A basic knowledge of normal brain development and maturation provides the essential foundation for understanding congenital malformations, the subject of the final part of this book.

This text approaches embryology step by step, discussing different aspects of CNS development with their relevant pathology. Some concepts have already been elucidated in previous chapters. Myelination maturation from birth to age three was discussed in Chapter 31 with inherited metabolic disorders, and development of the ventricles and choroid plexus was presented in conjunction with the discussion of hydrocephalus and CSF disorders in Chapter 34.

Here, we briefly consider normal development of the cerebral hemispheres and cerebellum. We first focus on the basics of neurulation and neural tube closure, then turn our attention to how the neural tube flexes, bends, and evolves into the forebrain, midbrain, and hindbrain. Developmental errors and the resulting malformations that may occur at each stage are briefly summarized. (They are discussed in detail in subsequent chapters.)

Growth of the cerebral hemispheres with their elaboration into lobes, the development of sulci and gyri, patterns of gray matter migration, and layering of the neocortex are all succinctly delineated. Development of the three major brain commissures (corpus callosum, anterior commissure, and hippocampal commissure) is detailed in Chapter 37 as a prelude to our consideration of callosal anomalies.

We then touch lightly on the complex choreography required for proper development of the midbrain and hindbrain structures (pons, cerebellum, and medulla). We include a brief discussion of how the midbrain and cerebellum develop. The final section of this chapter suggests an approach to analyzing brain malformations.

Cerebral Hemisphere Formation

The major embryologic events in brain development begin with neurulation, neuronal proliferation, and neuronal migration. The processes of operculization, gyral and sulcal development, and the earliest steps in myelination all take place later, between gestational weeks 11 and birth.

Neurulation

Neural Tube and Brain Vesicles

(35-1) Graphic shows the formation and closure of the neural tube. The neural plate (red) forms, folds, and fuses in the midline. The neural and cutaneous ectoderm then separate. Notochord (green) and neural crest (blue) are shown.

develops at the cranial end of the embryo as a thickening of ectoderm on either side of the midline.

During the fourth fetal week, the neural plate indents and thickens laterally, forming the neural folds. The neural folds bend upward, meet in the midline, and then fuse to form the neural tube. The primitive notochord lies ventral to the neural tube, and the neural crest cells are extruded and migrate laterally. The neural tube forms the brain and spinal cord, whereas the neural crest gives rise to peripheral nerves, roots, and ganglia of the autonomic nervous system (35-1).

As the neural tube closes, the neuroectoderm (which will form the CNS) separates from the cutaneous ectoderm in a process known as disjunction. Upon completion of disjunction, the cutaneous ectoderm fuses in the midline, dorsal to the closed neural tube.

Neural tube closure probably begins at two or three levels in the middle of the embryo (35-2). Closure proceeds bidirectionally in a zipper-like fashion along the length of embryo. The cephalic and caudal ends of the neural tube (the so-called anterior and posterior neuropores) do not fuse until the twenty-fifth and twenty-seventh gestational days, respectively.

Three primary brain vesicles—the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain)—also form during the fourth week. The embryonic brain grows rapidly and begins to bend, forming several flexures (35-3).

During the fifth week, the forebrain further divides into two vesicles, forming the telencephalon and the diencephalon. The hindbrain divides into the metencephalon and

(35-2) The neural tube closes in a bidirectional zipper-like manner, starting in the middle and proceeding toward both ends.

myelencephalon. Together with the mesencephalon, the brain now has five definitive or "secondary" vesicles (35-4).

Neurulation Errors

Errors in neurulation result in a spectrum of congenital anomalies. The most severe is anencephaly—essentially complete absence of the cerebral hemispheres—which is caused by failure of the anterior neuropore to close (see Chapter 38). Various types of cephaloceles also result from abnormalities of neurulation.

Incomplete closure of the posterior neuropore results in spina bifida. If the neuroectoderm fails to separate completely from the cutaneous ectoderm, myelomeningocele results.

Abnormal neurulation of the hindbrain leads to a Chiari 2 malformation (see Chapter 36).

Neuronal Proliferation

Embryonic Stem Cells

Pluripotent embryonic stem cells are derived from the inner cell mass of the 4- to 5-day blastocyst. These cells are able to proliferate and differentiate into all three germ layers (ectoderm, mesoderm, endoderm). MicroRNAs seem to play an important role as genetic regulators of stem cell development, differentiation, growth, and neurogenesis.

Histogenesis of Neurons and Glia

As the cerebral vesicles develop and expand, layers of stem cells arise around the primitive ventricular ependyma, forming the germinal matrix. These neural stem cells (NSCs) are multipotent cells that generate the main CNS phenotypes, i.e.,

(35-3) Development of primary vesicles is depicted. The prosencephalon (green) gives rise to the forebrain, the mesencephalon (purple) to the midbrain, and the rhombencephalon (light blue) to the hindbrain.

neurons, astrocytes, and oligodendrocytes. NSCs are found primarily in the germinal zones (see Chapter 16).

Pluripotent NSCs in the specialized subventricular zone of the germinal matrix give rise to neuroblasts ("primitive" or "young" neurons) that migrate through the developing telencephalon to form the cortical mantle zone, the precursor of the definitive cortex. Axons from the migrating neurons form an intermediate zone between the germinal matrix and cortical mantle that will eventually become the cerebral white matter.

Some NSCs become specialized radial glial cells (RGCs) that will eventually span the entire hemisphere from the ventricular ependyma to the pia. RGCs are also stem cells and can give rise to both neurons and glia. Elongated cell bodies of the RGCs serve as a "rope ladder" that guides migrating neurons from the germinal matrix to the cortex.

Astrocytes arise from two sources: glial progenitor cells in the ventricular zone and RGCs in the intermediate zone. Oligodendrocytes arise from oligodendrocyte precursor cells in the ventricular and subventricular zones. Before differentiating into myelinating oligodendrocytes, these precursor cells proliferate, migrate, and then spread throughout the CNS.

Errors in Histogenesis

Errors in histogenesis and differentiation result in a number of embryonal neoplasms, including medulloblastoma and primitive neuroectodermal tumors. Problems with NSC proliferation and differentiation also contribute to malformations of cortical development (see below).

(35-4) The brain develops flexures as prosencephalon gives rise to telencephalon (green) and diencephalon (red). Mesencephalon (purple) elongates while rhombencephalon gives rise to metencephalon (yellow) and myelencephalon (light blue).

Neuronal Migration

As a result of steadily improving imaging techniques, malformations of cerebral cortical development (MCDs) are now being identified with greater frequency. Understanding how neurons are formed, migrate, organize, and then connect is essential to recognizing and understanding MCDs.

Genesis of Cortical Neurons

Neurogenesis occurs in a predictable manner with sequential generation of specific neural subtypes from designated areas in the germinal matrix. For example, glutamatergic cerebral cortical neurons arise in dorsal ventricular zones, whereas GABAergic neurons destined for the striatum originate in the more ventral zones.

Once the "young" neurons have been generated in the germinal matrix and dorsal ventricular zones, they must leave their "home" to reach their final destination (the cortex). The definitive cerebral cortex develops through a highly ordered process of neuronal proliferation, migration, and differentiation. The neocortex of the cerebral hemispheres has six cell layers, each with its own distinctive pattern of organization and connections.

Neuronal Migration

Migration of newly proliferated neurons occurs along scaffolding provided by the RGCs. Neurons travel from the germinal zone to the cortical mantle in a generally "inside-out" sequence. Cells initially form the deepest layer of the cortex with each successive migration ascending farther outward and progressively forming more superficial layers. Each migrating

(35-5) Embryonic brain at 22 weeks is mostly agyric with shallow lateral cerebral (sylvian) fissures . Prosencephalon (green), metencephalon (yellow), myelencephalon (light blue) are shown. Mesencephalic and midbrain structures are not visible.

group passes through layers already laid down by the earlierarriving cells.

Peak neuronal migration occurs between 11-15 fetal weeks although migration continues up to 35 weeks.

Errors in Neuronal Migration and Cortical

Organization

The primary result of errors at these stages are malformations of cortical development. Problems with NSC proliferation or differentiation, migration, and cortical organization can all result in developmental anomalies of the neocortex. Examples include microcephaly, megalencephaly, heterotopias, cortical dysplasias, and lissencephaly.

Operculization, Sulcation, and

Gyration

Lobulation and Operculization

The cerebral hemispheres first appear as outpouchings of the embryonic telencephalon. The hemispheres are initially almost featureless; the cortex is thin and smooth. The fetal cerebral vasculature covers the brain surface in a basket-like network of thin-walled, undifferentiated vessels.

The cerebral hemispheres expand, first covering the diencephalon and then the midbrain and hindbrain. The roofs of the hemispheres grow more rapidly than the floors. As the hemispheres elongate and rotate, they assume a "C" shape with the caudal ends turning ventrally to form the temporal lobes.

(35-6) With advancing gestational age, multiple secondary and tertiary gyri develop, and the number and complexity of the cerebellar folia increase.

Sulcation and Gyration

Sulcation and gyration—the progressive folding of the telencephalon into a complex pattern of lobes and gyri—occurs relatively late in embryonic development. Shallow triangular surface indentations along the sides of the hemisphere—the beginnings of the lateral cerebral (sylvian) fissures—first appear between the fourth and fifth fetal months (35-5).

As the forebrain enlarges, the emerging frontal, parietal, and temporal lobes begin to overhang the lateral fissures, forming the opercula. As the opercula develop and the lateral indentations deepen, cortex that was once on the brain surface becomes completely covered (35-6). This tissue—now buried in the depths of the lateral cerebral (sylvian) fissures—forms the insula ("island of Reil"). The sylvian fissures gradually lose their "open" fetal configuration and assume their narrow slit-like adult configuration.

The definitive middle cerebral arteries follow the indented surfaces of the insulae, first dipping into and then out of the sylvian fissures to ramify over the lateral surfaces of the frontal, parietal, and temporal lobes.

After the sylvian fissures form (35-7), the next groups of surface indentations to appear are the calcarine and parietooccipital sulci (35-8), followed by the central sulci (35- 9). Gyral development occurs most rapidly around the sensorimotor and visual pathways.

Anomalies in Sulcation and Gyration

Developmental errors in operculization, sulcation, and gyration are relatively uncommon. Microcephaly with

(35-7A) Axial T2WI shows a 26-week, 5-day premature infant. The lateral cerebral (sylvian) fissures are just beginning to form. The hypointensity around the ventricles is mostly in the germinal matrix.

simplified gyral pattern and microlissencephaly are representative anomalies that have too few gyri and abnormally shallow sulci.

Myelination

Myelination occurs in an orderly, predictable manner and can be detected as early as 20 fetal weeks. Normal brain myelination patterns as well as abnormalities in myelin formation and maintenance are discussed in greater detail in Chapter 31. In general, myelination proceeds from inferior to superior, from back to front, and from central to peripheral.

Midbrain and Hindbrain

Development

We now summarize the major embryologic events involved in forming the midbrain and hindbrain. A description of the consequences of errors in their development follows.

Major Embryologic Events

The mesencephalon gives rise to the brainstem, and the rhombencephalon elaborates into the medulla, pons, and cerebellum. Each is "patterned" along both the rostral-caudal and dorsal-ventral axes. The mesencephalon is divided into ventral (tegmentum) and dorsal (tectum) regions. Likewise, the metencephalon is divided into ventral (pons) and dorsal (cerebellum) regions.

The pons is formed by a proliferation of cells and fiber tracts along the ventral metencephalon. The alar plates of the rhombencephalon ("rhombencephalic lips") thicken to form

(35-7B) Image through the corona radiata shows that the brain is almost completely smooth with only a few shallow sulci. Waves of hypointense migrating neurons give the WM a layered and "smudgy" appearance.

cerebellar plates, which in turn proliferate and eventually form the two cerebellar hemispheres and midline vermis. Embryologically, the cerebellum is an extension of the midline and thus part of the dorsal pons.

The rhombencephalic lips fuse, forming the cerebellar commissures in the roof of the fourth ventricle. Each hemisphere subsequently fuses and fissures in a cranial-to- caudal direction.

Formation of the fourth ventricle is a complex process. A ridge of developing choroid plexus divides the emerging fourth ventricle into anterior and posterior membranous areas. Normally, the anterior membrane is incorporated into the developing choroid plexus, whereas the posterior membranous area persists and eventually cavitates, forming the midline foramen of Magendie. Precisely how and when the lateral foramina open is unknown.

Midbrain-Hindbrain Anomalies

A number of different classifications of midbrain and hindbrain malformations have been proposed. Barkovich et al. use an approach that categorizes lesions according to developmental and genetic considerations. Such a system makes consummate sense and certainly aids understanding the pathogenesis of these fascinating anomalies. However, the more traditional morphologic-based approach in which malformations are grouped according to imaging findings is the simplest for radiologists to follow. The interested reader is referred to the publications cited at the end of Chapter 36.