NEURAL PLASTICITY VOLUME 8, NO. 1-2, 2001

Neural Compensations After Lesion of the Cerebral Cortex

Bryan Kolb,* Russell Brown, Alane Witt-Lajeunesse and Robbin Gibb

Department ofPsychology & Neuroscience, University ofLethbridge,Lethbridge, AB TIK 3M4, Canada

ABSTRACT KEYWORDS

Functional improvement after corticalinjury can be stimulated by various factorsincluding experience, psychomotor stimulants,gonadal hormones, and neurotrophic factors.The timing of the administration of thesefactors may be critical, however. For example,factors such as gonadal hormones, nerve growthfactor, or psychomotor stimulants may act toeither enhance or retard recovery, dependingupon the timing of administration. Nicotine, forinstance, stimulates recovery if given after an

injury but is without neuroprotective effect andmay actually retard recovery if it is given onlypreinjury. A related timing problem concernsthe interaction of different treatments. Forexample, behavioral therapies may act, in part,via their action in stimulating the endogenousproduction of trophic factors. Thus, combiningbehavioral therapies with pharmacologicaladministration of compounds to increase theavailability of trophic factors enhances functionaloutcome. Finally, anatomical evidence suggeststhat the mechanism of action of many treatmentsis through changes in dendritic arborization,which presumably reflects changes in synapticorganization. Factors that enhance dendriticchange stimulate functional compensation,whereas factors that retard or block dendriticchange block or retard compensation.

recovery, synaptogenesis, psychomotor stimulants,therapy, neurotrophic factors

INTRODUCTION

One of the challenges for behavioral neuro-science is to find ways to stimulate the brain tocompensate for injury to the cerebral cortex. Oneof the obstacles to compensation, however, is thatfunctions are relatively localized in the cerebralcortex. Indeed, during the 100 years that followedBroca’s first paper in 1861 showing cerebrallocalization of language, the concept of functionallocalization dominated the neurological sciences.The bulk of the evidence emphasized the synapticconnectivity of cerebral areas, with the generalimplication that the brain was largely hard-wired.There is little doubt, for example, that functions ofthe occipital cortex are dependent upon visualinput and appropriate output connections. It is thusimpractical to imagine that the somatosensorycortex would be able to participate in the recoveryof visual functions. The last 25 years has shown amarked change in thinking, however, as it is nowclear that the cerebrum is capable of considerableplasticity. The challenge is to find a way tostimulate the remaining parts of localized neuralcircuits to do ’more with less’. On the surface,

*Corresponding author:tel: 403-329-2405; fax: 403-329-2555e-mail: Kolb@uleth.ca

(C)Freund & Pettman, U.K., 2001

B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

given that cerebral regions are already presumablyworking to capacity, this would seem to be aninsolvable problem. But there have been clues forover 100 years that cerebral organization may be atleast somewhat flexible. For example, it has beenknown since the late 1800s that damage to the lefthemisphere of children does not necessarily lead topermanent language deficits. As early as 1877,Barlow reported on a young boy who had a seriallesion of the left and then right frontal lobe. Theboy was initially aphasic after a left-side lesion butrecovered, only to become aphasic again after aright-side lesion. Even Broca was aware that childrenmight not be so dependent on the left frontaloperculum and wrote,

I am convinced that a lesion of the left third

frontal convolution, apt to produce lastingaphemia [aphasia] in an adult, will not preventa small child from learning to talk (Finger &Almli, 1988, p. 122).

More recent research has shown not only thatBroca was correct, but it has provided anexplanation for how the brain is able toaccomplish this. For example, Rasmussen andMilner (1977) showed that infants with unilateralinjury to the anterior speech zone shift language tothe opposite hemisphere (e.g., Buckner &Petersen, 2000; Kinsboume, 1971; Vallar, 1990).Thus, it appears that at least some functions canshow compensation by recruiting the intact,opposite hemisphere. But what about thepossibility of the residual regions in the injuredhemisphere showing some form of compensatorychange? Although this is apparently less common,there is accumulating evidence that some degree offunctional compensation is possible from theactivation of perilesion regions of the injuredhemisphere, both in patients and laboratory animals(e.g., Glees & Cole, 1950; Jenkins & Merzenich,1987). Furthermore, computer modeling hasshown the possibility of functional compensation

in the cortical response to focal damage (Reggia etal., 2000).

In sum, although there is little doubt that thereis considerable localization of function in thecerebral cortex, there has been a rediscovery oftheideas that the brain may be flexible after an injury(for a historical review see Benton & Tranel,2000). With the recognition that some form offunctional compensation is possible after cerebralinjury, we are left with two fundamental questions.First, what are the neural mechanisms underlyingthe observed compensatory changes? Second, is itpossible to enhance these changes and thuspotentiate recovery? These questions have guidedour research program and will be the focus of theremainder ofthis article.

BACKGROUND AND ASSUMPTIONS

As we begin, we must first consider severalassumptions that underlie our thinking about brainstructure and function. First, it is assumed that thestructural properties of neurons, such as theamount of dendritic space or the number ofsynapses, reflect their function. It follows thatchanges in the structure of neurons will reflectchanges in the function of neurons and, ultimately,behavior. Second, it is assumed that many, andperhaps most, gross neuronal changes will bevisible using light microscopy and appropriatehistological stains. It is generally assumed in theliterature that evidence of change is most likely tobe found at the synapse and that synaptic changescan be measured by the analysis of either pre- orpostsynaptic structure. Although synapses can onlybe visualized using electron microscopic methods,it is possible to infer the presence of synapses bythe presence of either axonal terminals or dendriticspace. In our studies, we have chosen to use anadaptation of the Golgi technique. A majoradvantage of the Golgi technique is that a small

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX

percentage of neurons (1% to 5%) are stained andthese neurons are stained completely. It is thuspossible to draw the individual neurons and toquantify the amount of dendritic space available,as well as the location and density of dendriticspines. The latter measures are used because theycan be taken as estimates first of the total space forsynapses (i.e., dendritic length) and of the densityof excitatory synapses (i.e., spine density). It isestimated that about 95% of excitatory synapsesare located on dendrites and most of those arefound on spines (e.g., Buell & Coleman, 1985).

Third, it is assumed that changes in neuronalstructure reflect changes in connectivity. Thesechanges are unlikely to involve novel connectionsfrom regions that were not previously connectedbut rather an enhancement or deterioration ofexisting connections. Nicoll and Blakemore (1993)estimated that roughly 70% of the excitatorysynapses on any layer II/III pyramidal cells arederived from pyramidal cells in the near vicinity. Itis reasonable to predict, therefore, that mostchanges in cortical connectivity result fromchanges in connections with neighboring neurons.

Fourth, it is assumed that most recovery offunction will be mediated by cortical cireuitry.Decorticated rats show virtually no functionalrecovery, even if the decortication is achievedshortly after birth (e.g., Kolb & Whishaw, 1981).Furthermore, anatomical studies have shown littleor no evidence of reorganization of connections indecorticated rats (e.g., Kolb et al., 1984). Finally,rats with hemidecortications early in life do showfunctional compensation, but this is correlatedwith changes in the dendritic structure andconnections of neurons in the intact hemisphererather than in subcortical structures (Kolb et al.,1992).

Fifth, it is assumed that functional improvementafter cortical injury is most likely to representcompensation rather than actual recovery of theoriginal behavior. This assumption is consistent

with the concept of functional localization notedearlier. Nevertheless, from a practical clinicalperspective it matters little whether the brain isperforming a behavioral function in the same waythat it did prior to injury. The real goal is tostimulate the brain to produce behaviors that willallow a person to resume at least a partially normallifestyle.

CORTICAL PLASTICITY AND FUNCTIONALCOMPENSATION AFTER FRONTAL

LOBE INJURY

There is considerable evidence that rats withneocortical lesions do show spontaneous return ofsome lost behaviors if the lesion is small. Forexample, Whishaw (2000) has shown in an elegantseries of studies that rats with small motor cortexlesions are initially severely impaired in skilledforelimb reaching tasks but over a 15-day periodthey show significant improvement (see alsoRowntree & Kolb, 1997). Animals with largerlesions show far less return of function, however,and. when it occurs, it may take many weeks ormonths to stabilize (e.g., Kolb et al., in press). Asimilar result can be seen in rats with bilateralremoval of the medial frontal cortex. For example,Kolb (1995) showed that there is improvement inmaze performance but not skilled motor behavior,after bilateral medial frontal lesions in rats. If thelesions are made very large, however, there is nocompensation even for the spatial mazeperformance (e.g., Kolb & Gibb, 1991). SubsequentGolgi analyses have revealed that if there isfunctional improvement, there is an initialdecrease in dendritic arborization in perilesionregions (i.e., pyramidal neurons in adjacentsensorimotor cortex), and this decrease is laterfollowed by an increase that is temporally lockedto the functional improvement. (A parallel result isseen after lesions in the hippocampal system as

B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

well [Steward, 1991]). Thus, it seems likely thatthe observed recovery is supported, at least in part,by the reorganization of intrinsic cortical circuits.We hasten to point out, however, that thisreorganization is insufficient to influence recoveryof skilled motor sequences or of species typicalbehaviors (e.g., food hoarding, nest building,social behavior). Nevertheless, the brain-behaviorcorrelation with at least some functionalcompensation is encouraging and suggests thattreatments that increase the dendritic changesmight also enhance functional improvement.

One circumstance under which there is a betterfunctional outcome occurs when cortical injuryoccurs at particular times during development.Perhaps the best known studies on the effects ofearly brain injury on behavior were thoseperformed by Margaret Kennard in the late 1930s(e.g., Kennard, 1942). She made unilateral motorcortex lesions in infant and adult monkeys. Thebehavioral impairments in the infant monkeyswere milder than those in the adults, which ledKennard to hypothesize that there had been achange in cortical organization in the infants andthese changes supported the behavioral recovery.In particular, she hypothesized that if somesynapses were removed as a consequence of braininjury, "others would be formed in less usualcombinations" and that "it is possible that factorswhich facilitate cortical organization in the normalyoung are the same by which reorganization isaccomplished in the imperfect cortex after injury"(Kennard, 1942; 239). Kennard’s findings wereseductive because they were consistent with theevidence noted above that infants with lefthemisphere damage were not aphasic. On the otherhand, there were dissenting views that suggestedthat early brain damage might actually be worse,or at least no better, than later injury (e.g., Hebb,1947; Goldman, 1974). One clear hypothesis fromthese studies is that whatever conditions allow

substantial functional recovery after infant injuryshould be associated with one type of synapticreorganization (presumably reflecting an increasein total synapses), whereas those conditions thatdo not allow recovery or make the outcome worseshould be associated with synaptic loss. In order totest this hypothesis, we removed the frontal cortexof different groups of rats at various ages rangingfrom embryonic day 18 (the gestation period of arat is about 22 days), through infancy andadolescence (e.g., Kolb, 1995). The behavioralresults can be illustrated by the skilled reachingand spatial navigation performance of rats withremoval of the frontal cortex on embryonic day 18(El 8), posmatal day 1 (P1), P5, P10, or P90 (i.e.,adult). In the former task, rats are trained to reachthrough a slot to grasp food (Whishaw, 2000)whereas in the spatial task the rats are trained tofind a hidden platform in a swimming pool(Morris, 1981). Figure 1 shows that rats withlesions on day 1 show severe deficits relative tocontrol animals, whereas rats with lesions on dayP5 or in adulthood show intermediate deficits, andthose with E18 or P10 lesions show no deficit atall. Similar results are also seen when the motor,posterior parietal, posterior cingulate, or occipitalcortex are damaged at similar ages (e.g., Kolb etal., 2000; 1987). Subsequent Golgi analysisshowed that those groups that show functionalrestitution also show an increase in dendriticarborization and/or spine density (e.g., Kolb &Gibb, 1993; Kolb et al., 1997) (see Fig. 2).

The results of our developmental studiestherefore show three important points.1. It is the precise developmental age at the time

of cortical injury that is important inpredicting recovery in the rat. Damage duringthe period of neurogenesis, which in the ratcortex is from about E12 to E20, appears to beassociated with a good functional outcome

(see also Hicks & D’Amato, 1961); damage in

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX

700

600

500

400

300

200

100

0Control Adult P10 P5 P1 E18

Fig. 1: Morris Water Task Latency. Performance of rats on the Morris water task after medial frontal lesions atdifferent development ages ranging from embryonic day 18 (E18), to postnatal days (P1), 5, 10, or adulthood.

the first week of life, which is a time of neuralmigration and the initiation of synapticformation, is associated with a dismal outcome;damage in the second week of life, which is atime of maximal astrocyte generation andsynapse development, results in a excellentfunctional outcome; and, damage after 2 weeksleads to progressively more severe chronicbehavioral loss. A similar pattern of resultscan be seen in parallel studies of the effects ofcortical lesions in kittens by Villablanca andhis colleagues (e.g. Villablanca et al., 1993).Given that recovery is especially poor afterinjury during the first few days of life, itshould be possible to initiate treatments thatwill improve this dismal outcome. We shallsee that there are.The changes in synaptic organization that wehave seen most likely reflect a remodeling of

intrinsic connectivity of the cortex and do notreflect changes in the organization of cortico-subcortical connections.In order to examine the possibility that there

might also be changes in cortical connectivity withother structures, we used retrograde tracingtechniques to map the cortical-cortical, cortical-thalamic, and cortical-fugal pathways after frontalor motor cortex lesions on days 1 or 10. Theresults were surprising as animals with frontallesions on day 1 showed massive changes incortical connectivity but these animals had theworst behavioral outcome (Kolb et al., 2001a;200 lb; Kolb et al., 1994). Furthermore, we showedthat the abnormal pathways did not reflect thecreation of new connections so much as theyreflected a failure of pruning of connections thatare normally discarded during development. Thiswas demonstrated by our finding that newborn

B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

Day 1 Day 10

Fig. 2: Drawings illustrating the effects of early frontal lesions on the development of dendritic arborization and spinedensity atter frontal lesions on postnatal days or 10.

animals have extensive aberrant pathways that dieoff during the first week of life. If the cortex isdamaged during this time, however, some of thesepathways fail to die off, leaving the animal withabnormal circuitry that is not seen in normallydeveloping animals. Some of this unusual circuitrycould prove helpful after an injury, but given thatnormal animals shed such circuitry, it seems likelythat it could prove equally disadvantageous tomaintain such circuitry. Indeed, both hypothesesare confirmed. Rats with infant motor cortex

lesions do show sparing of some motor skills(Whishaw & Kolb, 1988) but apparently at theprice of impairments in other cognitive functions(e.g. Kolb et al., 2000). Subsequent identificationof the motor representation in the cortex showedthat the motor map had moved into posteriorcortex (Kleim et al., unpublished). It thereforeseems likely that the presence of abnormalcorticofugal pathways after early cortical injurymay be as disruptive as it is helpful, a concept thatTeuber (1975) referred to as ’crowding’.

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX

TABLE 1

Modification ofthe effects of frontal cortical injury

Treatment Result Basic reference

A. Adult injury

Complex housing after lesion Functional recovery:reversal ofneuronal atrophy

Kolb& Gibb, 1991

NGF Functional recoveryreversal ofneuronal atrophy

Kolb et al., 1997

bFGF Functional recovery Witt-Lajeunesse & Kolb,unpublished

Nicotine Functional recovery Brown et al., 2000a; 2000b

B. Infant Injury

Tactile stimulation after P4 lesion Functional recovery:reversal ofneuronal atrophy

Kolb & Gibb, 2001

Complex housing after P1-5 lesion Functional recovery Kolb et al., unpublished

Prenatal nicotine before P3 lesion Functional recovery McKenna et al., 2000

bFGF after P3 lesion Functional recovery Kolb et al., 2000

Stimulating plasticity and recovery after cortical

injury in adults

Rehabilitative programs have been widelyused for decades to treat people with corticalinjury but to date, few well-controlled clinicalstudies document either the benefits, if any, fromthese programs or the conditions under whichmaximum benefits can be expected. Nonetheless,it is generally assumed that recovery should bestimulated by either some sort of rehabilitativetherapy, pharmacotherapy, or a combination. Wehave undertaken a series of studies in which we

systematically examined these three possibilitiesby investigating the following:

1. the effects of specific rehabilitative trainingversus more generalized experience;

2. the effects of neurotrophic factors with andwithout rehabilitative training; and

3. the effects of a psychomotor stimulant (nicotine)(see Table 1).

The results of our studies reveal three basic

results.1. First, placing animals in complex environments

stimulates the recovery of motor functions,whereas training animals daily on a skilledmotor task is without benefit (e.g. Kolb & Gibb,1991; Whishaw, 2000; Witt-Lajeunesse & Kolb,unpublished). Consider the following example.

B. KOLB, A. WITT-LAJEUNESS AND R. GIBB

12o t100

80

60

40

20

No TrainReach Train

T

Control Lesion bFGFFig. 3: Summary of the interactive effects of behavioural training and treatment with basic Fibroblast Growth Factor

after motor cortical injury in adulthood. Neither training nor bFGF stimulated recovery alone but incombination they were effective in significantly improving skilled reaching performance.

In one study we manipulated postoperat!veexperience of animals with unilateral motorcortex lesions, which produced severe deficitsin skilled fore-limb use, by providing one oftwo different treatments. In the first, the animalswere trained daily to reach through bars toobtain food (see Whishaw, 2000, for details).In the second, they were placed for 24 hours aday in complex environments, in which therewere novel stimuli and ample opportunity forboth sensory and motor stimulation. In bothcases, the animals were tested biweekly on aseries of motor tasks over a 12-week period.The results showed that whereas animals in thecomplex environments showed significantfunctional compensation over the post-operative period, those animals that were

trained daily showed no benefit whatsoever(Witt-Lajeunesse & Kolb, unpublished). It is

interesting to note here that placing animals incomplex environments has been shown toincrease the production of neurotrophic factors,such as basic Fibroblast Growth Factor (bFGF),whereas simple training does not appear tohave such an action (e.g., Gomez-Pinilla, et al.,1998). Thus, it is possible that behavioraltreatments could alter recovery indirectly throughtheir action on the production of neurotrophicfactors.Second, the administration of neurotrophicfactors stimulated functional improvement. Inparticular, Nerve Growth Factor (NGF)stimulated partial restitution of motor functionsafter unilateral motor cortex stroke (Kolb etal., 1997). In contrast, treatment with bFGFdid not enhance recovery unless animals alsoreceived daily training on a skilled motor task(see Fig. 3). In other words, whereas neither

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX

rehabilitative training nor bFGF worked alone,in combination they produced significantfunctional recovery.Third, treating animals both pre- and post-injury with the psychomotor stimulant nicotinestimulated recovery of spatial learning aftermedial frontal and hippocampal lesions,respectively (Brown et al., 2000a,b). Treatinganimals only post-operatively was less effective,although there was still significant benefit.Pretreatment alone with nicotine was withoutany benefit. The nicotine results parallel otherfindings that another psycho-motor stimulant,amphetamine, also has been reported tofacilitate functional recovery (e.g. Feeney &Sutton, 1987; Goldstein & Hulsebosch, 1999).

From our Golgi studies summarized earlier, wewould predict that the treatments that stimulatefunctional recovery also stimulate dendritic growth.

Although our anatomical analyses are as yetincomplete, we have preliminary evidence that thisis indeed the case. We have shown, for example,that housing lesion animals in complex environmentsproduced widespread increases in dendriticarborization of cortical neurons (e.g., Kolb & Gibb,1991). Similarly, NGF infusion stimulated wide-spread increases in dendritic arbor and spinedensity in pyramidal cells in rats with corticallesions, and this was correlated with functionalcompensation (Kolb et al., 1997) (see Fig. 4).

Finally, we have shown that repeated injectionsof nicotine stimulated large changes in dendriticarborization in prefrontal cortex and nucleusaccumbens of otherwise normal animals (Brown &Kolb, 2001). We have not yet examined theneurons in nicotine-treated lesion animals, but ourprediction is that nicotine stimulates compensatorydendritic growth in animals with cerebral lesionsin adulthood.

Fig. 4:

Control NGF

Lesion NGF+Lesion

Examples of layer V pyramidal cells taken from the motor cortex (Fr2) of a saline-treated sham and lesion rat(let) and an NGF-treated sham and lesion rat (right). The inset illustrates spine density in a typical terminal tufffrom the basilar fields. (After Kolb et al., 1997).

10 B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

Stimulating plasticity and recovery after corticalinjury in infants

Because the animal with a cortical lesion inthe first days of life is functionally devastated inadulthood and because it shows atrophy of corticalneurons, we anticipated that such animals shouldbenefit the most from therapeutic interventions.Furthermore, given that we knew that the infantbrain is particularly plastic after injury around 10days of age, we reasoned that the brain would beespecially responsive to other experiences at thisage as well. This proved to be the case. In oneseries of studies, animals were given frontal orposterior parietal lesions at 4 days of age,following by tactile stimulation until weaning.Tactile stimulation with a small paintbrush for 15minutes, three times per day, for just 10 dayspermanently alters the morphological and neuro-chemical structure of the cortex of normal animalsbut has even bigger effects on the cortex of aninjured brain (Kolb & Gibb, unpublished). Thus,rats with tactile stimulation show an unexpectedlylarge attenuation of the behavioral deficitsofcerebral injury as a result of this rather brief’therapy’. In fact, the rats with posterior parietallesions on day 4 showed substantial recovery ofperformance in various spatial and motor tasks,such as skilled reaching. This is a stunningreversal of a devastating functional loss normallyseen in animals with such injuries at this age.Analysis of the brains showed a reversal of theatrophy ofthe remaining cortical neurons normallyassociated with such early lesions. Thus, atreatment that reversed the dendritic atrophy afterperinatal lesions also reversed the severefunctional disturbance from the early lesion.

In parallel studies, we have placed rats that hadcortical lesions in the first week of life in complexenvironments for 3 months, beginning at the time ofweaning or in adulthood. The animals placed in theenvironments as juveniles showed a dramatic

reversal of functional impairments that wascorrelated with increased cortical thickness (e.g.Kolb & Elliott, 1987). The dramatic improvement inthe animals with the earliest injuries carries animportant message for it suggests that even theyoung animal with substantial neural atrophy andbehavioral dysfunction is capable of considerableneuroplasticity and functional recovery in responseto behavioral therapy. When animals with similarinjuries were placed into enriched environments asadults they showed a less impressive reversal offunctional losses, although they did show markedreversal of dendritic atrophy (Kolb et al., 2001). Thebrain thus appears to be capable of considerableenvironment-mediated modification after early injury,although the timing of the postinjury therapy doesappear to make some difference (Table 2). Perhapsthe synaptic organization of the remaining brain canbe more easily remodeled if the reorganizationoccurs while the brain is still developing, whereas itis more difficult to remodel a brain with infantinjuries once the synaptic organization has stabilizedin adulthood.

One reasonable question we might ask is justhow complex or enriched environments for ratsrelate to environmental stimulation for children. Inparticular, it seems likely that standard laboratoryhousing for rats is rather sterile compared to theusual environment of feral rats so if we try togeneralize to humans we are left wondering howstimulating an environment would have to be inorder to induce functional changes in humaninfants. One way to answer this question is toconsider what animals do in the complexenvironments. They are provided with novelobjects to interact with every few days; they get alot of sensory input and motor activity as theymove about the compounds; and, they haveconsiderable social experience as they live ingroups of six to eight other animals. Theexperience is thus perceptually and sociallystimulating, motorically demanding, and is

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX 11

continuous for several weeks or months. Althoughwe do not know which aspects of this experienceare the most important, our guess is that allcontribute because they stimulate different typesof brain activity. Thus, our best guess as wegeneralize to human infants is that therapies wouldinclude perceptual stimulation, including novelty,as well as social interaction and motor activities.

In view of our findings that both neurotrophicfactors and nicotine could stimulate functionalrecovery after cortical injury, we also asked whethersuch treatments might influence functional recoveryafter cortical injury in infancy.

In one series of studies, rats were givenbilateral frontal lesions on postnatal day 3 and thengiven daily injections ofbFGF for a week (Kolb etal., 2000). This treatment led to a dramaticimprovement in functional outcome that wasequivalent to that seen in animals placed incomplex environments at weaning. In anotherseries of experiments, female rats were implantedwith minipumps that subcutaneously infusednicotine throughout their pregnancy. The infantswere given frontal lesions on postnatal day 3, butno further treatment with nicotine. Again, there wasa significant benefit to nicotine treatment, althoughin this case it was nicotine that was administeredbefore the cortical injury and, indeed, before birth(McKenna et al., 2000). We have not yet completedour Golgi analyses of the bFGF and nicotine-treatedbrains, but the prediction is clear: the treated animalsare expected to show a reversal of the dendriticatrophy that normally characterizes the brain withcortical injury in the first few days of life.

In sum, the infant-damaged brain is especiallyresponsive to both behavioral and pharmacologicaltreatments that are initiated in infancy. Importantly,in the one study in which behavioral treatment wasinitiated in adulthood, there was a significantlyattenuated functional benefit. This latter resultimplies that therapeutic programs should beinitiated early after cortical injury in infants if they

are to be effective in leading to significantfunctional compensation. Our finding that prenatalnicotine treatment can influence recovery fromlater brain injury is intriguing and leads us towonder how other prenatal events might influencefunctional recovery from cortical injury either ininfancy or adulthood and, additionally, whethersuch events might interact with postnatal treatments.

Stimulating neurogenesis after cortical injury

Although we have emphasized changes inremaining cortical neurons after injury, recentadvances in our understanding of the nature ofstem cell activity in the postnatal brain (e.g. Gouldet al., 1999; Weiss et al., 1998) leads one toquestion whether it might be possible to stimulateneurogenesis after cortical injury. In the course ofstudying the effect of restricted lesions of themedial frontal cortex or olfactory bulb, wediscovered that, in contrast to lesions elsewhere inthe cerebrum, midline telencephalic lesions onpostnatal day 7 to 12 led to the spontaneousregeneration of the lost regions, or at least partialregeneration of the lost regions (Fig. 5). Similarinjuries either before or after this temporalwindow did not produce such a result. Analysis ofthe medial frontal region showed that the areacontained newly generated neurons that formed atleast some ofthe normal connections of this region(Kolb et al., 1998). Furthermore, animals with thisregrown cortex appeared virtually normal on

many, although not all, behavioral measures (Kolbet al., 1997). Additional studies showed that if weremoved the regrown tissue, functional recoverywas eliminated (Temesvary et al., 1998). Parallelstudies found that it was possible to blockregeneration of the tissue with prenatal injectionsof the mitotic marker bromodeoxyuridine (BrdU),and in this case there was no recovery of function

(Kolb et al., 1998), a result that implies that theregrown tissue was supporting recovery. Thus, in

12 B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

Fig. 5: Photographs ofbrains ofrats that had either no treatment or a medial frontal lesion on posmatal day 10.

the absence of the regrown tissue, either becausewe blocked the growth or because we removed thetissue, function was lost.

Our findings that neurogenesis could spontan-eously occur, at least under special circumstances,following cortical lesions in infancy have led us toask whether it might be possible to induce neuro-genesis in adulthood. Indeed, there are now severalreports that stem cell activity is stimulated aftercerebral injury in rats (e.g., Altman & Bayer,1993). We approached this problem by infusing a

cocktail of neurotrophic factors (includingepidermal growth factor, bFGF, and NGF) into thelateral ventricles of animals given either unilateralor bilateral cortical lesions. The results have beenat once both stimulating and disappointing. Inparticular, we have found that the neurotrophiccocktail does stimulate massive generation ofundifferentiated cells that migrate to the lesion sitebut, to our chagrin, these cells fail to differentiateand ultimately die (Kolb et al., 1998). Further-more, behavioral studies have found no evidence

NEURAL COMPENSATIONS AFTER LESION OF THE CEREBRAL CORTEX 13

of any functional benefit. Thus, although it is clearthat it is possible to mobilize the brain to generatenew cells, we have not yet been able to stimulatethe brain to generate functioning neurons. Notehowever, that our earlier studies showed that acombination of neurotrophic factors and behavioraltherapy was more effective in stimulating functionalrecovery than either treatment alone, so it ispossible that experience may interact with theneurotrophie treatments to encourage celldifferentiation and functional improvement. Thisremains to be seen.

CONCLUSIONS

One of the most intriguing questions inbehavioral neuroscience concerns the manner inwhich the brain, and especially the neocortex, canmodify its structure and ultimately its functionthroughout one’s lifetime, and in particular inresponse to an injury. As the preceding review hassuggested, the injured cortex can be modified byvarious treatments, and this modification ismodulated by various factors. Several basicconclusions can be extracted.

Experience alters the synaptic organization ofthe cortex. It is possible to visualize with alight microscope the morphological changes inthe cortex that reflect synaptic modification.The neuronal changes can be quantified asincreases or decreases in the amount ofdendritic arborization, as well as in the densityof dendritic spines.There can be compensatory plastic changes inthe brain following brain injury that aresimilar in kind to those observed when animalslearn from experience. These injury-inducedchanges are also age-dependent and are

thought to reflect the age-related recoveryobserved after brain injury at different timesthroughout the lifetime. For example, animals

with cortical injuries in the first week of lifeshow decreased dendritic arborization that isassociated with a poor functional outcome. Incontrast, animals with cortical injuries in thesecond week of life show increased dendriticarborization and a good functional outcome.Changes in synaptic organization arecorrelated with changes in behavior. Animalswith extensive dendritic growth relative tountreated animals show facilitated performanceon many types ofbehavioral measures, especiallymeasures of cognitive activity. Animals withdendritic atrophy show severe behavioralimpairments and little functional recovery.The similarity between the plastic changes inthe brain in response to injury or experiencesuggests that there may be basic mechanismsof synaptic change in the mammalian cortexthat are used in many forms of synapticplasticity. This is an encouraging possibility,for it allows hope that we will be able toimprove recovery from cerebral injury bytaking advantage of the innate mechanismsthat the brain uses for other forms of plasticity.Injury-induced changes in cortical structureare modified by experience. Furthermore,brains that show the least change in responseto a cortical injury appear to be the mostresponsive to experience. For instance, animalswith neonatal brain injuries show a poorfunctional outcome and an atrophy of corticalneurons, but these animals show dramaticfunctional recovery and marked synapticgrowth in response to environmental manipu-lations. This is encouraging for it suggests thatbehavioral therapies should be especiallyhelpful in reversing some of the devastatingconsequences of brain damage in the latterperiods of prenatal development in humaninfants.Not all experiences are equally effective inchanging behavior after cortical injury. Training

14 B. KOLB, R. BROWN, A. WITT-LAJEUNESSE AND R. GIBB

animals on specific motor patterns, such asskilled reaching, is not effective in facilitatingrecovery. In contrast, placing animals incomplex environments in which they havevaried social, sensory, and motor experiences,is effective in stimulating recovery.Neurotrophie factors influence plastic changesin the cortex. More importantly in the currentcontext, the production of neurotrophins isinfluenced by experience. Thus, one reasonwhy behavioral therapies may be affeetive inchanging the brain is that the behavioralchanges brought about by specific experiencesactually stimulate the brain to produceneurotrophins. This link between behavior,neurotrophins, and plasticity requires furtherstudy, especially in the context of designingtherapies for restitution offunction.Psychomotor stimulants, such as nicotine, areeffective in stimulating functional recoveryafter cortical injury, either in infancy or inadulthood. Nicotine is most effective when itis administered both before and after injury,although there is a beneficial effect of justpostinjury administration.It is possible to generate new neurons aftercortical injury and, at least in infancy, theseneurons are capable of supporting functionalrecovery. It remains to be seen if new neuronscan function aider cortical injury in adultanimals.

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