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Brain Development & Plasticity

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1 Brain Development & Plasticity
Dr. Elizabeth Sheppard Developmental Cognitive Neuropsychology (C8CLDC) Child Clinical Neuropsychology (C8DCHN)

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 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.

4 Developmental Cognitive Neuropsychology: The “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 Development: General 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 years) approx g; gradual decline) Postnatal increase in brain weight due to differentiation, growth and maturation of existing neurons (not formation of new neurons).

7 Brain Development: General 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)

8 Developmental Cognitive Neuropsychology: The “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 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).

9 Brain Development: General 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.

10 Brain Development: General 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)

11 Brain Development: Influences
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.)

12 Brain Development: Influences
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 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.

14 Prenatal CNS Development: Structural 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

15 Prenatal CNS Development: Structural 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

16 Prenatal CNS Development: Structural 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

17 Prenatal CNS Development: Structural 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: Lobar holoprosencephaly From:

18 Prenatal CNS Development: Cellular 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

19 Prenatal CNS Development: Cellular basis
3. Four primary components: cell body axon dendrites presynaptic terminals (from Kolb & Whishaw, 1996) 1. 2. 4.

20 Prenatal CNS Development: Cellular 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)

21 Prenatal CNS Development: Cellular 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.

22 Prenatal CNS Development: Cellular 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

23 Prenatal CNS Development: Cellular 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) Neurogenesis Migration Differentiation & maturation Cell death & synaptic pruning

24 Brain Development: Influences
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)

25 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 morphology Later disruption  impact on migrational activity & neuronal differentiation

26 Prenatal CNS Development: Disruptions
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.

27 Prenatal CNS Development: Disruptions
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.

28 Prenatal CNS Development: Malformations of cortical development
Right Left 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)

29 Prenatal CNS Development: Malformations of cortical development
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. (from Anderson et al., 2001)

30 Prenatal CNS Development: Malformations of cortical development
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. (from Anderson et al., 2001)

31 Prenatal CNS Development: Malformations of cortical development
Right Left 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)

32 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): dendritic aborisation synaptogenesis myelination

33 Postnatal Development: CNS elaboration
Dendritic aborisation: Additive process, no evidence of regression or pruning of dendrites (e.g., Huttenlocher, 1996) Dendritic branching begins as early as gestation and continues until birth. Major changes occur postnatally, including increased length and branching. Most dramatic development occurs between postnatal weeks 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 Development: CNS elaboration
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

35 Postnatal Development: CNS 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 (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

36 Postnatal Development: CNS 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 Development: CNS 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.

39 Brain Development: Influences
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; 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.

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, Blakemore, C. (1974). Development of functional connections in the mammalian visual system. British Medical Bulletin, 30, Fuster, J. (1993). Frontal lobes. Current Opinion in Neurobiology, 3, Goldman-Rakic, P.S. (1997). Development of cortical circuitry and cognitive functions. Child Development, 58, 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.

46 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, Molliver, M.E., Kostovic, I., Van der Loos, H. (1973). The development of synapses in cerebral cortex in the human fetus. Brain Research, 50, 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, Papalia, D. & Olds, S. (1992). Human Development (5th ed.). New York: McGraw-Hill. Rakic, P. (1988). Specification of cerebral cortical areas. Science, 241, Valk, J. & Van der Knapp, M.S. (1992). Toxic encephalopathy. American Journal of Neuroradiation, 13,

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