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

Various levels of analysis:

Molecular

Synaptic

Cellular

Network

Systems

CORRELATES OF PLASTICITY

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

Kleim JA et al. Neurobiol Learn

Mem 2002; 77:63–77.

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

PLASTICITY AFTER DEVELOPMENTAL TBI

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

HERITABILITY

Terry E. (2004)

Trends Cogn Sci 8,7

GENES AND COGNITION

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

CONCLUSIONS

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

TAKE HOME MESSAGE…

ROME PALIDORO

S. MARINELLA

Children’s Hospital Bambino Gesù

enrico.castelli@opbg.net