brain development & plasticity dr. elizabeth sheppard developmental cognitive neuropsychology...

Brain Development & Plasticity

Dr. Elizabeth Sheppard

Developmental Cognitive Neuropsychology

(C8CLDC)

Child Clinical Neuropsychology

(C8DCHN)

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

1.Structural features2.Cellular basis (proliferation, migration, differentiation)3.Disruptions to prenatal development

* Postnatal brain development1.Dendritic aborisation2.Synaptogenesis3.Myelination

* Specialisation or functional plasticity?

Developmental Cognitive Neuropsychology:

The “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.



*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?

Brain Development: General Principles

1.) ProtractedProtracted period of brain development: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 formationPostnatal development elaboration of CNS

(connectivity)

Brain Development:General principals

1.) ProtractedProtracted period of brain development: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).


* 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)



1.) ProtractedProtracted period of brain developmentperiod of brain development2.) PropertiesProperties of brain development: of brain development:

* Nature of brain development is believed to be:1. hierarchical (cerebellar/brain stem areas, then posterior

areas, and lastly anterior regions, especially frontal cortex)

2. 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)

3. stage-like (follows a series of precise and genetically pre-determined stages; partially pre-requisite sequence of complicated and over-lapping processes).


1.) 1.) ProtractedProtracted period of brain development period of brain development2.) 2.) PropertiesProperties of brain development of brain development3.) Two 3.) Two major processesmajor processes operate: operate:

1. Process of addition- ongoing accumulation or growth- E.G.1. myelination (stage-like progression)- E.G.2. dendritic aborisation (continual

progression)2. 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.


1.) 1.) Protracted Protracted period of brain developmentperiod of brain development2.) 2.) Properties Properties of brain developmentof brain development3.) 3.) Two major processes Two major processes operateoperate4.) 4.) CriticalCritical or or “sensitive” periods“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)

Brain Development:Influences

* Various influences can impact on brain development. These include:

1. Direct CNS injury or insult (e.g., stroke, tumour, trauma) 2. Environmental factors (e.g., malnutrition, sensory

deprivation)3. Environmental toxins (e.g., lead, radiation) 4. Psychosocial factors (e.g., quality of mother-child

relationship, level of available stimulation, social support structures, access to resources etc.)


* Impact may not be static. Cascading influences on brain maturation may occur. For example:

1. meningitis or febrile convulsions hippocampal sclerosis epilepsy (Ounstead et al., 1966)

2. cranial irradiation (treatment for cerebral tumour orleukaemia) delayed cerebral pathology, especially cerebral calcifications and other white matter pathology (Matsumoto et al., 1995; Paakko et al., 1992)

Prenatal CNS Development:Structural 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.


* 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/


* 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


* Neural tube differentiates along three dimensions:1. Length major subdivisions of CNS (forebrain &

midbrain, & spinal cord)2. Circumference sensory & motor systems

3. Radius different layering patterns & cell types


Disruption of neural tube differentiationDisruption of neural tube differentiation failure of failure of formation of structural divisions. Include: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: AlobarFrom: http://www.urmc.rochester.edu

Lobar holoprosencephaly From: http://uiowa.edu)

Prenatal CNS Development:Cellular basis

* CNS contains two main classes of cells:1. Neurons produced by division of neuroblasts2. 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


*Four primary components:1. cell body2. axon3. dendrites4. presynaptic terminals

(from Kolb & Whishaw, 1996)

1.

2.

3.

4.


* Structure of neurons comprise four primary components:1. the cell body (metabolic functions of neuron, holds RNA

& DNA)2. the axon, long projection from cell body (conducts nerve

impulses away from cell body. Mature axon covered by coating of myelin rapid neural transmission)

3. 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)

4. the presynaptic terminals (neurotransmitters are stored and released, cross the synaptic cleft activate neurons at postsynapse)


* Glial cells:– Supportive and nutrient role– Nine times as many glial cells as neurons– Lack axons– Several subtypes, including:

1. Astrocytes (form blood-brain barrier, support cellular structure of brain, direct migration of neurons, clean up and plug injury sites)

2. Oligodendrocytes (speed up neural transmission by coating axons with myelin)

3. 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.


* Prenatal brain development follows a genetically predetermined sequence involving three major mechanisms:

1. Proliferation - cell generation2. 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.

3. 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


* 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)

Neurogenesis

Migration

Differentiation &maturation

Cell death &synaptic pruning


* 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)

Prenatal CNS Development:Disruptions

* 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 morphologyLater disruption impact on migrational activity &

neuronal differentiation


* Examples of differences in timing of insult on prenatal brain development include:

1. Induction (dorsal) weeks 3-4Myelomeningocele (spina bifida). Failure of closure of the spinal cord. Arises from genetic or nutritional factors. Results in motor & perceptual deficits.

2. Induction (ventral) weeks 5-6Holoprosencephaly. Failure to form two hemispheres. Often genetic origin. Usually incompatible with life.

3. Proliferation 2-5 monthsMicroencephaly. Early cessation of cell division abnormally small head. Genetic or trauma factors, e.g., infection, fetal alcohol syndrome. Associated with low intellectual abilities.


* Examples of differences in timing of insult on prenatal brain development include:

4. Migration 2-5 monthsLissencephaly, Schizencephaly, Dysplasias

5. DifferentiationPorencephaly. Large cystic lesions, usually bilateral.

Occurs at5-7 months gestation. Usually of traumatic/vascular/infectious origin. Often results in retardation and epilepsy.

Prenatal CNS Development:Malformations 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)

Right Left


* 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.


Right Left


* 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.


Right Left


* hemimegencephaly:– markedly abnormal left hemisphere with thickened, irregular cortex, excessive white matter, heterotopic grey matter, and a dilated, dysmorphic lateral ventrical


Right Left

Postnatal Development:CNS 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):

1. dendritic aborisation2. synaptogenesis 3. myelination


* 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).


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

1997).Newborn 1 month old 3 months old 6 months old


* 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 (Heschl’s 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


* 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).

Postnatal Development

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

From Huttenlocher (2002)

Additive/Regressive Processes:


* 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.


* 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)

Human brain development: Postnatal

influences

* Sensory Sensory deprivation of deprivation of input affects input affects synaptic density synaptic density in kittensin kittens

From Huttenlocher (2002)

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:

1. 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).

Specialisation or functional plasticity of the cerebral cortex

2. Undifferentiated cortex:– cortex is initially undifferentiated but becomes

increasingly specialised in function throughout postnatal period (e.g., Killackey, 1990; O’Leary, 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.

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.

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.1. General principles of CNS development: Nowakowski, R.S. &

Hayes, N.L.2. Intrinsic and extrinsic determinants of neocortical parcellation: A

radial model: Rakic, P.3. Positrom Emission Tomography study of human brain functional

development: Chugani, H.T., Phelps, M.E. & Mazziotta, J.C.4. Morphmetric study of human cerebral cortex development:

Huttenlocher, P.R.

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 cortical circuitry and cognitive functions. Child Development, 58, 601-622.* Huttenlocher, P.R. (1994). Synaptogenesis in human cerebral cortex. In G. Dawson & K. Fischer (Eds.), Human behaviour and the developing brain. New York: Guilford Press.* Huttenlocher, P.R. (1996). Morphometric study of human cerebral cortex development. In M. Johnson (Ed.), Brain development and cognition: A reader. Cambridge, MA: Blackwell.* Johnson, M.H. (1997). Developmental Cognitive Neuroscience. Oxford: Blackwell Publishers Ltd. * Killackey, H. (1990). Neocortical expansion: An attempt towards relating phylogeny and ontogeny. Journal of Cognitive Neuroscience, 2, 1-17.* Kolb, B. (1995). Brain plasticity and behavior. Hillsdale, NJ: Lawrence Erlbaum Associates Inc.* Kolb, B. & Wishaw, Q. (1996). Fundamentals of human neuropsychology (4th ed.). New York: W.H. Freeman.

References

* Matsumoto, T., Takahashi, S., Sato, A., Imaizumi, M., Higano, S., Sakamoto, K., Asakawa, H., & Tada, K. (1995). Leukoencephalopathy in childhood hematopic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy: An MR analysis. International Journal of Radiation Oncology and Biological Physics, 32, 913-918.* Molliver, M.E., Kostovic, I., Van der Loos, H. (1973). The development of synapses in cerebral cortex in the human fetus. Brain Research, 50, 403-407.* O’Leary, D. (1989). Do cortical areas emerge from a protocortex? Trends in Neurosciences, 12, 400- 406.* Ounstead, C., Lindsey, J.T., & Norman, R.M. (1966). Biological factors in temporal lobe epilepsy (Clicnics in Developmental Medicine No. 22). London: Heinemann Medical Books.* Paakko, E., Vainionpaa, L., Lanning, M., Laitinen, J., & Pyhtinen, J. (1992). White matter changes in children treated for acute lymphoblastic leukemia. Cancer, 70, 2728-2733.* Papalia, D. & Olds, S. (1992). Human Development (5th ed.). New York: McGraw-Hill.* Rakic, P. (1988). Specification of cerebral cortical areas. Science, 241, 170-176.* Valk, J. & Van der Knapp, M.S. (1992). Toxic encephalopathy. American Journal of Neuroradiation, 13, 747-760.

brain development & plasticity dr. elizabeth sheppard developmental cognitive neuropsychology...

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