FETAL BRAIN GROWTH
IN THE FIRST
TRIMESTER
After initial brain morphogenesis is complete, and neural crest migration has established the peripheral nervous system (see Plate 1-4), several bendings, invaginations, and evaginations transform the geometry of the developing brain. The addition of neurons via neurogenesis, which begins in the first trimester, underlies these movements. Neurogenesis reaches a maximum during midgestation to late gestation and ceases (with few exceptions) shortly after birth. Accordingly, as brain morphology emerges, neurons that will form brain circuits differentiate for a lifetime of electrical signaling.
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At 49 days of age (see top, Plate 1-9), the brain and spinal cord undergo further
bending that situates both appropriately in the developing head and trunk. The cephalic
flexure moves the diencephalon and telencephalon nearly parallel with the
hindbrain. The pontine flexure anticipates the location of the
cerebellum and pons, and the cervical flexure positions the spinal cord
parallel to the body axis. At this stage, telencephalic and diencephalic
landmarks are clearly visible: olfactory bulbs in the telencephalon; the
optic cup, eventually located farther from the diencephalon as it
generates the neural retina; the infundibulum (hypophysis), the
rudimentary stalk of the pituitary gland; and the epiphysis, which
forms the pineal gland.
Within 1.5 months, differential
growth yields an even more mature embryonic brain and spinal cord. This
reflects disproportionate growth of the cerebral hemi- spheres (or
neopallium), from the posterior telencephalon, primarily due to addition of
neural stem cells that generate neurons of the mature cerebral cortex. Dysregulation
of this process has dramatic consequences. Mutations that result in microcephaly—dramatic
reduction of cerebral hemisphere size—occur in genes that influence this
expansion of cortical neural stem cells. Disproportionate cerebral hemisphere
growth makes the diencephalon a “deep” structure, occluded from view.
Diencephalic subdivisions, including the thalamus, epithalamus (habenular
nuclei and pineal gland), hypothalamus, and posterior pituitary (neurohypophysis)
are only seen by dissection, imaging, or histologic sectioning.
The hindbrain also undergoes
dramatic changes. The posterior (tectum) and anterior (tegmentum) mesencephalon
becomes distinct: a groove or sulcus divides two evaginating structures: the superior
and inferior colliculi. The superior colliculus integrates visual
information and motor commands for eye and head movements, and the inferior
colliculus localizes sound in register with head movements. The posterior
rhombencephalon expands dramatically as the rudimentary cerebellum becomes
visible. The cerebellum is derived from stem cells in or near the roof of
the fourth ventricle as well as progenitors that migrate from other
rhombencephalic and mesencephalic locations. Local neurogenesis in the roof of
the fourth ventricle, as well as migration of additional progenitors, results
in dramatic cerebellar growth. The anterior rhombencephalon appears as the
rudimentary pons, which expands dramatically as axons from the cerebral
cortex innervate pontine relay neurons that project to the cerebellum.
The final dramatic change during
this period is differentiation of spinal cord regions that innervate limbs or
axial musculature. Posterior to the cervical flexure, the spinal cord appears
broader, a region referred to as the cervical enlargement that includes
larger numbers of motor and sensory relay
neurons that innervate or receive inputs from muscles and sensory receptors in
the shoulders, arms, and hands. The spinal cord then narrows, and this region,
the thoracic cord, includes motor and sensory neurons that innervate or
receive sensory inputs from axial musculature as well as preganglionic
neurons that project to the autonomic ganglia of the sympathetic chain for
central regulation of the sympathetic branch of the autonomic nervous system.
The spinal cord expands again in the lumbar enlargement, reflecting
larger numbers of motor and sensory relay neurons dedicated to the legs and
feet. Finally, the narrow posterior region, the sacral cord, innervates
and receives information from the pelvic and gluteal muscles. Thus
differentiation in the spinal cord reflects distinct functional demands of arms
and legs versus trunk and posterior midline structures.
As brain morphogenesis advances, the
ventricles, defined initially by the space enclosed by the neural tube, become
highly differentiated. The dramatic growth of the cerebral hemispheres is
matched by growth of two bilaterally symmetric lateral ventricles.
Their c shape reflects development
of “deep” telencephalic structures, including the hippocampus and basal ganglia. Continuity between the lateral and third
ventricles (surrounded by the diencephalon) occurs at the intraventricular foramen of Monro. Occluding
this opening leads to one type of noncommunicating hydrocephalus (see below).
Cerebrospinal fluid trapped in the lateral ventricles causes secondary
expansion of the cerebral hemispheres and overlying cranium (a second form, communicating
hydrocephalus, reflects impaired reabsorption of CSF). The third ventricle
also has a modest invagination, the infundibular recess, that reflects
the position of the pituitary gland. The cerebral aqueduct, surrounded
by the mesencephalon, and the fourth ventricle, defined by the
rhombencephalon, become well defined. Occlusion of the cerebral aqueduct— aqueductal
stenosis—is the most common noncommunicating hydrocephalus. In the fourth
ventricle, a series of openings, the foramen of Luschka and Magendie establish
continuity between the ventricles and subarachnoid space between the arachnoid
and the pia, the innermost meningeal layer. These apertures permit
CSF to flow into the subarachnoid space to mechanically cushion the brain as
well as distribute signaling molecules to the developing meninges and the
external surface of the developing brain. Occlusion of these foramina, which is
rare, also leads to noncommunicating hydrocephalus. The fourth ventricle
narrows dramatically in the medulla, defining the central canal that extends most
of the length of the spinal cord.
