Download DEVELOPMENT OF NERVOUS SYSTEM 3rd week – neural plate

DEVELOPMENT OF NERVOUS SYSTEM
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3rd week – neural plate/groove develop
Notochord and paraxial mesenchyme induce ectoderm to differentiate
o  neural plate
Signaling molecules important to these processes
o TGF-beta
o Shh (sonic hedgehog)
o BMPs
Neural tube differentiates into CNS
Neural crest gives rise to cells forming most of PNS/ANS
@ 22 days (3-4 weeks), neural folds have fused
o Except at the ends, where they are still spread apart
Neurulation – formation of the neural plate and tube
o Begins during 4th week
o Cranial 2/3 of plate and tube = future brain
o Caudal 1/3 of plate and tube = future spinal cord
o Fusion of the neural folds proceeds both cranially and caudally
 Only small areas of the tube remain open at both ends
o Lumen of the neural tube becomes neural canal
 This communicates w/ amniotic cavity
o Rostral neuropore closes @ 25th day, caudal neuropore closes @ 27th
Closure of the neuropores coincides w/ establishment of vascular circulation for the tube
The walls of the neural tube thicken to form brain and spinal cord
Neural canal forms ventricular system of brain
o Also forms central canal of the spinal cord
Nonclosure of neural tube
o Theory is that there are multiple, possibly five, closure sites involved in tube formation
DEVELOPMENT OF SPINAL CORD
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Spinal cord develops from caudal part of neural plate and caudal eminence
Central canal forms from thickening of neural tube walls
Wall of neural tube is made of neuroepithelial cells
o These make up the ventricular zone, or ependymal layer
 This gives rise to all neurons and macroglial cells in spinal cord
 Macroglial cells are larger members of neuroglial cell family
 Includes astrocytes and oligodendrocytes
o The outer parts of the neuroepithelial cells form a marginal zone
 This becomes white matter of spinal cord
 Axons grow into marginal zone from nerve cell bodies
Some neuroepithelial cells in the ventricular zone divide
o They differentiate into neuroblasts
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These neuroblasts form an intermediate zone
 Between ventricular and marginal zones
o Neuroblasts become neurons as they develop cytoplasmic processes
After neuroblast formation is done, more neuroepithelial cells divide
o These differentiate into glioblasts
 Supporting cells of CNS
 Glioblasts migrate from ventricular zone into intermediate/marginal zones
 Some become astrocytes
 Others become oligodendrocytes
Now that glioblast formation is finished, neuroepithelial cells divide into yet another cell type
o Ependymal cells – form the ependyma
 The ependymal lines the central canal of the spinal cord
Neuroepithelial progenitor cells are controlled by sonic hedgehog (not a joke)
Microglia – scattered throughout gray/white matter
o Derived from mesenchymal cells
o Microglia invade the CNS late in the fetal period
 By this time the CNS has been vascularized
o They originate in bone marrow
o They are part of the mononuclear phagocytic cell group
All this craziness done by the neuroepithelial cells has now changed the shape of neural tube
o Walls are thick, roof/floor-plates are thin
o Differential thickening occurs in walls of spinal cord
 This forms a shallow longitudinal groove on each side of the spinal cord
 Groove is called sulcus limitans
 It separates the alar plate from the basal plate
 Alar plate is dorsal, basal plate is ventral
Alar and basal plates make longitudinal bulges thru most of the developing spinal cord
o This regional separate is important
 The alar plate becomes associated w/ afferent functions
 The basal plate becomes associated w/ efferent functions
Cell bodies in alar plates make dorsal gray columns
o These extend the length of the cord
o Neurons in these columns constitute afferent nuclei
Alar plates enlarge and form dorsal median septum
Cell bodies from basal plates make the ventral AND lateral gray columns
o Axons of ventral horn (ventral column in transverse section) grow out of cord
 They then form the ventral roots of spinal nerves
Basal plates enlarge and bulge ventrally on each side of median plane
o This forms the ventral median septum
o It also forms the ventral median fissure
 A deep longitudinal groove on the ventral surface of spinal cord
DEVELOPMENT OF SPINAL GANGLIA
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Neurons in spinal ganglia are derived from neural crest cells
Both processes of spinal ganglion cell have axon structure characteristics
o But the peripheral process is a dendrite b/c there is conduction towards cell body
Peripheral processes of spinal ganglion cell pass in spinal nerves
o They go to sensory endings in somatic or visceral structures
Central processes enter spinal cord
o They constitute the dorsal roots of spinal nerves
DEVELOPMENT OF MENINGES
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Meninges develop from neural crest cells and mesenchyme
o During days 20 (week 3) and 35 (week 5)
o These migrate to surround the neural tube
o And this forms the primordial meninges
o External layer thickens to form dura mater
o Internal layer is made of pia mater and arachnoid mater
 Collectively called leptomeninges
 Fluid-filled spaces appear in the leptomeninges
 These form the subarachnoid space
 In an adult, arachnoid trabeculae are evidence of the single-layer origin
CSF forms during 5th week
POSITIONAL CHANGES OF SPINAL CORD
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In the embryo, the spinal cord extends the entire length of the vertebral canal
Spinal nerves pass thru intervertebral foramina
o They pass thru OPPOSITE their level of origin
Vertebral column and dura mater grow faster than cord
o This changes the positional relationship of the spinal nerves
o In an adult, the cord usually ends inferior to L1
o Spinal nerve roots run obliquely
 From cord to corresponding level of vertebral column
o Nerve roots inferior to end of cord (medullary cone) form a structure
 This structure is a bundle of spinal nerve roots called cauda equine
 It arises from the lumbosacral enlargement and medullary cone
o Dura and arachnoid mater usually end at S2 in adult
 But pia mater does not
 Distal to caudal end of cord, it forms a long thread
o The filum terminale
o This indicates the original level of the caudal end of cord
o It extends from medullary cone to first coccygeal vertebra
MYELINATION OF NERVE FIBERS
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Myelin sheaths start to form during late fetal period
o They continue to form during first postnatal year
Beta-1 integrins regulate the process
Fiber tracts start working when they become myelinated
Motor roots get myelinated before sensory
Oligodendrocytes myelinate fibers of spinal cord
Myelin sheaths around axons of peripheral nerve fibers are made
o This Is done by neurolemma, or sheath of Schwann cells
 These are analogous to oligodendrocytes
 Neurolemma are derived from neural crest cells
 The neural crest cells migrate peripherally around axons of neurons
o At 20 weeks, peripheral nerve fibers have white appearance
 This is caused by the myelin deposition
BIRTH DEFECTS IN SPINAL CORD
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Most defects are due to failure of fusion of neural arch(es)
o This can happen during 4th week
Neural tube defects affect tissues over spinal cord
Birth defects of embryonic neural arches are called spina bifida
o Spina bifida = nonfusion of halves of the neural arches
Dermal sinus
o Associated w/ closure of tube and formation of meninges in lumbosacral cord
o Caused by failed detachment of surface ectoderm from neuroectoderm/meninges
o This cause meninges to be continuous with a narrow channel
 This narrow channel leads to a dimple of the skin @ sacral region
 This indicates region of closure of caudal neuropore
 And the last place of separation between surface ectoderm and tube
Spina bifida occulta
o Results from failure of embryonic halves of neural arches to fuse
o Happens in L5/S1 vertebra of 10% of normal folks
Spina bifida cystica
o Diverse group of disorders, all w/ protrusion of spinal cord/meninges thru defect
 This defect is in the vertebral arch
o There is a meningeal cyst associated with these defects, hence the name
o If cyst has meninges and CSF
 it is called spina bifida w/ meningocele
 Spinal cord/roots are normally positioned
o BUT may be spinal cord defects
o If cord and/or roots are contained within cyst
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Defect is called spina bifida w/ meningomyelocele
 Severe cases may involve many vertebrae and be assoc’d w/ calvaria
o Calvaria is partial absence of brain
o There may also by facial abnormalities (meroencephaly)
o Death is inevitable
o Spina bifida cystica typically has corresponding dermatome loss
 Along with skeletal muscle paralysis
 Level of lesion determines area of anesthesia and muscles affected
 Sphincter paralysis is common w/ lumbosacral meningomyelocele
 Almost always causes saddle anesthesia
o Meroencephaly is suspicious in utero if there is a high AFP level in amniotic fluid
 Amniocentesis is used on pregnant women with high serum AFP
o Ultrasound is useful imaging modality
Meningomyelocele is more common than meningocele
o Some cases may have craniolacunia
 This is defective calvaria development
 This causes depressed, nonossified areas of inner bone surface of calvaria
Myeloschisis
o Most severe type of spina bifida
o Spinal cord is open in affected area
 This is because neural folds failed to fuse
o Cord appears as flattened mass of nervous tissue
o Defect causes permanent paralysis/weakness of lower limbs
Etiology
o Folic acid supplementation by mom reduces incidence of neural tube defects
o Low B12 levels may increase risk for NTDs
o Drugs such as valproic acid increase risk
DEVELOPMENT OF BRAIN
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Brain begins to form in third week when neural plate/tube are developing
Cranial aspect of neural tube becomes brain
Fusion of neural folds in cranial regions and closure of rostal neuropore occur
o This makes three primary brain vesicles
 Forebrain (prosencephalon)
 Midbrain (mesencaphelon)
 Hindbrain (rhomboencephalon)
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5 week – forebrain divides into 2 secondary brain vesicles
o Telencephalon and diencephalon
Midbrain does not divide
Hindbrain partly divides into 2 vesicles
o Metencephalon and myelencephalon
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So now you have 5 secondary brain vesicles
Brain then bends ventrally with head fold
o This produces midbrain flexure and cervical flexure
Later on, unequal growth of brain between these flexures produces a new flexure
o It is called the pontine flexure
o It goes in the opposite direction
o This thins the roof of the hindbrain
Initially, the brain looks a lot like the spinal cord
o But the brain flexures give it some variation
o The sulcus limitans goes cranially to junction of midbrain/forebrain
o Alar and basal plates can only be seen in the midbrain and hindbrain
HINDBRAIN
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Cervical flexure separates hindbrain from spinal cord
o This later becomes the neighborhood of C1 near foramen magnum
The pontine flexure divides hindbrain into two parts
o Caudal (myelencephalon) part
 This becomes the medulla
o Rostral (metencephalon) part
 This becomes the pons and cerebellum
Cavity of hindbrain becomes 4th ventricle and central canal of medulla
Myencephalon
o Caudal part resembles spinal cord
o Neural canal forms central canal
o Unlike in spinal cord, neuroblasts from alar plates go to marginal zone
 Where they form gray matter
 Gracile nuclei medially
 Cuneate nuclei laterally
 Correspondingly-named tracts enter medulla from spinal cord
o Ventral part of medulla has pyramids
 These are made of corticospinal fibers coming down from cerebral cortex
o Pontine flexure moves lateral walls of medulla further out
 This stretches the roof plates
 Cavity of future fourth ventricle becomes rhomboid-shaped
 Alar plate now lies lateral to basal plates
 Motor nuclei develop medial to sensory nuclei
o Neuroblasts in basal plates of medulla develop into motor neurons
 This also happened in the spinal cord
 Neuroblasts make 3 cell columns on each side:
 General somatic efferent (most medial)
o Neurons of hypoglossal nerve
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Special visceral efferent
o Neurons to muscles from pharyngeal arches
 General visceral efferent (most lateral)
o Neurons of vagus/glossopharyngeal nerves
o Neuroblasts in alar plates of medulla form 4 columns on each side
 General visceral afferent (most medial)
 Gets impulses from viscera
 Special visceral afferent
 Gets taste fibers
 General somatic afferent
 Gets impulses from head surface
 Special somatic afferent
 Gets impulses from ear
o Some neuroblasts from alar plates migrate ventrally
 They then form neurons in the olivary nuclei
Metencephalon
o Walls form pons and cerebellum
o Cavity forms superior part of 4th ventricle
o Just like in rostral part of myelencephlon, pontine flexure splits the walls of pons
 This spreads the gray matter into 4th ventricle floor
o Just like in the myelencaphelon, neuroblasts in basal plate make 3 motor nuclei per side
o Cerebellum develops from dorsal alar plates
 Swellings first impinge on 4th ventricle, then enlarge/fuse in median plne
 They then overgrow rostral half of 4th ventricle and ovelap pons/medulla
o Neuroblasts in intermediate zone of alar plates go to marginal zone
 There, they differentiate into neurons of cerebellar cortex
o Other neuroblasts make central nuclei
 The largest of these is the dentate nucleus
o Cells from alar plates also create
 Pontine nuclei
 Cochlear and vestibular nuclei
 Sensory nuclei of trigeminal nerve
o Cerebellum structure:
 Flocculonodular lobe
 Has connections w/ vestibular apparatus
 Vermis and anterior lobe
 Associated w/ sensory data from limbs
 Posterior lobe
 Selective control of limb movements
o Nerve fibers connect cerebral/cerebellar cortices w/ spinal
 They then pass thru the marginal layer of ventral part of metencephalon
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This regions of brainstem is called pons
o Band of nerve fibers crosses median plane and forms ridge
CHOROID PLEXUSES AND CEREBROSPINAL FLUID
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Thin ependymal roof of 4th ventricle is covered by pia mater
o This came from mesenchyme of hindbrain
o This membrane + ependymal roof = tela choroidea
 This invaginates the fourth ventricle
 In the ventricle, it differentiates into choroid plexus
o These are arteries of pia mater
 Same thing then happens in 3rd ventricle and lateral ventricles
Choroid plexuses secrete ventricular fluid
o This becomes CSF
Thin roof of 4th ventricle evaginates in three places
o 2 foramen of Luscha (lateral)
o 1 foramen of Magendia (medial)
o These let CSF enter the subarachnoid space from 4th ventricle
Main place CSF gets absorbed into venous system is called arachnoid villi
o These are protrustions of arachnoid mater into dural venous sinuses
MIDBRAIN
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Undergoes the least change of any part of brain except caudal hindbrain
Neural canal narrows to become cerebral aqueduct
Neuroblasts migrate from alar plate of midbrain
o They go to the tectum (roof) and aggregate to form four large neuron groups
 1 pair of superior colliculi
 Visual reflexes
 1 pair of inferior colliculi
 Auditory reflexes
 These look like a set of 4 Dippin’ Dots sitting on the midbrain
Neuroblasts from basal plates create various neuron groups in tegmentum of midbrain
Substantia nigra is a layer of gray matter next to the cerebral peduncle
Fibers growing from cerebrum form the crus cerebri (cerebral peduncles) anteriorly
o They become more prominent as more descending fiber groups pass thru midbrain
FOREBRAIN
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As rostral neuropore closes, two outgrowths appear
o Optic vesicles – one on each side of forebrain
 These will form retinae and optic nerves
Also, telencephalic vesicles arise
o These will make the cerebral hemispheres
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 Their cavities will become lateral ventricles
Rostral part of forebrain is telencephalon
Caudal part is diencephalon
The cavities of these two ^^^ contribute to the 3rd ventricle, helped by the diencephalon
DIENCEPHALON
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In 3rd ventricle, 3 swellings appear; they later become the
o Thalamus, hypothalamus, epithalamus
Thalamus develops on each side of 3rd ventricle
o They meet and fuse in the midline in most brains
 This forms a bridge of gray matter called the interthalmic adhesion
Hypothalamus comes from proliferation of neuroblasts in intermediate zone of diencephalon
o This involves differential expression of Wnt/beta-catenin signaling
o Nuclei for endocrine and homeostasis activites develop
o Mammillary bodies form pea-sized swellings on ventral hypothalamus
Epithalamus comes from roof and wall of diencephalons
Pineal gland develops as diverticulum of diencephalon roof
Pituitary gland is ectodermal in origin and comes from two sources:
o Hypophysial diverticulum
o Neurohypophysial diverticulum
This explains the double origin of the pituitary gland tissue:
o Adrenohypophysis from oral ectoderm
o Neurohypophysis from neuroectoderm
@ 3rd week, hypophysial diverticulum starts to project/elongate/constrict from stomodeum roof
o By 5th week, it has contacted the infundibulum
 This is a ventral downgrowth of diencephalon
Stalk to hypophysial diverticulum goes between chondrification centers of cranial bones
6th week – connection of diverticulum w/ oral cavity degenerates
Cells of wall of diverticulum proliferate to make the pars anterior of pituitary gland
o Later an extension grows around infudibular stem
 Called the pars tuberalis
On other side of diverticulum wall, pars intermedia appears
Neurohypophysis
o Infundibulum creates median eminence, infundibular stem, and pars nervosa
o Distal infundibulum becomes solid
o Pituicytes form from neuroepithelial cells
 These are close relatives of neuroglial cells
o Infundibular stem attaches to hypothalamic area
TELENCEPHALON
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Made up of median part and two lateral diverticula
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Lateral diverticula are called cerebral vesicles
 These will make the cerebral hemispheres
o Cavity of median part forms anterior part of 3rd ventricle
Along choroid fissure, medial wall of cerebral hemisphere becomes thin
o This later becomes the choroid plexus of lateral ventricle
Cerebral hemispheres expand and cover, in order:
o Diencephalon, midbrain, then hindbrain
o Hemispheres eventually run into each other
 Mesenchyme sandwiched in the longitudinal fissure  cerebral falx
 This is made of dura mater
Corpus striatum shows up @ week 6
o It is a swelling on floor of cerebral hemisphere
o This structure “puts the brakes” on the expansion of the hemisphere floor
 But the cortical walls keep on growing
 This leads to the C-shape of the cerebral hemispheres
 Consequently, the lateral ventricle adjust and also get C-shaped
Caudal end of cerebral hemisphere turns ventral and rostrally
o This forms the temporal lobe
 Since the lateral ventricle and choroid fissure are also carried…
 … the temporal horn of the lateral ventricle is also formed
o Here, the hemisphere wall gets invaginated
o This happens along the choroid fissure by pia mater
o This forms choroid plexus of temporal horn
Cerebal cortex differentiates and corpus striatum gets divided
o It divides into caudate and lentiform nuclei
o The pathway of fibers that made the division is called the internal capsule
CEREBRAL COMMISSURES
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Cerebral commisures are groups of nerve fibers
o These fibers connect corresponding parts of the hemispheres
One important commissure crosses in the lamina terminalis
o This is in the rostral end of forebrain, around the diencephalon and optic chiasm
o This is the natural pathway from one hemisphere to another
First commissures that form are anterior and hippocampal commissures
o Anterior connects olfactory bulbs and related areas
o Hippocampal connects… well, hippocampal formations!
The largest cerebral commissure is the corpus callosum
o This extends beyond the lamina terminalis
The rest of the lamina terminalis is between the corpus callosum and fornix
o It gets stretched and becomes the septum pellucidum
Optic chiasm forms ventral lamina terminalis
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It comes from medial retinae fibers
 These cross to join the optic tract of the opposite side
Walls of the hemispheres initially have 3 typical zones of neural tube
o Ventricular, intermediate, and marginal
o Later, a fourth one joins the fun
 This is the subventricular zone
o Cells of intermediate zone migrate to marginal zone
 This gives rise to cortical layers
o Peripherally-located gray matter passes axons centrally
 These form the white-matter body called the medullary center
Gyri and sulci appear due to infolding of the cerebral cortex
o This allows a pretty big increase in surface area
The cortex over the corpus striatum grows slowly
o The corpus striatum is forgotten about and overgrown
 It becomes the insula (island)
 It lies beneath what is called the lateral sulcus
BIRTH DEFECTS OF BRAIN
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Abnormal histogenesis of cerebral cortex  seizures and mental problems
Embryo/fetus exposed to virus/radiation during weeks 8-16  intellectual maldevelopment
Prenatal factors such as infection, thyroid disorder, and Rh factor  cerebral palsy
Encephalocele
o Herniation of intracranial contents thru defect in cranium
o Most common in occipital region
o Hernia has various combinations of meninges, brain, and ventricular system
Merocencephaly
o Severe defect of calvaria/brain
o Caused by failure of rostral neuropore to close @ 4th week
o Most of fore/mid/hind brain and calvaria are absent!
o Most of the embryo’s brain is sticking out of the cranium (exencephaly)
o Nervous tissues degenerates and nothing is left but spongy hindbrain
o A common lethal defect
 More common in females
o Acrania – complete/partial absence of neurocranium – always co-occurs
o May have rachischisis if tube closure defect is really bad
o Most common severe defect in stillborn fetuses
o Could be caused by excess amniotic fluid
 Maybe from fetus not being able to swallow fluid  placenta
Microcephaly
o Calvaria and brain are small
 But face is normal size
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Gross mental deficiency occurs b/w brain is underdeveloped
This is caused by inadequate pressure from the growing brain
If autosomal recessive, embryonic growth is reduced
 But brain structure is unaffected
o Exposure to radiation, infectious agents, and drugs can contribute to risk
o Small head could result from premature synostosis (osseous union) of sutures
Agenesis of corpus callosum
o May be asymptomatic
o Seizures and mental problems are common
Hydrocephalus
o In rare cases, caused by choroid plexus adenoma
o Impaired circulation could be from congenital aqueductal stenosis
 This is often X-linked
 But most of the time, it is viral or intraventricular hemorrhage
o Blood in subarach space  cisterns/arach villi damage
 Called nonobstuctive/communicating hydrocephalus
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o All ventricles enlarged if 4 ventricle or subarach spaces are blocked
o Only lateral and 3rd ventricles enlarged if cerebral aqueduct is blocked
o Often causes thinning of calvaria bones, prominent forehead…
o … atrophy of cerebral cortex/white matter…
o … and compressed basal ganglia/diencephalon
Holoprosencephaly
o Caused by incomplete separation of hemispheres
o Most include facial abnormalities
o Materal diabetes and teratogens contribute
o Eyes may be abnormally close together
Hydranencephaly
o Hemispheres are absent or consist of nothing but membranous sacs
o Infants could be normal at birth, but head grows excessively afterwards
o Ventriculoperitoneal shunt prevents further enlargement of neurocranium
o Mental development and cognitive development fail
o May be from early blockage of blood flow to areas served by internal carotid aa
Arnold-chiari malformation
o Most common birth defect of cerebellum
o Tongue-like projection of medulla
o Inferior displacement of vermis  foramen magnum  cervical canal
o Absorption of CSF is compromised
 Entire ventricular system is distended
o Posterior cranial fossa is unusually small
Mental deficiency
o Can be caused by maternal alcohol abuse, metabolic disorders, infections, trauma, etc.
o Weeks 8-16 is period of greatest sensitivity to brain damage from radiation