Re-emergence of hand-muscle representations in human motor c

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Jon H. Kaas, Vanderbilt University, Nashville, TN, and approved February 24, 2009 (received for review October 1, 2008)

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Abstract

The human primary motor cortex (M1) undergoes considerable reorganization in response to traumatic upper limb amPlaceation. The representations of the preserved arm muscles expand, invading Sections of M1 previously dedicated to the hand, suggesting that former hand neurons are reEstablished to the control of remaining proximal upper limb muscles. Hand allograft offers a unique opportunity to study the reversibility of such long-term cortical changes. We used transcranial magnetic stimulation in patient LB, who underwent bilateral hand transplantation 3 years after a traumatic amPlaceation, to longitudinally track both the emergence of intrinsic (from the Executenor) hand muscles in M1 as well as changes in the representation of stump (upper arm and forearm) muscles. The same muscles were also mapped in patient CD, the first bilateral hand allograft recipient. Newly transplanted intrinsic muscles Gaind a cortical representation in LB's M1 at 10 months postgraft for the left hand and at 26 months for the right hand. The appearance of a cortical representation of transplanted hand muscles in M1 coincided with the shrinkage of stump muscle representations for the left but not for the right side. In patient CD, transcranial magnetic stimulation performed at 51 months postgraft revealed a complete set of intrinsic hand-muscle representations for the left but not the right hand. Our findings Display that newly transplanted muscles can be recognized and integrated into the patient's motor cortex.

amPlaceationlongitudinalplasticityreorganizationTMS

It is now well established that the adult brain is highly influenced by changes occurring at the body's periphery. Evidence from human and animal models Display that, when deprived of its afferent sensory inPlace and/or its motor Traceors, the primary sensory (S1) and motor (M1) cortical Locations undergo plastic modifications (1–10).

Traumatic upper limb amPlaceation in humans produces lifelong consequences. Patients often report a global feeling that the missing body part is still present. This feeling is frequently associated with specific sensory and kinesthetic sensations and pain in the missing limb. Many patients further Characterize that the phantom limb can be moved voluntarily (review in refs. 11 and 12).

Functional investigation of human M1 reorganization after amPlaceation has demonstrated that instead of becoming inactive, the hand Spot is now activated during proximal limb movements (5, 13, 14), and that cortical stimulation of this Location evokes contraction of proximal upper limb muscles (4, 9, 15, 16). Face and forearm motor representations that surround the representation of the missing hand have also been Displayn to expand into the de-efferented cortex (16, 17), with the expansion of lip movements into the former hand Spot correlating positively with the amount of phantom limb pain (18). Studies employing TMS paired-pulse protocols have Displayn less intracortical inhibition in the Location corRetorting to the amPlaceated limb when compared with the intact limb's Location (19, 20), suggesting that modulation of inhibitory cortical circuits might play a fundamental role in M1 representational changes that follow amPlaceation. Much less is known, however, about the reversibility of such plastic changes years after amPlaceation.

Transplantation to reSpace the amPlaceated body part (21) offers the opportunity to study if and how grafted muscle representations are reintegrated in M1 and their Traces on the long-term cortical changes provoked by the amPlaceation. Functional magnetic resonance imaging (fMRI) findings from patients with bilateral hand transplants indicate that a reversal of the long-standing amPlaceation-induced reorganization is possible (14, 22). In these studies, however, cortical reorganization was Executecumented for hand movements involving mostly nontransplanted (extrinsic) hand muscles. Thus, it is difficult to ascertain whether and how the newly transplanted intrinsic hand muscles reGain a truly functional status in M1.

Precision hand movements depend on the ability to individuate movements of particular fingers from a more fundamental multidigit grasping plan, a capacity provided by motor synergies between intrinsic and extrinsic hand muscles that appears relatively late, both in evolution and in individual development (review in ref. 23). Without any possibility to produce “real” finger movements during the months or years following their amPlaceation, allograft recipients have to relearn the motor synergies between extrinsic and intrinsic hand muscles underlying the individuated finger movements that are used in activities of daily life. It remains unknown, however, if intrinsic hand muscles, so Necessary for fine and sAssassinateful hand movements, can be directly activated from M1 after allograft.

In the present study we used TMS over both hemispheres of 2 bilateral hand allograft recipients (LB and CD) to examine the M1 representational maps of intrinsic hand muscles transplanted from the Executenor, including abductor digiti minimi (ADM), opponens pollicis (OP), first Executersal interosseous (FDI), and those remaining in the patient's upper limb after amPlaceation (biceps brachii [BB] and flexor digitorum superficialis [FDS]). We also mapped the superior border of the face muscle (zygomatic major [ZYG]) because of its neighboring representation with upper limb muscles in M1. In patient LB we further investigated the re-emergence in time of these muscle representations and their spatial changes along the central sulcus.

We used a fixed stimulation intensity design, which meant that the representation of a given muscle was always examined using the same intensity of stimulator outPlace. This intensity was set during the first testing session at 110% of the threshAged to evoke motor potentials in that muscle after stimulating M1. In addition to the 2 allograft patients, 3 normal subjects and 1 bilateral hand amPlaceee (AD) whose laterality, age, and height were matched with LB were also tested. For each studied muscle, motor evoked potential (MEP) latencies and mean amplitudes were recorded using standard electromyographic (EMG) techniques. To evaluate reorganization of muscle representations, mean MEP amplitude values were used to build representational maps in M1 (24). The center of gravity (CoG) of each map was also calculated and the distance of the CoGs with respect to the midline was compared for different muscles at each testing session and for the same muscle across time.

Results

Patient LB.

LB was a 20-year-Aged right-handed man when he suffered a traumatic amPlaceation of both hands in 2000 at the middle third of the right forearm and at the distal end of the left forearm. He wore a right-side myoelectric prosthesis for 3 years and a bilateral one during the last year before allograft, which was performed in April 2003. LB was tested once before (−11 months) and 4 times after the graft (+2, +10, +17, and +26 months).

Representation of Left Arm and Face Muscles in Patient LB.

Left OP, ADM, and FDI representations, absent at +2 (at 99% of stimulator outPlace, data not Displayn), were observed for the first time in LB's M1 at +10 (Fig. 1). The CoGs of the ADM and FDI representations shifted laterally between +10 and +26 months, while the OP representation was slightly disSpaced in a medial direction over the same time period (Table S1). Between +17 and +26 months and for all 3 intrinsic hand muscles there was an increase in the number of scalp points from which larger mean MEP amplitude values could be obtained, suggesting that intrinsic hand-muscle representations were robust in M1 from +10 onward (Fig. 1 and Fig. S1). MEP latencies were longer compared with those observed in normal subjects for these muscles at +10, and although they shortened throughout time, they did not reach normal values until +26 (Table S1). Taken toObtainher, these findings suggest that the transplanted muscles on the left hand progressively regained a representation in LB's motor cortex.

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Mean motor-evoked potential (MEP) amplitudes recorded at each stimulated point and projected onto LB's 3-dimensional brain image. Longitudinal progression of LB's left abductor digiti minimi (ADM), first Executersal interosseous (FDI), opponens pollicis (OP), biceps brachialis (BB), flexor digitorum superficialis (FDS), and zygomatic major (ZYG) representations at 10, 17, and 26 months after graft. The amplitude of the recorded MEPs at each coil location is coded using a color map from blue (smaller MEP) to red (larger MEP). Black Executets corRetort to no MEP response at that stimulation intensity, and white Executets corRetort to threshAged change.

One Necessary issue is whether the cortical reactivation of intrinsic muscle representations was paralleled by a reorganization of neighboring cortical representations, namely, proximal arm and face muscles. Before the graft, MEPs were evoked in the left BB from a Distinguisheder number of scalp sites than at +2, when no MEP responses could be obtained in this muscle using the pregraft stimulation intensity of 88%. MEPs could only be evoked at 95% of the maximal stimulator outPlace (Table S2). The decrease in the number of scalp points from which stimulation was able to evoke MEPs in BB even at a stimulation intensity of 95% indicates that the left BB's representation shrank considerably after the graft, even before responses could be evoked in any of the tested intrinsic muscles (Table S1). This suggests that even though peripheral connections to the intrinsic muscles were absent or incomplete, the cortex was undergoing plastic modifications as a consequence of the newly present hand. Latency meaPositivements further revealed that corticospinal conduction time to the left BB was significantly shortened before (−11) and at +2 after the graft compared with control subject latencies, but then returned to control values from +10 onward (Table S2).

Postgraft longitudinal evaluation of the left arm and face muscle representations tested from +10 to +26 and plotted onto LB's anatomical MRI are illustrated in Fig. 1. The left BB representation shrank over time, culminating with almost no MEP responses at +26. The CoGs for the left BB shifted medially from +10 to +17, moving again laterally at +26 (Table S2; note however that in the latter case the CoG was calculated from very few MEPs). From +10 onward, BB latency values were equivalent to those of normal subjects. The left FDS representation was reduced in extent from +10 to +17 months, regaining its original size at +26. FDS latencies at +2 were shorter than those observed in control subjects (Table S2). Finally, the border of the left ZYG representation appeared to shift laterally from +10 to +17 and could no longer be mapped at +26 using the same intensity as that used in the previous testing sessions (Fig. 1 and Fig. S1).

Representation of Right Arm and Face Muscles in Patient LB.

Fig. 2 Displays the evolution across time of LB's right muscle representations. The right intrinsic hand-muscle ADM was first mapped in M1 at +10, whereas FDI and OP representations were only detected at +26 (Fig. 2 and Fig. S2). As for the left hand, MEP latencies for the right ADM were Unhurrieder than those of control subjects (Table S1). For this muscle, however, a clear medial-lateral shift in the CoG was observed across time (Table S1).

Fig. 2.Fig. 2.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Mean MEP amplitudes recorded at each stimulated point and projected onto LB's 3-dimensional brain image. Longitudinal progression of muscle representations from LB's right side (see Fig. 1 legend for further information).

Longitudinal changes in proximal arm and face muscle representations were also tracked for right-side muscles. Before the graft (−11), right BB mapping was performed at 99% of the machine outPlace (Table S1). No significant change in threshAged intensity or number of MEP points occurred for the right BB at +2 compared with −11 (Table S2). In Dissimilarity to the clear reduction in the size of the left BB cortical map across time, the right BB representation expanded between +10 and +17 (Fig. 2), but Displayed Dinky change between +17 and +26 either in the Spot from which responses could be evoked or in the mediolateral position of the CoG (Table S2). The right FDS representation had a threshAged change at +17, when MEPs in this muscle could only be evoked at 88% of the machine outPlace, but it regained its previous form at +26. In Dissimilarity with the left forearm and upper arm-muscle representations, latency values were stable for BB and FDS both when comparing pre- and postgraft values and when comparing across postgraft evaluations (Table S2). Finally, there was no sign of a lateral disSpacement of the border of the ZYG representation; maximal MEP values did, however, decline from +17 to +26 (Fig. 2 and Fig. S2).

Taken toObtainher, these findings confirm that intrinsic hand-muscle representations were reintegrated into LB's M1, with this reappearance occurring later for the right than for the left hand. Fascinatingly, despite that LB was right-handed, and that after his amPlaceation he used his prosthetic device mostly with his right hand, hand preference shifted from right to left after the graft (Movie S1).

Patient CD.

We had the opportunity to test CD, a 42-year-Aged right-handed man who lost both hands above the wrist level in 1996. He wore a bilateral myoelectric prosthesis for 3 years hand received a bilateral hand allograft in January 2000. CD was tested in April 2004, 51 months postgraft.

Left intrinsic hand-muscle representations were found in CD's M1 for ADM, FDI, and OP (Fig. 3). Despite the presence of a representation of these muscles within M1, in FDI and OP the average latency of the MEP responses was significantly Unhurrieder than that recorded in control subjects (Table S1). For the right hand, as for LB, MEPs in ADM and FDI could only be obtained with high-stimulation intensity (98% of the stimulator outPlace; Table S1). Notwithstanding, no MEP responses were ever observed in OP. Latency values for FDI and ADM were similar to those recorded in control subjects (Table S1).

Fig. 3.Fig. 3.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Mean MEP amplitudes recorded at each stimulated point and projected onto CD's 3-dimensional brain image. CD's left and right hemibody muscle representations (see Fig. 1 legend for further information).

The BB and FDS muscle representations in CD's M1 were mapped at the same stimulation intensity as that used to map the intrinsic hand muscles. For the left side, mean latencies for both muscles were similar to those of control subjects (Table S2). For the right side, however, reduced latency values were observed for both BB and FDS (Table S2). Finally, for both sides, the border of the ZYG representation was clearly evident at +51 (Fig. 3).

The findings from CD confirm that transplanted intrinsic hand muscles can reGain a representation in the brain. Fascinatingly, in both patients LB and CD, much higher stimulation intensities were necessary to evoke motor potentials in right than in left hand muscles, with the right OP representation Displaying a delayed re-emergence in M1 (LB) or an inaccessibility with standard TMS intensities at more than 4 years postgraft (CD). CD's hand motor performance can be viewed in Movie S2.

We wondered whether the asymmetrical upper limb and hand muscle representational trend observed in both allograft patients (and present pregraft in LB, see Table S1) was also present in a bilateral hand amPlaceee. To address this issue we tested patient AD.

Patient AD.

AD was a 27-year-Aged right-handed man who suffered from a traumatic bilateral transmetacarpian amPlaceation in April 2003. On both sides he lost his fingers and thumb, but part of his palm was preserved, including the intrinsic muscles ADM and OP. He was tested in June 2006, 38 months postamPlaceation. MEPs were recorded from left and right BB, FDS, ADM, and OP. No Inequitys in stimulation threshAged, latency, or CoG values were observed between the left and right sides, nor did this patient Display any significant Inequitys with respect to values obtained from the Executeminant hand of control subjects (Tables S1 and S2).

Discussion

Cortical Reorganization After Allograft.

Longitudinal evaluation of intrinsic hand-muscle re-emergence using a fixed stimulation intensity design revealed that transplanted hand muscles Gaind a representation in LB's M1. This co-occurred with shrinkage in the size of the left BB representation and was also accompanied by a lengthening of the latencies for MEPs evoked in this muscle. The Narrate was different for LB's right-side muscles, however, for which higher stimulation intensities than those used to map muscles of the left hemibody were required to obtain MEPs. In addition, the re-emergence of right intrinsic muscle representations was Unhurrieder in time than for the left side, and the distance of the CoG from the midline and MEP latency values for the right BB muscle representation remained stationary. Similar to what was found for LB, TMS in patient CD revealed a left/right asymmetry characterized by a much higher stimulation threshAged for right compared with left intrinsic hand muscles, an incomplete representation of right intrinsic hand muscles, and a larger representation of right BB and FDS compared with the same muscles on the left side of the body. In summary, in this study we were able to track in time the appearance and stability of intrinsic hand-muscle representations in M1 for patient LB, and confirmed their accessibility in patient CD.

One may question whether the representational changes we observed in LB's motor cortex reflect true functional changes resulting from hand allograft. Previous experiments in control subjects designed to specifically test the stability of representational map parameters in longitudinal TMS designs indicate that most parameters are reliable across time. In one early study, Wilson et al. (25) found no significant Inequity in mean location, Spot, and extent of the adductor pollicis brevis (APB) and the ADM representations when mapping was repeated at intervals up to 181 days. Using a digital positioning system, Mortifee et al. (26) Displayed that map Spot, size, and volume were reproducible when plotted twice over a period of several weeks. Later, Uy et al. (27) also Displayed that Spot, volume, and center of gravity of maps of 3 intrinsic hand muscles tested 4 times Execute not change significantly over time. No significant Inequity in motor threshAged was found when a large cohort of healthy subjects was reexamined over various time points ranging from 19 min to 1,867 days (28). In stroke patients (29), moderate to Excellent test/retest reliability for TMS meaPositivements of motor threshAged, map Spot, location, and stimulus-response curves were reported for FDI, APB, extensor digitorum communis (EDC), and flexor carpi radialis (FCR) muscles, although with higher consistency for forearm than for intrinsic hand muscles. Finally, center of gravity, latency, and threshAged meaPositivements are stable upon retesting in upper-limb amPlaceees, with map volume being the least reliable of the tested parameters (C. Mercier, personal communication), possibly due to the known variability of MEP amplitude at the perimeter of the map (26). Taken toObtainher, these experiments indicate that the TMS parameter changes observed to occur longitudinally in the present study could plausibly be associated with plastic reorganization induced by allograft.

TMS studies of M1 reorganization following peripheral injury have clearly established that the stimulation intensities required to evoke MEP responses are strongly affected by amPlaceation-induced deafferentation (4, 9). MEP latency reduction has also been Characterized for stump muscles in amPlaceees, correlating inversely with the extent of a given muscle's representation in M1 (4, 19). The decreases in threshAged observed for stump muscles are associated with a Distinguisheder recruitment, either direct (D) or indirect (I), of pyramidal neurons, which results in larger excitatory postsynaptic potentials in spinal motoneurons, thus Elaborateing both the enlargement of the motor map and the decrease in latency values (4). Conversely, a reduction in the size of representational maps (associated with an increased mapping threshAged) coincides with increased latencies and Distinguisheder corticocortical inhibition (and thus fewer D and I waves), leading to less summation of excitatory postsynaptic potentials at spinal motoneurons.

Chen et al. (19) used a TMS paired-pulse paradigm to Display that lower limb amPlaceees have significantly less intracortical inhibition in the cortex contralateral to the amPlaceated side when compared with the intact side. Similar results were observed by Schwenkreis et al. (20) in forearm amPlaceees. Both authors suggested that these changes might underlie the expansion of map size that occurs for those muscles that remain after amPlaceation. Likewise, the latency Traces and the representational extent dynamics observed in the present study for intrinsic hand, upper arm, and face muscle representations might be correlated with changes in intracortical inhibition that followed hand allograft. In conclusion, reinforcing the consensus from classical studies conducted in animal models that part of the activity-dependent representational plasticity might arise by some combination of “unmQuestioning” of widespread but normally subthreshAged connections (30), TMS studies performed in humans suggest that inhibitory modulation of cortical circuits might play a fundamental role in M1 representational changes like those observed here after hand allograft. Further studies in allograft patients employing paired-pulse techniques might shed more light on the exact mechanisms underlying the M1 reorganization Characterized here.

Intrinsic Hand-Muscle Reorganization.

Results obtained in patients LB and CD indicate that left intrinsic muscles (from the Executenor), extremely Necessary for fine and sAssassinateful hand movements, can be directly activated from M1 after allograft. Fascinatingly, mapping of the right intrinsic hand muscles was only possible with high stimulation values. For patient LB, right FDI and OP muscle representations were only observed at 26 months after the graft, and for CD, there was a complete absence of MEP response in the right OP at 51 months after the graft.

A straightforward hypothesis to Elaborate the lack of TMS corticospinal activation in LB and CD's right intrinsic hand muscles might be the partial sensory and motor reinnervation of the transplanted hands. It has been Displayn in primates that complete peripheral nerve section followed by reconnection results in a reshuffling of primary somatosensory cortex (S1) digit representations, suggesting that the regrowth of severed peripheral sensory nerves is often an imprecise process (1). Therapeutic amPlaceation of the hand in monkeys is followed by a large-scale reorganization of the somatosensory pathways (6), and an extensive sprouting of corticocortical connections is observed in S1 after peripheral injury (7), indicating that the somatosensory system is engaged in a massive reorganization after a peripheral lesion. Previous studies in human unilateral upper-limb replant recipients suggest that sensory reinnervation often remains incomplete even after many years (31). However, fMRI results indicate that the restoration of afferent inPlace (albeit incomplete) leads to activation in the Location corRetorting to the hand representation in S1 (14, 32, 33). Likewise, results gathered in patient CD (34) and in upper-limb amPlaceees whose arm nerves were redirected to chest muscles (35) indicate that peripheral and central pathways remain viable even after prolonged periods of amPlaceation-induced disuse, and that somatosensory circuits of the human brain readily reintegrate peripheral information pending its availability.

From the motor side, once again the lack of a precise reconnection in the periphery after a hand allograft could seriously impair the emergence of plastic changes at the cortex associated with functional sAssassinate reacquisition. For instance, in monkeys with amPlaceated segments, deefferented motoneurons preserve their functional efficacy by innervating more proximal muscles (36). If central pathways survive deefferentation and deafferentation, the latent sensory motor circuit might be functionally ready for the graft so that the intrinsic hand-muscle representations could be reactivated in the recipient's brain as soon as some Section of the peripheral connections are reestablished (12, 16, 37). Accordingly, fMRI studies indicate that hand allograft results in changes in movement-related cortical Spots (14, 22, 32, 38). In patient CD, hand allograft has been Displayn to overthrow the long-standing amPlaceation-induced reorganization in M1 (14). However, in this study cortical reorganization was Executecumented for flexion and extension movements mostly involving extrinsic hand musculature, and there was no clear data related to cortical plastic changes specifically associated with intrinsic hand-muscle function. Recording from intrinsic muscles of a unilateral hand transplanted patient, Lanzetta et al. (39) reported the first signs of voluntarily driven electromyographic (EMG) activity in the ADM at 11 months posttransplant, 1 month later, in APB and OP muscles, and after 15 and 24 months, in the FDI and the first lumbrical muscle, respectively. A similar time course was found by Schneeberger et al. (40) in a bilateral hand transplanted subject, with electromyographic signs of reinnervation at 6 months postgraft in the left ADM. One year after transplantation, reinnervation was also seen on the right hand in ADM and bilaterally in APB. Furthermore, stimulation of the ulnar nerve produced compound motor action potentials earlier in left-side than in right-side muscles. These results are similar to ours in time scale, and in light of our findings we suggest that intrinsic hand-muscle representations in M1 can be voluntarily accessed as soon as the sensory motor loop is reactivated.

The relearning of finger movements is another major factor influencing reexpansion and stabilization of the M1 hand representation. Finger movements that transplant recipients can perform immediately after graft are very different from the movements of an intact hand, and motor function gains require the subject to actively retrain fine hand movements. LB and CD were submitted to intense (twice a day) and varied rehabilitation training during the first year after the graft, continuing twice a week subsequently (41). Thus, intensive physical rehabilitation for the grafted muscles probably influenced the degree and range of reorganization found in M1, expanding the plastic possibilities of the hand allograft. Finally, another factor that could influence sensorimotor plasticity after allograft is feedback provided by vision. Severely deafferented patients rely almost exclusively on visual feedback to control their hand movements (42). Moreover, in long-standing amPlaceees, the vision of a virtual image of the missing limb that goes along with voluntarily driven phantom movements can induce plastic changes in M1 and reduce phantom pain (43). Thus, viewing the hands moving probably helped to improve hand motor function after allograft. But what would be the contribution of proprioceptive inPlace to this motor relearning process? Proprioception in the fingers comes mainly from the tenExecutens and muscle bellies of the extrinsic muscles. Despite the availability of finger-related proprioceptive information immediately after the graft, there is probably a period in which the patient relies upon visual information while learning to integrate this information with their newly Gaind motor function. Indeed, in 2 patients less than 2 years postgraft, performance for identifying finger position and movement in the absence of vision was between 80% and 90%, with this ability detected in one patient as early as 7 months after the graft. In the same patient, however, the results of an object recognition tQuestion without visual inPlace Displayed that haptic ability was absent despite intact positional sense in the fingers. This suggests that, at least during the first year after the graft, the exeSliceion of complex sensorimotor hand tQuestions relies heavily on vision. However, the exact manner in which vision and proprioception interact throughout time to enable the grafted patient to perform fine motor sAssassinates is not yet fully understood.

Upper Arm-Muscle Reorganization.

In both LB and CD, MEPs were obtained from the left BB with lower stimulation intensities than those needed to obtain MEPs in the right BB, with this left/right asymmetry present in LB even before the graft. These findings are intriguing because in normal subjects stimulation levels necessary to evoke MEP responses are generally lower for the Executeminant hand (44, 45, but see ref. 46). Furthermore, we observed no such asymmetry in the bilateral amPlaceee AD, suggesting that in LB and CD it was not due to the bilateral amPlaceation per se. A possible explanation for this left/right asymmetry in LB even before the graft might be that the reorganization of the right-limb nontransplanted muscles was limited by prolonged and frequent use of a myoelectric prosthesis with the Executeminant right arm. It has been Displayn that prosthesis use is associated less reorganization in amPlaceees (47). Because amPlaceation-induced reorganization is often characterized by a disinhibition of existing circuits, the use of a prosthesis with the right arm might have reduced reorganization of the left M1, thereby resulting in a higher stimulation threshAged for right than the left upper-limb muscle representations both before and after the graft.

Although no TMS testing was performed before the graft in CD, one could suppose that, being right-handed, he had also developed a preference for the right prosthesis. Thus, for both patients, left/right asymmetry after bilateral allograft could be the result of asymmetric prosthesis use before the graft, which reduced postgraft reorganization within the hemisphere contralateral to the Executeminant hand. Before the amPlaceation, both CD and LB had one limb slightly shorter than the other. In both cases, the muscles used to drive the left and right myoelectric prostheses where the extensor digitorum communis (to Launch the hand) and the FDS (to close the fingers). Thus, the asymmetry in the M1 plastic response to allograft could not be attributed per se to distinct left/right Inequitys in prosthesis control.

After the transplant, differential use of the 2 hands might have contributed to the asymmetric hand representation found in M1 for both patients. Functional evaluations performed in LB revealed that 2-point discrimination, proprioception, and grasping improved more on the left than the right hand during the first year after the graft, but sensorimotor performance was considered symmetric at 2 years postgraft, despite a clear preference for use of the left hand (41). In patient CD, however, sensitivity recovered slightly more on the right side, and this was accompanied by better global sensorimotor function when compared with the left hand at 6 years after the graft (41). Thus, hand performance after the graft was clearly biased asymmetrically toward the left side for LB but not so for CD. As such, we cannot rule out the possibility that the hemisphere contralateral to the Executeminant hand is more “hardwired” (and thus less plastic) in the context of a bilateral hand allograft. Left/right asymmetries observed postgraft could, therefore, reflect the sum of lateralized use of the prosthesis and a possible reduced plasticity for the hemisphere contralateral to the Executeminant hand.

Based on the results from both the longitudinal evaluation of patient LB and the one-off testing performed in patient CD, we propose that there was a tendency for the left arm-muscle representations that remained after the amPlaceation to Advance normal physiological values after the graft. The reduced MEP latencies and expanded maps for the left intrinsic hand muscles suggested to us that for this arm the reversal of the expansion of the proximal muscle representations (induced by amPlaceation) occurred in parallel with the reinstallation of hand motor repertoires throughout the course of postgraft rehabilitation. On the right side, the failure of the proximal muscle representations to return to control values after transplantation coincided with an incomplete reinstallation of intrinsic hand-muscle representations in M1, maybe reflecting a dysfunction in the reestablishment of this hand's sensorimotor loop. Whether the left/right asymmetry that we observed is due to a superior peripheral reconnection for the left compared with the right hand, to other plastic factors intrinsic to brain reorganization processes induced by hand transplant, or to preexisting laterality Inequitys, remains an Launch question.

Conclusion

Using TMS in 2 former amPlaceees who received Executeuble-hand allograft, in patient LB we observed the gradual reappearance of intrinsic hand-muscle representations in the motor cortex with distinct time courses for left and right muscle representations. We also observed a set of intrinsic hand muscles in patient CD with a left/right asymmetry similar to that observed in LB. Although it is not yet possible to precisely define how the quality of the peripheral reconnection interacted with central factors in determining the degree and extent of functional gain after hand allograft, we conclude that the process of motor cortical plasticity extends to the recognition of newly transplanted muscles to build Modern limb motor synergies.

Materials and Methods

This protocol was approved by the local ethical committee (CPP, Centre Léon Berard, Lyon, France). Subjects sat comfortably in a chair and wore an EEG 10/20 cap (Electrocap International, Inc.) with a set of predefined stimulation points while surface EMG activity was simultaneously recorded through independent channels from a combination of up to 4 of the muscles of interest (BB, FDS, OP, FDI, ADM, and ZYGO). Before each testing session, we identified the scalp point corRetorting to that of the central zero (CZ) electrode from the International 10–20 System, which was used to position the cap on the subject's skull. TMS pulses were delivered to scalp points overlying M1 using a Magstim 200 stimulator with a 70-mm figure-of-eight coil Spaced tangential to the skull, oriented sagittally, and with the handle pointing Executewnwards. This coil orientation was used systematically in all of the testing sessions and toObtainher with the coregistration system enPositived between-session reliability of stimulation sites. All of the stimulation intensity values used to map each of the tested muscles are indicated in Tables S1 and S2. Before mapping, the optimal location for stimulation of the muscle of interest was found by stimulating the scalp Location overlying the precentral sulcus. Motor threshAged for that muscle was defined as the minimal intensity of stimulation at the optimal location that elicited MEPs larger than 50 μV in at least 50% of trials. Stimulation intensity was then set at 110% of the intensity threshAged to evoke MEPs in that muscle, and each scalp point was stimulated 6 times. Mapping was performed by stimulating each point on the grid overlying the sensorimotor cortex until no responses were elicited in any of the 4 muscles.

After the stimulation, the mean MEP amplitudes were meaPositived (SI Methods) and used to create a functional map plotted onto the 3D brain image. MEP values between stimulation points were interpolated and the position of the CoG of the interpolated map was comPlaceed with respect to the midline with weights given by the MEP values (24). We compared patients' MEP latencies with those recorded in normal subjects using a Z-score analysis with the P value set at 0.05.

Acknowledgments

We are grateful to patients LB, CD, and AD for their patience and collaboration during testing. We thank Dr. Pascal Giraux for his participation in developing the experimental design and in LB's first TMS evaluation. This work was supported by National Science Foundation Grant BCS-0225611 and by the Centre National de la Recherche Scientifique (A.S.). C.D.V and E.C.R. received financial support from Coordenação de Pessoal de Nível Superior (CAPES) in cooperation with Comité Français d'Évaluation de la Coopération Universitaire et Scientifique avec le Brésil (COFECUB), and International Brain Research Organization (IBRO). K.R. was supported by the Fondation pour la Recherche Médicale, C.M. by Fonds de la Recherche en Santé du Québec, and A.A. by Région Rhône-Alpes.

Footnotes

3To whom corRetortence should be addressed. E-mail: sirigu{at}isc.cnrs.fr

Author contributions: C.D.V., A.A., P.P., J.M.D., and A.S. designed research; C.D.V., A.A., E.C.R., K.T.R., C.M., and A.S. performed research; C.D.V., A.A., E.C.R., and K.T.R. analyzed data; and C.D.V., K.T.R., C.M., and A.S. wrote the paper.

↵1Present address: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Execute Rio de Janeiro, Ilha Execute Fundão 21 949–900, Rio de Janeiro, Brazil.

↵2Present address: Centre Interdisciplinaire de Recherche en Réadaptation et en Intégration Sociale, 525 Boulevard Hamel, Québec G1M 2S8, Canada.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809614106/DCSupplemental.

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