The DEVELOPMENT of the NERVOUS SYSTEM Joselito B. Diaz, MD, FPNA COLLEGE OF REHABILITATION SCIENCES

Origin of the Nervous System At day 16 after conception, the embryo consists of three germ layers Ectoderm Mesoderm Endoderm

Neural Plate 3rd week of development, in the dorsum of the embryo, a pear-shaped ectodermal plate rostral to the primitive knot developed The nervous system developed from the neural plate

Neural Plate Notochord and paraxial mesoderm induce the overlying ectoderm to differentiate into the neural plate

Primary Neurulation Rapid cell proliferation at the margins of the neural plate Neural groove forms between the neural folds

Primary Neurulation Neural folds grow towards each other to form the neural tube On the 22nd day, fusion begins at the level of the future lower medulla Closure proceeds in cranial and caudal directions

Primary Neurulation Rostral neuropore closes at the 25th day of gestation Caudal neuropore closes at the 27th day of gestation Rostral 2/3 – brain Caudal 1/3 – spinal cord up to the lumbar area

Neural Crest Cells from the lateral margin of the deepening neural groove Not incorporated in the neural tube but forms temporarily a strip of ectodermal cells between the neural tube and the overlying ectoderm Migrates to the dorsolateral aspect of the neural tube

Neural Crest The neural crest cells give rise to the following structures Dorsal root ganglia Sensory ganglia of cranial nerves (CN V, VII, IX, X) Autonomic ganglia Chromaffin cells of the adrenal medulla Schwann cells Melanocytes Arachnoid and pia mater Mesenchyme of the branchial arches

Secondary Neurulation Caudal neural tube formation i.e. sacral and coccygeal segments Begins at 28th to 32nd day of gestation Caudal eminence enlarges and cavitates Attach to neural tube and cavity becomes continuous

Neural Tube Defects Result in various errors of neural tube closure Accompanied by alterations of axial skeleton as well as of overlying meningovascular and dermal covering Congenital malformations associated with defective primary neurulation are called dysraphic defects Most dysraphic defects occur at the level of the anterior or posterior neuropore

Neural Tube Defects Dysaphic defects in order of decreasing severity Craniorachischisis totalis Anencephaly Rachischisis Encephalocele Spina bifida Congenital abnormalities associated with defective secondary neurulation are known as myelodysplasia

Craniorachischisis Totalis

Anencephaly

Rachischisis

Encephalocele

Encephalocele

Spina Bifida

Spina Bifida Spina bifida occulta Meningocele Myelomeningocele

Tethered Cord

3 Primary Brain Vesicles Following closure of the anterior neuropore, rapid growth of neural tissue in the cranial region On the 4th week of development, the cephalic end shows 3 dilatations, the primary brain vesicles, and 2 flexures

Primary Brain Vesicles Prosencephalon (forebrain) Mesencephalon (midbrain) Rhombencephalon (hindbrain) The caudal portion of the neural tube forms the spinal cord The 3 part brain begins to assume a “C”-shape by the formation of the cephalic flexure at the level of the mesencephalon and the cervical flexure between the hindbrain and spinal cord Primary Brain Vesicles

5 Secondary Brain Vesicles On the 5th week of development, the 3 part brain begins to develop 5 vesicles The prosencephalon subdivides into two parts: telencephalon and diencephalon At the cephalic flexure, the mesencephalon remains tubular and undivided The rhombencephalon subdivides into two parts: metencephalon and myelencephalon

Secondary Brain Vesicles The mesencephalon is separated from the rhombencephalon by a deep furrow, the rhombencephalic isthmus The pontine flexure separates the metencephalon and myelencephalon

Primary Division of the Developing Brain Primary vesicle Primary division Subdivision Adult structures Forebrain vesicle Prosencephalon Telencephalon (lateral ventricles) Cerebral cortex, subcortical white matter, amygdala, basal ganglia, hippocampus, olfactory bulb and tract Diencephalon (third ventricle) Thalamus, hypothalamus, epithalamus, subthalamus, optic nerve and retina Midbrain vesicle Mesencephalon (cerebral aqueduct) Mesencephalon Midbrain Hindbrain vesicle Rhombencephalon (fourth ventricle) Metencephalon Pons, cerebellum Myelencephalon Medulla oblongata

Development of the Spinal Cord

Neuroepithelium After closure, cells of the original single layered tube divide to form a pseudostratified neuroepithelium Also known as matrix cells

Neuronal Proliferation Stem cells in the periphery replicate their DNA then migrate towards the cavity of the tube and divide; the two daughter cells then migrate back to the periphery “to and fro migration” Rate can be 250,000/min

First Wave of Proliferation In the earliest phase, stem cells divide symmetrically to produce two additional stem cells Later phase, asymmetrical division – 1 stem cell and 1 post-mitotic neuronal cell (neuroblast)

Intermediate or mantle zone Ventricular or germinal zone

Second Wave of Proliferation “Switch point” Stem cells stopped making neuroblasts and produces glioblasts The ventricular layer differentiates into the ependymal lining of the ventricles and central canal

Neuroblasts and Glioblasts

Neuroblasts give rise to nerve fibers that grows peripherally and form a layer external to the mantle zone called the marginal zone Mantle zone will form the gray matter while the marginal zone will form the white matter of the spinal cord

Spinal Cord Development As the spinal cord develops, neuroblasts in the mantle layer proliferate in 2 zones In cross section the mantle layer develops a characteristic “butterfly”-shape of gray matter The lateral walls of the tube thicken but leave a shallow, longitudinal groove called the sulcus limitans which separates the developing gray matter Dorsal alar plate Ventral basal plate

Spinal Cord Development The neuroblasts in the basal plate will give rise to the motor neurons of the of the anterior horn The neuroblasts in the alar plate will become the sensory neurons of the posterior horn The lumen of the spinal cord becomes the central canal Anterior median fissure and posterior median septum

Anterior (Ventral) Motor Roots of the Spinal Nerves The medial group of motor neurons form large multipolar cells whose axons supply the musculature of the body The lateral group of motor neurons give rise to autonomic preganglionic fibers (intermediolateral cell column) T1-L2: sympathetic outflow S2-S4: parasympathetic outflow

Posterior (Dorsal) Sensory Roots of the Spinal Nerves The first neurons of the sensory pathway are derived from the neural crest cells Each neuroblast (Dorsal root ganglion cell) develops 2 processes The central processes enter the spinal cord The peripheral processes join the motor axons and becomes the spinal nerve

The Sectional Organization of the Spinal Cord

Positional Changes of the Cord In the first 2 months of development, the spinal cord extends the entire length of the vertebral column and the spinal nerves pass through the intervertebral foramina at their level of origin

Positional Changes of the Cord With increasing age, the vertebral column lengthen more rapidly than the spinal cord At birth, the terminal end of the spinal cord lies at the level of the 3rd lumbar vertebra The anterior and posterior roots of the spinal nerves below L1 descend within the vertebral canal until they reach their appropriate exits through the intervertebral foramina

Positional Changes of the Cord Filum terminale: the slender fibrous strand of pia mater which attach the coccygeal cord to the coccyx Cauda equina: collectively, the anterior and posterior roots of the spinal nerves below L1 and the filum terminale

Development of the Brain

Development of the Brain Neuroblasts of the brainstem develop in a manner similar to the spinal cord From the medulla through the midbrain, alar and basal plates form motor and sensory columns of cells that supply cranial nerves However, the organization of alar and basal plates differ from of the spinal cord in that 1) in the medulla and pons, the alar plate lies lateral to the basal plate, not dorsal to it, since the 4th ventricle is “open” 2) there are migrations of neuroblasts of both plates from the ventricular floor to other locations The diencephalon and cerebral hemispheres develop from the alar plate The cerebellum also develops from the alar plate

Medulla The expansion of fourth ventricle moved the alar plates laterally The neuroblasts at the basal plates form the motor nuclei of the CN IX, X, XI and XII The neuroblasts of the alar plates form the sensory nuclei of the CN V, VIII, IX and X, the gracile and cuneate nuclei and the olivary nuclei

Medulla (Myelencephalon) The roof plate of the myelencephalon consists of a single layer of ependymal cells covered by a vascular mesenchyme, the pia mater The two combined are known as the tela choroidea Vascular tufts of tela choroidea project into the cavity of the fourth ventricle to form the choroid plexus, which produces the cerebrospinal fluid

Medulla (Myelencephalon) Local resorptions of the roof plate occur at the 4th and 5th month of development Lateral foramina of Luschka and median foramen of Magendie Escape of cerebrospinal fluid from the ventricles into the subarachnoid space

Pons (Metencephalon) The pons arises from the anterior part of the metencephalon but also receives cellular contributions form the alar plate of the myelencephalon The neuroblasts of the basal plate form the motor nuclei of the CN V, VI and VII The neuroblasts of the alar plate form the sensory nuclei of the CN V, VII, VIII and the pontine nuclei The axons of the pontine nuclei grow transversely to enter the developing cerebellum

Cerebellum (metencephalon) Formed from the posterior part of the alar plates of the metencephalon On the 5th-6th week of development, the rhombic lips project caudally over the roof plate of the fourth ventricle and unite with each other in the midline to form the cerebellar plate By the 12th week, the plate shows the small midline vermis and two lateral hemispheres

Cerebellum The neuroblasts from the ventricular zone migrates toward the surface of the cerebellum to form the cerebellar cortex Other neuroblasts remain close to the ventricular zone and differentiate into the cerebellar nuclei (dentate, emboliform, globose and fastigial nuclei)

Midbrain (mesencephalon) The midbrain is the least modified of the brainstem structures with regard to basal and alar plates Neuroblasts of alar plates migrate to form the inferior and superior colliculi and the mesencephalic nucleus of CN V Neuroblasts in the basal plates will form the motor nuclei of CN III and IV The embryologic origin of the red nucleus and substantia nigra (from alar or basal plates) are uncertain The cavity of the original neural tube is little modified in the adult midbrain except to be narrowed by growth of the surrounding midbrain structures; it remains as the narrow cerebral aqueduct Midbrain (mesencephalon)

Diencephalon The diencephalon develops from the median portion of the prosencephalon and consists of a roof plate and two alar plates but lacks the floor and basal plates The most caudal part of the roof plate develops into the pineal body or epiphysis The tela choroidea gives rise to the choroid plexus of the third ventricle

Diencephalon The alar plates form the lateral walls of the diencephalon The hypothalamic sulcus divides the plate into a dorsal thalamus and a ventral hypothalamus With continued growth of the thalami, the third ventricle becomes narrowed and the two thalami may fuse forming the interthalamic connection or massa intermedia

Telencephalon The telencephalon consists of two lateral outpocketings, the cerebral hemispheres and a median portion, the lamina terminalis The lateral ventricles communicate with the third ventricle through the interventricular foramina of Monro

Cerebral Hemisphere Each cerebral hemispheres arise at the beginning of the 5th week of development At the basal part of the hemispheres, the corpus striatum arises Dorsomedial portion, the caudate nucleus Ventrolateral portion, the lentiform or lenticular nucleus (putamen and globus pallidus)

Cerebral hemispheres The mesenchyme between the cerebral hemispheres condenses to form the falx cerebri The cerebral hemispheres continue to grow and expand, first anteriorly to form the frontal lobes, then laterally and superiorly to form the parietal lobes and finally posteriorly and inferiorly to produce the occipital and temporal lobes The cortex covering the lentiform nucleus, the insula, lags in growth and later overgrown by the adjacent temporal, frontal and parietal lobes

Cerebral Hemispheres Ascending and descending tracts of the cerebral hemispheres pass between the thalamus and caudate nucleus medially and lentiform nucleus laterally Collectively known as the internal capsule

Cerebral Cortex The neuroblasts from the ventricular zone migrates toward the surface of the cerebral hemispheres to form the cerebral cortex At the final part of fetal life, the surface of the cerebral hemispheres grows so rapidly that many gyri separated by fissures or sulci appear on its surface

Schizencephaly

Lissencephaly

Polymicrogyria

Commissures The lamina terminalis forms a bridge between the two hemispheres and enables nerve fibers to pass from one cerebral hemisphere to the other Anterior commissure: connects the olfactory bulb and the two temporal lobes Fornix: connects the hippocampus in each hemispheres Corpus callosum: massive connection between hemispheres Optic chiasm: contains fibers from the medial halves of the retinae

Myelination in the Central Nervous System Formed by the oligodendroglia At 4th month of development, myelination begins in the sensory fibers in the cervical spinal cord and then extends caudally Myelination in the brain begins at the 6th month but is restricted to the basal ganglia At birth, the brain is largely unmyelinated Myelination is not haphazard but systematic, occurring in different nerve fibers at specific times Myelination within the CNS progresses most rapidly after birth and continues up to adult life

The DEVELOPMENT of the NERVOUS SYSTEM Joselito B. Diaz, MD, FPNA COLLEGE OF REHABILITATION SCIENCES