Abstract
Myelination is characterized by the acquisition of the highly specialized myelin membrane around axons. It begins before birth within the caudal brain stem and progresses rostrally to the forebrain, with the most rapid and dramatic period of human central myelination within the first 2 years of postnatal life. It is during this critical period that myelin is initially laid down in virtually all white matter tracts, with the last site to myelinate intracortical fibers of the cerebral cortex, where myelination extends steadily into the third decade. The process of myelination begins with proliferation of oligodendroglia, which align along axons. The plasma membranes of the oligodendroglia become elaborated as the myelin membrane. The progression of the oligodendroglial lineage proceeds through four basic stages, beginning with the oligodendroglial progenitor and continuing successively with the preoligodendrocyte, immature oligodendrocyte, and mature oligodendrocyte. The molecular determinants of myelination include growth factors, hormones, cytokines, surface receptors, and secreted ligands. The process of myelination follows orderly, predictable sequences in which different fiber tracts begin to myelinate before or after birth, and progress at different rates, with tracts that are “fast,” “intermediate,” and “slow” myelinators relative to each other. Three principal mechanisms are considered in disorders of myelination: (1) arrested or abnormal development of oligodendrocyte precursors; (2) oligodendroglial dysfunction leadling to myelin breakdown; and (3) primary axonal disorders causing aberrant signaling and impaired trophic interactions with developing oligodendrocytes. Impairment in myelination occurs in a variety of disorders, including leukodystrophies, neuronal degenerations, amino acid and organic acidopathies, mitochondrial and peroxisomal disorders, and infections, among others.
Keywords
preoligodendrocyte, myelin membrane
Myelination is characterized by the acquisition of the highly specialized myelin membrane around axons. The time period of myelination in the human is long, beginning mainly in the second trimester of pregnancy and continuing into adult life Myelination in the brain begins before birth within the caudal brain stem and progresses rostrally to the forebrain, with the most rapid and dramatic period of human central myelination within the first 2 years of postnatal life. It is during this critical period that myelin is initially laid down in virtually all white matter tracts, with the last site to myelinate intracortical fibers of the cerebral cortex, where myelination extends steadily into the third decade.
Normal Development
The process of myelination begins with proliferation of oligodendroglia, which align along axons ( Table 8.1 ). The plasma membranes of the oligodendroglia become elaborated as the myelin membrane of the central nervous system (CNS). Thus myelination is considered best in two phases: first, oligodendroglial proliferation and differentiation, and second, myelin deposition around axons.
Peak time period |
Birth to years postnatal |
Major events |
Oligodendroglial proliferation, migration, differentiation, and alignment → myelin sheaths |
Oligodendroglial Development
The progression of the oligodendroglial lineage (OL) proceeds through four basic stages , beginning with the oligodendroglial progenitor and continuing successively with the preoligodendrocyte, the immature oligodendrocyte, and the mature oligodendrocyte ( Fig. 8.1 ). Oligodendrocytes originate from progenitors in the subventricular zone and also from radial glial progenitors (see Chapter 7 ). The early phase in oligodendroglial lineage arising from progenitors is a mitotically active migratory cell recognized by the monoclonal antibodies A2B5 and NG2. This cell is generated from midgestation to the early postnatal period. As this cell migrates into the cerebral white matter, oligodendroglial differentiation proceeds to the preoligodendrocyte, a multipolar cell that retains proliferative capacity and is recognized by a monoclonal antibody to sulfatide (O4). The waves of migration of these cells may be the anatomical correlate of the periventricular bands visualized on magnetic resonance imaging (MRI) scans of the premature infant. The O4 positive preoligodendrocyte is the predominant oligodendroglial phase before term and accounts for 90% of the total oligodendroglial population until 28 weeks of gestation ( Fig. 8.2 ). (The O4 cell differentiates into the postmitotic immature oligodendrocyte, a richly multipolar cell recognized by a monoclonal antibody to galactocerebroside [O1].) The proportion of O1 cells among the entire oligodendroglial population rises from 5% to 10% before 28 weeks of gestation to 30% to 40% during the premature period and to approximately 50% at term (see Fig. 8.2 ). In the third trimester of gestation, the O1 cells can be observed to develop striking linear extensions as they wrap around axons in preparation for myelination. This premyelination encasement of axons contributes to an important MRI correlate, the increase in directionality of water diffusion measured as increase in relative anisotropy (RA) (see later) ( Fig. 8.3 ). This process is followed by differentiation to the mature oligodendrocyte, a strikingly multipolar cell with membrane sheets and recognition by antibodies to myelin basic protein (MBP) and proteolipid protein. This cell becomes the predominant oligodendroglial stage in the months following term and gives rise to myelination.
Human Myelinogenesis Is Stage-Specific and Initiated Only by the O1 Immature Oligodendroglial Lineage
In the well-studied human optic radiation, cell bodies of immature OLs are present by at least 18 gestational weeks, but the first myelin sheaths are not detected until around 30 weeks. During human parietal white matter development, the percentage of immature OLs in the cerebral white matter remains relatively stable until around 30 weeks, at which time the number of immature OLs increases markedly. One explanation for the prolonged arrest of human immature OLs in a premyelinating state before 30 weeks may be the lack of appropriate extrinsic factors that switch immature OLs to a myelinating phenotype. Axon-dependent mechanisms that involve trophic/growth factors appear to play an important role in the timing of the immature OL commitment to myelinogenesis . The onset of myelination of the optic radiation around 30 weeks coincides with the evolution of the visual evoked response between 32 and 35 weeks to the principal waveforms that closely resemble the mature response that is observed by 39 weeks. Consistent with these observations, there is no apparent contact between immature OLs and axons before the onset of myelinogenesis ( Fig. 8.4 ). The initiation of myelinogenesis around 30 weeks is preceded by the appearance of a subset of specialized OL processes, pioneer processes that contact and wrap around axons. These initial contact sites serve to anchor the OL before it initiates the spiral wrapping of myelin along the same or other axon segments ( Fig. 8.5 ).
There is a transitional phase of myelinogenesis during which the O4O1 premyelin sheath first forms (see Fig. 8.4 ), and then later begins to incorporate MBP. Before active myelination, certain MBP isoforms localize to the oligodendroglial cell body and nucleus and later are selectively transported to intracellular regions of myelin compaction. Hence, the mechanism for spatial segregation of MBP mRNAs to the myelin sheath develops, as OLs become mature myelinating cells. MBP is inserted after the generation of a rudimentary premyelin sheath, providing support for the concept that compact myelin is generated after the insertion of MBP into the premyelin sheath.
Recent neuroimaging studies of living newborns between 24 and 40 weeks postconception with diffusion tensor MRI showed changes in water diffusion that correlate with our morphological data. Thus, in central white matter, RA, a measure of preferred directionality of water parallel to fiber tracts, increases markedly from 28 to 40 weeks. This increase in anisotropic diffusion occurred in parallel with a decline in overall water diffusion, as measured by the apparent diffusion coefficient. This combination of findings implies restriction of diffusion perpendicular to fiber tracts and could relate to the ensheathment of fibers by OL processes, as shown in our study.
The molecular determinants of the process of myelination include a variety of growth factors, hormones, cytokines, surface receptors, and secreted ligands. a
a References .
These molecules include basic fibroblast growth factor, neurotrophin-3, platelet-derived growth factor, insulin-like growth factors, nerve growth factor, transferrin, iron, members of the interleukin-6 family, thyroid hormone, neuregulin, erbB receptors, semaphorins, neuropilin receptors, ephrin, Eph receptors, and Nogo and Nogo receptors. Programmed cell death is an important feature of oligodendroglial development, as it is for neurons (see Chapter 7 ). Data show that approximately 50% of oligodendroglia will undergo apoptosis during development.Myelination in Human Brain Regions
The most informative of the anatomical descriptions of the progress of myelination in the human brain are those by Yakovlev and Lecours and Gilles, Kinney, and co-workers. Using the Loyez method for staining myelin, Yakovlev and Lecours defined the development of myelin in 25 areas of the human nervous system ( Fig. 8.6 ). Because approximately 7 to 10 myelin lamellae are necessary for resolution by light microscopy, it is not surprising that electron microscopic data demonstrated that the onset of myelination in various brain areas occurs several weeks or more before the onset indicated in Fig. 8.6 . Nevertheless, the data of Yakovlev and Lecours provide important information. Several general points can be made on the basis of current knowledge. The process of myelination follows orderly, predictable sequences in which different fiber tracts begin to myelinate before or after birth, and progress at different rates, with tracts that are fast , intermediate , and slow myelinators relative to each other.
Myelination Rules
Myelination follows a set of rules, understanding of which helps in the assessment of the status of myelination in different neurological disorders ( Table 8.2 ). The rules are not inviolate, and one rule may supersede another at a particular time or region. Nevertheless, a general understanding of these rules facilitates understanding of the process, and of human brain development in general. First, myelination begins in the peripheral nervous system, where motor roots myelinate before sensory roots. Second, shortly thereafter and before birth, myelin appears in the CNS in the brain stem and cerebellum in components of some major sensory systems (e.g., medial lemniscus for somesthetic stimuli; lateral lemniscus, trapezoid body, and brachium of the inferior colliculus for auditory stimuli) and in components of some major motor systems (e.g., corticospinal tract in the midbrain and pons and superior cerebellar peduncle). In general, however, and in contrast to the peripheral nervous system, myelination in central sensory systems tends to precede that in central motor systems. Third, myelination within the cerebral hemispheres, particularly those regions involved in higher level associative functions and sensory discriminations (e.g., association areas, intracortical neuropil, and cerebral commissures), occurs well after birth and progresses over decades.
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A study of 162 cases at a single children’s hospital provided further insight into the progress of myelination from prenatal life through childhood. General agreement exists between these data and those obtained by Yakovlev and Lecours, despite the latter’s smaller sample size. The median post-term age at which mature myelin was observed in selected brain areas is depicted in Table 8.3 . Of the major general rules concerning cerebral myelination in the human, five from the anatomical study of Kinney and co-workers should be emphasized: (1) proximal pathways myelinate before distal pathways, (2) sensory pathways myelinate before motor pathways, (3) projection pathways myelinate before cerebral associative pathways, (4) central cerebral sites myelinate before cerebral poles, and (5) occipital poles myelinate before frontotemporal poles. The latter two points are illustrated in Fig. 8.7 . Overall, the fastest changes in myelination occurred within the first 8 postnatal months. The similarities between the neuroanatomical data and findings made in vivo by MRI (see Chapter 10 ) are striking, although MRI showed myelin somewhat earlier, especially in the preterm infant (e.g., myelin in the posterior limb of the internal capsule at 36 postceptional weeks versus 44 weeks in the anatomical study). This difference may relate to the ability of MRI to detect very early myelin wrapping.
≤68 WEEKS | 70–107 WEEKS | 119–142 WEEKS | >144 WEEKS | |
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Sensory system | Optic tract Optic chiasm | |||
Auditory | Brachium inferior colliculus | |||
Other | Tractus solitaries | |||
Pyramidal system | Posterior limb | Pyramid | Cervical CST | |
Midbrain CST | Thoracic CST | |||
Pons CST | Lumbar CST | |||
Extrapyramidal system | Hilus inferior olive Amiculum inferior Capsule red nucleus Peridentate Middle-cerebellar Peduncle | Dentate hilus Ansa lenticularis Pontocerebellar fibers Cerebellum lateral Hemisphere | Globus pallidus | Central tegmental tract |
Central white matter | ||||
Commissures and capsules | Posterior limb Central corona radiate | |||
Limbic system | Stria medullaris thalami | Anterior commissure Outer |
In Tables 8.3 and 8.4 the fiber tracts and white matter regions (e.g., temporal pole) are divided into those sites that begin myelination before and after birth, functional systems, for example, sensory systems versus motor versus limbic, and tempo of myelination, that is, fast (within 6 months), ranging to over 8 months (>144 weeks) without attainment of mature staining by the Luxol Fast Blue method. This representation of the process of myelination highlights fast, intermediate, and slow myelinators. Moreover, the data help to illustrate the point that disease processes that are acute, if early in the first year of life, can preferentially affect fast myelinators, whereas disease processes that extend over protracted periods are likely to detrimentally affect slow myelinating systems.
≤68 WEEKS | 70–109 WEEKS | 119–142 WEEKS | >144 WEEKS | |
---|---|---|---|---|
Sensory system Visual | Optic radiation proximal Optic radiation distal | SAF calcarine cortex | Stripe of Gennari | |
Auditory | Auditory radiation proximal | Heschl’s gyrus | ||
Other | Lateral olfactory stria | |||
Pyramidal | ||||
Extrapyramidal system | Lateral crus pedunculi | Medial crus pedunculi Putaminal pencils | ||
Central white matter | Distal radiation to precentral gyrus Posterior frontal Posterior parietal Occipital pole | Temporal lobe at LGN Temporal pole Frontal pole SAF all sites | ||
Commissures and capsules | Corpus callosum body Splenium | Rostrum Anterior limb External capsule | Anterior commissure Inner | Extreme capsule |
Limbic system | Cingulum | Mammillothalamic tract Alveus, fimbria | Medial fornix Lateral fornix |