Developmental Stages:

1. Pre-embryonic stage: conception to 14 days

2. Embryonic: 15 days to the end of 8th week

3. Fetal: 8th week to birth

The timeline starts from day of fertilization = Day 1

The formation of the nervous system occurs during the embryonic stage in 2 phases

Phase 1 - Day 18 to 26 (Neural Tube Formation)

Phase 2 - Day 28 onward (Brain Formation)

Neural Tube Development: Neurulation

1. starts as a flat disc of cells of neuroepithelial cells (neural stem cells) → creating the neural plate ( from the Neuro-ectoderm)

2. Convergence occurs as the neural plate boarders are drawn together, It folds/fuses dorsally creating the neural tube

3. The Mesoderm → become muscles and limbs

   1. growth of the mesoderm helps folding of the neural plate to the neural tube

   2. 2 types of Mesoderm = Somatic & Splanchnic Mesoderm

4. The Neural crest cell will form portions of the PNS

5. The somite region each section is aligned to be a myotome, dermatome, sclerotome

   1. Myotome (medial): becomes specific muscle group, sensation specific for each spinal level

   2. Dermatome (lateral): becomes specific connective tissue and consistent test for level of spinal damage

   3. Sclerotome ( mediolateral): becomes specific assigned regions of the skeleton (vertebrae)

Autonomic Nerves to the Heart and Lungs

The flat neural plate (sheet of cells) rolls from the top down and bottom up (in a bean shape)

• The heart forms above the head and folds down bringing the “face” down

• The pelvis abdominal cavity/pelvis fold up

• The sheet continues to fold until you end up with a “belly button”

Neural Tube Formation: Day 18-26

• Formation of the neural plate, neural stem cells build up on top of the endoderm, mesoderm and ectoderm (bottom to top)

• The neural groove forms as the somite (precedent to skeletal formation) grows

• Once the tube finally closes it creates a SUPERIOR neuropore and INFERIOR neuropore (these do not close till day 27-30)

• As the tube closes longitudinally 2 layers surround the tube

  • Mantle Layer: gray matter

  • Marginal Layer: White matter

    • This is where we see differentiation … gray matter: ganglia, cell bodies, “processing of information” and white matter: tracts, columns, fascicules, axons, “communication highways”

• Following the tube being formed then we the neural crest plate where we find neural stem cells

• NC stem cells care pluripotent meaning that they can become any structure or contribute to any region of development…cells are not yet “labeled”

  • they can become peripheral sensory neurons, myelin cells, autonomic neurons, pancreatic islets…etc.

The tube…

• Rostral neuropore (superior neurospore): closes at day 25

• Caudal neuropore: closes around day 27

Spinal Cord Formation

When it comes to spinal cord formation timing is everything…

• Closing too early can allow the brain to close with an open spinal cord

• Closing too late where the brain is open and the spinal cord is closed so there is now no connection b/w the brain and spinal cord

  • With issues regarding spinal cord formation it always “depends” cases can vary in severity and there could be a 50/50 viability

  • This is why there are frequent checks with expecting mothers in the initial phases

As soon as the tube closes we see the formation of the gray and white matter…(past the mantle and marginal layer?)

Differentiation occurs in the LATERAL walls of the neural tube (farthest exterior Marginal Zone = white matter as you move medially Ventricular/Intermediate Zone = Gray Matter)

These walls create…

• Roof Plate

• Floor Plate

  • This is where motor and sensory neurons cross…if we see malformations in development then we know that there was no “cross connections”

The 2 plates are separated by a longitudinal groove, separating the 2 populations of cells by the sulcus limitans

• Alar Plate (dorsally) aka the association/sensory plate…form interneurons and projection neurons (gray matter is derived from this plate = dorsal horn)

• Basal Plate (ventrally) aka the motor plate cells bodies grow from the plate to innervate the myotome region

  Always…

  • Sensory = Dorsal

  • Motor = Ventral

As the embryo grows we’ll see crossing of axons, initially more motor crossing on the floor plate…once the axons begin to crowd the floor plate they will grow out into the muscles and limbs (stimulated to grow out)

• If the floor plate does not from properly it will be reflected in limb formation

• It is at the Floor and Roof plate is where crossing over occurs from either end

As these nerves/axon grow we begin to Myelination in the 4th fetal month and the process is completed around the 3rd year of life

• Different systems have different timelines

• This is why we see children learning things at different times as their peers → due to the rate of myelination

• Nervous tissue forms prior to myelination even beginning

Structures associated with the neural tube (as fibers from the association and motor plate grow out)

• The mesoderm divides into somites

  • Anteromedial portion: Sclerotome, becomes vertebrae & skull

  • Posteromedial portion: Myotome, becomes muscles

  • Lateral Portion: Dermatome, becomes the dermis

• Nerves will go out and grab/be pulled as these portions grow

• Nerves can end up connecting in the wrong place, skeletal malformations are attributed to this

• Issues can also arise as limbs grow faster than the nervous tissue

The Motor Plate → ventral horn of the spinal cord

• motor neurons

• interneurons

The Association Plate → dorsal horn of the spinal cord

• Projection neuron

• interneurons

  • makes special interneurons so that the spinal cord can communicate to itself

Peripheral System and Neural Crest Cells

“Where are neural crest cells?”…these stems can become anything

• spinal ganglion cells

• medulla of the adrenal gland

• melanocytes in the dermis

• pineal gland

• PNS: myelin sheath (Schwann Cells)

• head, neck, face (brachial arches)

• Cranial Nerves 5 (trigeminal), 7 (facial), 9 (glossopharyngeal), 10 (vagus)

  • This is how we can possibly have issues with parasympathetic communication w/ the heart

Also within sensory ganglia (dorsal root ganglia)

• sensory unipolar neurons

• surrounded by satellite cells and Schwann cells (also neural crest cells)

Sympathetic Ganglia (fight or flight)

• multipolar neurons

• sympathetic trunk (white communicating rami)

• these start in the head/face and migrate down to heart and lungs so the nerves are very long

Parasympathetic Ganglia (rest & digest)

• on the walls of organs (abdomen & thorax)

• supply the viscera of head, neck, thorax and abdomen

• Cranial Nerves 3 (oculomotor), 5 (trigeminal), 7 (facial), 9 (glossopharyngeal), 10 (vagus)

• Splanchnic mesoderm (w/in embryo) DOES NOT SUPPLY SKIN

Central Nervous System & Brain Organization

Brain formation we see starting around day 28 with the folding of the head & face

The 3 portions (we see within the embryo)

• Forebrain

• Midbrain

• Hindbrain

The neural tube begins to enlarge as it fills with CFS

Occurs during the Embryonic Stage in the phase beginning on Day 28

Hindbrain → into 2 section

• Upper = Metencephalon

• Lower = Myelencephalom

These structure become the medulla, pons, cerebellum (little brain) = ALL APART OF THE BRAINSTEM/CEREBELLUM = motor control region

• 4th ventricle

• Central canal

  Mantle (inner gray matter) → basal nuclei & cortex

  • gray matter starts on the inside and travels out to the periphery

  • “Where the thinking part connects to the moving part”

Midbrain → STAYS MIDBRAIN the entire developmental process

• As it grows the central canal becomes the cerebral aqueduct in the midbrain (connecting the 3rd & 4th ventricles)

• Forebrain ( 2 regions)

  • Posterior → Diencephalon

  • Anterior → Telencephalon…grows around the diencephalon

    • formation of 2 lateral ventricles

The shape of the brain is determined by the shape of the skull so as structures develop contained to the area…they push down and around.

Changes with Fetus Growth

This process emerges from the neuron cell body, the forward end expands to form a growth cone

Aganglionic (nerves are missing) Mega-colon: deformity represents a failure of the neural crest cells migrate into the lowest portion of the hindgut

• Failure of growth cone

• If migration of the neurons fail you will have areas without control

• The concern that the innervation of the gut is properly developed otherwise it will continue to enlarge

  Synapse Elimination

• As fetus grows its immature receive motor-neuron input from more than one presynaptic cell

• As the fetus grows synapses are “shed” to create mature relationships and this continues after birth (PRUNE as they mature)

• We see this as children reach milestones of development, unnecessary synapses are eliminated (NOT RELATED TO CELL DEATH)

Neural Connections (issues) → developing musculature

• Fiber type is dependent on innervation…fast twitch muscles (or muscles that should be) can be converted to slow twitch muscles if innervated by slow twitch neuron (vice-versa)…not an end all be all still a plastic system you can utilize more fast twitch muscles as you develop)

• Cannot have proper motor control w/out proper motor connections

• Myelination begins in the 4th fetal month and is completed around the 3rd year of life

• In terms of deficits you cannot recognize damage to the nervous system during the early stages it is not evident till the damaged systems are fully functional (why at times we cannot tell till critical milestones are not achieved by children)

Developmental Problems (or where they can occur)

Skeleton & Spinal Nerve Organization

• As the fetus develops the neural tube will wait till the sclerotome (future vertebrae) split till it is able to “send” nerves to innervate muscles/limbs…until this happens there is not stimulation of the muscles

Vertebral Column

• Vertebral column and dura mater grows faster than the spinal cord → this will cause the caudal spinal cord to lie at a higher level

• (Is it supposed to stretch the caudal equina)*

Tethered Spinal Cord

• The spinal cord attaches to a deformity of the vertebral column and does not shift

• Within the lower levels patients can experience loss/failure to develop proper bowel function, use of lower extremities, even bladder control

Cranial Pore Closure

• Anencephaly: closure defect, incomplete development of the Childs cranial vault

  • absence of major portion of brain, skull and scalp that occurs during the embryonic development

  • Occurs when the rostral/superior end of the neural tube fails to close b/w 23rd-26th day

  • This deformity does have a direct correlation with lifespan

  • In some cases depending on the severity and support/care received the patient can live longer than expected lifespan

• Meningoencephalocele: brain tissue involvement, cranium bifidum (brain tissue malformation)

• Meningocele: No brain tissue involved, cranium bifidum (brain tissue malformation)

(Neural tube Defects)

Arnold Chiari Malformation: developmental deformity of the hindbrain, affecting the brainstem and associated cranial nerves

• Type 1: often asymptomatic

• Type 2: causes progressive hydrocephalus (build up of fluid in ventricles), paralysis of the sternocleidomastoid muscle, deafness, bilateral weakness of lateral eye movement

  These patients still have…

• good cognitive/forebrain function

• this does effect their ability to learn and makes communication difficult

Spina Bifida

• Resulting when the inferior neuropore does NOT CLOSE

• 3 types of spina bifida cystica

  • Meningocele: malformation of the spinal tube itself w/out any of the neural tissue

  • Myelomeningocele: deformation of the spinal tube w/the involvement of neural tissue→ deficits/deformities in the lower extremities

  • Myeloschisi (aka Occult-a): this is where we see abnormal amount of hair growth over the affected region, possibly due to the over stimulation of the region

Prenatal Care: Folic Acid

• Critical that it is being taken by the mom prior to the nervous system developing

• BEFORE DAY 16

• In the US folic acid is added in most wheat products (now discussion about enriching corn flour products as well)

Spinal Muscular Atrophy

• Autosomal recessive disorder: motor neurons w/cell bodies in the spinal cord that innervate muscles degenerate in Utero

• MOST COMMON genetic defect is deletion of the survival motor neuron 1 gene…issues are seen with motor skills, no real brain deficits and normal cognitive skills

Exposure to Alcohol in Utero (especially w/in the first 30 days)

• If a mother consumes alcohol within the early stages of pregnancy → fetal alcohol syndrome or alcohol related birth defects

• Set list of telling features :

  • abnormally small head

  • (indistinct philtrum) absent cupids bow

  • thin upper lip

  • short vertical space b/w open eyelids

• Effects on the FOREBRAIN

  • Cognitive

  • Movement

  • Behavioral Problems

  • Impaired intelligence, memory, language, attention, reaction time

  • Visuospatial abilities

  • Decision-making skills

  • Goal-oriented behavior

  • Fine/gross motor skills

  • Social and adaptive functioning

Exposure to alcohol/cocaine can cause an issue where essentially the fetus does not make enough nerves or doesn’t make enough normal connections (not making enough nervous tissue/connections)

• Disturbance of neural proliferation

• Symptoms: difficulty with attention and impulse control

When it comes to recovery (from brain damage) we see that there is a big difference in outcomes b/w perinatal and adult brain injuries

• As perinatal/fetus experience injuries to their brains, it is able to reconfigure and continue to still develop (synaptic repatterining)

• As adults experience injuries their brains lose descending control because development is complete, inappropriate connection, abnormal spinal motor circuits do not compound dysfunction as their brains are static and have lost all plasticity