CORTICAL PLASTICITY AND RECOVERY OF FUNCTIONS AFTER TBI IN CHILDHOOD
Brain injury acquired during childhood or adolescence. Which specific care ? Which support ? - Brussels 2009
Department of Pediatric Rehabilitation Children’s Hospital Bambino Gesù – Rome (Italy)
Enrico Castelli
Cortical plasticity is the capability of the cerebral
cortex to alter its functional organization as
a result of experience
PLASTICITY
Nudo RJ (2006) J Am Soc Exp NeuroTher, 3:420-427
In both normal and injured animals:
cortical representational maps are altered
synapses change their morphology
dendrites and spines grow and contract
axons change their trajectory
Various neurotransmitters are modulated
synapses are potentiated or depressed
to a limited extent, new neurons differentiateand survive
CORRELATES OF PLASTICITY
ENVIRONMENTAL ENRICHMENT AND ACTIVITY- DEPENDENT PLASTICITY
In all sensory and motor areas of the cerebral cortex that
have been studied, significant functional and structural
changes have been observed as a result of experience.
1. Butefisch CM et al. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 2000;97:3661–3665.
2. Cheung SW et al. Plasticity in primary auditory cortex of monkeys with altered vocal production. J Neurosci 2005;25:2490 –2503.
3. Jones EG. Cortical and subcortical contributions to activity-dependent plasticity in primate somatosensory cortex. Annu Rev Neurosci 2000;23:1–37.
4. Kleim JA et al. Motor learning-dependent synaptogenesis is localized to functionally reorganized motor cortex. Neurobiol Learn Mem 2002;77:63–77.
5. Meliza CD, Dan Y. Receptive-field modification in rat visual cortex induced by paired visual stimulation and single-cell spiking. Neuron 2006;49:183–189.
6. Stettler DD et al. Axons and synaptic boutons are highly dynamic in adult visual cortex. Neuron 2006;49:877– 887.
In comparison to rats in a motor activity control group, ratstrained on a skilled reaching task exhibited:
an areal expansion of wrist and digit movementrepresentations within the motor cortex
significantly more synapses per neuron than controlswithin layer V of the caudal forelimb area
ACTIVITY-DEPENDENT PLASTICITY
USE DEPENDENT VS LEARNING DEPENDENT PLASTICITY
In all sensory and motor areas of the cerebral cortex thathave been studied, significant functional and structuralchanges have been observed as a result of experience.
Changes in cortical maps are driven by specific aspects ofbehavioral demand (i.e, skill acquisition), and are not simplythe result of repetitive use.
If this phenomenon generalizes to injured brains, thenrehabilitation techniques should be optimal if they induceincreasing levels of motor skill. Repetitive use alone isunlikely to induce large-scale, long-lasting changes.
Plautz EJ. Effect of ripetitive motor training on movement representation in adultsquirrel monkeys: role of use vs learning. Neurobiol Learn Mem, 2000, 74:27-55
In vivo intracortical
mapping using micro stimulation
CORTICAL PLASTICITY IS RELATED TO LEARNING !
Plautz EJ et al. Effect of ripetitive motor training on movement representation in adult squirrel monkeys: role of
use vs learning. Neurobiology Learn Mem, 2000, 74:27-55
Small Well
Large Well
Remple MS et al. Sensitivity of cortical movement
representations to motor experience: evidence that
skill learning but not strength training induces cortical reorganization. Behav Brain Research,
2001, 123:133-141
Rapp. mov.distali
Rapp. mov.prossimali
CONTROLLI
USE DEPENDENT VS LEARNING DEPENDENT PLASTICITY
LOCAL PLASTICITY AFTER LESIONS IN THE MOTOR CORTEX
Between 3 and 14 days, rats demonstrate increased GAP-43 immunoreactivity, suggesting neurite outgrowth.
Between 14 and 60 days postinfarct, synaptophysinstaining is elevated, signifying increased synaptogenesis.
Surviving neurons become hyperexcitable, withassociated up-regulation of NMDA receptors anddownregulation of GABAa receptors.
Axonal sprouting occurs in the peri-infarct area.
Growth inhibition is suppressed for about 1 month post-infarct and is followed by “waves” of growth promotionwhich may modulate the brain’s self-repair processes.Carmichael ST. Cellular and molecular mechanisms of neural repair afer stroke:making waves. Ann Neurol 2006,59:735-742.
Carmichael ST. Cellular and molecular mechanisms of neural repair afer stroke: making
waves. Ann Neurol 2006,59:735-742
REMOTE PLASTICITY AFTER LESIONS IN THE MOTOR CORTEX
After stroke, neuroanatomical changes occur notonly in the peri-infarct cortex, but also in remoteareas, such as the contralesional hemisphere.Nudo RJ. Mechanisms for recovery of motor function following cortical damage.2006,Curr Op NeuroBiol,16:638-644
After injury, a large number of cortical areas aredeprived of intracortical connections and theirneurons terminals lie in ischemic territories.
New projection pathway resulting from theischemic infarct represent a repair strategy of thecortex to re-engage the areas.
Nudo RJ. Mechanisms for recovery of motor function following cortical damage. 2006,Curr Op NeuroBiol,16:638-644
MODULATING NEUROPLASTICITYBehavior is one of the most powerful modulators
of post-injury recovery (i.e. constraint-inducedmovement therapy).
Taub E, Uswatte G, King DK, Morris D.
A placebo-controlled trial of
constraint-induced movement therapy for upper extremity
after stroke.
Stroke 2006;37:1045–1049.
Jeff Biernaskie and Dale Corbett. Enriched Rehabilitative Training PromotesImproved Forelimb Motor Function and Enhanced Dendritic Growth after FocalIschemic Injury. Journal of Neuroscience, July 15, 2001, 21(14):5272–5280
Neuronal plasticity is enhanced in the developing brainand children appear to learn more quickly than adults:
they can easily acquire new languages, learn to playinga musical instrument, acquire to play sports
impaired vision early in life from strabismus or oculardisorders can lead to permanent amblyopia because ofreorganization of central visual pathways
early hearing impairment can lead to impaired centralauditory perception
children also recover from certain brain injuries morereadily than adults
PLASTICITY IN THE DEVELOPING BRAIN
MAJOR EVENTS IN HUMANCEREBRAL DEVELOPMENT
Gestational age - weeks post conception
Primary neurulation
Prosencephalic development
Neuroblast proliferation and differentiation
Neuronal migration
Cortical organization
10 20 30 400
GENE AND PROTEIN EXPRESSION
Gene expressionchanges by functionalcategory after mild orsevere developmentalTBI.
Genes associated toNeurotransmission /plasticity and growthfactors/hormonesrepresent a muchlarger percentage ofdownregulated thanupregulated genes.
60 genes
96 genes
Premature 1 3 60
1,3 2 4 6
Months
Years
COX-Golgi preparation of the leg area of the motor cortex (100x)
Development of the cerebral cortex in children is characterized by anearly postnatal burst in synaptogenesis followed by activity-dependent pruning of excessive synapses in the postnatal period.This probably contributes to cortical plasticity by providing an excessof synapses to be selected based on experience during childhood.
OVERPRODUCTION AND PRUNING OF SYNAPSES IN THE DEVELOPING BRAIN
Huttenlocher PR (1997) J Comp Neurol 387:167–178
A major potential mechanism of alterations in developmentalneuroplasticity following TBI involves changes in neurotransmission.Clinically, dysfunctional neurotransmission has been implicated inmany sequelae of pediatric TBI, including memory impairment andattention problems.
CHANGE IN NEUROTRASMISSION
Changes in the frequency orstrength of activation acrosssynapses can result in long-termincreases or decreases in theirstrength, referred to as eitherlong-term potentiation (LTP) orlong-term depression (LTD),respectively.
Citri A, Malenka RC (2008) Neuropsychopharmacology 33:18–41.
TBI to the developing brain is distinct from adult TBI inmany ways:
the developing brain is more malleable to externalstimuli, a characteristic that has often been touted as asignificant advantage with regard to recovery of function.However, children who suffer TBI are well known todevelop chronic cognitive and behavioral disturbances[Ewing-Cobbs, 1998; Jaffe, 1993; Levin, 2002].
Infants and toddlers might arguably have the mostplasticity and yet actually seem to have some of the worstdevelopmental outcomes after significant TBI (Barlow,2005; Levin, 2003).
TBI TO THE DEVELOPING BRAIN
Static (adult) model
In a static (adult) model, a givenfunction remains constant overtime. If an injury occurs, theremay be a permanent deficit(dotted line) or an acutereduction in function that slowlyrecovers over time. At somepoint, if and when the level offunction returns to the premorbidlevel, recovery is said to becomplete (dashed line).
RECOVERY TO BASELINE
C Giza (2006) Dev Neurosci 28:364-379
In a developing model, the level offunction in normal subjects ischanging over time. Afterdevelopmental injury, whilefunctional recovery may return tothe premorbid baseline (dashedline), the baseline function ofnormal peers has already moved on(solid line). The duration ofrecovery, the rate of functionalchange and the presence/timing ofcritical windows all becomeimportant measures to determinewhether the injured immature braincan actually fully recover to an agematched baseline after injury.
RECOVERY TO BASELINE
Dynamic (developing) model
It is also possible that the immaturebrain may appear to have acomplete functional recovery, butthat the strength of this recovery islimited.
One final related concept to beintroduced is that of ‘growing intothe lesion’. This idea purports thatif a particular function is notnormally well developed at the timeof injury, then such a deficit maynot necessarily be observed until alater developmental stage.
RECOVERY TO BASELINE
Dynamic (developing) model C Giza (2006) Dev Neurosci 28:364-379
An additional critical considerationwhen managing or investigatingrecovery from developmental braininjury is the presence of salientenvironmental stimuli.
it is important to realize that brainmaturation occurs in situationswhere environmental conditionsand training are superimposedupon normal developmentalchanges. Both normal maturationalchanges and response toenvironmental stimuli will affectoutcomes from pediatric TBI.
RECOVERY TO BASELINE
Dynamic (interventional) model
Cortical plasticity is related to learning of new skills
Skill learning but not strength training induces corticalreorganization
Behavior is one of the most powerful modulators of recovery
Neuronal plasticity is enhanced in the developing brain and childrenappear to learn more quickly than adults
TBI to the developing brain is distinct from adult TBI
Infants and toddlers have some of the worst developmentaloutcomes after significant TBI
‘Growing into the lesion’, a deficit may not necessarily be observeduntil a later developmental stage
Rehabilitation team must pay attention to these variables in order totailor the best treatment strategy after TBI in developmental age
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