After comple- tion of these stages, myelination starts to extend to- wards the cerebellar folia, gradually shaping the ’ar- bor vitae’ of the cerebellum.

We could make the assessment more detailed and add more structures: pyramidal tracts, medial lem- niscus, and medial longitudinal fasciculus, structures that can be distinguished in good-quality images of the brain stem and cerebellum. A similar diagram could be produced for the mesencephalic structures, where the signal intensity, of the red nucleus, the sub- stantia nigra, the corticospinal tracts, medial lemnis- cus, and inferior calicles changes with time, depend- ing on the pulse sequence used.

4.5 Myelination: Timetables 43 Table 4.4. Signal intensities of peripheral white matter relative to white matter on long TR SE images

Short TE Long TE

stage age UWM MWM UWM MWM

I 1st month ↓ ↑ ↑ =

II 2nd month = = ↑↑ =

III 3rd-6th month ↑ = ↑↑ =

IV 7th-9th month = =

V >9th month ↓ ↓↓

↑↑ hyperintense; ↑ slightly hyperintense; = isointense; ↓ slightly hypointense; ↓↓ hypointense; MWM myelinated white matter;

UWM unmyelinated white matter; TE echo time

Fig. 4.3. Myelination of the posterior fossa (nd nucleus dentatus;

mcp middle cere- bellar peduncle;

V vermis cerebelli;

1 peridentate white matter;

2 corpus medullare;

3 peripheral white matter; IV fourth ventricle)

Fig. 4.4. Myelination and gyration are both part of the matu- ration process of the brain. These axial T

-weighted images obtained in infants with gestational ages (GAs) of 23, 27, and 35 weeks demonstrate brain maturation in that period. At 23 weeks of gestation the germinal matrix is visible at the trigonum, frontal horns and caudothalamic notch. The brain surface is still smooth. The sylvian fissure is hardly visible. At

27 weeks there are still remains of the germinal matrix, but it is less conspicuous. At 35 weeks of gestation myelination has started in the posterior limb of the internal capsule. (The dark dot represents the corticospinal motor tract.) The gyral devel- opment over this period is beautifully shown in these images.

From Childs and Ramenghi et al. (2001), with permission

Quantitative measurements can be used to assess myelination of the brain in general, and in different structures in particular. Examples are measurements of T

, T

, ADC, FA, and MTR.

It is clear that myelination is not the only concern as far as development of the CNS is concerned. Pro- gression of gyration should be included in an inven- tory of brain maturation. For premature children such a maturation index has been proposed (Childs et al. 2001), which provides a standardized method of assessing cerebral maturation. Four parameters are assessed in this scale: cortical folding, myelination, germinal matrix distribution, and glial cell migration (see also Fig. 4.4).

4.6 Gyration

The brain of premature children and neonates is im- mature, not only in myelination but also in develop- ment in gyri (gyration). Histopathological, intrauter- ine ultrasound and MR studies have yielded insight into the development of some major fissures, which provide landmarks of gyral development: the inter- hemispheric fissure (before 15 weeks of GA), the pari- eto-occipital fissure, the calcarine fissure, the central rolandic sulcus (visible at a GA of 23–25 weeks), and the development of the insula, visible at a GA of 18 weeks, with overriding frontal, temporal and pari- etal opercula at 28–29 weeks’ gestation (Chi et al.

1977).

For MRI, insight into gyral development from the age of 26–28 weeks gestation is most important, as preterm infants often come for MRI. In premature in- fants the cerebral cortex is still entirely or relatively smooth and lacking in sulci, depending on the post- conceptional age of the infant. Over time, shallow sul- ci develop in an ordered sequence. The sulci increase in number and become deeper. The gyri become in- creasingly branched. Most of the process of a conver- sion of a smooth, lissencephalic brain into a nearly fully developed cortical gyral pattern occurs between 26 and 44 weeks of gestation. The mature pattern of gyri and sulci is normally reached at the age of 3 months after term. In our study of gyral develop- ment in preterm and term neonates (Van der Knaap et al. 1996) gyral development was graded for differ-

ent brain areas using a five-point scoring system (Fig. 4.5): (1) The surface is smooth without gyri and sulci or there is, at most, some undulation of the cor- tical surface area. (2) Width of the gyri is greater than the depth of the sulci. (3) Width of the gyri is equal to the depth of the sulci. (4) Width of the gyri is less than the depth of the sulci. (5) Gyri and sulci are branched. Seven cortical areas were studied separate- ly: (1) the frontal lobe minus the area of the central sulcus, (2) the area of the central sulcus, (3) the pari- etal lobe minus the area of the central sulcus, (4) the occipital lobe minus the medial area, (5) the medial occipital area, (6) the posterior part of the temporal lobe, and (7) the anterior part of the temporal lobe.

The five stages of gyration distinguished are shown in Figs. 4.6–4.10. The ages of the children ranged from 30 to 42 weeks. At all ages the development of the rolandic area and the medial part of the occipital lobe (areas 2 and 5) was most advanced. In the pari- etal area, occipital area and posterior temporal area (areas 3, 4, and 6), an intermediate rate of gyral devel- opment was found. Gyral development was slowest and latest in the frontal and anterior temporal areas (areas 1 and 7).

4.6 Gyration 45

Fig. 4.5. A–D. Patterns of sulcus configuration for gyral devel-

opment score 2 (A or B), score 3 (C), and score 4 (D). From Van

der Knaap et al. (1996), with permission

Fig. 4.6. Sagittal T

-weighted, and coronal and transverse T

-weighted images in a preterm infant at a GA of 30 weeks, showing stage 1 gyration. The depth of the central, parieto- occipital and calcarine sulci is about equal to the width of the

bordering gyrus. The frontal and temporal cortical surface is smooth; the cortex is slightly undulating in the posterior area.

From Van der Knaap et al. (1996), with permission

4.6 Gyration 47

Fig. 4.7. Preterm infant at a GA of 32 weeks. Sagittal T

- and coronal and transverse T

-weighted images show gyration stage 2. The central and calcarine sulci are now deeper than

the bordering gyri. Compared with stage 1 sulci are better

defined and increased in number in the remaining areas. From

Van der Knaap et al. (1996), with permission

Fig. 4.8. Gyration at a GA of 36 weeks. Sagittal and coronal T

- and transverse T

-weighted images demonstrate stage 3 gyration. The central sulcus and sulci of the medial occipital area are now becoming branched. Sulci are becoming better

defined and more numerous.The depth of the sulci is equal or

greater than the width of the gyri in most areas. From Van der

Knaap et al. (1996), with permission

4.6 Gyration 49

Fig. 4.9. Gyration at a GA of 39 weeks. Sagittal and coronal T

- and transverse T

-weighted images depict stage 4 gyra- tion. The central and sulci of the medial occipital area are now branched. The number of sulci and gyri has increased again.

The sulci have a closed form in most areas. The depth of the

majority of sulci is greater than that of the bordering gyri.From

Van der Knaap et al. (1996), with permission

Fig. 4.10. Gyration at a GA of 42 weeks, depicted on sagittal T

-weighted, and coronal and transverse T

-weighted images, show-

ing stage 5 gyration. Branching of sulci is now seen in all areas. From Van der Knaap et al. (1996), with permission

4.7 Delayed Myelination, Irregular Myelination, Hypomyelination, and Arrest of Myelination

Once MRI criteria for normal progress of myelination have been established, it is possible to diagnose delays in this process. If it is true that myelination expresses functional maturity a correlation between delay in myelination and delayed development of psychomo- tor functions can be expected. Roughly speaking, this appears to be the case. We have been able to confirm it in a group of children with hydrocephalus, in whom MRI and neuropsychological data were obtained be- fore and twice after shunting. There was a strong cor- relation between (a) the progress of myelination as compared with the normal myelination standard and (b) the progress of mental development as compared with the normal developmental standard. It is impor- tant to follow up the progress of myelination in any child in whom a delay is suspected, to see whether, and if so when, the child catches up with normal myelination. It might be assumed that a longer delay in the restoration of the normal pattern would coin- cide with a poorer prognosis.

There are many possible causes for a delay in myelination: hypoxia–ischemia, congenital infec- tions, congenital malformations, chromosomal ab- normalities, congenital heart failure, postnatal infec- tions, hydrocephalus, hypothyroidism, hypercorti- solism, hypocortisolism, fetal intoxications, malnutri- tion, and inborn errors of metabolism. The delay is usually bilateral and symmetrical, but unilateral delay is seen in cases with hemimegalencephaly, unilateral porencephalic cysts, cerebral hemiatrophy, or unilat- eral periventricular leukomalacia.

The critical period in myelin development was ini- tially thought to coincide with the proliferation of myelin-forming cells, rather than with the period of membrane accumulation. The mechanism of ’stunt- ing’ of oligodendroglial proliferation as a cause of hy- pomyelination has been under discussion, because in animal research no major deficits of oligodendro- cytes could ever be established, except in severely starved animals. Therefore the induction of myelin membrane formation, rather than cell proliferation, seems to be the actual critical event. Damage in criti- cal periods is often limited to areas in which myelina- tion is beginning at that time. This knowledge is help- ful in establishing the time of insult in infants and children.

Irregular myelination with local or generalized hypermyelination, or myelination not following the normal routes of progress, is rare, but is seen occa- sionally. Hypermyelination, or advanced myelination, has been observed in patients with Sturge-Weber syndrome. It has been suggested that epileptic seizures may stimulate myelination. However, ad- vanced myelination or hypermyelination is not seen in most patients with infantile forms of epilepsy. Lo- cal hypermyelination in the basal ganglia is manifest histologically as the so-called status marmoratus, a late sequela of perinatal hypoxia. In this case the myelination does not involve the proper targets and does not occur around axons but around astrocytic extensions. Because of the low signal intensity of the basal ganglia on T

-weighted images and the dark ap- pearance of myelin in this sequence, MRI has so far not succeeded in identifying this condition.

Hypomyelination or arrest of myelination occurs in Pelizaeus-Merzbacher disease, a disorder of proteo- lipid protein synthesis, one of the major myelin pro- teins. In this disorder no myelin, or only very little, is produced. In Salla disease, a lysosomal storage disor- der, and DNA repair disorders such as Cockayne syn- drome and trichothiodystrophy with sun hypersensi- tivity hypomyelination is also present. To establish a secure diagnosis of retarded or arrested myelination, at least two observations sufficiently far apart are necessary.

4.8 Iconography of Myelination and Gyration

Illustrations in this chapter show the progress of gyration (Figs. 4.4–4.10) and myelination in normal neonates and infants (Figs. 4.11–4.23). Many exam- ples of disturbances of myelination are found in the other chapters in this book. In Table 4.4 the myelina- tion of some important structures on MRI is indicat- ed. In some cases a more detailed look at structures in relation to their surroundings is useful, in order to see how contrast changes over time. The structures in the posterior fossa are a good example (Fig. 4.3). We also include an example of diffusion-weighted imaging in estimating the progress of myelination (Fig. 4.24).

4.8 Iconography of Myelination and Gyration 51

Fig. 4.11. Myelination at a GA of 32 weeks. The sagittal T

- weighted series (upper row) shows the features of the prema- ture brain nicely: lack of gyration in the frontal areas, with some gyration in the parietal and occipital lobes.The midsagit- tal image shows myelin present in the medulla oblongata, the

dorsal part of the pons, the mesencephalon, and the corpus

medullare of the cerebellum. The transverse T

-weighted se-

ries shows the same features and gives a good impression of

the high water content of the unmyelinated white matter

4.8 Iconography of Myelination and Gyration 53

Fig. 4.12. Myelination at a GA of 39 weeks. A sagittal T

- weighted SE series is shown from right to left.In the brain stem, the basis pontis is still not myelinated (arrow). The corpus cal-

losum is still thin and also unmyelinated. From the basal gan-

glia, myelinated white matter tracts can be followed towards

the post-rolandic gyrus (arrows)

Fig. 4.13. Myelination 2 weeks after birth at term, as seen on a T

-weighted transverse inversion recovery (IR) series. Myeli- nation is seen in the medulla oblongata, middle cerebellar peduncle, tegmentum pontis (especially medial lemniscus, arrows), colliculus inferior, decussation of the superior cerebel-

lar peduncles, optic tracts, posterior limb of the internal cap-

sule, white matter tracts in the basal ganglia and ascending

tracts towards the post-rolandic gyrus. Note in the upper im-

ages that cortical gray matter is also myelinated

4.8 Iconography of Myelination and Gyration 55

Fig. 4.14. T

-weighted transverse series of myelination 2 weeks after birth at term for comparison. Cerebellar myelina- tion is still in stage 1: the hilus of the dentate nucleus is bright;

the dentate nucleus is surrounded by a dark band (arrow), again followed by bright cerebellar white matter. Contrast in- version of these structures during the progress of myelination

will give clues to the age of myelination. On T

-weighted

images the tegmentum pontis (arrow) and mesencephalon

are darker than the ventral pons. Myelin can also be seen in

the superior vermis, posterior limb of the internal capsule,

basal ganglia and ascending tracts into the post-rolandic

gyrus (arrows)

Fig. 4.15. In the posterior fossa T

-weighted images show that cerebellar myelination has progressed to stage 2 in this 2-month-old infant.The bright ring around the dentate nucle- us has disappeared, but the peripheral white matter of the cerebellum is still bright.There is still a difference between the

basis pontis and tegmentum pontis, although much less pro-

nounced than before. In the mesencephalon, the pyramidal

tracts and decussation of the superior cerebellar peduncles

can be identified

4.8 Iconography of Myelination and Gyration 57

Fig. 4.16. IR images at 3 months. The myelinated structures can easily be identified. Note the beginning of myelination in the pyramidal tracts in the mesencephalon (large white arrow) and the strongly myelinated decussation of the superior cere- bellar peduncles (small black arrow). The colliculus inferior (black arrow) and the auditory tracts are also clearly myelinat-

ed. The optic tract is myelinated, as is the optic radiation. The

posterior limb of the internal capsule is fully myelinated at the

postnatal age of 2 weeks. Myelin has now spread to the pre-

central gyrus and will advance dorsally and ventrally to myeli-

nate the occipital, the frontal and, finally, the temporal lobes

Fig. 4.17. At the age of 5 months the genu of the corpus callosum starts to myelinate. On IR images myelination will soon appear

to be complete. T

-weighted images will then be more useful in providing information about maturation of the brain

4.8 Iconography of Myelination and Gyration 59

Fig. 4.18. T

-weighted series at 4 months of age. In the pons, basis and tegmentum have a low signal; the medial lemniscus has an even lower signal (arrow), as do the middle cerebellar peduncles. The corpus medullare of the cerebellum is myeli- nated, but myelination is not yet extending towards the cor- tex. At the level of the mesencephalon, the decussation of the

superior cerebellar peducles, the colliculus inferior (arrow), the

pyramidal tracts,the corpus mamillare and the optic tract have

a low signal. The posterior limb of the internal capsule is also

dark (arrows). A difference is visible between the unmyelinat-

ed white matter in the frontal and temporal regions and the

occipital and parietal region where myelination has started

Fig. 4.19. T

-weighted coronal images at the age of 4 months, showing the difference between still unmyelinated white matter

in the frontal and temporal lobe and the more advanced myelination posteriorly

4.8 Iconography of Myelination and Gyration 61

Fig. 4.20. Myelination at 7–8 months of age. On the T

- weighted images the central parts are now myelinated, includ- ing the genu of the corpus callosum. The crossover between

gray and white matter in the occipital and parietal areas has started; there is little contrast between gray and white matter.

In the frontal and temporal regions this is not yet the case

Fig. 4.21. Myelination at 12–13 months. The adult contrast is now emerging in all lobes except the temporal lobe, the latest to

myelinate. The T

-weighted series shows that the spread of myelin into the arcuate fibers is still not complete

4.8 Iconography of Myelination and Gyration 63

Fig. 4.22. Adult pattern of myelination on T

-weighted images in a 5-year-old child.The temporal lobes now also show the adult

gray–white matter contrast

Fig. 4.23. Adult pattern of myelination on T

-weighted (IR) images. These images were taken from a 5-year-old boy

Fig. 4.24. Diffusion-weighted-

imaging (DWI) and diffusion

tensor imaging (DTI) allow further

refinement and quantitation of

the progress of myelination. These

images depict single-shot EPI with

single diffusion gradient in slice,

read or phase direction at b=1000,

showing anisotropy of myelinated

fibers depending on the gradient

direction in a baby boy 3 months

of age

4.8 Iconography of Myelination and Gyration 65

Fig. 4.25. Images demonstrating evolution of FA over time, measured with 12+1 diffusion gradient settings

Table 4.5. Myelination on MRI: chronological table (WM white matter). From: Yakovlev and Lecours (1967), with permission Regions of CNS Fetal age (weeks) Postnatal age (weeks) Postnatal age (months)

24 28 32 36 40 4 8 12 16 20 6 9 12 >12

Cerebellar peduncles + + ++ +++ +++ +++ +++ +++ +++ +++ +++ +++

Tegmentum pontis + + + ++ ++ +++ +++ +++ +++ +++ +++

Basis pontis + + ++ +++ +++ +++ +++

Medial lemniscus + ++ ++ +++ +++ +++ +++ +++

Pyramidal tracts + + + + + + ++ ++ +++

Optic nerve + ++ ++ +++ +++ +++ +++ +++ +++

Optic radiation + + ++ +++ +++ +++ +++ +++

Internal capsule,

posterior limb + ++ +++ +++ +++ +++ +++ +++ +++ +++ +++

Internal capsule,

anterior limb + + ++ +++ +++ +++

Corpus callosum splenium + + ++ ++ ++ +++ +++

Corpus callosum genu + + ++ +++

Parieto-occipital WM + ++ ++ +++ +++ +++ +++ +++

Frontal WM + ++

Temporal WM +

Further re-

finement of

myelination

in subcortical

arcuate fibers

continues for

several years