Brain

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Brain Development

• Peter D. Patrick, Ph.D.
• Associate Professor of Clinical Pediatrics
• Pediatric Psychologist/Neuropsychologist
• Childrens Medical Center, University of Virginia
• PDP2n_at_Virginia.edu September 2, 2004

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Objectives

• Overview of basic neuroanatomy
• Review of age related trends
• Focus on cortical/frontal lobe development
• Focus on development of executive skills

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Stages of Neuronal Development

• Neuralization
• Differentiation
• Cell migration
• Dendritic sprouting
• Synaptogenesis
• Myelination
• Pruning and Apoptosis

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Neural Axis
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Neurogenesis

• Predominantly prenatal with some post natal
  development (dentate gyrus, hippocampus)
• Inside out development
• Older phylogenetic areas develop before more
  recently evolved (e.g. Ventral thalamus vs.
  Dorsal thalamus)
• Larger motor cells form before smaller sensory
  cells

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Migration

• Considerable individual variation within and
  between species.
• Radial glial cells provide signaling guidance.
• Cortical sub-plate provides architectural
  scaffolding.
• Migration is not limited just to prenatal period.
• Hypothalamus.
• Errors in migration Used as model for
  psychopathology.
• Autism, schizophrenia.
• Fetal alcohol syndrome, etc.

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Connectivity Synaptogenesis

• Synaptogenesis
• Subcortical begins early in prenatal development
  and mostly completed prior to birth
• Cortical/basal ganglia begins later and extends
  into postnatal period
• Most active period from birth to approximately
  5-6 years of age
• Timing of Neurotransmitter development
• Early appearance of GABA
• Later appearance of glutamate
• Monoamine emergence is dominant early
• Neurotransmitters serve a neurotrophic role early
• Serotonin example of early neurotrophic role in
  cortical connections
• Norepinephrine/acetylcholine roles in neural
  plasticity

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Pruning and Refinement

• Neuronal proliferation is followed by a period of
  elimination prior to and following birth.
• As much as 50 of existing connections are
  eliminated
• Apoptosis (a flower losing its petals)
• Axonal proliferation and retraction occurs prior
  to birth.
• Corpus callosum collaterals eliminated
• Cortical-cortical paths are eliminated
• For example, Layer V visual cortex eliminates
  spinal cord projections
• Role of signaling agents better understood
• Generalized e.g. NGF,BDNF,IGF-1
• Or specific e.g. GDNF specific to dopamine

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Neurotransmitter Development
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Developmental Axis
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Basic Developmental Divisions
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Prosencephalon
Mesencephalon
Rhombencephalon
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Limbic System
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Limbic Cortex and Hypothalamus
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Cortex-Limbic Circuit
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Amygdala Efferent Pathways
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Central Fear Circuit

• Amygdala afferents
• Sensory afferents to the amygdala through the
  thalamus
• Neocortex -gt medial prefrontal to the amygdala
• Hippocampus (mixed afferent-efferent)
• Cingulate cortex (mixed)
• Entorhinal cortex (mixed)
• Orbital frontal to the amygdala (mixed)

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Central Fear Circuit

• Efferent pathways from the amygdala
• Stria terminalis
• Amygdalofugal circuit
• Amygdalofugal network
• Olfactory division
• Cortical division
• Autonomic division

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Amygdala Efferents to the Hypothalamus and
Brainstem
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Development of Cortical Mantle
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Basal Ganglia
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Basal GangliaDirect and Indirect Pathways
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Higher Cortical Development

• Experience-dependent synaptogenesis
• Experience helps to organize the cortex
• Chemical imprinting
• Gonadal steroids
• Receptor imprinting Prior to and after birth
  increasing evidence that neurotransmitters
  influence long term structure (e.g. prenatal
  stimulant exposure)
• Alterations in up down regulation
• Neurotransmitters as neurotrophic factors
• Long-term potentiation and depression
• Plasticity and medication use

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Long-Term Potentiation

• Three distinct phases
• First, following multiple excitations there is
  exaggerated neurotransmitter availability at the
  pre-synaptic bouton
• Second, active post-synaptic receptor
  reconstruction and intracellular signaling
• Third, retrograde-synaptic communications which
  signals the end of phase one (e.g. nitrous oxide
  role)

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Long-Term Potentiation
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Age Related Cortical Changes

• First rapid growth phase is in first 18 months
• Primarily motor and sensory projections
• Development from posterior to anterior direction
• White track expansion from anterior to posterior
• Primarily from 6 to 13 years of age
• Connectivity primarily to temporal and parietal
  areas
• Second rapid growth phase prior to pre-puberty
• 11yrs females, 12 yrs males
• Primarily in frontal cortex and tertiary
  overlapping areas

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Age Related Changes
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Myelin Development
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Frontal Architecture
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Frontal Lobe Systems

• Motor and Pre-motor systems
• Dorsal lateral
• Working memory
• Model building/reconstitution
• Orbital temporal
• Inhibition
• Emotional modulation
• Medial
• Emotional/motivational modulation

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Orbital-frontal Injury
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Dorso-lateral Frontal Cortex
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Dorsal Lateral
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Medial Frontal Injury
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Neuropsychological Development

• Nervous system
• Supporting structures
• Neurotransmitters/Neuropeptides
• Chemical communication
• Endocrine
• Hormone communication

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Luria (1968)

• Historically
• Luria used the term, executive functions, to
  describe higher order mental ability that
  addressed self-directed behaviors

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Neuropsychological Development of Executive Skills

• Increasing ability to inhibit unwanted response
• Increasing mental fluency
• Protection against distraction
• Increasing ability to organize, model and
  reconstruct increasing volumes of information
• Reconstitution and model building
• Planning and strategy development

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Barkley (1997)Model of Executive Skills

• Inhibition
• Filtering out competing stimuli
• Working memory
• Initially perceptual
• Verbal
• Internalization of language
• Gradual internalization process
• Self-regulation of affect and drive
• Reconstitution model building
• Motor fluency, control and syntax
• Existing repertoire of responses

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Barkleys Model
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Executive Development

• Core elements arise very early in life and
  develop in parallel
• Through time the elements are integrated into an
  overriding set of routines that guide mature,
  adult behaviors

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Individual Differences in Executive Function
Espy et al, in Developmental Variations in
Learning, 2002

• Early emergence of elements
• Similar overlapping sequence of events in all
  children
• Infant demonstrate preferences

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Executive Development

• Styles of executive function are probably
  distributed in the population
• Typical and atypical styles exist without
  pathological implications

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Executive Development

• Criteria or threshold for executive dysfunction
  is not understood or established
• Styles that compromise
• Health
• Social functioning
• Productivity

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Differential development of attention and
executive functionsKlenberg, L, et al,
Developmental Neuropsychology Aug 2001

• Developmental Sequence
• Motor inhibition
• Impulse control
• Selective sustained attention
• Fluency
• Separate Factor Analysis Clusters
• Inhibition
• Attention visual and auditory
• Fluency

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Treatment and Management

• Environmental management
• Skill building, social competency
• Socialization, group membership
• Medical interventions