Brain Development

1
Brain Development Plasticity

• Dr. Elizabeth Sheppard

2
Learning objectives

• Consider the role of brain development in the
  study of childhood
• cognitive disorders
• General principles of brain development
• Influences on brain development
• Prenatal brain development
• Structural features
• Cellular basis (proliferation, migration,
  differentiation)
• Disruptions to prenatal development
• Postnatal brain development
• Dendritic aborisation
• Synaptogenesis
• Myelination
• Specialisation or functional plasticity?

3
Developmental Cognitive NeuropsychologyThe
Neuro Dimension

• Why look at brain development?
• DCN how are cognitive functions may be
  disordered during development?
• Adult Cognitive Neuropsychology has shown there
  to be a close relationship between brain and
  behaviour (e.g., localisation of function).
  Assumes breakdown within a stable or static
  system.
• But development dynamic process. Complex
  interaction between neurological, cognitive, and
  psychosocial factors.
• Need to understand the neural mechanisms involved
  in brain development to fully appreciate the
  relationship between the developing brain and
  cognitive functions.

4
Developmental Cognitive NeuropsychologyThe
Neuro Dimension

• Key aspects of CNS development for DCN
• 1.Is there a relationship between changes in
  brain structure/function and cognitive
  development?
• 2.Recovery of impaired cognitive functions
  Higher during certain periods of brain
  development? Is neural plasticity simply a
  response to insults or a driving mechanism in
  development?
• 3.What is the role of environmental influences
  on brain maturation? Can changes in environment
  influence cognitive development and
  rehabilitation? What are the negative
  consequences of disadvantaged environments?

5
Brain Development General Principles

• 1.) Protracted period of brain development
• The CNS starts to develop early in gestation and
  continues through
• infancy and childhood to adolescence and into
  adulthood.
• Prenatal development ? structural formation
• Postnatal development ? elaboration of CNS
  
• 
  (connectivity)

6
Brain DevelopmentGeneral principals

• 1.) Protracted period of brain development
• Ongoing process throughout gestation and
  childhood.
• Unique to humans.
• Fastest rate occurs prenatally. Approx. 250,000
  new brain cells formed every minute (Papalia
  Olds, 1992).
• Structural morphology of brain complete at birth
  but growth continues postnatally (birth approx.
  400 g early adulthood (peaking 18-30 years)
  approx. 1500 g gradual decline)
• Postnatal increase in brain weight due to
  differentiation, growth and maturation of
  existing neurons (not formation of new neurons).

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Brain DevelopmentGeneral principals

• Stages of human brain development throughout
  gestation.
• About day 40 of embryonic life CNS begins to
  develop.
• Around day 100, brain is recognisable in its
  mature form.
• (from Johnson, 1997)

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Developmental Cognitive NeuropsychologyThe
Neuro Dimension

• 1.) Protracted period of brain development
• 2.) Properties of brain development
• Nature of brain development is believed to be
• hierarchical (cerebellar/brain stem areas, then
  posterior areas, and lastly anterior regions,
  especially frontal cortex)
• stepwise (growth spurts in weeks 24-25 gestation
  (completion of neuronal generation), early
  infancy (dendritic synaptic development
  myelination), then again at 7-10 years, and in
  early adolescence)
• stage-like (follows a series of precise and
  genetically pre-determined stages partially
  pre-requisite sequence of complicated and
  over-lapping processes).

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Brain DevelopmentGeneral principals

• 1.) Protracted period of brain development
• 2.) Properties of brain development
• 3.) Two major processes operate
• Process of addition
• ongoing accumulation or growth
• E.G.1. myelination (stage-like progression)
• E.G.2. dendritic aborisation (continual
  progression)
• Process of regression
• initial overproduction followed by elimination of
  redundant elements
• E.G.1. Number of neurons prenatally is in excess
  of number required by mature brain. Redundant
  neurons die off during stage of differentiation.
• E.G.2. Number of synapses formed postnatally
• Not considered detrimental. Fine-tuning of system.

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Brain DevelopmentGeneral principals

• 1.) Protracted period of brain development
• 2.) Properties of brain development
• 3.) Two major processes operate
• 4.) Critical or sensitive periods
• Stage in developmental sequence during which a
  behavioural function experiences major
  progression
• If progression does not occur appropriately then
  it may never occur.
• E.G. Visual deprivation during critical periods
  results in irreversible effects on ongoing
  maturation of particular visual processes
  (Blakemore, 1974).
• E.G.2. In humans, removal of cataracts after
  early infancy affects particular visual processes
  (e.g., face processing, LeGrand et al., 2003)

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Brain DevelopmentInfluences

• Various influences can impact on brain
  development. These include
• Direct CNS injury or insult (e.g., stroke,
  tumour, trauma)
• Environmental factors (e.g., malnutrition,
  sensory deprivation)
• Environmental toxins (e.g., lead, radiation)
• Psychosocial factors (e.g., quality of
  mother-child relationship, level of available
  stimulation, social support structures, access to
  resources etc.)

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Brain DevelopmentInfluences

• Impact may not be static. Cascading influences on
  brain maturation may occur. For example
• meningitis or febrile convulsions ? hippocampal
  sclerosis ?
• epilepsy (Ounstead et al., 1966)
• cranial irradiation (treatment for cerebral
  tumour or
• leukaemia) ? delayed cerebral pathology,
  especially cerebral
• calcifications and other white matter pathology
  (Matsumoto et al., 1995 Paakko et al., 1992)

13
Prenatal CNS DevelopmentStructural features

• Prenatal brain development resembles that of
  other vertebrates.
• Soon after conception, the fertilized cell
  undergoes process of rapid cell division ?
  cluster of proliferating cells called the
  blastocyst.
• Within a few days, blastocyst differentiates into
  three-layered structure called the embryonic
  disc.

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Prenatal CNS DevelopmentStructural features

• Embryonic disc further differentiates into major
  organic systems
• Endoderm (inner layer) ? internal organs (e.g.,
  digestive etc)
• Mesoderm (middle layer) ? skeletal muscular
  structures
• - Ectoderm (outer layer) ? skin surface
  nervous system

From http//www.howe.k12.ok.us/
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Prenatal CNS DevelopmentStructural features

• CNS begins with a process called neurolation.
• Portion of ectoderm folds in on itself ? hollow
  cylinder called the neural tube.
• Disruption ? serious structural abnormalities
• incomplete closure of spinal cord
• (myelomeningocele) ? spina bifida
• incomplete closure of neural tube
• (anencephaly) ? absent skull vault i.e.
• no brain (incompatible with life)

Spina Bifida Association - Wisconsin
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Prenatal CNS DevelopmentStructural features

• Neural tube differentiates along three
  dimensions
• Length ? major subdivisions of CNS (forebrain
  midbrain, spinal cord)
• Circumference ? sensory motor systems
• Radius ? different layering patterns cell types

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Prenatal CNS DevelopmentStructural features

• Disruption of neural tube differentiation?
  failure of formation of structural divisions.
  Include
• - E.G.1. Failure to form two cerebral hemispheres
  (holoprosencephaly)
• - E.G.2. Incomplete fusion of the skull
  (craniosynostosis)

Holoprosencephaly Alobar From
http//www.urmc.rochester.edu
Lobar holoprosencephaly From http//uiowa.edu)
18
Prenatal CNS DevelopmentCellular basis

• CNS contains two main classes of cells
• Neurons ? produced by division of neuroblasts
• Glial cells ? produced by division of glioblasts
• Neurons
• Basic functional (computational) unit of the CNS
• Transmit impulses within complex network of
  interconnecting brain cells
• Enormous variety of neurons, depending on
  function - all with similar basic structure

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Prenatal CNS DevelopmentCellular basis
3.

• Four primary components
• cell body
• axon
• dendrites
• presynaptic terminals
• (from Kolb Whishaw, 1996)

1.
2.
4.
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Prenatal CNS DevelopmentCellular basis

• Structure of neurons comprise four primary
  components
• the cell body (metabolic functions of neuron,
  holds RNA DNA)
• the axon, long projection from cell body
  (conducts nerve impulses away from cell body.
  Mature axon covered by coating of myelin ? rapid
  neural transmission)
• the dendrites, branch off from cell body (receive
  and conduct impulses from other neurons towards
  cell body. Dendritic spines locus of the synapse
  ? information is transmitted between neurons)
• the presynaptic terminals (neurotransmitters are
  stored and released, cross the synaptic cleft ?
  activate neurons at postsynapse)

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Prenatal CNS DevelopmentCellular basis

• Glial cells
• Supportive and nutrient role
• Nine times as many glial cells as neurons
• Lack axons
• Several subtypes, including
• Astrocytes (form blood-brain barrier, support
  cellular structure of brain, direct migration of
  neurons, clean up and plug injury sites)
• Oligodendrocytes (speed up neural transmission by
  coating axons with myelin)
• Microglia (clean up tissue around injury sites,
  primarily in grey matter)
• Relatively immature in early stages of brain
  development. Continue to generate with increased
  CNS maturity.

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Prenatal CNS DevelopmentCellular basis

• Prenatal brain development follows a genetically
  predetermined sequence involving three major
  mechanisms
• Proliferation - cell generation
• Migration - young neurons move to their permanent
  locations.
• Two forms (i) Passive cell displacement -
  oldest cells pushed away from newer cells ?
  outside-to- inside spatiotemporal gradient.
• (ii) Active migration - young cells move past
• previously generated cells ? inside-out
  gradient.
• Differentiation - complex process in which cells
  become committed to specialised systems.
  Involves (i) development of cell bodies (ii)
  selective cell death (iii) dendritic and axonal
  growth (iv) formation of synaptic connections

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Prenatal CNS DevelopmentCellular basis

• Major developmental processes occurring prenatal
  brain development.
• Each successive process commences prior to the
  completion of the previous one.
• Final processes are heterochronous across
  cortical areas.
• (from Anderson et al.,2001)

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Brain DevelopmentInfluences

• Risk factors affecting prenatal brain development
  include
• Maternal stress and age
• Maternal health (e.g., history of infection,
  rubella, AIDS, herpes simplex)
• Maternal drug and alcohol addiction (smoking,
  alcohol, marijuana, cocaine, heroin)
• Environmental toxins (lead, radiation, trauma)

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Prenatal CNS DevelopmentDisruptions

• Interruptions to the major developmental
  processes of prenatal brain development can have
  severe consequences for ongoing development
  (including cognitive development).
• Timing of the insult may be more important to
  outcome than the nature and severity of the
  insult during prenatal development.
• Earlier disruption ? impact on gross cerebral
  morphology
• Later disruption ? impact on migrational activity
  neuronal differentiation

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Prenatal CNS DevelopmentDisruptions

• Examples of differences in timing of insult on
  prenatal brain development include
• Induction (dorsal) weeks 3-4
• Myelomeningocele (spina bifida). Failure of
  closure of the spinal cord. Arises from genetic
  or nutritional factors. Results in motor
  perceptual deficits.
• Induction (ventral) weeks 5-6
• Holoprosencephaly. Failure to form two
  hemispheres. Often genetic origin. Usually
  incompatible with life.
• Proliferation 2-5 months
• Microencephaly. Early cessation of cell division
  ? abnormally small head. Genetic or trauma
  factors, e.g., infection, fetal alcohol syndrome.
  Associated with low intellectual abilities.

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Prenatal CNS DevelopmentDisruptions

• Examples of differences in timing of insult on
  prenatal brain development include
• Migration 2-5 months
• Lissencephaly, Schizencephaly, Dysplasias
• Differentiation
• Porencephaly. Large cystic lesions, usually
  bilateral. Occurs at
• 5-7 months gestation. Usually of
  traumatic/vascular/
• infectious origin. Often results in retardation
  and epilepsy.

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Prenatal CNS DevelopmentMalformations of
cortical development

• Classical lissencephaly
• smooth gyral pattern and
• thickened cortex
• migrational disorder
• between weeks 11-13
• severe mental retardation,
• seizures, neuromotor
• disorders.
• (from Anderson et al., 2001)

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Prenatal CNS DevelopmentMalformations of
cortical development

• unilateral schizencephaly
• grey matter-lined cleft in
• right posterior frontal lobe
• communicating with right
• lateral ventricle
• migration disorder at 8
• weeks
• mental retardation,
• seizures, neuromotor
• disorders.
• (from Anderson et al., 2001)

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Prenatal CNS DevelopmentMalformations of
cortical development

• Focal cortical dysplasia
• evidence of poor grey-
• white matter differentiation
• and low white matter signal in
• the right hemisphere
• migrational disorder with
• multiple origins
• results in epilepsy, learning
• disability, schizophrenia.
• (from Anderson et al., 2001)

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Prenatal CNS DevelopmentMalformations of
cortical development

• hemimegencephaly
• markedly abnormal left
• hemisphere with thickened,
• irregular cortex, excessive
• white matter, heterotopic
• grey matter, and a dilated,
• dysmorphic lateral ventrical
• (from Anderson et al., 2001)

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Postnatal DevelopmentCNS elaboration

• Protracted process. Occurs throughout childhood
  and into adolescence.
• Brain quadruples in size from birth to adulthood.
  Occurs not because of increase in number of
  neurons (which is established at birth) but
  because of three processes of elaboration
  (additive)
• dendritic aborisation
• synaptogenesis
• myelination

33
Postnatal DevelopmentCNS elaboration

• Dendritic aborisation
• Additive process, no evidence of regression or
  pruning of dendrites (e.g., Huttenlocher, 1996)
• Dendritic branching begins as early as 25-30
  gestation and continues until birth.
• Major changes occur postnatally, including
  increased length and branching.
• Most dramatic development occurs between
  postnatal weeks 5-21. Adult levels at 5-6 months
  (Becker et al., 1984).
• Development in the frontal areas may continue
  until age 7 (Huttenlocher, 1996).
• Environmental stimulation/deprivation can
  increase/hinder the process (e.g., Kolb, 1995).

34
Postnatal DevelopmentCNS elaboration

• Cellular structure of visual cortex from birth to
  6 months. Shows increased connectivity in brain
  during this period. (From Johnson, 1997).

35
Postnatal DevelopmentCNS elaboration

• Synaptogensis
• Synaptic connections increase from birth, with
  bursts of rapid
• growth at various stages within different
  cerebral regions
• - V1 peak in density between 4-12 months (150
  of adult)
• - A1 (Heschls gyrus) similar
• - Prefrontal cortex density increase is much
  slower, peak only after first year
• - Begins in 2nd trimester of gestation
  (Molliver et al., 1973)
• Most development is postnatal
• Regressive process (initial over-production then
  reduction)
• Synapses initially unspecified in function
  (Huttenlocher, 1994)
• As neural circuits emerge synapses become
  utilised in these
• functional systems
• Unspecified synapses regress, starting after 1
  year

36
Postnatal DevelopmentCNS elaboration

• Synaptogensis
• Relatively immune to environmental
  stimulation/deprivation
• (Goldman-Rakic et al., 1997)
• Parallel pattern of development of
  neurotransmitter levels
• (Huttenlocher, 1994) i.e. although
  counter-intuitive, there is
• some consistency in this rise-and-fall pattern
  of development
• Redundancy of synapses may be associated with
  functional
• plasticity (Huttenlocher, 1994).

37
Postnatal Development
Additive/Regressive Processes

• Rise and fall of synaptic density for visual
  (open circles), auditory (filled circles) and
  prefrontal cortex (crossbars)
• From Huttenlocher (2002)

38
Postnatal DevelopmentCNS elaboration

• Myelination
• Mostly postnatal process, with rapid development
  in first 3
• years but continuing, at a slower pace, into
  second decade
• (Valk Van der Knapp, 1992)
• Hierarchical progression (e.g., Fuster, 1993)
• proximal before distal
• sensory before motor
• projection before association
• central before poles
• posterior before anterior
• Gradual increase in thickness of myelin sheaths
• Rate varies across cerebral regions, with
  frontal lobes
• becoming myelinated last
• Disruption to process leads to reduced speed of
  response,
• attention, processing capacity, IQ.

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Brain DevelopmentInfluences

• Risk factors affecting postnatal brain
  development include
• Birth complications (e.g., anoxia, prematurity)
• Nutrition
• Cerebral infection
• Environmental toxins (lead, radiation, trauma)
• Environment experience (e.g. normal sensory
  experiences vs. sensory deprivation)

40
Human brain development Postnatal influences

• Sensory deprivation of input affects synaptic
  density in kittens
• From Huttenlocher (2002)

41
Specialisation or functional plasticity of the
cerebral cortex

• How do different brain areas specialise?
• Two major opposing views on functional
  specialisation within the
• cerebral cortex
• Prespecified functional organisation
• - cortical differentiation begins
  prenatally with cortical structure and function
  established prior to postnatal
• experience (Rakic, 1988), by
  intrinsic factors.
• neuronal proliferation migration suggest
  neurons are
• preprogrammed to form particular
  cerebral structures
• that subsume particular functions
  (Johnson, 1997).

42
Specialisation or functional plasticity of the
cerebral cortex

• Undifferentiated cortex
• cortex is initially undifferentiated but becomes
  increasingly specialised in function throughout
  postnatal period (e.g., Killackey, 1990 OLeary,
  1989) due to extrinsic factors like input from
  other parts of brain
• suggests cortical regions could subsume a variety
  of functions depending on the sensory input they
  receive.
• if cerebral damage occurs before specialisation
  is complete functional localisation may be
  permanently altered.

43
Specialisation or functional plasticity of the
cerebral cortex

• Considerable disagreement over these two
  viewpoints e.g. Temple vs. Johnson
• Temple - plasticity is response to brain damage
  but not a driving force in development.
  Maturational account (preformist nativist)
  Areas come online at different points in
  development, according to a genetically specified
  plan.
• - Johnson argues middle-ground position whereby
  large scale regions are prespecified, while
  establishment of small-scale functional areas
  require activity-dependent processes. Interactive
  Specialisation Account (neuroconstructivist)
  Experience is necessary to build functional
  long-range connections between areas that earlier
  in development are not connected as effectively.
  These connections drive specialisation mutually
  across areas.

44
Background Reading

• Anderson, V., Northam, E., Hendy, J., Wrennall,
  J. (2001). Developmental Neuropsychology A
  Clinical Approach. Hove Psychology Press.
  Chapter 2.
• Johnson, M.H. (2000). Developmental Cognitive
  Neuroscience. Oxford
• Blackwell Publishers Ltd. Chapter 2.
• Johnson, M.H., Munakata, Y., Gilmore, R.O.
  (Eds). (2002). Brain
• Development and Cognition A Reader. Oxford
  Blackwell Publishing. Part II.
• General principles of CNS development
  Nowakowski, R.S. Hayes, N.L.
• Intrinsic and extrinsic determinants of
  neocortical parcellation A radial model Rakic,
  P.
• Positrom Emission Tomography study of human brain
  functional development Chugani, H.T., Phelps,
  M.E. Mazziotta, J.C.
• Morphmetric study of human cerebral cortex
  development Huttenlocher, P.R.

45
References

• Anderson, V., Northam, E., Hendy, J.,
  Wrennall, J. (2001). Developmental
  Neuropsychology A
• Clinical Approach. Hove Psychology Press.
• Becker, L., Armstrong, D., Chan, F., Wood, M.
  (1984). Dendritic development in human occipital
• cortical neurons. Developmental Brain
  Research, 13, 117-124.
• Blakemore, C. (1974). Development of functional
  connections in the mammalian visual system.
  British
• Medical Bulletin, 30, 152-157.
• Fuster, J. (1993). Frontal lobes. Current
  Opinion in Neurobiology, 3, 160-165.
• Goldman-Rakic, P.S. (1997). Development of
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• Development, 58, 601-622.
• Huttenlocher, P.R. (1994). Synaptogenesis in
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• Human behaviour and the developing brain. New
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• Huttenlocher, P.R. (1996). Morphometric study of
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• (Ed.), Brain development and cognition A
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• Johnson, M.H. (1997). Developmental Cognitive
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• Killackey, H. (1990). Neocortical expansion An
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• Journal of Cognitive Neuroscience, 2, 1-17.
• Kolb, B. (1995). Brain plasticity and behavior.
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• Kolb, B. Wishaw, Q. (1996). Fundamentals of
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46
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