Thurs 107

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Thurs 10/7
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Nervous system End of Embryonic period 7 weeks
after conception 5 divisions of adult brain are
present in rudimentary form. 1. Forebrain A.
Telencephalon B. Diencephalon 2. Midbrain
A. Mesencephalon 3. Hindbrain A.
Metencephalon B. Myelencephalon
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From Neuroscience for Kids webpage
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• Development in the Fetal Period
• formation of cortex
• continued proliferation and migration (before
  and after birth)
• elaboration and differentiation
• synaptogenesis and myelination
• apoptosis in some areas
• birth occurs - most processes continue

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• Human Postnatal Brain Development
• Infancy
• overproduction of neurons and synapses beginning
  in fetal period and continuing to about 18 months
  of age
• apoptosis and pruning of synapses continues to
  about 2 years of age
• Adolescent Period another wave of development

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• Postnatal brain development
• Differentiation and synaptogenesis and apoptosis
  continue
• prefrontal cortex, cerebellum, and hippocampus
  complete development postnatally
• certain fiber tracts serving the prefrontal
  cortex are not completely formed until after
  adolescence (reductions in inputs due to
  apoptotic pruning)

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• Adolescent Brain Development
• overproduction of neurons and their axons
  peaking at 11 years in girls 12 years in boys
• pruning through age 20 with final stages
  occurring in highest brain areas prefrontal
  cortex and lateral temporal lobes
• Overproduction then pruning of receptors for
  several systems (DA, 5HT, GABA/BZD, ACH, GLU)
• major decline in excitatory stimulation of
  cortex (from diffuse to focal)

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From Gogtay et al, 2004. 13 children were scanned
at 2 year intervals from 4-20 years. Blue
represents a decline in gray matter density
(neuronal density).
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• Endpoints of Abnormal Development
• Death
• Malformation
• Growth Retardation
• Functional Deficit

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Environment influences development at every
stage 1. Preimplantation - death 2. Embryonic
period - malformation, effects on growth,
functional problems 3. Fetal period - growth,
functional problems, altered differentiation,
synaptogenesis, myelination, apoptosis
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• Types of environmental influences upon
  development
• maternal health
• maternal nutrition
• infections
• drug use
• environmental chemicals
• physical restrictions or damage

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Teratology - study of abnormal development Teratog
en - an agent that causes abnormal development
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Teratogens of the CNS Radiation Antimitotic
agents (cancer treatments) Certain
illnesses Hormonal disruptors Pesticides Abnorm
al amounts of certain vitamins or minerals
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Teratogens of the CNS Prescription drugs -
Accutane (treatment of acne) Anticonvulsants Envi
ronmental chemicals - lead, mercury, PCBs Drugs
of abuse - alcohol
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• Variables Governing Susceptibility
• Gestational Age at Exposure
• Genotype
• Characteristics of Agent
• Mechanism of Action
• Amount
• Route

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• Research Designs and Issues Important in
  Associating Prenatal Events with Postnatal
  Outcomes
• 1. Criteria For Inclusion of Participants
• Prospective Identification
• Reliable Pre - Peri- natal History
• Known Socioeconomic Status
• - Parental Occupational Level
• - Parental Educational Level

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• 2. Criteria For Exclusion of Participants
• Mental Retardation in either Parent
• Prenatal Exposure to other Harmful Agents
• Chromosomal/Genetic Abnormality
• Brain Damage Sustained in Childhood
• - illness
• - injury

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3. Need for Comprehensive Assessment of Physical
Features A thorough morphological exam is done
to detect dysmorphology abnormalities of
structure
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• 4. Need for Comprehensive Assessment of Function
  (to capture effects on any brain area)
• Medical status
• General Mental Ability
• Sensory Ability
• Sensory/Perceptual/Motor Integration
• Motor Coordination
• Planning/Organization/Attention
• Language Based Abilities
• Reasoning Ability

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• Potential Neurobehavioral Teratogens
• Teratogens known to alter brain development
• Psychoactive Agents known to act on the CNS -
  drugs, chemicals, hormones
• Compounds that are harmful to the adult brain
  and behavior - Neurotoxicants

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Teratology - study of abnormal development Teratog
en - an environmental agent that causes abnormal
development Neurobehavioral Teratology study of
abnormal brain or behavioral development
resulting from an environmental exposure
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• Known Human Neurobehavioral Teratogens
• Rubella
• Cytomegalovirus
• X-Irradiation
• Retinoic Acids
• Anticonvulsant Drugs (Phenytoin Valproic
  Acid Phenobarbital Carbamazepine)
• Drugs of Abuse (Alcohol Heroin Methadone
  Methamphetamine Cocaine)

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• Known Neurobehavioral Teratogens (continued)
• Methylmercury
• Lead
• PCBs

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• Causes of Behavioral Dysfunction
• Reduced Number of Neurons
• Migration Defects
• Abnormalities of Cytoarchitecture
• Neurochemical Disturbances

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• The individual agents/drugs selected allow
  certain principles to be illustrated
• Some things are evident at birth some are not.
• Generally, neurobehavioral teratogens impair the
  function of more children than the number
  affected with malformations our techniques are
  not yet good enough to detect structural brain
  abnormalities at birth.
• Some agents do not cause structural
  malformations, but do compromise behavior.
• Agents that are harmful during pregnancy may also
  be harmful during childhood brain development.

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Adverse Outcome Due to Prenatal Rubella (From
Alford, Pass, and Stagno, 1983) 30 of infants
are symptomatic at birth Heart
Defects Microcephaly Deafness Growth
Retardation Retinopathy Cataracts
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Rubella continued Of those symptomatic at birth,
80 show neurobehavioral problems in
childhood Hearing loss Language
disorders Visual abnorm. Motor
disorders Hormonal abnorm. Cognitive
dysfunction Dental Defects Emotional disorders
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Rubella continued Of the 70 of infants who are
not symptomatic at birth, 70 show Hearing
loss Language disorders Visual abnorm. Motor
disorders Hormonal abnorm. Cognitive
dysfunction Dental defects Emotional disorders
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Teratogenic Effects of Radiation

• Mental retardation
• Highest risk during major neuronal migration, at
  8-15 weeks. Incidence increases with dose. At 1
  Gy fetal dose, 75 experience severe retardation
• At 16-25 weeks, fetus shows no increase in mental
  retardation at doses lt 0.5 Gy
• IQ - Risk factor associated with diminution of IQ
  is 21-33 points at 1 Gy to fetus on 8-15 weeks.
• Microcephaly
• observed in 30 children of 1000 exposed in
  Hiroshima and Nagasaki pregnant women
• the effect lt0.3 Gy is not significantly
  different from control

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• Accutane pill used to treat cystic acne
• a synthetic Vitamin A (a retinoic acid)
• isotretinoin

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• Accutane interferes with the development of
• Central Nervous System
• Craniofacial structures
• The Heart
• The Thymus and Parathyroid Glands
• Other organ systems

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• Embryonic Exposure to Accutane (Isotretinoin)
• Spontaneous Abortion (40)
• Major Malformations (35)
• Prematurity 16

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• CNS Abnormalities
• Cerebellar Hypoplasia (small cerebellum)
• Absence or Reduced Size of the Cerebellar
  Vermis (a part of the cerebellum)
• Ventriculomegaly (4th) enlargement of the 4th
  ventricle
• Cranial Nerve Abnormalities (optic oculomotor)

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• Additional CNS Abnormalities (visible on
  autopsy Lammer and Armstrong, 1991)
• Pons
• Medulla
• Thalamus
• Hippocampus
• Heterotopias in Frontal Cortex
• reduced myelination

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Figure 1. Mental ability of children exposed to
isotretinoin during embryonic development.
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• Is vulnerability to the CNS effects of retinoic
  acid seen in adolescence?
• controversial human data suggest that some
  individuals of unspecified ages may experience
  depression, suicidality, or psychosis following
  Accutane treatment (Wysowski, Pitts, and Beitz,
  2001 Bremner, 2003)
• long term effects are unknown
• 2 studies in adolescent mice show that 21 days
  of treatment with 1 mg/kg/day 13 cis RA reduces
  hippocampal cell survival (Sakai et al, 2004) and
  reduces spatial learning (Crandall et al, 2004)
• reduced hippocampal neurogenesis has been shown
  in depression (increased during antidepressant
  treatment)