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European Volume) Journal of Hand Surgery (British and

DOI: 10.1054/jhsb.1999.0339 2000; 25; 242 Journal of Hand Surgery (British and European Volume)

G. LUNDBORG Brain Plasticity and Hand Surgery: an Overview

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BRAIN PLASTICITY AND HAND SURGERY: AN OVERVIEW

G. LUNDBORG

From the Department of Hand Surgery, MalmoÈ University Hospital, MalmoÈ, Sweden

The hand is an extension of the brain, and the hand is projected and represented in large areas ofthe motor and sensory cortex. The brain is a complicated neural network which continuouslyremodels itself as a result of changes in sensory input. Such synaptic reorganizational changes maybe activity-dependent, based on alterations in hand activity and tactile experience, or a result ofdea�erentiation such as nerve injury or amputation. Inferior recovery of functional sensibilityfollowing nerve repair, as well as phantom experiences in virtual, amputated limbs are phenomenare¯ecting profound cortical reorganizational changes. Surgical procedures on the hand are alwaysaccompanied by synaptic reorganizational changes in the brain cortex, and the outcome from manyhand surgical procedures is to a large extent dependent on brain plasticity.Journal of Hand Surgery (British and European Volume, 2000) 25B: 3: 242±252

The human hand has often been described as an``extension of the brain''. There are several reasons forthis concept. The hand is a symbol for identity, a mirrorof the mind and a tool of the soul in the way ourpersonality and psyche is expressed in gestures andmovements in the body language (Lundborg, 1997). Thedelicate sensibility of the hand makes it a sense organ,the sense of touch being essential for exploration of thesurrounding world (Katz, 1989; Klatsky et al., 1987;Manske, 1999; Vermeij, 1999). The sensibility of thehand is extremely well developed, and in active touchour ®ngertips can be used to identify delicate structures,forms and textures without using sight.

Sensory perception is a central nervous experienceand the hand and the brain are functionally intimatelylinked together. The existence of cortical and subcorticaltopographic maps of the body surface has been welldocumented in primates as well as humans (Kaas, 1983).In the somatosensory cortex each body part is projectedin its own representation within the postcentral gyrus ofthe parietal lobe (Fig 1). Body parts with specially welldeveloped sensibility occupy larger cortical territoriesthan those with less developed sensibility. The hand andthe lips together occupy a very substantial part of thesomatosensory brain cortex.

Tactile stimuli from individual ®ngers result in actionpotentials which pass through the dorsal root ganglia,up the dorsal column of the spinal cord and throughintermediate relay stations (cuneate nucleus in the brainstem and ventroposterior nucleus in thalamus) on theirway to the contralateral cerebral cortex. Within eachnucleus there is a precise somatotopic map correspond-ing to locations of the original stimuli, and at alllevels plastic synaptic reorganizations may take place(Florence et al., 1997; Kaas, 1991).

The hand and ®nger representation, located inBrodmann's area 3B in the somatosensory cortex, havebeen meticulously outlined in primates by directrecording techniques from the cortical surface by

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Merzernich and co-workers and others (Kaas, 1997;Merzenich and Jenkins, 1993; Merzenich et al., 1978;1987). For de®ning a ``map'' of the hand the skinsurfaces e�ective for exciting neurons have beendetermined for cortical neurons within a given corticalarea by carefully exploring the skin with ®ne mechanicalprobes at the same time as recordings are made from thecortical surface. The cortical receptive ®eld de®ned ateach sample site is the skin surface that, when stimulatedmechanically, excites one or more cortical neuron(s) atthe location. Typical cortical receptive ®elds are shownin Figure 2. Receptive ®elds recorded at nearby sampledlocations normally slightly overlap on the skin. Theextent of overlapping, and thereby also the acuity of ®netactile discrimination, may change in speci®c situations(further discussed below). Modern brain imagingtechniques have shown an organization and mappingof the body surface in humans analogous to that foundin monkeys, individual ®ngers of the hand beingrepresented in well de®ned cortical band shaped areas.

The somatosensory cortex is topographically mappednot only along its surface ± it also processes a number ofdistinct cellular layers arrayed vertically, perpendicularto the surface. Thus, we are dealing with an extremelycomplicated three-dimensional neuronal organizationwhere cells in the various layers of the vertical columnsrespond to stimuli from individual parts of the hand,and where each layer sends projections on to other brainareas for further integration. In this way tactileinformation from the hand, generated by active touchforms the base for further processing and corticalinterpretation of the sensory message, resulting inperception of characteristics of objects such as forms,shapes and textures and also qualities like density,elasticity, softness and temperature. The sublime dis-criminative capacity of the hand is a result of asophisticated interaction between central nervous me-chanisms and a large number of nerve endings andmechanoreceptors in the ®ngertips, responding to

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Fig 1 The cortical body map with reference to sensory (posterior to central sulcus) and motor (anterior to central sulcus) functions. Transversesections through sensory cortex (upper left) and motor cortex (upper right) illustrates the somatotopic organization of the body parts. Thehomunculus ®gure comprises body parts in sizes proportional to their projectional areas in the brain. The hand and the face areas are veryclose and together occupy a substantial part of the sensory cortex. [Modi®ed from Lundborg (1999).]

BRAIN PLASTICITY AND HAND SURGERY 243

various types of sensory stimuli including vibra-tion and dynamic/static touch (Edin, 1992; Edin andJohansson, 1995; Johansson et al., 1992; Johansson andWestling, 1984; Vallbo and Johansson, 1984).

Until about 25 years ago it was ®rmly believed thatthe cortical mapping of body parts was ®rmly estab-lished in the adult brain and the widespread assumptionwas that sensory representations in the mature brain are®xed and incapable of functional reorganization. How-ever, with time accumulating clinical observations haveindicated that the brain is far more plastic than waspreviously believed, and that the potential for corticalfunctional re-organization is a factor of considerablepractical as well as theoretical interest (Bach-y-Rita,1967; 1981; 1990; 1994; Buonomano and Merzenich,1998; Wynn-Parry and Salter, 1976). Merzenich and co-workers, using sophisticated techniques for directrecording from the brain cortex of primates (Merzenichet al., 1978; 1983; 1984; 1987), presented neurophysio-logical evidence of a capacity for reorganization in thesomatosensory cortex of adult primates as a result ofrestricted dea�erentiation, for instance transection ofthe median nerve or amputation. Later studies haveclearly demonstrated that such ``plasticity'' of the brain,involving extensive functional reorganizations, can infact occur also as a result of changed sensory experienceand performance of the hand, local anesthesia, as well asvarious surgical procedures (such as separation ofsyndactylies and island ¯ap transfers). As a result ofsuch events a functional synaptic reorganization in brain


cortex can start within seconds and go on for very longtime.

Recent brain imaging techniques like positron emis-sion tomography (PET), single photon emission com-puted tomography (SPECT), functional magneticresonance imaging (fMRI) and magnetoencephalogra-phy (MEG) have demonstrated that similar changesmay also occur in the human brain. For instance,extensive use of hands and ®ngers may result inenlargement of the corresponding projectional areas inthe brain (Elbert et al., 1995; Pasqual-Leone and Torres,1993). Amputation of extremities or parts of extremitiesmay lead to strange perceptional abnormalities such asphantom experiences and disturbed body image (Floret al., 1995; Knecht et al., 1995; Ramachandran et al.,1992). Nerve transection and repair leads to a verysigni®cant functional reorganization in the correspond-ing cortical areas as a result of misdirection ofoutgrowing axons and aberrant innervation of periph-eral skin areas. These developing concepts have pre-sented new explanations for the variable and oftendisappointing results of peripheral nerve surgery, as wellas the di�erences in outcome from nerve repair betweenyoung and adult individuals.

Taken together, evolving concepts during the last twodecades have substantially increased our understandingof the impact that surgical procedures in hand andextremities may have on the functional organization ofthe brain. Many of our results from surgery, whetherencouraging or disappointing, can be explained by



Fig 2 Activity-dependent changes in cortical mapping (area 3b),schematically demonstrated through a magnifying glass, andexamples on corresponding changes in ®nger receptive ®eldsinduced by behaviourally controlled tasks (owl monkeys).Receptive ®elds are indicated by circles and ellipsoids in handoutlines. (a) Normally there is a well organized cortical map ofthe hand and ®ngers in area 3b with sharp borderlines betweenindividual ®ngers (D1±D5) and between the ®ngers and thepalm (P). The hairy skin of the dorsal part of hand and ®ngers(dotted areas) is projected adjacent to the digits and also insmall patches in between individual digital representations.Receptive ®elds in ®ngers, as indicated schematically to theright, slightly overlap one another. (b) Moving stimulus appliedto distal phalanges of second and third ®ngers. The twostimulated ®ngers expand their cortical territories. The receptive®elds in the distal phalanges become unusually small withminimal overlapping. (c) Monotonous repetitive hand move-ment results in signi®cant changes in cortical mapping. Thehand representations become markedly degraded with dedi�er-entiation of cortical representations of skin of the hand. Thereceptive ®elds in ®ngers become very large, some of them evenoverlapping adjacent ®ngers. [Based on results and drawingsfrom Jenkins et al. (1990), Merzenich and Jenkins (1993),Merzenich et al. (1978; 1987), Byl et al. (1996).]

244 THE JOURNAL OF HAND SURGERY VOL. 25B No. 3 JUNE 2000

central nervous changes rather than peripheral events.The aim of this comprehensive review is to present somerelevant data of importance for surgeons dealing withsuch hand and extremity problems which can beexpected to induce functional reorganizational processesin the brain.


WHAT IS PLASTICITY?

Plasticity in general can be de®ned as ``the capability ofbeing moulded''. Synaptic plasticity can be de®ned asthe ability of synapses to change as circumstancesrequire. They may alter function, such as increasing ordecreasing their sensitivity; or they may increase ordecrease in actual numbers. This phenomenon isthought to be the main source of the overall plasticityof nervous system pathways.

Plasticity in the cerebral cortex refers to a change inproperties of cortical neurons (Ebner et al., 1997). Suchchanges can be detected in animal experiments withelectrophysiological recording techniques, and in hu-mans analogous studies can be performed with variousnoninvasive brain analysis techniques. The process ofplastic reorganization is a system-wide phenomenoninvolving both cortical and subcortical representations(Kaas, 1991; Nicolelis et al., 1998).

Cortical plasticity can be induced by changes inactivity levels that are conveyed from peripheral nervesand then transmitted to the cortex. Cortical synapsesreadily respond to changes in input activity by changingtheir strength or e�cacy as a result of ``synapticcompetition''. In this way changes in ``synapticstrength'' may be activity-dependent and there are manyexamples of how cortical plasticity can be inducedsimply by changes in neural activity from the periphery.Increase in tactile stimuli may result in long-termpotentiation (LTP) of cortical synapses while low ratesof stimulation result in a response-decrease called long-term depression (LTD). Striking examples of activity-dependent cortical plasticity are, for instance, the®ndings from a number of studies on rats when whiskersare trimmed on one side of the face (Diamond et al.,1993; Ebner et al., 1997; Nicolelis et al., 1998). Within1 to 3 days after trimming of all but two whiskers, cor-tical responses to stimuli from the intact whiskers arestrengthened and those to the trimmed whiskers becomeless able to drive cortical cells (Diamond et al., 1993).

Much attention has been paid to the biochemicalmechanisms underlying plasticity and reorganizationalchanges occurring in the somatosensory cortex. Themain excitatory neurotransmittor in the mammalianbrain is the aminoacid glutamate, and among glutamatereceptors the NMDA receptors (responding to N-methyl-D-aspartate) have gained the greatest attention(Ebner et al., 1997). The synaptic strengthening isthought to involve the NMDA receptor complex sinceonly limited reorganization occurs in the somatosensorycortex if NMDA receptors are blocked during therecovery period following nerve injury (Florence et al.,1997; Garraghty and Muja, 1996; Kano et al., 1991),and it has also been demonstrated that glutamatereceptor blockage at cortical synapses has consequencesfor cortical functional organization during development(Fox et al., 1996). Rapid activity-dependent changesmay re¯ect inhibitory and facilitory modi®cations in




synaptic functions (Ebner et al., 1997). More long-standing de-a�erentiations, like those produced byamputation and nerve injuries, may re¯ect ± at least inpart ± formation of new connections (Florence et al.,1997; 1998).

Activity-dependent alterations may occur also in themotor cortex. For instance, it has been demonstrated inmonkeys that after behavioural training for tasksrequiring skilled use of digits the corresponding digitrepresentation in motor cortex expands; these changesmay be progressive and reversible (Nudo et al., 1997).

CORTICAL REORGANIZATION AS A RESULT OFCHANGES IN SENSORY EXPERIENCE ANDPERFORMANCE

It has been demonstrated in several experiments onprimates that cortical functional reorganizationalchanges in the cortical representational ®elds may occurin a use-dependent manner. Extensive active use ofspeci®c ®ngers as well as new sensory experiences in thehand may result in such functional reorganization in thesomatosensory cortex (Fig 2). In experimental animalstudies, areas 3a and 3b in primates have been mappedbefore and after several weeks of a period of behaviou-rally controlled hand use. For instance, owl monkeyswere conditioned in a task that produced movingcutaneous stimulation of a limited sector of skin onthe distal phalanges of one ®ngers; in order to obtainfood the distal aspect of the distal segment of digitsmaintained contact with a ridged rotating stimulus diskfor 10 to 15 seconds per banana pellet reward. Analysisof cortical mapping data several weeks after such atraining period showed that the stimulated skin surfaceswere now represented over extended cortical areas. Thereceptive ®elds of the ®ngers were unusually small and infact represented the stimulated skin surface in very ®nespatial grain (Jenkins et al., 1990; Merzenich andJenkins, 1993). In these situations every small skin locusprovided sensory inputs that could e�ectively competewith inputs from nonstimulated skin areas. As aconsequence, smaller than normal receptive ®elds aregenerated as the cortical network creates an abnormally®ne-graded, spatially devolved representation of thestimulated skin surface.

It can be assumed that any behaviourally importantuse of the hand requiring delicate sensory feedback anddiscrimination would have impacts on the details ofcorresponding cortical representations as well as the sizeof receptive ®elds in the ®ngers (cf. Braille reading,discussed below) and that active touch, associated withuse of the hand as an ``exploratory'' organ in ®nesensory task, may lead by cortical synaptic changes toincreased skills. It is well known that practice of hapticskills in general generates substantial improvements inrecognition skills, stimulus discrimination and alsomotor performance (Gibson, 1953). There are reasons

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to believe that such improvement in skill and capacitymay be due to practice-induced cortical representationalchanges, and that synaptic plasticity associated withlong-term learning processes in general can explainmany such phenomena.

In other experiments adult owl monkeys were trainedto use the normal hand in a frequency discriminationtask. The animals were trained to detect a di�erence inthe frequency of sequentially applied tactile stimulipresented to a constant, restricted location on theglabrous skin of a single ®nger by a vibrating probe.The animals were trained to identify a 20 Hz stimuli,and correct responses were rewarded with a food pellet.By decreasing the threshold for frequency discrimina-tion over time, the animals' ability to make even ®nerdiscrimination of frequencies was improved by thetraining. In these experiments the stimulus was broughtdown repeatedly on to a constant skin site restricted to asmall part of a segment of one ®nger and the monkeywas trained to make distinctions about the temporalpatterns of applied stimulation (Recanzone et al., 1992a;1992b; 1992c; 1992d). It was found that the frequencydi�erence discrimination performance of the monkeysimproved progressively with training. The corticalrepresentation of the trained hands became substantiallymore complex in topographic details than the represen-tations of the unstimulated hands. In well-trainedmonkeys a large cortical area representing the stimu-lated skin area, signi®cantly greater than on the controlside, emerged. However, the receptive ®elds representingthe trained skin were signi®cantly larger than on thecontrol digits, the largest receptive ®elds being centeredin the zone of representation of stimulated skin.Receptive ®elds also enlarged all across the zones ofrepresentation of adjacent ®ngers. Thus, the trainingresulted in a genuine progressive improvement intemporal acuity speci®c to the trained skin (frequencydiscrimination capacity), but due to the increase in sizeof receptive ®elds, spatial acuity and haptic abilitiesprobably became worse. In clinical terms the experi-ments illustrate that tactile capacity can presumably besubstantially degraded by certain forms of conditioningor training. The ®ndings may presumably have relevancefor the disturbance in sensibility and ®ne motorfunctions seen in patients exposed to vibration byhandheld tools (Cederlund et al., 1998).

It has been shown that in humans cortical functionalreorganization can also take place as a result of changesin peripheral sensory performance and experience. Forinstance, in young string instrument players the left(®ngering) hand representation in somatosensory cortexhas been found to be larger than that of the right hand(Elbert et al., 1995). On both sides the hand representa-tions are larger than those in matched controls whonever played the violin. The extent of cortical reorga-nization is correlated to the age at which the childinitially began to play the violin. The interpretation ofthese data is that the cortical representation of the digits

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had expanded as a function of prolonged high frequencyperipheral input activity, in this case the result of dailypractice. It has also been shown that in blind Braillereaders, ``reading'' with the index ®nger, there is anexpanded sensory and motor cortical representation ofthis ®nger relative to that of non-reading ®ngers and tothat of matched control individuals (Pasqual-Leone andTorres, 1993). Interestingly enough it has been demon-strated that the visual cortex is very active in Braillereaders who are actively reading during the imaging, butnot as a result of passive stimulation of the ®nger by aBraille reading device (Sadato et al., 1996).

In reconstructive hand surgery a striking example ofbrain plasticity is how stereognosis in the hands ofchildren su�ering from cerebral palsy may be improvedby surgery that is aimed at exposure of the palm to theenvironment. With severe ¯exion deformity of the wristin spastic disease the hand is not exposed to tactileexperiences and stereognosis functions are poor. Such``sleeping sensibility'' can, however, be awoken follow-ing a tendon transfer which releases the wrist contrac-ture and puts the hand in a more functional position sothat the palm of the hand can be subjected to new tactilestimuli (Dahlin et al., 1998a, 1998b).

However, there may also be potential negativeconsequences of frequent and stereotype use of ®ngers.Repetitive tasks may be implicated in dystonias (writer'scramp) and ``repetitive strain injuries'' (RSI) (Byl andMelnick, 1997; Byl et al., 1996). It seems that overactingthe normal mechanisms by stereotyped use of the ®ngersmay result in signi®cant cortical reorganization. Inexperimental studies primates were required to squeezeand release a pistol grip in less than three-quarters of asecond in a stereotyped fashion to obtain its foodreward. With time the animals' capacity to perform thistask declined and they showed remarkable di�culties inopening and closing their hands. An unusual represen-tation of the surface of the trained hand in cortical area3b could be demonstrated (Fig 2c). The hand represen-tation was found to be markedly degraded in thesemonkeys as characterized by a dedi�erentiation of thecortical representation of the skin of the hand mani-fested by receptive ®elds that were 10 to 20 times largerthan normal. Many receptive ®elds emerged thatcovered the entire glabrous surface of individual digitsor that extended across the surface of two or moredigits. A break-down of the normally sharp delineationsbetween the receptive ®elds for individual ®ngers wasseen, and some cortical neurons responded to a touchanywhere on the front of the hand. Thus, there was adegradation of cortical representation of sensory in-formation guiding ®ne motor hand movements and itwas felt that these ®ndings might help to explaindyscoordination phenomena with disturbances in ®nemotor function as a result of long-term stereotyped andmonotoneous use of the ®ngers. Analogous ®ndingshave been made by Bara-Jimanez et al. (1998) indystonic patients by the use of a large number of


external scalp electrodes. Similar observations have alsobeen made in dystonic musicians by the use of MRItechniques (Elbert et al., 1998) and in patients withwriter's cramp by the use of PET technique (Tempel andPerlmutter, 1993). Speci®c therapeutic programs havebeen suggested to compensate for such central nervousorganization alterations (Candia et al., 1999).

EFFECTS OF LOCAL ANAESTHESIA

The synaptic plasticity of the adult brain allows veryrapid functional reorganizations. Cortical receptive ®eldshifts can be detected within a few seconds afterinduction of peripheral sensory dea�erentiation suchas digital amputation (Calford and Tweedale, 1988) aswell as injury to digital nerves (Calford and Tweedale,1991) and the median and radial nerves of primates(Silva et al., 1996). Local anaesthetic blocks may induceprompt shifts in neuronal receptive ®elds, lasting foronly a few hours (Nakahama et al., 1966; Nicolelis et al.,1993; Pettit and Schwark, 1993; Rossini et al., 1994).Neurons displayed their normal receptive ®elds as soonas the e�ect of the local anaesthesia wore o�. The®ndings suggest that the adult somatosensory cortex hasthe capacity for considerable rapidly reversible func-tional reorganizations over a very brief period of time.

SURGICAL PROCEDURES

Separation of syndactyly

Remodelling of the cortical area 3b has been observed inprimates subjected to surgical fusion of two ®ngers: thepreviously sharply distinguished cortical receptive ®eldsof the individual ®ngers were no longer evidentfollowing surgery and there was a ``fusion'' in thecortical representation of the ®ngers (Allard et al.,1991). With separation of fused ®ngers the reversedreorganization took place. Analogous observations havebeen made in humans. In patients born with fused®ngers, presurgical maps based on magnetoencephalo-graphy have shown no separate representational corticalareas, corresponding to the fused ®ngers, whereas post-surgical maps have revealed that the cortex hasreorganized so that the separated digits were separatedin the cortical areas (Mogilner et al., 1993).

Island ¯ap transfer

A well known technique to resurface the pulp of thethumb with sensate skin is to use an innervated pedicledskin island ¯ap transposed from the ulnar part ofthe ring ®nger to the thumb (Paneva-Holevich andHolevich, 1991; Tubiana and Duparc, 1961). In primateexperiments such procedures result in a functionalremodelling of area 3b corresponding to the thumbreceptive ®elds (Merzenich and Jenkins, 1993;Merzenich et al., 1993). After 3 months the cortical




representation of the island skin, which was formerly inthe fourth digit cortical representational area disap-peared from that cortical sector and instead emerged intopographic relationship to the representation of thesurface of the thumb. In a clinical perspective corre-sponding ®ndings would indicate that a patient under-going such a pedicled island ¯ap transfer would, in time,perceive tactile stimuli to the innervated ¯ap as touchingthe thumb instead of the ring ®nger. However, clinicalexperience indicates that this may occur only to a limitedextent in adult patients, a fact that could be explainedby di�erent capacities for cortical reorganization andsynaptic plasticity between monkeys and humans.

AMPUTATION

It is well known that people who have lost a limb orparts of an extremity may often su�er from strange andembarrassing ``phantom limb sensations'' after theamputation. Such patients may experience a virtualempty space which may have quite an impact on theirbody image (Berlucchi and Aglioti, 1997; Rama-chandran, 1998). Clinical data as well as results frombrain imaging investigations provide evidence that acortical reorganization may rapidly occur after anamputation. Touching a body part may evoke asensation in the limb that has been amputated and thetouch may be associated with phantom pain e�ects (Floret al., 1995; Knecht et al., 1995; McAllister and Calder,1995; Ramachandran et al., 1992). A well knownphenomenon is that touching areas on the face or upperarm may induce tactile sensations referenced to a losthand (Halligan et al., 1994; Ramachandran, 1993;Ramachandran et al., 1992). The phenomenon is dueto a rapid cortical reorganization with expansion ofadjacent cortical areas into the area previously activatedby inputs from the amputated limb. Such a reorganiza-tion of sensory pathways may occur very soon afteramputation in humans: in less than 24 hours afteramputation of an arm, stimuli applied on the ipsilateralface can be referred in a precise, topographicallyorganized modality-speci®c manner to distinct pointsin the phantom limb (Borsook et al., 1998). Such aphenomenon may be due to the rapid unmasking ofordinarily silent inputs rather than sprouting of newaxon terminals, e.g. a result from disinhibition ofordinarily inactive synapses.

Thus, amputation of a limb is followed by asigni®cant cortical reorganization, a phenomenon whichis re¯ected also in reorganizations of cortical blood ¯ow(Kew et al., 1994). Amputees may su�er from variousextents of phantom sensations and such phantomsensations may be painful or not painful. It has beensuggested that the amount of phantom pain might beassociated with the extent of cortical reorganizationwhich takes place following the amputation. Using non-invasive brain imaging techniques a strong relationship

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between the amount of cortical reorganization and themagnitude of phantom limb pain experienced after armamputation has been reported (Birbaumer et al., 1997;Flor et al., 1995; 1998; Knecht et al., 1995, 1998a,1998b). It was proposed that phantom-limb pain may berelated to, and may be a consequence of, plastic changesin the primary somatosensory cortex. Prevention of suchplastic changes could therefore, hypothetically be apotential way to prevent occurrence of phantom limbpain, for instance by pharmacological blocking ofglutamate-receptors. As stated above, blockage of suchreceptors may prevent or interfere with functionalreorganization following nerve injury and during devel-opment. Treatment with ketamine (an NMDAS-recep-tor antagonist) has been successfully tried for thetreatment of phantom pain (Nikolajsen et al., 1996;1997). However, the aetiology of phantom pain isprobably very complex and to a large extent unknown(Katz, 1992; Melzack, 1990). It has been suggested thatphantom sensations may activate a memory track(Melzack, 1990) and that the mechanism for theamputation injury may thereby play a role. Neuromag-netic source imaging has revealed minimal reorganiza-tion of the primary somatosensory cortex in congenitalamputees and traumatic amputees without pain whileamputees with phantom limb pain showed massivecortical reorganization (Flor et al., 1998).

Amputation of a limb is also followed by corticalreorganization in the motor cortex, although it has beenshown by the use of fMRI techniques that representa-tional areas in the motor cortex, normally drivingmovements of the hand, may be well preserved followingamputation. Motor cortex activity was studied byErsland et al. (1996) during real (left hand) andimaginary (right hand) ®nger tapping in a man whohad his right arm amputated 1.5 years earlier. He wasinstructed alternately to move the intact left hand ®ngersand to imagine tapping the ®ngers on the amputatedright hand. Activation was observed in the right motorcortex during ®nger tapping with the intact left hand,and a corresponding activation in the left motor cortexfor imaginary movements of the ®ngers of the ampu-tated right hand.

The physiology of phantom sensations can be bestunderstood in the light of primate experiments.(Merzenich et al., 1984; Nicolelis, 1997). It has beendemonstrated that phantom limbs could in fact beexplained as true physiological responses. Merzenichet al. (1984) amputated the mid ®nger of primates andlater stimulated the digits on the hand that were adja-cent to the amputation stump (Fig 3). By using microelec-trodes to detect activity in neurons in various corticalareas it was found that the region of the somatosensorycortex that originally responded to stimulation of theamputated ®nger was now triggered every time the twoadjacent ®ngers were touched (Merzenich and Jenkins,1993; Merzenich et al., 1984). Immediately follow-ing digital amputation, receptive ®elds representing

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Fig 3 Changes in cortical mapping (area 3b) due to dea�erentiationsuch as amputation and nerve injury, followed by axonaloutgrowth. (a) Normal cortical representation of ®ngers.(b) Median nerve transection. The cortical area correspondingto the median nerve becomes silent due to acute deprivation ofa�erent in¯ow. (c) Median nerve transection, regeneration notallowed. One month later the cortical area, previously receivinginput from the median nerve, is now occupied by expandingcortical representations of dorsal radial-innervated skin andulnar innervated skin of the hand. (d) Crushed median nerve,recovery phase. The cortical representation of ®ngers and palmhas returned to practically normal. (e) Median nerve transec-tion, repair and axonal regeneration. Recovery phase. There isa total remodelling of the cortical median nerve representationcharacterized by small discontinuous patches, some of themoverlapping, responding to inputs in a somatotopic disorga-nized pattern. (f) Amputation of mid®nger. Representations ofthe second and fourth digits expand to occupy the areapreviously receiving input from the mid®nger. [Based on resultsand drawings from Merzenich and Jenkins (1993), Merzenichet al. (1983a; 1983b; 1984), Wall et al. (1983; 1986), Allard et al.(1991).]


surrounding skin surfaces greatly enlarged and ex-panded over the cortical area that previously repre-sented the middle ®nger. In the monkey experimentsmost or all of the area formerly representing the missing


digit was occupied by new inputs from the adjacent®ngers and subadjacent palm (Merzenich et al., 1984),evidence of expansion of topographic representation.

NERVE INJURY

Transection of a peripheral nerve represents a partialdea�erentiation with immediate and long-standingin¯uence on the representational area in brain cortexcorresponding to that speci®c nerve (Garraghty et al.,1994; Merzenich et al., 1983; Silva et al., 1996; Wallet al., 1986). For instance, transection of a median nerveof primates immediately results in a silent ``black hole''in the somatosensory brain cortex corresponding to theprojectional areas of thumb, index ®nger, middle ®ngerand half ring ®nger (Fig 3). Signi®cant inputs restrictedto the dorsum of the hand and digits were immediately``unmasked'' by the median nerve transection(Merzenich et al., 1983) and gradually the adjacentulnar territory expands to occupy a substantial area ofthe former median nerve territory (Silva et al., 1996).Within 1 week its cortical territory is completelyoccupied by expanding adjacent cortical areas represent-ing surfaces on the dorsum of the hand as well as theglabrous skin of the radial and ulnar parts of the hand.Initially this emerging input is crude and emergingreceptive ®elds are abnormally large and overlapping.However, with time the cortical topography is subjectedto further extensive re®nement and within 2 to 3 weeksthe topography of representation of the new inputs inthis zone is re®ned and shows sharp borderlines betweenthe expanding territories from adjacent cortical areas(Merzenich and Jenkins, 1993; Wall et al., 1986).

Thus, the former median nerve cortical territory israpidly occupied by the adjacent cortical areas followingdea�erentiation. After this the subsequent developmentis dependent on the nature of the nerve lesion. If themedian nerve is not permitted to regenerate theextensive reorganization of the cortical map, as de-scribed above, persists so that the cortical area,previously receiving input from the median nerve,remains completely occupied by expanding adjacentcortical areas (Fig 3c). If we are dealing with a crushinjury, followed by regeneration, the picture is totallydi�erent ± since regenerating axons can follow theiroriginal Schwann cell tubes they also reach their originalskin locations (Lundborg, 1988). The resulting corticalrepresentation of the median nerve innervating skinareas after regeneration will therefore not substantiallydi�er from the normal representation (Fig 3d) (Wallet al., 1983).

However, if the median nerve is subjected to transec-tion and repair there will be a completely di�erentcortical remodelling scenario. Due to randomizedgrowth in the repair zone and misdirection in axonalgrowth the original skin areas will, to a large extent, notbe reinnervated by their original axons. This will result




in signi®cant reorganizational changes in the cortex,speci®cally restricted to those regions where input fromthe median nerve are normally represented (Fig 3e)(Florence et al., 1994; Jain et al., 1998; Kaas andFlorence, 1997; Wall et al., 1986). In primate experi-ments the median nerve did not recapture all of itsoriginal territory. The former well de®ned band-likecortical representations of individual ®ngers nowdisappeared and changed into dispersed discontinuousislands. Any previously well de®ned functional skinsurface, e.g. the thumb, the segment of a ®nger or apalmar pad, became represented across multiple smallpatches within the regenerated nerve cortical area. Thefunctional features of cortical regions that recoveredtactile responsiveness from reinnervated skin regionswas abnormal in several respects. These regionscontained several recording sites with abnormallylocated or multiple cutaneous receptive ®elds (Wallet al., 1986). Over a long period of observation thecortical representational loci of many skin sits appearedto change continuously, and often markedly, and thelocation of map discontinuities also shifted signi®cantlyover time. Thus, nerve transection results in bothimmediate and progressively developing changes in thecortical maps of a skin surface (Merzenich et al., 1983).

Fig 4 Principles for sensory reeducation following median nerve injury around ball in somatosensory cortex. (b) Following nerve transectioto axonal misdirection and subsequent functional reorganization inand tactile impressions are combined to train the brain to underst


Plastic synaptic change occur also in the cuneate nucleusat the brain stem level (Florence et al., 1994).

The functional reorganizational changes in cortexfollowing nerve repair correspond well to the situationin humans in whom, for example, median nerve suturein adults results in loss of ®ne sensory functions such astactile gnosis/stereognosis (McAllister and Calder,1995). The hand ``speaks a new language to the brain'',and a period of sensory reeducation (Fig. 4) is requiredto acquire functional sensibility as described by Wynn-Parry and Salter (1976), Dellon (1981), Callahan (1990)and Imai et al. (1991). According to this principle thebrain is ``reprogrammed'' in a re-learning process whereitems of increasing ``di�culty'' are touched andexplored with the eyes open or closed. An alternativesense (vision) is used to improve the de®cient sense(sensation).

Little is known about the true synaptic events takingplace during sensory reeducation. The training maymake the mind cope with new, more or less perma-nent, cortical reorganizations in the somatosensoryarea, thereby regaining a capability to understandshapes, forms and textures. The training might perhapseven modify and reverse the abnormal cortical maptowards a more normal pattern. However, whatever the

nd repair. (a) Diagrammatic representation of normal ``mapping'' of an and regenerating nerve ®bres, the mapping is completely changed duethe sensory cortex. (c, d) In the sensory reeducation programme, visualand the ``new language spoken by the hand''. [From Lundborg (1999).]




mechanism, a growing number of studies of corticalplasticity reveal that remodelling of cortical representa-tions is to a great extent a function of the behaviouralstate and a function of the strength of reward orpunishment in behavioural training (Merzenich andJenkins, 1993). Thus, cortical remodelling and change inreceptive ®elds towards smaller sizes as a result oftraining based on moving stimulation do not occurwhen animals are stimulated on routine stimulusschedules with the stimulation unattended. It seems thatnon-associated ``meaningless'' inputs can actually drivenegative representation of changes in cortical represen-tations while training with the use of positive reinforcingstimuli has a positive in¯uence. In such a behaviouralcontext representational changes progress graduallyover a relatively slow daily improvement schedule.

The clinical implications is that sensory reeducationshould be carried out in a positive environment. Passive,unattended or occasionally attended exercises are oflimited value for driving central representationalchanges. The more important the training exercise, themore powerful its consequences. The more feedback asubject gets, relevant to correct response performance,the faster useful representational changes can be driven.The practice setting in which the patient is continuallywell rewarded for correct performance trials willgenerate the most rapid representational changes(Merzenich and Jenkins, 1993).

From the therapeutic point of view, rehabilitationfollowing injuries in the peripheral nervous system mayhave some interesting analogies with injuries in thecentral nervous system, such as stroke. In bothsituations functional recovery is greatly dependent onbrain plasticity and cortical functional reorganization(Johansson and Grabowski, 1994). In animal experi-ments it has been observed that amphetamine, nora-drenalin and other alpha-adrenergic stimulating drugs,when combined with physical therapy, can improvefunctional outcome after cortical lesions (Chrisostomoet al., 1988; Goldstein and Davies, 1990; Hovda andFenney, 1984; Johansson and Grabowski, 1994; Suttonand Feeny, 1992) whereas alpha-antagonists may have anegative e�ect. Sensory reeducation following nervelesions to facilitate and improve the necessary corticalfunctional reorganizations in the somatosensory cortexcombined with drug therapy may perhaps be a way toimprove the outcome in the future.

Various factors may help to explain the ability byadults to compensate for cortical reorganization afternerve injury. Cognitive capacity factors may play animportant role for the functional outcome followingnerve repair, and variations in such factors ± especiallyverbal learning and visio-spatial logic capacity ± mayhelp to explain variables in recovery of functionalsensibility following nerve repair (RoseÂ n et al., 1994).

However, the most signi®cant factor to explaindi�erences in recovery of functional sensibility is theage of the patient (RoseÂ n et al., 1994). It is well known


that sensory recovery following nerve injury and repairis much better in young patients than adult patients(Almquist and Eeg-Olofsson, 1970; Almquist et al.,1983; Kallio and VastamaÈ ki, 1993; OÈ nne, 1962;Stromberg et al., 1961; Tajima and Imai, 1989); a factthat has usually been explained by factors like shorterregeneration distances and greater regeneration poten-tial. A major explanation is that there is probably ahigher potential for brain plasticity in children com-pared to adults. Such a di�erence has recently beendemonstrated in experiments carried out on fetalmonkeys. Following median nerve section and surgicalrepair in immature monkeys the resulting representationof the reinnervated hand in primary somatosensorycortex is quite orderly in spite of there being little or notopographic order in the regenerated median nerve(Florence et al., 1996). The ®ndings indicate that thereare mechanisms in the developing brain that can createcortical topography despite disordered sensory inputs.

Acknowledgements

Our research on nerve injuries is supported by the Swedish Medical ResearchCouncil (01588), Lund University and MalmoÈ University Hospital.

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