TIMELINE: Reconstructing functional systems after lesions of cerebral cortex

© 2001 Macmillan Magazines Ltd

PERSPECTIVES

(TIMELINE), curiosity in the topic waned as sci-entific attention entered, first, a period ofinterest in the cerebral localization of func-tion, and later, an era dominated by the anti-localizationists. Neither period could accom-modate the concept of neural plasticity, northe idea that functional localization could be induced to change. As a result, only a fewstudies were carried out between the mid-nineteenth century and the third quarter ofthe twentieth century. These important, yetlargely neglected studies form the essentialfoundation for current and future thinking onthe redirection of brain development and thebuilding of new brain systems after earlylesions of the cerebral cortex (TIMELINE).

Rebuilding postulated and confirmedAfter his discovery that the left inferior frontalcortex was the cerebral centre for speech15,16,Broca postulated that the right hemispherecould become the speech hemisphere if therelevant region in the left hemisphere wasabsent17 (TIMELINE). He believed this to be themost reasonable explanation to account forthe relatively unimpaired, articulate speech ina woman who was missing Broca’s area in theleft frontal lobe. In 1877, Barlow18 confirmedBroca’s speculation in a boy who sufferedsequential lesions of the left and right hemi-spheres that included inferior frontal cortex.Barlow noted recovery after the initial, lefthemisphere lesion, and a subsequent loss oflanguage after damage to the right hemi-sphere. These observations necessarilyimplied a fundamental change in corticalorganization that permitted the sparing of

speech production. In this way, the possibilitythat the young brain is plastic was recognized.A century later, Rasmussen and Milner19

injected amytal into the carotid artery toanaesthetize a single cerebral hemisphere, andconfirmed that speech centres could reorga-nize to the right hemisphere in children thatsuffered left hemisphere damage before 6years of age. These observations also indi-cated that the spared cortex could represent adifferent constellation of functions thanwould normally be observed.

In 1876, Soltmann20 reported an equallydecisive, but barely influential experiment,showing functional sparing and the plasticcapacities of the young cerebral cortex afterearly focal damage to the motor cortex.Soltmann adopted procedures akin to thoseused by Fritsch and Hitzig in their pioneer-ing experiments on the localization of cere-bral functions in dogs21, but he applied themto the very young brain. Even by today’sstandards, Soltmann’s multidisciplinaryapproach was a model of experimentation,because he combined electrophysiologicalstimulation, ablations and behavioural assaysto test, first, when the motor cortex gainedcontrol over peripheral musculature, andlater, the repercussions of ablation. His pio-neering work should be regarded as one of themost significant discoveries in experimentalneuroplasticity.

Soltmann20 studied the impact of ablatingthe cortical motor regions. When unilaterallesions were made before the onset of electri-cal excitability of the motor cortex, no weak-ness was detected contralateral to the lesion.However, lesions made when the motor cor-tex was becoming electrically excitable pro-duced abnormal locomotor patterns, but theimpairments dissipated. The basis for thesparing of function seemed to lie in the take-over of peripheral musculature by theremaining cerebral cortex. Indeed, using elec-trical stimulation, Soltmann confirmed thatthe intact motor cortex of the opposite sidewas responsible (compare FIG. 1a with FIG. 1b).Stimulation of the forepaw region of the

The young brain is enormously resilient toearly injury. This resiliency contrasts withthe severe and permanent impairmentsthat frequently accompany equivalentdamage to the mature cerebrum. Forexample, damage to Broca’s area rendersthe patient unable to speak, but equivalentdamage early in life does not have suchdevastating effects. Here we review thehistory of the study of early lesion-inducedplasticity, and delineate the features of thedeveloping brain that permit it to overcomethe effects of early cerebral lesions. Wealso speculate on future avenues ofinvestigation that should help us tocomprehend how young brains arenaturally rebuilt after early lesions.

The young human brain is highly plastic.Although brain lesions can interfere with theinnate development of architecture, connectiv-ity and mapping of functions, they also triggermodifications in structure, wiring and repre-sentations. In some cases, these modificationsare adaptive and result in a sparing of functionsthat would be lost or severely handicapped byequivalent lesions incurred later in life1–7 (BOX 1).Analogous studies in animals foster similarconclusions8–10. Moreover, the degree of func-tional sparing varies systematically with the ageat which the cortical damage occurs, and isaccompanied by anatomically demonstrablechanges in brain wiring9,11–14.

This view gained hold only over the past25 years. After an auspicious start in thecapable hands and minds of Broca, Soltmannand Barlow in the mid-nineteenth century

NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | DECEMBER 2001 | 911

Reconstructing functional systemsafter lesions of cerebral cortex

Bertram R. Payne and Stephen G. Lomber

T I M E L I N E

© 2001 Macmillan Magazines Ltd912 | DECEMBER 2001 | VOLUME 2 www.nature.com/reviews/neuro

P E R S P E C T I V E S

hemidecortication. So, the rigidity induced bydecerebration in very young cats and rabbitswas markedly attenuated compared with thesevere rigidity observed after decerebration ofolder animals23–27. In addition, cases in whichchildren differed in their response to cerebralinjury were noted28–30. Taylor31 suggested thatcompensations occur before regions areindelibly stamped with the mature functions,and Gowers32 noted retained sensibilities afterearly lesions of sensory cortices.

Rebuilding revisitedSix decades later, before the antilocalization-ists took firm hold, Kennard33–39 confirmedthe observations of Soltmann by showing asparing of function after lesions of the motorcortex in young primates. Kennard foundthat sparing was greatest in the youngest ani-mals, that it ended at 3 years of age, and that itwas greater in humans and chimpanzees thanin other primates with smaller brains. Afterunilateral motor cortex lesions, subsequentlesions in non-human primates implicatedseveral areas in the functional sparing. Theyincluded motor and premotor regions in theopposite hemisphere (FIG. 1b), as initiallyshown by Soltmann, or motor, premotor andsensorimotor regions of the already damagedhemisphere (FIG. 1c). In this case, electrical

was never detected in intact dogs, or in dogsthat were lesioned after the motor cortex hadbecome functional.

These ideas were not pursued at the time,because they directly challenged Fritsch andHitzig’s idea of cortical centres of function.But other contemporaneous studies also indi-cated that there was something differentabout the young brain and its response toinjury. Vulpian22 suggested that young ani-mals withstood better the procedure of

remaining motor cortex evoked muscularcontractions of both the contralateral andipsilateral forepaws, although the bilateralcontractions could not be fractionated out toseparate contralateral and ipsilateral regions.By contrast, hindpaw contractions werestrictly contralateral and could be evokedfrom motor cortices of each hemisphere;there was no need for a functional take-over.Presumably, the hindpaw region of the oper-ated side remained intact. Bilateral movement

(1915–1926) Differences in functionalorganization of young brains notedindependently by Brown23, Weed26

and Langworthy24,25.

Goldmanrecognizesage, gender,experienceandenvironmentinfluenceoutcome ofearlylesions108–110.

(1891–1899)• Clinical notes made

independently by Freudand Rie28, Sachs29, andOsler 30, on neuralcompensations afterlesions in children.

• Taylor shows thatcompensations occurbefore regions are indeliblystamped with functions 31.

(1890–1930)Cerebral plasticityruns against attemptsto map cerebraloperations. Interest inrepercussions ofearly lesions wanes.

Cornwell et al.identify functionalcompensations byextrastriate cortexafter primary visualcortex lesions49.

(1965–1970) Hubel and Wieselshow early experience modifiesneuronal ocular dominance40–42.

Hubel, Wiesel and LeVayuse transneuronal tracingto show anatomical basisof ocular dominanceplasticity44. Rasmussenand Milner use intracarotidamytal injections toconfirm Barlow’s insight19.

Transcranialmagneticstimulation (TMS)used to showmodified pathwaysin humans96.

System-wide rebuilding ofvisual system after earlyvisual cortex lesions57.Moore et al. show earlylesion-induced plasticity inmonkey visual system69.

(1989,1993) Spectrum of sparedbehaviours identifiedafter early visual cortexlesions11–13.

Spear et al.identify functionalcompensationsby extrastriateneurons afterearly visualcortex lesions 50.

• Recognition of lesion-induced plasticity in human visualsystem.

• Studies of responses to lesions by other systems atother stages of development.

• Use of functional magnetic resonance imaging and TMSto probe rebuilt systems.

• Identification of factors that influence neuron survival anddeath, and modification of pathways.

• Development of effective strategies to treat brain lesions.

• Moore et al. show sparing ofmotion processing after earlylesions of monkey visual cortex70.

• Adaptiveness of pathways rebuiltafter early lesions of primary visualcortex shown68.

Vargha-Khadem et al. extend plasticperiod of language system120.

Bachevalier andMishkin showfunctional sparingafter early lesions oftemporal cortex10.

First rewiredvisual pathwaysidentified afterearly visualcortex lesions58.

1861 1877 1890 1891 1915 1936 1965 1975 1977 1978 1980 1984 1989 1991 1994 1996 1997 2001 Future

Timeline | Evolution of concepts on the repercussions of early cerebral lesions

• Broca localizes speech centre15,16.• Broca proposes right cerebral hemisphere responsible

for speech in absence of left hemisphere speech area17.• Vulpian suggests greater viability of young animals for

hemidecortication experiments22.• Experimental evidence by Fritsch and Hitzig for cerebral

localization of function in laboratory animals21.• Model experiment of Soltmann. Use of multiple

techniques to show and explain functional take-over byintact cortex after early motor cortex lesion20.

• Barlow confirms Broca’s proposal18.

Box 1 | Functional status after lesions

Competent behavioural performance is characterized by accurate neural processing and action,and it provides the normative basis in measuring lesion-induced modifications in neural andbehavioural performance. There are three types of behavioural performance after a lesion:

• Residual function describes the neural and behavioural performance levels that remain afterlesions of the mature brain. Specific deficits induced by focal cerebral damage form the basis ofthe concept of cerebral localization of function.

• Recovered function describes neural and behavioural capacities that emerge from, and aresuperior to, the residual functions after lesions. The magnitude of recovery can vary, but it israrely complete. Embodied in the concept of ‘recovery’ is the prior presence of a given behaviour.Recovery is not accompanied by a gross rewiring of brain pathways.

• Spared functions are capabilities that are present after lesions incurred earlier in life, beforefaculties had fully matured. Spared functions are superior to both residual and recoveredperformance levels. They result from either an unmasking of existing pathways, or the altereddevelopment of brain pathways. Here we concentrate on long-term repercussions that are basedon the latter alterations. The magnitude of sparing varies in an age-dependent way, andaccording to the extent and position of the lesion.

(1936–1943) • Cerebral plasticity

runs against views ofantilocalizationists.

• Soltmann’s findingsconfirmed.

• ‘Kennard Principle’established33–39.



Convergence of techniquesThe stage was set for the convergence ofbehavioural, physiological, anatomical andpathway-tracing techniques to investigate therepercussions of early cerebral lesions in acomprehensive way. Some of the most com-plete information we have is on the sequelae ofearly damage to the cat primary visual cortex.

First postnatal week. Convincing evidence ofsparing of cerebral visual functions after abla-tion of primary visual cortex during the firstpostnatal week was provided by Cornwell,Payne and Lomber11–14,48,49. The sparinginvolved certain learned (for example,masked pattern discriminations) and reflex-ive (for example, visually guided orientingand optokinetic nystagmus) visual functionsthat are normally linked to the temporal andparietal regions of cerebral cortex, respec-tively (TABLE 1). Electrophysiological and abla-tion methods were used to show the involve-ment of extrastriate regions in sparing13,49. Atabout the same time, Spear et al.50 showedthat individual neurons in visuoparietal cor-tex undergo functional compensation, and

stimulation showed that intact cortices sur-rounding the lesion were more readilyexcitable39. Although the relative contribu-tions of the different regions to the sparingcould not be ascertained in any detail, the datasupported the view that sparing of functionswas attributable to functional reorganizationin intact portions of the cerebral cortex.These conclusions were termed by Teuber as‘Kennard Principle’8,27.

It is noteworthy that there were instanceswhen no sparing was evident. For example,lesions of area 8 in infant monkeys resulted in apermanent, adult-like paresis of conjugate eyemovements. Similarly, ablation of the occipitallobes in young monkeys was not accompaniedby a return of vision38. This result indicatedthat in the absence of some system-specificsubstrate for sparing, no sparing occurred.

Redirection of construction acceptedAlthough Hubel and Wiesel did not study theeffects of lesions per se, their work ushered inan era of intense activity that saw the emer-gence and acceptance of neuroplasticity, onecentury after the pioneering work of Broca,

Barlow and Soltmann. Hubel and Wieselshowed that the input received by each eyeduring early life has a profound impact inshaping the responsiveness of individual corti-cal neurons. By closing one or both eyes, or bymisaligning the visual axes to modify visualexposure, they disrupted and redirected thenormal developmental process. Normally,both eyes drive most visual cortex neurons incats and monkeys, but when visual experiencewas modified, the cortical neurons were per-manently changed40,41. In cases of monoculardeprivation, the cats were unable to use thedeprived eye to guide their behaviour effec-tively, although sight through the other eyewas normal42,43. By contrast, similar proce-dures carried out on mature animals had noimpact on cortical neurons or behaviour41,43,44.Subsequently, trans-synaptic tracing showedthat the physiological modifications could beaccounted for by expansion and retraction ofthe cortical territories innervated by the leftand right eyes44–47. This body of work is asimportant as the work of Soltmann, because italso showed that the development of theimmature brain could be redirected.


a Organization of corticospinal pathways

Cervicalspinal cord

Distalforelimb

Expandedpathway

Brainstem

Primary motorcortex

Red nucleus

b Rebuilding by intact hemisphere

Lesion

c Rebuilding by juxtalesional regions

1

2

3

PM

SM

Figure 1 | Reconstructing motor systems. a | The organization of mono- and disynaptic corticospinal pathways. The dominant pathway is monosynaptic andcrossed. The supplementary pathway is disynaptic through the ipsilateral red nucleus. The secondary limb is crossed. Direct projection to ipsilateral cervical cordis minor. Projections from the motor cortex and red nucleus are shown in blue and red, respectively. b | Unilateral ablation of the forelimb region of the motor cortexleads to expansion by the intact hemisphere (orange) of both ipsilateral corticospinal projections (1), crossed cortical projections to the red nucleus (2), as well asrecrossing of already crossed corticospinal fibres (3). Some projections might be bilaterally collateralized. Secondary projections from the red nucleus normallycross the midline. In this system, the intact hemisphere gains control of the ipsilateral distal forelimb musculature. Pathways to the contralateral cervical spinal cordare intact, so movement evoked by stimulation of intact motor cortex might be bilateral. c | Unilateral ablation of the monkey hand region induces a remapping andcompression of the hand region onto juxtalesional cortex (dark blue), with capture of descending projections. Further contributions from premotor (PM) and post-central sensorimotor (SM) cortices are indicated (orange). The damaged hemisphere establishes much of the control over complex hand movements.



of intact cats (TABLE 1), and neurons in supra-sylvian cortex do not adopt the properties ofneurons eliminated by ablation of the pri-mary visual cortex66. Even so, the visual sys-tem undergoes a substantial rebuild in theaftermath of the lesion, and the rebuildingdiffers after lesions sustained at differentpoints in the developmental continuum.

A ‘different’ brain? Local deactivations bycooling of parietal and temporal regions con-firm reorganization of cerebral functionsacross the remaining cortices. Tests of visuallyguided orienting and form discrimination,two functions subserved by parietal and tem-poral cortices, respectively67, show functionalreorganization of neural substrates that con-tribute to visually guided behaviours. The roleof middle suprasylvian cortex in orienting ismuted, and the role of the ventral posteriorsuprasylvian cortex is heightened, whereas thereverse pattern is seen during form discrimi-nations68 (FIG. 2b,c). These data show that atleast two highly localizable functions of nor-mal cerebral cortex are remapped across thecortical surface as a result of the early lesion ofprimary visual cortex. The cortical visual sys-tem and its afferents are reconstructed, andnew cortical centres of function emerge as aresult of the plasticity of the visual system.

Monkey and human visual systemsThe immature monkey and human visual sys-tems seem to have a similar latent flexibility tocompensate for the deficits induced by damageto the primary visual cortex early in life57. Forexample, monkeys that sustain lesions at 5–6weeks of age can detect and localize stimuliwithin a cortical ‘scotoma’ with a greater levelof accuracy than monkeys that suffer lesionslater69. They are also more effective at discrimi-nating differences in the direction of motion ofdot fields, but only when the size of the mov-ing field is large70. These observations matchfindings in humans who suffered damage tothe primary visual cortex in childhood.Subjects with lesions of the primary visual cor-tex sustained in adulthood are completelyunaware of visual stimuli71,72. However, peoplewith earlier lesions can switch to an ‘aware’mode in which they are conscious of the pres-ence of stimuli, and can verbally report onstimulus position, direction and velocity, pro-vided that stimulus parameters are largeenough73–77. High performance in the unawaremode is linked to activity in the superior col-liculus78, whereas performance in the awaremode is linked to activity in visuoparietal andprefrontal cortices73,78,79.Visuotemporal cor-tices can also be activated with colouredimages of natural objects79. These results show

glion cells means that all spared neural oper-ations and behaviours depend on expandedpathways that originate in α (Y) and γ (W)retinal ganglion cells (FIG. 2a).

First postnatal month. The effects of primaryvisual cortex lesions suffered at the end of thefirst postnatal month differ from the repercus-sions observed after earlier lesions. Many β retinal ganglion cells survive56,62, and moreexpanded transgeniculate pathways provide alarger conduit for visual signals to reach visuo-parietal cortex56,63. Accordingly, the breadth ofneuronal compensations is greater63. Thesefeatures are matched by normal behaviouralacuity63 and by relatively good discriminationof patterns when contrast is low65. These aretwo new items that can be added to the com-pendium of visually guided behaviours thatare spared by early lesions of the primaryvisual cortex.

Extrastriate cortex is obligatory. Visuoparietaland visuotemporal cortices are obligatory forthe sparing of visually guided behaviours,because lesions that extend beyond primaryvisual cortex provide no evidence for sparingof cortically dependent visual functions13,49.This absence of sparing is understandable,because little or no cerebral machinery is leftto process visual signals related to the cortex-dependent tasks, and it shows that an appro-priate substrate must remain for neural com-pensations to emerge. However, the breadthand depth of the compensations achieved byextrastriate cortex are not complete afterlesions limited to primary visual cortex. Thisis because performance levels seldom equatefully with the highly proficient performances

that the properties of binocularity, spatialsummation within the receptive field anddirection selectivity are spared. Tracing stud-ies showing a comprehensive restructuring ofthe visual system supported the involvementof extrastriate cortex. This restructuringincluded sets of visual pathways from thethalamus, the superior colliculus and atypicalcortical regions, to the visuoparietal andvisuotemporal cortices51–57 (FIG. 2a). Theseexpansions were considered to be adaptive,because they are linked to neural compensa-tions and spared visual operations that opti-mize the interactions of the subject with theenvironment under the new conditions. Suchpositive features are a distinguishing charac-teristic of the plastic capacities of the brain,and they should be differentiated from non-specific and disordered alterations in path-ways, which might also be induced by lesionsbut that have no useful function.

Sparing of function is limited; early lesionsalso induce permanent impairments in someaspects of visually guided behaviour. Forexample, discrimination of simple patterns inthe presence of distracting borders is poor(TABLE 1), and can be linked to a partial dis-connection of extrastriate regions of cortexfrom ascending signals. Pattern vision underlow contrast (TABLE 1) is also greatly impaired.This impairment is accounted for by theselective, transneuronal, retrograde degenera-tion of β (or X) retinal ganglion cells58 (FIG. 2a).In early-lesioned cats, the impairment can beconsidered as a basic visual defect. Gudden59,Ganser60 and Von Monakow61, contemporariesof Soltmann, identified a similar heightenedvulnerability of immature neurons to distantlesions. The absence of visual β retinal gan-

Table 1 | Spared and impaired behaviours

Adult lesion Week-1 lesion

Parietal cortex: reflex, action, space

Depth (visual cliff)13,49 – – – – – –

Optokinetic nystagmus13 – – – – –

Visual orienting13,14 – – – – –

Auditory orienting14,132 +++++ +++++

Temporal cortex: form, learning, memory

Object recognition11,12 – ++++

Simple pattern recognition11,12 – – ++++

Masked pattern recognition: surround11,12 – – – – – – – – – –

Masked pattern recognition: overlain grid11,12 – – – – – –*

Masked pattern recognition: low contrast65 – – – – – – – – – –

Spared and impaired basic and cognitive visual functions after lesions of the primary visual cortex sustained inadulthood or during the first postnatal week. Tasks are grouped according to the neural structure thatcontributes most fully to the neural operations in intact cats. +++++, normal, high level of performance;– – – – – , performance reduced to chance levels or abolished. Superior performance by the week-1-lesiongroup compared with the adult-lesion group reflects the sparing of visually guided behaviour. *No or lesserdeficit following two-stage lesions.



nucleus87 and from immature, bilaterally col-lateralized axons in the spinal cord91,92. Inmonkey, unilateral damage of the hand rep-resentation in motor cortex results in normaluse of the contralateral hand in global gripmovements, but precision grip movementsare less dexterous93. In agreement withKennard and McCulloch39, electrical stimula-tion has implicated a new, compressed ipsi-lesional representation of the hand in thecompensation (FIG. 1c). Inactivation of themodified representation severely impairedmovements that were otherwise possible, andconfirmed this view93. For comparison, func-tional recovery after lesions of the handregion in adult monkeys involves ipsilesionalpremotor cortex, and is not as complete94.

Cerebral lesions in infants also inducefunctional reorganization. After large lesions,both passive movement of a hemiplegic handand median nerve electrical stimulation pro-duce foci of activation in contralesional sen-sorimotor cortex, as assessed by functionalmagnetic resonance imaging (fMRI) andevoked potentials95. Likewise, magnetic brainstimulation of intact motor cortex evokescompound muscle action potentials in theipsilateral upper limb. The potentials are con-sistently shorter in latency and larger inamplitude than the equivalent potentialsevoked in patients that acquired damage later,indicating that ipsilateral pathways mighthave been strengthened after early lesions96

(FIG. 1b). Similar studies of much younger sub-jects showed that better motor function wasassociated with topographically differentiatedipsilateral and contralateral representations inthe intact hemisphere97. Moreover, ininstances of mirror movements in the twohands, electromyographic recordings showthat left and right motor neuron pools receivecommon synaptic input from undamagedmotor cortex through branched axons98. Bycontrast, other studies of humans confirm theobservations of Rouiller et al.93 on monkeys,indicating an involvement of the ipsilesionalcortex in functional sparing99.

The exact factors that govern intrahemi-spheric versus interhemispheric reorganizationafter sensorimotor lesions are not well under-stood. Reorganization is probably influencedby overall cerebral capacity, actual size of themotor cortex, fractional size of the lesion, theavailability of sufficient and appropriate juxta-lesional cortex, the absence or presence of tran-sient corticospinal projections86,91,100, and thematurational status of the system and its levelof control at the time of the lesion20. Overall,it is clear that when the opposite hemispheretakes over functions of the damaged region,the homologous cortex is a main contributor

that visual signals reach extrastriate regionsalong pathways that bypass the damaged pri-mary visual cortex, and that these signals aresufficient in themselves for visual discrimina-tions, conscious awareness and the ability toreport verbally on some stimulus attributes.These pathways could include limbs thatascend either through the superior colliculusand the pulvinar nucleus, or along survivingretino–geniculo–prestriate projections80,81,which are able to activate prestriate corticeswith a lag of only 20 ms (REF. 82). Moreover, acti-vation is greater after lesions sustained earlier inlife. However, the substantial death of β retinalganglion cells almost certainly limits globalsparing83,84, as it does in cats. However, struc-ture and function of the visual system afterlesion in humans seem to differ in fundamentalways from the normal visual system. Thesparing of visual functions in humans after

early lesions of primary visual cortex awaitsdetailed studies and general acceptance.

Reconstruction of other systemsSensorimotor cortex. Early cortical lesionsalso modify the structure and function ofthe sensorimotor systems, as first shown bySoltmann. Early unilateral lesions of catsensorimotor cortex, before significantgrowth of corticospinal axons into thespinal grey matter85,86, results in expandeddescending pathways from the intact hemi-sphere87–90 (FIG. 1b). These pathways couldaccount for Soltmann’s functional observa-tions (compare FIG. 1a with FIG. 1b). In rats,the expansions involve direct ipsilateralpathways and a recrossing of contralateralcorticospinal projections89, whereas in cats,the expansions might result from retentionof immature crossed projections to the red


a Rebuilt visual system b Redistribution of functions

c Behavioural performance

Visuoparietal

VisuotemporalSC

LGN

Locus of cortical operationsVisuoparietal:visual orienting

Intact

P1 lesion

Impact of cooling deactivation

Parietal

Temporal

Parietal and temporal

+++++

++++

–––

–

––––

+++++

++++

–

––––

––––

+++++

+++++

No effect

–––––

Not tested

+++++

+++++

No effect

No effect

No effect

Visuotemporal:pattern recognition

Auditory temporal:auditory orienting

Visuotemporal:object recognition

W,Y

W,Y

Primary visual cortex

LP/PulP

P

T

M

Eye

W,YX

Figure 2 | Rebuilding a highly functional visual system. a | Comprehensive rebuilding of the cat visualsystem by expansion of pathways. Rebuilding was induced by ablation of primary visual cortex (grey) duringthe first postnatal week. Pathway expansions are shown in red; degenerated elements of the visual systemare in yellow; unknown modifications are in green. Degenerated elements are normally strongly connectedwith the primary visual cortex. Interrupted line represents possible expansion of a known reciprocalpathway. Retino–geniculo–cortical expansions are greater after ablations sustained at 1 month of age, andretinal degeneration is less pronounced. b | Representation of the primary visual cortex lesion (grey) and theredistribution of cortical operations between parietal (P) and temporal (T) visual cortices. c | The performanceof intact cats, and cats that sustained lesions to the primary visual cortex (P1) during the first postnataldays. +++++, high (normal) behavioural performance; ++++, slightly impaired behavioural performance.Poor performance of cats with lesions sustained in adulthood is shown in TABLE 1. Behavioural performancetested during cooling deactivation of the visuoparietal and temporal cortices is shown. –, mild deficit; – – – ,moderate to severe impairment; – – – – – , performance abolished or reduced to chance levels. Note theabsence of impact of the lesion on visual pattern recognition and auditory orienting, and the absence of aneffect of parietal cooling on object recognition. The cooling of visual structures has no impact on orienting tosound stimuli, yet cooling of visuotemporal cortex reduces the recall of object discriminations to chancelevels, as it does in intact cats67. During combined cooling of visuoparietal and visuotemporal regions, thecat is unable to reorient its attention, and is unable to recall differences in complex patterns.



to functional sparing. However, it is notknown whether non-homologous regionsalso contribute. For example, when functionsare represented in multiple functional layers,some functional components in the intactbrain might be inhibited as long as they areprimarily represented elsewhere in the cere-bral cortex. After a lesion, the inhibited motorrepresentations might be unmasked and contribute to the sparing of functions (BOX 1).

Temporal cortex. Temporal lobe systems arealso remodelled after early lesions, and thereis evidence for both sparing of functions andpermanent impairments. The inferior tem-poral lobe consists of several divisions thatinclude areas TE and TEO. In monkeys, earlylesions of area TE spare visual recognitionmemory in delayed non-matching to samplewhen short delays are used, and impairmentswith longer delays are only mild10. The spar-ing might be linked to lesion-modified pro-jections from area TEO to the lateral basalnucleus of the amygdala that bypass area TEto reach regions normally innervated by theablated TE101. Information on the functionalrepercussions of lesions of components of thetemporal lobe in human infants and childrenis very limited, except in the case of therapyfor frequent seizures102.

Prefrontal cortex. Lesions of circumscribedregions of the monkey prefrontal cortexsustained during the perinatal period (within2 months before or after birth) result in a preservation of cognitive functions ondelayed-response and spatial-alternationtasks. By contrast, performance is affected inadolescent or adult monkeys as a result ofequivalent lesions103–107. Moreover, gender,environment, age at surgery, experience andage at assessment all influence outcome9,108. Itseems that the relatively ‘uncommitted’, ormore immature, dorsolateral prefrontal cortexcan subsume functions of the orbitofrontalcortex, but not vice versa109. An equally plau-sible interpretation is that evolutionarily newercortex might adapt readily when older cortexis damaged, but older cortex cannot substi-tute for newer cortical functions. Regardlessof interpretation, the sparing can be linked tothe survival of neurons in the mediodorsalnucleus, and to the development of modifiedprojections and rebuilt pathways105,110.

Reconstruction mechanismsThe reconstruction process involves a com-plex interplay of factors. Their exact spec-trum depends on the time and place of thelesion, and the maturational status of neu-rons and fibre systems. There are at least four

Visuoparietalcortex

Primaryvisual cortex

LGN

Optic radiations

a Lesion-induced degenerations

Lesion

Intact projections

• Migration of neurons• Reduced apoptosis

• Sprouting• Re-routing

b Attraction

Expansion

• Dendrites• Axonal arborization

Migration of neurons

Stabilization

• Ephemeral collateral• Ephemeral sole projection

LGNLGN

c Partial ablation with compression of antecedent projections

Normal visual projections

EyeEye

Figure 3 | Rebuilding a system after an early lesion. The example given corresponds to thegeniculocortical visual system. Similar schema can be applied elsewhere in the visual system, and to othersystems. a | The dominant projection system from the lateral geniculate nucleus (LGN) through the primaryvisual cortex131 (areas 17 and 18 shown in green) to visuoparietal cortex is shown. Lesion induces bothanterograde degeneration and deafferents the visuoparietal cortex, and the retrograde degeneration ofmany LGN neurons is observed. b | Modes of pathway expansion are depicted. Migration: the migrationof additional neurons and/or reduced apoptosis contribute to increases in pathways. Attraction: the lesioneliminates a target of the LGN neuron and creates space in the visuoparietal cortex, which attractsbypassing axons to sprout if the axon has reached the cortical plate and is damaged by the lesion, or tore-route if the axon escapes damage but is deprived of its normal target because its growing tip is still inthe optic radiation. Stabilization: the lesion damages an axon in the cortical plate and triggers stabilizationof a normally ephemeral projection to visuoparietal cortex. The stabilization of ephemeral axons could alsooccur solely by the partial deafferentation of visuoparietal cortex when a collateral to primary visual cortexis absent. Resilience of neurons might be greater if the axon is not damaged by the lesion. Expansion:expanded dendritic (in LGN) and axonal (in visuoparietal cortex) arborizations afford greater levels ofconnectivity. c | Example of compression of a projection. Left: normal visual projections. Right:compressed projection. This case corresponds to the primary projection system (retina) on its targetstructure (LGN) after partial destruction of a secondary target (primary visual cortex).



could be at work for sensory, perceptual,cognitive and motor functions.

Humans. Studies of the plastic capacity of theimmature human brain, and its ability toovercome challenges to its normal develop-ment, are of enormous importance. The iden-tification of spared and impaired functions inpeople with circumscribed lesions acquiredacross a spectrum of ages will be highly bene-ficial. For example, well-characterized batter-ies of stimuli and tasks can be used, togetherwith evoked potentials, fMRI and transcranialmagnetic stimulation, to probe reconfiguredcerebral systems. Moreover, the temporal limitof plasticity should be tested more thoroughlyin view of the fact that, for example, articu-lated, well-structured language can be firstacquired as late as 9 years of age and by theright hemisphere alone120.

Animal models. Parallel studies should be car-ried out on laboratory animals. New fMRImethods that allow the resolution of func-tional brain architecture at the level of corticalcolumns121, and reversible deactivation tech-niques, will be increasingly important inprobing the contributions of rewired circuitsto neural compensations68,93, and to establishcausal links between modified pathways andspared cerebral functions.

It will also be valuable to ascertain whetheror not there is a ‘price’ to pay for the redistrib-ution of functions. Are neural operations thatare normally associated with certain regionsreduced, displaced or ‘crowded out’ (as pro-posed by Teuber122) as these regions makecontributions to new aspects of behaviour?This change in function is a possibility, becauseit is known that visuospatial abilities arereduced when a sparing of language functionsis shown in humans1,122.

Another important avenue of investigationin sensory systems will be the detailed analysisof transneuronal, retrograde, degenerativerepercussions that extend out towards theperiphery and limit the signals that enter therebuilt central systems. For example, rewiringof the damaged retina is likely to be substan-tial56,58, and knowledge of this rewiring willprobably provide important clues to the sig-nals that form the foundation of cognitivefunction and behaviour.

Immature neurons. The key element for therebuilding of neural systems is the enormouspotential of immature neurons to modify con-nections. They are the building blocks ofneural compensations and organized behav-iour. Understanding the repercussions of earlycerebral lesions will require the application of

main ways in which a pathway can increase insize and exert an influence on target structuresin response to a lesion elsewhere in the system(FIG. 3). They include: accretion of new neu-rons or reduced apoptosis of the cells thatproject to the target structure, redirection orsprouting of axons to capitalize on the emer-gence of potential target space, stabilization ofephemeral projections, and expansion ofterminal arborizations in a target (FIG 3b).

All four mechanisms probably contributeto the rebuilding of functionally useful cerebralsystems, but it seems likely that there are certainearly periods when interventions trigger themost impressive reconstruction. The greatestrebuilding probably occurs during the normalblooming period, when much of normal corti-cal connectivity is established. For example, inboth the corticospinal and visual systems, thedegree of functional sparing and rebuilding aresubstantial during the developmental phase ofneuronal accumulation and pathway forma-tion111,112. In both of these systems, early lesionsprovide the opportunity to modify neuronmigratory path and ultimate destination, andpermit their outgrowing axons to becomeassociated with other developing fibre tractsthat lead axons to new targets (FIG. 3b). Thisperiod can be protracted, because the migra-tion of neurons can continue for long periodspostnatally, albeit at a low level113.

Lesions sustained after neurons havereached their destination limit the options forpathway modification, which probably rest onthe emergence of novel target space in thevicinity of axon trajectories. For example, inboth the corticospinal and geniculocorticalprojection systems, axons pass near the rednucleus and visuoparietal cortex, respectively,and enter space that is devoid of normal pro-jection systems (FIG. 1a and FIG. 3a). It is notknown if the target structure attracts axonsinto this space, whether the lesion triggers col-lateral sprouting, or whether errant orephemeral axons are stabilized in the deaffer-ented structure114–117 (FIG. 3b). Whatever theoutcome, the functional impact is heightenedby further expansions in terminal arboriza-tions and an increase in the numbers ofsynapses (FIG. 3b). The increase in projectionsmight be benefited by decreased apoptosis inthe projecting structure, which increases thenumber of neurons contributing to a path-way. In the target structure, the increase inprojections might benefit from an increase inthe terminal field available to projection sys-tems. However, increases in terminal fieldsmight be counterbalanced by diminishedchances of entering the targets due to severalfactors. These might include lowered attrac-tion from targets, reduced ability of axons to

extend branches, increased obstructions asother pathways mature between the fibre tra-jectory and the potential target structure, anddegeneration of immature cortical neuronsinduced by the distant lesion, as occurs in thethalamus and retina58,118.

New system components are not formedhaphazardly. For example, patterns of modi-fied projections in the cat visual system con-form to the general plan of thalamic innerva-tion of visuoparietal cortex. The focuseddistributions of projection neurons show thatonly specific subsets of immature neuronscan innervate visuoparietal cortex after theearly ablation of primary visual cortex53. Inthe lateral geniculate nucleus (LGN), theadditional neurons represent the lower visualfield, whereas most neurons in the lateral pos-terior nucleus represent the horizontal merid-ian. This non-equivalence might be linked todifferent modes by which LGN and lateralposterior thalamic axons establish projectionsto visuoparietal cortex. For example, the LGNneurons could stabilize ephemeral axons115,116

(FIG. 3b), whereas lateral posterior thalamicaxons might be attracted to invade the target(FIG. 3b). The combination of the two neuronalrepresentations matches the visual fieldcoordinates of neurons eliminated by theablation, and they contribute to a normalvisual field map in visuoparietal cortex50.

Another important element in restructur-ing a system is the compression of antecedentprojections onto fragments of neural struc-tures (FIG. 3c). For example, there is evidencethat retinal projections remap onto LGNneurons that survive ablation of the primaryvisual cortex119, and that ascending projec-tions remap onto remaining regions of themotor cortex93. The compression might beaccentuated by redirection of dendritegrowth to accommodate more afferentaxons55 (FIG. 3c), and expansion of axons inthe target56, although the expansion of singleaxon arborizations remains to be shown.

Future directionsThe preceding 25 years have seen the accep-tance of plasticity as an important phenome-non of self-organizing neural systems, andthe past decade stands out as a period whenlesion-induced brain rewiring was conclu-sively proven and shown to be adaptive. Inthe coming years, it will be essential to obtainaccurate pictures of the functions that arespared and impaired by early lesions, toextend that knowledge to other systems, agegroups and species, and to gain an under-standing of the cellular and molecular basesof functional sparing. It will also be impor-tant to ascertain whether similar mechanisms




premotor areas in infancy. J. Neurophysiol. 1, 477–496(1938).

35. Kennard, M. A. Relation of ‘spasticity’ to age in youngmonkeys and chimpanzees. Trans. Am. Neurol. Assoc.65, 58–62 (1939).

36. Kennard, M. A. Relation of age to motor impairment inman and subhuman primates. Arch. Neurol. Psychiatry44, 377–397(1940).

37. Kennard, M. A. Cortical reorganization of motor function.Arch. Neurol. 48, 227–240 (1942).

38. Kennard, M. A. & Fulton, J. F. Age and reorganization ofthe central nervous system. J. Mt Sinai Hosp. 9,594–606 (1942).

39. Kennard, M. A. & McCulloch, W. S. Motor response tostimulation of cerebral cortex in the absence of areas 4 and6 (Macaca mulatta). J. Neurophysiol. 6, 181–190 (1943).

40. Hubel D. H. & Wiesel, T. N. Binocular interaction in striatecortex of kittens raised with artificial squint. J. Neurophysiol. 28, 1041–1059 (1965).

41. Hubel D. H. & Wiesel, T. N. The period of susceptibility tothe physiological effects of unilateral eye closure inkittens. J. Physiol. (Lond.) 206, 419–436 (1970).

42. Dews, P. B. & Wiesel, T. N. Consequences of monoculardeprivation on visual behaviour in kittens. J. Physiol.(Lond.) 206, 437–455 (1970).

43. Mitchell, D. E. in Vision: Coding and Efficiency (ed.Blakemore, C.) 234–246 (Cambridge Univ. Press,Cambridge, 1990).

44. LeVay, S., Wiesel, T. N. & Hubel, D. H. The developmentof ocular dominance columns in normal and visuallydeprived monkeys. J. Comp. Neurol. 191, 1–51 (1980).

45. Hubel D. H., Wiesel, T. N. & LeVay, S. Plasticity of oculardominance columns in monkey striate cortex. Phil. Trans.R. Soc. Lond. B 278, 377–409 (1977).

46. Shatz, C. J. & Stryker, M. P. Ocular dominance in layer IVof the cat’s visual cortex and the effects of monoculardeprivation. J. Physiol. (Lond.) 281, 267–283 (1978).

47. Shatz, C. J., Lindstrom, S. & Wiesel, T. N. Thedistribution of afferents representing the right and lefteyes in the cat’s visual cortex. Brain Res. 131, 103–116(1977).

48. Doty, R. W. in The History of Neuroscience inAutobiography (ed. Squire, L.) 214–244 (Academic, SanDiego, 2001).

49. Cornwell, P., Overman, W. & Ross, C. Extent of recoveryfrom neonatal damage to the cortical visual system. J. Comp. Physiol. Psychol. 92, 255–270 (1978).

50. Spear, P. D., Kalil, R. E. & Tong, L. Functionalcompensation in lateral suprasylvian visual area followingneonatal visual cortex removal in cats. J. Neurophysiol.43, 851–869 (1980).

51. Kalil, R. E., Tong, L. L. & Spear, P. D. Thalamicprojections to the lateral suprasylvian visual area in catswith neonatal or adult visual cortex damage. J. Comp.Neurol. 314, 512–525 (1991).

52. Lomber, S. G., Payne, B. R., Cornwell, P. & Pearson, H.E. Capacity of the retinogeniculate pathway to reorganizefollowing ablation of visual cortical areas in developingand mature cats. J. Comp. Neurol. 338, 432–457 (1993).

53. Lomber, S. G., MacNeil, M. A. & Payne, B. R.Amplification of thalamic projections to middlesuprasylvian cortex following ablation of immatureprimary visual cortex in the cat. Cereb. Cortex 5,166–191 (1995).

54. MacNeil, M. A., Lomber, S. G. & Payne, B. R. Rewiring oftranscortical projections to middle suprasylvian cortexfollowing early removal of cat areas 17 and 18. Cereb.Cortex 6, 362–376 (1996).

55. MacNeil, M. A., Einstein, G. E. & Payne, B. R.Transgeniculate signal transmission to middlesuprasylvian extrastriate cortex in intact cats andfollowing early removal of areas 17 and 18: amorphological study. Exp. Brain Res. 114, 11–23 (1997).

56. Payne, B. R. & Lomber, S. G. Neuroplasticity in the cat’svisual system: origin, termination, expansion andincreased coupling in the retino–geniculo–middlesuprasylvian visual pathway following early lesions ofareas 17 and 18. Exp. Brain Res. 121, 334–349 (1998).

57. Payne, B. R., Lomber, S. G., MacNeil, M. A. & Cornwell,P. Evidence for greater sight in blindsight followingdamage of primary visual cortex early in life.Neuropsychologia 34, 741–774 (1996).

58. Payne, B. R., Pearson, H. E. & Cornwell, P.Transneuronal degeneration of β retinal ganglion cells inthe cat. Proc. R. Soc. Lond. B 222, 15–32 (1984).

59. Gudden, B. Experimentaluntersuchungen über dasperiphäre unde Zentrale nervensystem. Arch. Psychiatr.Nervenkr. 2, 693–723 (1869).

60. Ganser, S. Über die periphere und zentrale Anordnungder Sehnervenfasern and über das corpus bigeminumanterius. Arch. Psychiatr. Nervenkr. 13, 341–381 (1882).

6. Bates, E. in The Changing Nervous System:Neurobehavioral Consequences of Early Brain Disorders(eds. Broman, S. & Fletcher, J.) 214–253 (Oxford Univ.Press, Oxford, 1999).

7. Van den Hout, B. M. et al. Relation between visualperceptual impairment and neonatal ultrasound diagnosisin haemorrhagic-ischaemic brain lesions in 5-year-oldchildren. Dev. Med. Child Neurol. 42, 376–386 (2000).

8. Schneider, G. E. Is it really better to have a brain lesionearly? A revision of the ‘Kennard Principle’.Neuropsychologia 17, 557–583 (1979).

9. Goldman-Rakic, P. S., Isseroff, A., Schwartz, M. L. &Bugbee, N. M. in Handbook of Child Psychology: Biologyand Infancy Development, (ed. Mussen, P.) 281–344(Wiley, New York, 1983).

10. Bachevalier, J. & Mishkin, M. Effects of selective neonataltemporal lobe lesions on visual recognition memory inrhesus monkeys. J. Neurosci. 14, 2128–2139 (1994).

11. Cornwell, P. et al. Selective sparing after lesions of visualcortex in newborn kittens. Behav. Neurosci. 103,1176–1190 (1989).

12. Cornwell, P. & Payne, B. R. Visual discrimination by catsgiven lesions of visual cortex in one or two stages ininfancy or in one stage in adulthood. Behav. Neurosci.103, 1191–1199 (1989).

13. Shupert, C., Cornwell, P. & Payne, B. R. Differentialsparing of depth perception, orienting and optokineticnystagmus after neonatal versus adult lesions of corticalareas 17, 18 and 19 in the cat. Behav. Neurosci. 107,633–650 (1993).

14. Payne, B. R., Lomber, S. G. & Gelston, C. D. Gradedsparing of visually-guided orienting following primaryvisual cortex ablations within the first postnatal month.Behav. Brain Res. 117, 1–11 (2000).

15. Broca, P. Remarques sur la siège de la faculté du langagearticulé: suivies d’une observation d’aphémie (perte de laparole). Bulletins de la Société Anatomique 6, 330–357(1861).

16. Broca, P. Localisation des fontions cérébrales. Siège dulangage articulé. Bulletins de la Société d’Anthropologie4, 200–203 (1863).

17. Broca, P. Sur la siege de la faculté du langage articulédans l’hemisphere gauche du cerveau. Bulletins de laSociété d’Anthropologie 6, 377–393 (1865).

18. Barlow, T. On a case of double hemiplegia with cerebralsymmetrical lesions. Br. Med. J. 2, 103–104 (1877).

19. Rasmussen, T. & Milner, B. The role of early left-braininjury in determining the lateralization of cerebral speechfunctions. Ann. NY Acad. Sci. 299, 355–369 (1977).

20. Soltmann, O. Experimentalle Studien über die Functionendes Grosshirns der Neugeborenen. Jahrb. Kinderheilkd.9, 106–148 (1876).

21. Fritsch, G. & Hitzig, E. Über die elektrische Erregbarkeitdes Grosshirns. Arch. Anat. Physiol. Wiss. Med. 37,300–332 (1870)

22. Vulpian, A. Leçons dur la Physiologie Générale stComparée du Système Nerveux (Balliére, Paris, 1866).

23. Brown, T. G. On the activities of the central nervoussystem of the unborn foetus of the cat with a discussionof the question whether progression (walking, etc.) is a‘learnt’ complex. J. Physiol. (Lond.) 49, 208–215 (1915).

24. Langworthy, O. R. A physiological study of the reactionsof young decerebrate animals. Am. J. Physiol. 69,254–264 (1924).

25. Langworthy, O. R. Relation of onset of decerebrate rigidityto the time of myelination of tracts in the brain-stem andspinal cord of young animals. Contrib. Endocrinol. 17,127–140 (1926).

26. Weed, L. H. The reaction of kittens after decortication.Am. J. Physiol. 43, 131–157 (1917).

27. Finger, S. & Almli, C. R. in Brain Injury and Recovery:Theoretical and Controversial Issues (eds Finger, S.,LeVere, T. E., Almli, C. R. & Stein, D. G.) 117–132(Plenum, New York, 1988).

28. Freud, S. & Rie, O. Klinische Studie über des halbeitigeCerebrallahmung der Kinder (Moritz Perles, Vienna, 1891).

29. Sachs, B. A Treatise on the Nervous Diseases of Childrenfor Physicians and Students (William Wood & Co., NewYork, 1895).

30. Osler, W. The Cerebral Palsies of Children (H. K. Lewis,London, 1899).

31. Taylor, J. Paralysis and Other Diseases of the NervousSystem in Childhood and Early Life (J. & A. Churchill,London, 1905).

32. Gowers, W. R. A Manual of the Diseases of the NervousSystem (Blakiston, Son & Co., Philadelphia, 1907).

33. Kennard, M. A. Age and other factors in motor recoveryfrom precentral lesions in monkeys. Am. J. Physiol. 115,138–146 (1936).

34. Kennard, M. A. Reorganization of motor function in thecerebral cortex of monkeys deprived of motor and

multiple approaches to examine brainrewiring and neuron degeneration, to detectmodifications in neural activity, and to linkrepercussions to spared and impaired behav-iours. Studies will benefit from the cellular andmolecular analytical approaches that aredesigned to determine why some neurons diewhereas others survive, how neurons redirectaxons to new targets whereas others do not,and how signals delivered by the redirectedaxons influence the activities of target neurons.

Treatments. We predict that the use ofenriched environments and training strategieswill potentiate the natural capacity of the brainto compensate for lesion-induced deficits andallow relatively normal organized behaviour.We also suggest that pharmacological treat-ments will one day complement behaviouraltherapeutic strategies. For example, ampheta-mine attenuates the defects in depth discrimi-nation in cats with visual cortical lesions123,124,and moderates depressed neural activity asmeasured by cerebral oxidative metabolism125.In addition, transplants of embryonic visualcortex slow retrograde degeneration of LGNneurons after visual cortical lesions126–129, atten-uate apoptosis, and facilitate the migration ofnew nerve cells130. Importantly, these processesneed to be controlled to ensure that they canbe terminated after they have participated inneural compensations. Moreover, when cortexhas to be removed surgically, procedures car-ried out in two or more stages might be benefi-cial, because temporarily remaining tissuemight contribute to compensatory adjust-ments that are not possible after large, single-stage removals12,37. The adoption of multiplestrategies will maximize the natural capacity ofthe brain to minimize disruption of functionafter lesions.

Bertram R. Payne is at the Laboratory for VisualPerception and Cognition, Department of Anatomy

and Neurobiology, Boston University School ofMedicine, Boston, Massachusetts 02118, USA.

Stephen G. Lomber is at the Cerebral SystemsLaboratory, School of Human Development,

University of Texas at Dallas, Richardson,Texas 75083, USA.

Correspondence to B.R.P.e-mail: [email protected]

1. Milner, B. Sparing of language function after unilateral braindamage. Neurosci. Res. Prog. Bull. 2, 213–217 (1974).

2. Rudel, R. G., Teuber, H. L. & Twitchel, T. E. Levels ofimpairment of sensorimotor functions in children withearly brain damage. Neuropsychologia 12, 95–108 (1974).

3. Woods, B. T. The restricted effects of right-hemispherelesions after age one; Wechsler test data.Neuropsychologia 18, 65–70 (1981).

4. Ogden, J. Visuospatial and other ‘right-hemispheric’functions after long recovery periods in left-hemispherectomized subjects. Neuropsychologia 27,765–776 (1989).

5. Stiles, J. & Nass, R. Spatial grouping activity in youngchildren with congenital right or left hemisphere braininjury. Brain Cogn 15, 201–222 (1991).



112. Bayer, S. A., Altman, J., Russo, R. J., Dai, X. F. &Simmons, J. A. Cell migration in the rat embryonicneocortex. J. Comp. Neurol. 307, 499–516 (1991).

113. Gross, C. G. Neurogenesis in the adult brain: death of adogma. Nature Rev. Neurosci. 1, 67–73 (2000).

114. Cornwell, P., Ravizza, R. & Payne, B. Extrinsic visual andauditory cortical connections in the 4-day-old kitten. J. Comp. Neurol. 229, 97–120 (1984).

114. Bruce, L. L. & Stein, B. E. Transient projections from thelateral geniculate to the posteromedial lateralsuprasylvian visual cortex in kittens. J. Comp. Neurol.278, 287–302 (1988).

115. Tong, L., Kalil, R. E. & Spear, P. D. Development of theprojections from the dorsal lateral geniculate nucleus tothe lateral suprasylvian visual area of cortex in the cat. J. Comp. Neurol. 314, 526–533 (1991).

117. Kato, T., Hirano, A., Katagiri, T. & Sasaki, H. Transientuncrossed corticospinal fibers in the newborn rat.Neuropathol. Appl. Neurobiol. 11, 171–178 (1985).

118. Payne, B. R., Connors, C. & Cornwell, P. Survival anddeath of neurons in cortical area PMLS after removal ofareas 17, 18 and 19 from cats and kittens. Cereb. Cortex1, 469–491 (1991).

119. Murphy, E. H. & Kalil, R. E. Functional organization oflateral geniculate cells following removal of visual cortexin the newborn kitten. Science 206, 713–716 (1979).

120. Vargha-Khadem, F. et al. Onset of speech after lefthemispherectomy in a nine-year–old boy. Brain 120,159–182 (1997).

121. Kim, D. S., Duong, T. Q. & Kim, S. G. High-resolutionmapping of iso-orientation columns by fMRI. NatureNeurosci. 3, 164–169 (2000).

122. Teuber, H.-L. Outcome of severe damage to the nervoussystem. Ciba Found. Symp. 34, 95–115 (1975).

123. Feeney, D. M. & Hovda D. A. Reinstatement of binoculardepth perception by amphetamine and visual experienceafter visual cortex ablation. Brain Res. 342, 352–356(1985).

124. Hovda, D. A., Sutton, R. L. & Feeney, D. M.Amphetamine-induced recovery of visual cliffperformance after bilateral visual cortex ablation in cats:measurements of depth perception thresholds. Behav.Neurosci. 103, 574–584 (1989).

125. Sutton, R. L., Hovda, D. A., Chen, M. J. & Feeney, D. M.Alleviation of brain injury-induced cerebral metabolicdepression by amphetamine: a cytochrome oxidasestudy. Neural Plast. 7, 109–125 (2000).

126. Cunningham, T. J., Haun, F. & Chantler, P. D. Diffusibleproteins prolong survival of dorsal lateral geniculateneurons following occipital cortex lesions in newbornrats. Brain Res. 465, 133–141 (1987).

127. Eagleson, K. L., Cunningham, T. J. & Haun, F. Rescue ofboth rapidly and slowly degenerating neurons in thedorsal lateral geniculate nucleus of adult rats by acortically derived neuron survival factor. Exp. Neurol. 116,156–162 (1992).

128. Haun, F., Cunningham, T. J. & Rothblat, L. A. Neurotrophicand behavioral effects of occipital cortex transplants innewborn rats. Vis. Neurosci. 2, 189–198 (1989).

129. Haun, F. & Cunningham T. J. Recovery of frontal cortex-mediated visual behaviors following neurotrophic rescueof axotomized neurons in medial frontal cortex. J. Neurosci. 13, 614–622 (1993).

130. Ourednik, J., Ourednik, W. & Mitchell, D. E. Remodellingof lesioned kitten visual cortex after xenotransplantationof fetal mouse neopallium. J. Comp. Neurol. 395,91–111 (1998).

131. Payne, B. R. & Peters, A. in Cat Primary Visual Cortex(eds Payne, B. R. & Peters, A.) 1–130 (Academic, SanDiego, in the press).

132. Payne, B. R. & Lomber, S. G. in Virtual Lesions:Examining Cortical Function with Reversible Deactivation(eds Lomber, S. G. & Galuske, R. A. W.) (Oxford Univ.Press, Oxford, in the press).

AcknowledgementsThis work was supported by funds from the National Institute ofNeurological Diseases and Stroke.

Online links

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/cortical plasticity: use-dependent remodellingMIT Encyclopedia of Cognitive Sciences:http://cognet.mit.edu/MITECS/auditory plasticity | neural plasticityBertram Payne’s lab:http://www.bu.edu/anatneuro/faculty_framepage.htmlAccess to this interactive links box is free online.

61. Von Monakow, C. Experimentelle und pathologisch-anatomische Untersuchungen über die optischenCentren und Bahnen. Arch. Psychiatr. Nervenkr. 20,714–787 (1889).

62. Callahan, E. C., Tong, L. & Spear, P. D. Critical period forthe loss of retinal X-cells following visual cortex damage incats. Brain Res. 323, 302–306 (1984).

63. Tong, L., Kalil, R. E. & Spear, P. D. Critical periods forfunctional and anatomical compensation in lateralsuprasylvian visual area following removal of visual cortexin cats. J. Neurophysiol. 52, 941–960 (1984).

64. Mitchell, D. E. in Cat Primary Visual Cortex (eds Payne, B. R. & Peters, A.) 1–49 (Academic, San Diego, 2001).

65. Payne, B. R. System-wide repercussions and adaptiveplasticity: the sequelae of immature visual cortexdamage. Restor. Neurol. Neurosci. 15, 81–106 (2000).

66. Guido, W., Spear, P. D. & Tong, L. How complete is thephysiological compensation in extrastriate cortex aftervisual cortex damage in kittens? Exp. Brain Res. 91,455–466 (1992).

67. Lomber, S. G., Payne, B. R., Cornwell, P. & Long, K. D.Perceptual and cognitive visual functions of parietal andtemporal cortices of the cat. Cereb. Cortex 6, 673–695(1996).

68. Lomber, S. G. & Payne, B. R. Perinatal-lesion-inducedreorganization of cerebral functions revealed by reversiblecooling deactivation and attentional tasks. Cereb. Cortex11, 194–209 (2001).

69. Moore, T. M., Rodman, H. R., Repp, A. B., Gross, C. G. &Mezrich, R. S. Greater residual vision in monkeys afterstriate cortex damage in infancy. J. Neurophysiol. 76,3928–3933 (1996).

70. Moore, T. M., Rodman, H. R. & Gross, C. G. Direction ofmotion discrimination after early lesions of striate cortex(V1) of the macaque monkey. Proc. Natl Acad. Sci. USA98, 325–330 (2001).

71. Weiskrantz, L. Blindsight: a Case Study and Implications(Clarendon, Oxford, 1986).

72. Blythe, I. M., Kennard, C. & Ruddock, K. H. Residualvision in patients with retrogeniculate lesions of visualpathways. Brain 110, 887–905 (1987).

73. Barbur, J. L., Watson, J. D. G., Frackowiak, R. S. J. &Zeki, S. Conscious visual perception without V1. Brain116, 1293–1302 (1993).

74. Barbur, J. L., Harlow, A. & Weiskrantz, L. Spatial andtemporal response properties of residual vision in a caseof hemianopia. Phil. Trans. R. Soc. Lond. B 343, 157–166(1994).

75. Brent, P. J., Kennard, C. & Ruddock, K. H. Residual colorvision in a human hemianope: spectral responses andcolor discrimination. Proc. R. Soc. Lond. B 256, 219–225(1994).

76. Weiskrantz, L., Harlow, A. & Barbur, J. L. Factorsaffecting visual sensitivity in a hemianopic subject. Brain114, 2269–2282 (1991).

77. Weiskrantz, L., Barbur, J. L. & Sahraie, A. Parametersaffecting conscious versus unconscious visualdiscrimination with damage to the visual cortex (V1).Proc. Natl Acad. Sci. USA 92, 6122–6126 (1995).

78. Sahraie, A. et al. Pattern of neuronal activity associatedwith conscious and unconscious processing of visual signals. Proc. Natl Acad. Sci. USA 94, 9406–9411(1997).

79. Goebel, R., Muckli, L., Zanella, F. E., Singer, W. & Stoerig,P. Sustained extrastriate cortical activation without visualawareness revealed by fMRI studies on hemianopicpatients. Vision Res. 41, 1459–1474 (2001).

80. Hendrickson, A. E. & Dineen, J. T. Hypertrophy ofneurons in dorsal lateral geniculate nucleus followingstriate cortex lesions in infant monkeys. Neurosci. Lett.30, 217–222 (1982).

81. Rodman, H. R., Sorenson, K. M., Shim, A. J. & Hexter, D. P.Calbindin immunoreactivity in the geniculo–extrastriatesystem of the macaque: implications for heterogeneity inthe koniocellular pathway and recovery from corticaldamage. J. Comp. Neurol. 431, 168–181 (2001).

82. Rossion, B., De Gelder, B., Pourtois, G., Guerit, J. M. &Weiskrantz, L. Early extrastriate activity without primaryvisual cortex in humans. Neurosci. Lett. 279, 25–28(2000).

83. Weller, R. E. & Kaas, J. H. Parameters affecting the loss ofganglion cells of the retina following ablations of striatecortex in primates. Vis. Neurosci. 3, 327–349 (1989).

84. Cowey, A., Stoerig, P. & Perry, V. H. Transneuronalretrograde degeneration of retinal ganglion cells afterdamage to striate cortex in macaque monkeys: selectiveloss of P β cells. Neuroscience 29, 65–80 (1989).

85. Leonard, C. T. & Goldberger, M. E. Consequences ofdamage to the sensorimotor cortex in neonatal and adultcats. I. Sparing and recovery of function. Brain Res. 429,1–14 (1987).

86. Alisky, J. M., Swink, T. D. & Tolbert, D. L. The postnatalspatial and temporal development of corticospinalprojections in cats. Exp. Brain Res. 88, 265–276 (1992).

87. Leonard, C. T. & Goldberger, M. E. Consequences ofdamage to the sensorimotor cortex in neonatal and adultcats. II. Maintenance of exuberant projections. Brain Res.429, 15–30 (1987).

88. Murakami, F. & Higashi, S. Presence of crossedcorticorubral fibers and increase of crossed projectionsafter unilateral lesions of the cerebral cortex of the kitten: ademonstration using anterograde transport of Phaseolusvulgaris leucoagglutinin. Brain Res. 447, 98–108 (1988).

89. Barth, T. M. & Stanfield, B. B. The recovery of forelimb-placing behavior in rats with neonatal unilateral corticaldamage involves the remaining hemisphere. J. Neurosci.10, 3449–3459 (1990).

90. Ono, K., Yamano, T. & Shimada, M. Formation of anipsilateral corticospinal tract after ablation of cerebralcortex. Brain Dev. 13, 348–351 (1991).

91. Li, Q. & Martin, J. H. Postnatal development of differentialprojections from the caudal and rostral motor cortexsubregions. Exp. Brain Res. 134, 187–198 (2000).

92. Theriault, E. & Taton, W. G. Postnatal maturation ofpericruciate motor cortical projections within the kittenspinal cord. Brain Res. Dev. Brain Res. 45, 219–237 (1989).

93. Rouiller, E. M. et al. Dexterity in adult monkeys followingearly lesion of the motor cortical hand area: the role ofcortex adjacent to the lesion. Eur. J. Neurosci. 10,729–740 (1998).

94. Liu, Y. & Rouiller, E. M. Mechanisms of recovery ofdexterity following unilateral lesion of the sensorimotorcortex in adult monkeys. Exp. Brain Res. 128, 149–159(1999).

95. Holloway, V. et al. The reorganization of sensorimotorfunction in children after hemispherectomy. A functionalMRI and somatosensory evoked potential study. Brain123, 2432–2444 (2000).

96. Benecke, R., Meyer, B.-U. & Freund, H.-J.Reorganisation of descending motor pathways inpatients after hemispherectomy and severe hemisphericlesions demonstrated by magnetic resonancestimulation. Exp. Brain Res. 83, 419–426 (1991).

97. Pascual-Leone, A., Chugani, H. T. & Cohen, L. G.Reorganization of human motor pathways followinghemispherectomy. Ann. Neurol. 32, 261 (1992).

98. Farmer, S. F., Harrison, L. M., Ingram, D. A. & Stephens,J. A. Plasticity of central motor pathways in children withhemiplegic cerebral palsy. Neurology 41, 1505–1510(1991).

99. Carr, L. J., Harrison, L. M., Evans, A. L. & Stephens A. J.Patterns of central motor reorganization in hemiplegiccerebral palsy. Brain 116, 1223–1247 (1993).

100. Armand, J., Olivier, E., Edgley, S. A. & Lemon, R. N.Postnatal development of corticospinal projections frommotor cortex to the cervical enlargement in the macaquemonkey. J. Neurosci. 17, 251–266 (1997).

101. Webster, M. J., Ungerleider, L. G. & Bachevalier, J.Lesions of inferior temporal area TE in infant monkeysalter cortico–amygdalar projections. Neuroreport 2,769–772 (1991).

102. Duchowny, M. et al. Temporal lobectomy in earlychildhood. Epilepsia 33, 298–303 (1992).

103. Akert, K., Orth, O. S., Harlow, H. F. & Schlitz, K. A. Learnedbehavior of rhesus monkeys following neonatal bilateralprefrontal lobectomy. Science 132, 1944–1945 (1960).

104. Goldman, P. S. Functional development of the prefrontalcortex in early life and the problem of neuronal plasticity.Exp. Neurol. 32, 366–387 (1971).

105. Goldman, P. S. & Galkin, T. W. Prenatal removal of frontalassociation cortex in the fetal rhesus monkey: anatomicaland functional consequences in postnatal life. Brain Res.152, 451–485 (1978).

106. Harlow, H. F., Thompson, C. I., Blomquist, A. J. & Schlitz,K. A. Learning in rhesus monkeys after varying amountsof prefrontal lobe destruction during infancy andadolescence. Brain Res. 18, 343–353 (1970).

107. Tucker, T. J. & Kling, A. Differential effects of early and latelesions in frontal granular cortex in the monkey. BrainRes. 5, 377–389 (1967).

108. Goldman, P. S. The role of experience in recovery offunction following orbital prefrontal lesions in infantmonkeys. Neuropsychologia 14, 401–412 (1976).

109. Goldman, P. S. Developmental determinants of corticalplasticity. Acta Neurobiol. Exp. 32, 495–511 (1972).

110. Goldman, P. S. Neuronal plasticity in primatetelencephalon: anomalous projections induced byprenatal removal of frontal cortex. Science 202, 768–770(1978).

111. Luskin, M. B. & Shatz, C. J. Neurogenesis of the cat’sprimary visual cortex. J. Comp. Neurol. 242, 611–631(1985).


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TIMELINE: Reconstructing functional systems after lesions of cerebral cortex