Embryology, Central Nervous System

Mohamed Elshazzly; Michael J. Lopez; Vamsi Reddy; Omar Caban.

Last Update: April 3, 2023.
Introduction

Central nervous system (CNS) embryology is a broad subject. This article serves as a
summary of CNS organogenesis as well as a review the framework of embryology, the
embryogenesis of the brain and spinal cord, various tests that can be performed in utero
to test for CNS anomalies, and problems that may be encountered during
embryogenesis, with particular attention to the CNS.

The CNS system involves 3 germinal layers: ectoderm, mesoderm, and endoderm.

1. The ectoderm is the key initiating player in the embryogenesis of the CNS. The
ectoderm is further sub-specialized as the (1) surface ectoderm, which
differentiates into the epidermis, nails, and hair. The ectoderm is also sub-
specialized to form the (2) neural ectoderm, which gives rise to the neural tube
and neural crest, which subsequently give rise to the brain, spinal cord, and
peripheral nerves.
2. The endoderm gives rise to the lining of the gastrointestinal and respiratory
systems. It also gives rise to abdominal organs such as the liver, pancreas, and
bladder.
3. The mesoderm is differentiated into 3 parts:
• Paraxial mesoderm: This part of the mesoderm contains mostly somites which
give rise to the axial skeleton, dermis, and muscle.
• Intermediate mesoderm: This part of the mesoderm gives rise to the gonads,
kidneys, and urogenital structures.
• Lateral plate mesoderm is further classified into parietal mesoderm and visceral
mesoderm, which give rise to the limb skeleton and muscular wall of the gut tube,
respectively.
Embryological Transformations

Because these changes do not occur at once, embryology is a complicated subject. The
following timing of embryological developments, with particular attention to the CNS,
offers a greater understanding of the process.

• Weeks 1 to 3: Zygote formation, blastocyst, and gastrulation occur

• Mid-fourth week: Embryo is linear and uniform; notochord formation occurs
• Late-fourth week: Many forms of differential growth occur; upper limb buds always
develop before the lower limb bud
• Fifth week: Limb buds more pronounced
• Sixth week: Can begin to see eyes and auricular hillocks, which will develop into
the external ears
• Seventh week: Formation of eyes, ears, and fingers
 • Late eighth week: Formation of all organ systems
• Nine to 12 weeks (11 to 14 gestational age): Embryo has a large head, and small
body and this is the time where the body grows in an attempt to catch up with the
limbs. The genitalia can be recognized during this period giving a chance for
parents to find out the gender of the embryo.
• Thirteen to 16 weeks (15 to 18 gestational age): Coordinated limb developments
and ossification of skull occur; Ovaries differentiate and contain primordial ovarian
follicles that contain oogonia; the eyes face anteriorly, and ears are in place.
• Seventeen to 20 weeks (18 to 22 gestational ages): Eyebrows and head hair
visible at 20 weeks
• Twenty-one to 25 weeks (23 to 27 gestational age): Type II pneumocytes to
secrete surfactant. It is after this stage when babies are considered viable.
• Twenty-six to 29 weeks (28 to 31 gestational age): Eyelids open; the quantity of
white fat increases. The CNS has matured and can control breathing as well as
temperature function. Additionally, the bone marrow takes over (from the yolk sac)
as the major site of erythropoiesis.
• Thirty to 34 weeks (32 to 36 gestational age): Maturation and growth of organs
occur
Thirty-five to 38 weeks (37 to 40 gestational age): Baby now has a firm grasp with
hands. Testes may have descended in males.

Development

Embryogenesis: Weeks 2 to 8

Beginning with the trilaminar germ disc, which refers to the epiblast and hypoblast, the
epiblast cells undergo an epithelial-mesenchymal transition that replaces the hypoblast.
They also proliferate in the middle layer to form the mesoderm where it will remain
mesenchymal to form connective tissue. The primitive streak then starts to appear
superiorly from the thickened region of the ectoderm. It grows caudal to the cranial and
induces notochord formation. The ectoderm then invaginates as cells migrate to form
the primitive node and primitive pit where the notochordal process is formed.

1. The primitive pit is a depression at the center of the primitive node, which is an
opening in the notochordal canal.
2. Neurulation refers to the folding of the neural plate. The neural plate folds, via
induction from the notochord, into the neural tube, which then becomes the
neuroectoderm, which finally forms the CNS, namely the brain and spinal cord; the
brain from cranial two-thirds of the segment and spinal cord from caudal one-third
of the segment)
3. Neural Crest cells form dorsal root ganglia and connective tissue in the head and
neck.
4. Notochord:
• Defines longitudinal axis
• Forms parts of the intervertebral discs, and not the spinal cord or spine
• The notochordal process formed on top of the primitive node
 • Elongation of the notochordal process occurs caudally and goes upward to the
cranial end
The CNS is derived from the neuroectoderm: notochord induces the formation of the
neural plate (thickening of the ectodermal layer), which further differentiates to form
neural folds with a neural groove in between, leading to the formation of the neural tube
(via neurulation).

Spinal Cord

The spinal cord is formed from the neural plate, now contains 3 layers:

1. Ventricular layer that lines the central canal

2. Mantle layer that contains neuronal bodies, which will eventually form the gray
matter
3. Marginal layer that contains axons, and will eventually form the white matter
While this article summarizes the embryological changes that occur within the CNS, the
peripheral nervous system (PNS) is formed from neuroepithelial cells. These cells travel
from the pia mater to the ventricular layer of the spinal cord, where they differentiate
and migrate to form glioblasts (for example, support cells, Schwann cells), neurons, and
ependymal cells. As this information is often tested on boards, that myelin sheath, a
sheath composed of support cells, wraps around axons and insulates neurons to
increase the speed of neuronal conduction.

1. Myelination of peripheral axons occurs via the neurolemma, which comes from
Schwann cells (which come from neural crest cells).
2. Myelination of CNS axons occurs via oligodendrocytes, which are neuroepithelium
derivatives.
Three membranous layers cover the whole CNS:

1. Dura mater: derived from surrounding mesenchyme and is tough and durable.
2. Arachnoid mater: derived from neural crest; forms as a single layer with Pia mater.
3. Pia mater: derived from neural crest; intimately covers the CNS.
Brain

During brain formation, there are 3 primary brain vesicles that differentiate into 5
secondary brain vesicles. See image.

1. Prosencephalon, which becomes the forebrain: This later develops into the
cerebral hemispheres which contain structures underneath such as the
epithalamus, thalamus, and hypothalamus. This section of the brain is responsible
for consciousness, sensorimotor transformation, and sensory integration.
2. Mesencephalon, which becomes the midbrain: This part of the brain undergoes
little structure reorganization compared to the spinal cord and other brain vesicles.
3. Rhombencephalon, which becomes the hindbrain: This part can be further divided
into 3 segments:
1. Metencephalon: The dorsal growth of the cerebellum (integrates sensory
information to fine-tune output)
 2. Caudal myelencephalon: Similar to the structure of the spinal cord with “closed”
central canal of Medulla
3. Rostral myelencephalon: “Open part” of medulla; cerebrospinal fluid (CNF) is
produced via choroid plexus and leaks into the subarachnoid space.
Finally, the hypophysis gives rise to the pituitary gland, which has 2 origins. The
posterior pituitary is an outgrowth of the hypothalamus, and, therefore, has a direct
connection. On the other hand, the anterior pituitary is an ectodermal growth from the
mouth. It depends on a dense capillary network and communicates with the brain via
the vascular system.

Testing

• Non-invasive testing can be performed at 10 weeks of gestation. This tests for

cell-free DNA in the plasma of pregnant women and helps identify certain
anomalies or diseases.
• Amniocentesis, which is usually performed between 14 and 20 weeks, is the
sampling of the amniotic fluid to screen for fetal anomalies. This is a diagnostic
test.
• First-trimester testing looks for the risk of trisomy 21, trisomy 18, trisomy 13, and
other neural tube defects.
• Alpha-fetoprotein (AFP) is a hormone that is elevated in amniotic fluid in
anomalies of the CNS and ventral abdominal wall. It is decreased when the fetus
has trisomy 21, trisomy 18, or other chromosomal defects.
• Anatomy sonogram can be performed throughout pregnancy, but particularly
between weeks 16 to 22 to estimate the fetal weight and gestational age using
measurements from:
1. Head circumference
2. Biparietal diameter
3. Femur length (from epiphysis to epiphysis)
4. Abdominal circumference
Although beyond the scope of this article, there is also a Quad-screen test that can be
performed in the second trimester. The components of this screening test include AFP,
hCG, Estriol, and Inhibin-A.

Pathophysiology

Embryogenesis can be complicated and result in mild or extreme defects

(pathophysiological changes).

• Teratogenesis is defined as any external factor that can influence the growth of the
embryo. Embryos are highly susceptible and critical between weeks 3 and 8
because that is when organ systems develop.
• Dysraphism is the failure of fusion between symmetric halves of an anatomical
structure. These include, and are not limited to, spina bifida malformations.
1. Spina bifida occulta occurs when the vertebral column fails to fuse, but other
layers develop normally. It is the least severe form of dysraphism and usually
 affects the lumbosacral region (S1 to S2 most commonly). It can be associated
with moles, angioma, lipoma, and abnormal hair growth in the area of abnormality.
2. Spina bifida aperta occurs when there is an incomplete fusion of skin with or
without a cyst. The spinal cord is still covered by the arachnoid mater, thus
preserving subarachnoid space and preventing leakage of the CSF.
3. Spina bifida cystica is the most severe form of dysraphism. Patients may develop
urinary or fecal incontinence. 80% of these lesions occur in the lumbosacral
region.
Dysraphism in the cranium causes malformations analogous to spina bifida[8]:

1. Encephalocele: Protrusion of the brain into the subarachnoid space. It can be

associated with Chiari III malformation during part of the cerebellum protrudes,
and the spinal cord gets twisted. This is commonly associated with cleft lip and
palate.
2. Anencephaly is where the cerebral cortex and thalamic structures are generally
absent, but the cerebellum, brainstem, and spinal cord are present (but maybe
deformed). This can occur due to the failure of notochord signaling which is
necessary for median hinge point formation or induction of neural crest cell
maturation.
3. Holoprosencephaly: Failure of features to form along the midline of the face.
Features include a single central incisor, cyclopia, or unpaired cerebral
hemisphere.
4. Craniorachischisis totalis is when the entire neural plate fails to fold, and CNS is
open to the amniotic cavity. These are often associated with still-born fetuses.

Clinical Significance

Pathophysiological processes that can occur during embryogenesis are rare and do not
occur very often, and when they do, the newborn is alive and not stillborn. However, the
newborn may require certain surgeries to correct the craniofacial anomalies
before significant damage occurs. Furthermore, those babies born with spina bifida
require further evaluation with ultrasound and surgical correction of the spinal cord to
prevent herniation or other complications.

Clinically speaking, to avoid abnormal embryological development, the mother should

abstain from teratogens or any external factor that can influence the growth of the baby,
especially during weeks 3 through 8 of the embryogenesis. Significant teratogens
include alcohol, tobacco use, certain prescription drugs, and illicit drugs. Most
importantly, women seeking to get pregnant or who are pregnant take multivitamins,
especially folic acid supplements to aid with neurodevelopment.

REFERENCES

1. Donovan MF, Arbor TC, Bordoni B. StatPearls (internet). StatPearls Pub Mar 6,
2023. Embriology, York Sac.
2. Khan YS, AckermanKM. StatPearls Publishing; Treasure Island (FL): Apr 17, 2023.
Embrology, Week