A N S 5 3 6 – P E R I N A T O L O G Y
S P R I N G 2 0 1 6

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Prenatal CNS
Development
Examples of perinatal problems that effect the
CNS
Post-Natal CNS
Development
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Brain Injury at Birth
Male vs. Female Brain
ANS 536 - Perinatology - CNS Development

http://www.youtube.com/watch?v=UgT5rUQ9EmQ
ANS 536 - Perinatology - CNS Development

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Period of the Ovum:
 fertilization through implantation
Period of the Embryo:
 gastrulation through establishment of all major organ systems
Period of the Fetus:
 maturation of organ systems through birth
ANS 536 - Perinatology - CNS Development

 CNS development begins during the 3 rd gestational week in humans.
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Most rapid CNS development occurs during the 24 th gestational week.
Brain is not fully developed until adulthood (early 20’s).
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

Defined as: the transformation of the neural plate into the neural tube
ANS 536 - Perinatology - CNS Development

 neural plate: a thickened plate of ectoderm that gives rise to the neural tube and crests
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 Notochord: flexible rodshaped structure, derived from the mesoderm, that supports the primitive axis of the embryo
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Neural crest: transient, multipotent, migratory cell population
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Cells contribute to many different systems including peripheral nervous systems, skin, skeletal, adrenal glands, and GI tract
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

 From maturation of organ systems through birth
(GW 16-38).
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Characterized by a large increase in weight and large increase in nutrient demand.
Growth is mostly resulting from hypertrophy.
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ANS 536 - Perinatology - CNS Development

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 prosencephalon: forebrain mesencephalon: midbrain
 rhombencephalon: hindbrain
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ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

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 telencephalon: mature cerebrum diencephalon: thalamus, hypothalamus, pituitary mesencephalon: midbrain metencephalon: pons and the cerebellum myelencephalon: medulla oblongata
ANS 536 - Perinatology - CNS Development

http://www.youtube.com/watch?v=mMDPP-Wy3sI
ANS 536 - Perinatology - CNS Development

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Meninges: three protective layers surrounding the entire CNS
CSF: Cerebral Spinal Fluid
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Produced by the ventricles of the brain
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Flows down a pressure gradient from the ventricles to the subarachnoid space where it bathes the surface of the CNS and passes into the venous system
Replaced several times daily
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Can exchange freely with the extracellular fluid of the CNS: carries away metabolic waste and provides micronutrients
Provides cushion to brain
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

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Transmission of BVDV or BVD to the fetus at 30 to
45 days of gestation decreases conception rates and the viability of the embryo
Fetuses that become infected from 30 to 125 days of gestation and survive the infection will be born as
BVDV-infected calves. The BVDV infection will persist for the life of the animal, hence the term
“persistent infection,” or PI
ANS 536 - Perinatology - CNS Development

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Transmission of BVDV to the fetus after 120 to
150 days of gestation may result in abortion, stillbirth,
congenital defects, or birth of a live, normalappearing calf
Congenital anomalies are the most frequent outcome of infections that occur during days 125
to 175 of gestation.
Fetuses that become infected after 175 days are more resistant to infection because they are immunocompetent; however, these fetuses are more likely to experience a serious health problem during the first 10 months of life.
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

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Can be caused by congenital malformations of fluid ventricles or brain tumors
Symptoms of hydrocephalus vary with age, disease progression, and individual differences in tolerance to the condition.
For example, an infant's ability to compensate for increased CSF pressure and enlargement of the ventricles differs from an adult's. The infant skull can expand to accommodate the buildup of CSF because the sutures
(the fibrous joints that connect the bones of the skull) have not yet closed.
Treatments: there are no good treatments, can put in stents or drains to decrease CSF fluid, mostly euthanize
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

Neonatal Maladjustment Syndrome:
“Dummy Foal”
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Central nervous system asphyxia (lack of oxygen) before, during or after delivery
Mares with placental infections, hydrops, or those that have a red bag delivery (where the placenta separates from the uterus)
Premature foals are also susceptible
ANS 536 - Perinatology - CNS Development

Neonatal Maladjustment Syndrome:
“Dummy Foal”
Symptoms:
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Loss of sucking reflex
Seizures or convulsions
Emitting of strange, unusual whinnies or barking sounds
Lack of coordination
Weakness
Respiratory distress
Circulatory stress
Recumbency
Coma
Signs of blindness
Erratic movements and behavior
ANS 536 - Perinatology - CNS Development

Neonatal Maladjustment Syndrome:
“Dummy Foal”
 https://www.youtube.com/watch?v=qfyBv-KnMf0
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ANS 536 - Perinatology - CNS Development

 Infant’s brain is roughly 25% of its adult size at birth.
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75% developed by one year of age
80-90% developed by three years of age
 Full maturation does not occur until adulthood in humans (roughly 20-25 years old).
ANS 536 - Perinatology - CNS Development

 For first three years of life, a child’s brain has roughly twice as many synapses and an adult.
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Synapses used frequently become stronger.
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Synapses rarely used are more likely to be eliminated.
ANS 536 - Perinatology - CNS Development

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During the second year of life, the brain’s language center develops more synapses and becomes more interconnected
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Vocabulary often quadrupled during this time.
Rapid increase in rate of myelination.
Emotional awareness and self awareness develop.
ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

 Nature vs. Nurture
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Genes lay foundation for brain but final wiring is caused by an environmental effect
 Laboratory mice are virtually genetically identical.
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Dramatic difference seen in IQ
ANS 536 - Perinatology - CNS Development

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CNS development begins in utero and continues into adulthood.
Several transient structures undergo morphological and functional changes to give rise to a more mature system.
Several factors can impact the CNS: Disease, management, congenital development of fetus, birth trauma, etc.
Interaction between genetics and environment determine final CNS capacity and functionality.
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ANS 536 - Perinatology - CNS Development

 Very rare in the term infant (1 in 1,000 live births)
 Most often secondary to:
 Hemorrhage
 Focal cerebral infarction
 Hypoxic-ischemia cerebral injury
 Other causes:
 Metabolic disturbances related to inborn errors of metabolism
 Hypoglycemia
 Hyperbilirubinemia
 Infection/meningitis
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 Clinical expression:
 Subtle
 Mild hypotonia or hyperalert state
 Severe
 Stupor or coma
 Severity and extent of damage dictate short and long-term consequences
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 Intracranial hemorrhage
 Subarachnoid hemorrhage
 Subdural hemorrhage
 Epidural hemorrhage
 Intracerebral hemorrhage
ANS 536 - Perinatology - CNS Development

 Subarachnoid hemorrhage
 Primary
 Hemorrhage in the subarachnoid space
 Most common form of intracranial bleeding in term neonates
 Rupture of small veins bridging the leptomeninges is most common occurrence
 Secondary
 Extension of subdural, intraventricular, or intraparenchymal hemorrhages
 Occur less often
 Trauma, coagulation disorders and rupture of intracranial aneurysm or arteriovenous malformation can be responsible
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 Subdural hemorrhage
 Categorized by origin and direction of spread (supratentorial and infratentorial)
 Tears in the falx and tentorium or bridging cortical veins secondary to stretching can cause significant hemorrhage
 Most likely to occur during difficult vaginal deliveries
 Symptoms include: increased intracranial pressure, seizures, focal neurological deficits, herniation of the temporal lobe over the tentorial edge causing ipsilateral third nerve paralysis, large movements, decreased responsiveness, metabolic acidosis, hypoglycemia, anemia and hypotension
ANS 536 - Perinatology - CNS Development

 Epidural hemorrhage
 Rare lesion in the neonate (~2% of all cases)
 Hemorrhage occurs from branches of the middle meningeal artery or from major veins or venous sinuses
 Progressive neurological dysfunction and death are common results unless epidural hemorrhage is evacuated and further bleeding stopped
ANS 536 - Perinatology - CNS Development

 Intracerebral Hemorrhage
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Uncommon occurrence
Blood can be found within the germinal matrix, ventricles or parenchyma
Thalamus is a common site of hemorrhage
Predisposing factors include prior hypoxic –ischemic cerebral injury, sepsis, and coagulopathy
Can be observed in association with subarachnoid or subdural hemorrhage
Symptoms:
 Sudden onset of marked neurologic abnormalities,
 Signs of seizures, evidence of increased intracranial pressure and downward eye deviation
ANS 536 - Perinatology - CNS Development

 Cerebral infarction (perinatal stroke)
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Occurs 1 in 4,000 births
Causes:
 May occur from both embolic and thrombotic phenomena
 Intrapartum asphyxia , deficiency of one of the systemic coagulation inhibitors (ie, protein C or protein S), primary hemorrhage with vasospasm, meningitis, polycythemia, or ECMO
Etiology is unclear
Symptoms:
 Seizures or apnea, usually on the 2 nd postnatal day
ANS 536 - Perinatology - CNS Development

 Hypoxia –ischemia cerebral injury
 The brain injury that develops is an evolving process beginning at the insult and extends into the recovery period (reperfusion phase)
 Causes severe, long term neurological deficits in children (i.e. cerebral palsy)
 Impaired cerebral blood flow (CBF) in principle pathogenetic mechanism
 Interruption of placental blood flow and gas exchange (asphyxia)
 Fetal acidemia
 Cellular energy failure, acidosis, glutamate release, intracellular Ca +2 accumulation, lipid peroxidation and nitric oxide neurotoxicity serve to disrupt essential components of the cell with its ultimate death
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ANS 536 - Perinatology - CNS Development

 Occurs in infants exposed to opiates in utero due to maternal drug abuse during pregnancy
 Somewhere between 48-94% of infants exposed to opiates in utero develop clinical signs of withdrawal
 Severity of neonatal psychomotor behavior remains controversial
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 Health institutions should adopt an abstinence scoring method
 Lipsitz tool
 Simple numeric system using a value of >4 for significant signs of withdrawal
 Finnegan
 Weighted scoring of 31 items
 Neonates with psychomotor behavior are difficult to determine, and vary among institutions
 Inconsistent diagnosis and treatment
 Appropriate treatment?
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 Primary line of management:
 Pharmacologic treatment
 Opioids
 Methadone
 Sedative-hypnotic withdrawal
 Phenobarbital
 Secondary line of management:
 Intravenous morphine, clonidine, diazepam, oral morphine, phenobarbital, methadone, and tincture of opium
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ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

Differences During Embryonic Development:
 Differences seen as early as GW 26
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Thickening of CC in females that remained post birth
 Males outperformed females on motor and spatial cognitive tasks; females were faster in tasks of emotion identification and nonverbal reasoning
(Satterthwaite et al. 2014)
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ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

ANS 536 - Perinatology - CNS Development

D E F E C T S I N C O R T I C A L D E V E L O P M E N T

 Proliferative neuroepithelium forms a thick layer surrounding the ventricles in developing brain.
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 neural stem cells and neural progenitor cells neurons and glial cells formed migrate to the cortex
 Cortical Development Defects
 abnormal neuronal-glial proliferation
 abnormal neuronal migration
 abnormal cortical organization

Microcephaly:
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Defined as an abnormally small head circumference.
 diagnosed at birth or during childhood
Can result from over 450 disorders.
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Down Syndrome
Autosomal microcephaly (dominant or recessive)
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X-linked microcephaly

Lissencephaly:
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Defined as a lack of gyri and sulci.
 diagnosed at birth or soon after
Can result from many different environmental and/or genetic causes.
 uterine viral infection
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 insufficient uterine blood supply gene mutations

Polymicrogyria:
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Defined as an excessive number of undersized gyri.
 diagnosed at birth or during childhood
Several contributing factors but exact cause is poorly understood.

N E U R A L T U B E D E F E C T S

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Neural tube fuses 18-26 days after ovulation.
One of the most common congenital abnormalities.
Complex interaction between genetics and environment.

Genetic Factors:
 Family history of specific NTD.
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Mutations in enzymes involved in 1-carbon metabolism.
Environmental Factors:
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Maternal dietary folate deficiency.
Maternal induced folate deficiency.
 sodium valproate
 folate antagonists

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Folate and B12 important in reducing occurrence.
Required for production/maintenance of new cells.
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DNA synthesis – thymidine synthesis
Generation of CH3 groups; gene silencing and PTM

Schalinske & Smazal 2012

S
G
TS
U
T
Schalinske 2014

Schalinske & Smazal 2012

Open NTDs: brain and/or spinal cord are exposed at birth
 anencephaly
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 encephalocele spina bifida
Closed NTDs: spinal defect is covered by skin at birth
 lipomyelomeningocele
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 lipomeningocele tethered cord

Occurs when rostral neuropore fails to close.
 brain lacks all or part of the cerebrum
 parts of brain not covered by skin or bone

Occurs when rostral neuropore fails to close.
 sac-like protrusion or projection of the brain and covering membranes through an opening in the skull

Occurs when caudal neuropore fails to close.
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 backbone that protects the spinal cord does not form and close
3 sub-classifications

lipomyelomeningocele:
 lipoma covering the site of a myelomeningocele lipomeningocele:
 lipoma covering the site of a meningocele tethered cord:
 spinal cord is held taught at one end, unable to move freely as it should; results in stretching of spinal cord as child grows

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Performed between 16-18 weeks of gestation
 range 15-33 weeks of gestation
Measures maternal serum alpha-fetoprotein (AFP) concentrations
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Produced in liver fetus; leaks into amniotic fluid and ultimately gets into maternal blood

Amniocentesis:
 Performed between 16-22 weeks of gestation
 sample of amniotic fluid is obtained and submitted for testing
Chorionic Villus Sampling:
 Performed between 10-12 weeks of gestation
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Sample of the chorionic villi (placental tissue) taken and submitted for testing

Amniocentesis Video: http://www.youtube.com/watch?v=GZoswKIa4ic
Chorionic Villus Sampling Video: http://www.youtube.com/watch?v=sxEf_ddmpZk

Epigenetics: external modifications to DNA/RNA that regulate gene expression.
Epigenetic Mechanisms:
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DNA methylation
Modification of histone N-terminus
 non-coding RNAs

CH3 groups bind to CpG regions in the promoter region of genes to block transcription
 Results in silencing of that gene

Addition of function groups to the N-terminus of histones results in a change in chromatin conformation.
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Acetylation
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Methylation
Biotinylation
Condensed ↔ Relaxed

microRNAs:
Hybridize with mRNA to block translation. large non-coding RNAs:
Hybridize with DNA template to block transcription.

 Earliest stages of CNS development are most susceptible to epigenetic modification.
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Effects may be evident at birth or may not occur until later stages of adulthood
Epigenetic influences on brain development and plasticity. (Fagiolini et al.)

Precocial young: animals that are capable of a high degree of independent activity from birth
 cattle, guinea pig, sheep
Altricial young: young that are hatched or born in a very immature and helpless condition so as to require care for some time
 cats, dogs, humans

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Congenital CNS abnormalities can result from NTDs of issues in cortical development.
Epigenetic Changes can have profound and lasting effects on CNS.
CNS development and physiology varies between species.

ANS 536 - Perinatology - CNS Development