Cortical reorganization in motor cortex after graft of both hands

© 2001 Nature Publishing Group http://neurosci.nature.combrief communications© 2001 Nature Publishing Group http://neurosci.nature.comCortical reorganization inmotor cortex after graftof both handsPascal Giraux 1,2 , Angela Sirigu 1 , Fabien Schneider 3 andJean-Michel Dubernard 41 Institute for Cognitive Science, CNRS, 67 Bd Pinel, 69675 Bron, France2 Department of Physical Medicine, CHU, BD Pasteur, Saint-Etienne3 Radiology Department, CHU, BD Pasteur, Saint-Etienne4 Department of Surgical Transplant, E. Herriot Hospital, Place d’Arsonval, LyonCorrespondence should be addressed to A.S. (sirigu@isc.cnrs.fr)Cortical organization shifts after sensory deprivation, but thereversibility of this reorganization has not been studied. Here,using functional magnetic resonance imaging (fMRI), we investigatedthe dynamics of cortical reorganization in a patient’smotor cortex before and after bilateral hand transplantation. Wefound that amputation-induced cortical reorganization wasreversed following hand transplantation.How is the brain influenced by changes occurring at the body’speriphery? Contrary to the classical view of an essentially predeterminedneural wiring pattern, the motor system shows substantialplasticity 1 . In human amputees, the representation ofunaffected muscles expands such that the stump region representationinvades parts of sensorimotor cortex previously dedicatedto the amputated segment 2 . Patients whose upper limb is transplantedfollowing amputation provide the opportunity to studythe reversibility of cerebral organization after peripheral injury.We studied C.D., who underwent a bilateral hand transplantation3 in January 2000, in Lyon, France. C.D. sustained a traumaticamputation of both hands in 1996. We performed four identicalfMRI examinations (1 Tesla, Siemens, 4 sessions per examination,110 scans per session): six months before the graft and two, fourand six months afterward. We used an event-related design (1 eventeach 5 scans) with one task per session as follows: first, flexion andextension of the last four digits of the right hand; second, flexionand extension of the right elbow; third, flexion and extension ofthe last four digits of the left hand; fourth, flexion and extension ofthe left elbow. One trial corresponded to a single movement, with 21trials for each task. Using SPM99 software (Wellcome Departmentof Cognitive Neurology, UK) for the analysis, we chose a correctedthreshold at p < 0.05 (Z = 5.07). Statistical comparisons betweenconditions were done with an uncorrected threshold at p < 0.001(Z = 3.1). Before surgery, we monitored flexion and extension ofthe missing fingers by palpating the corresponding extrinsic musclecontractions at the forearm.We focused on activations in M1 and their evolution over time.Before surgery, movements of the right or left hand activated themost lateral part of the hand area in M1 (Fig. 1a). This region isspatially close to the face area, consistent with reports that tactilestimulation of the face induces sensations in the phantom handof amputees 4 . Six months after the graft, hand representationexpanded medially to occupy the entire hand region (Fig. 1a). LateralM1 sites activated by hand movements before the graft wereless active six months after the graft, and a medial site (correspondingto the hand knob area in normal subjects 5 ) not activebefore the graft became active afterward (Fig. 1c). Right handmovements already activated this new medial region2 months after the graft (versus before surgery, Z = 6.3; cluster size,78). This signal was significantly greater 4 months after surgery(versus 2 months, Z = 5.6; cluster size, 28), whereas no significantchanges were observed between the last two examinations. For lefthand movements, the displacement of activation was visible2 months after surgery (versus before surgery, Z = 5.3; cluster size,12) but significantly enhanced at 6 months (versus 4 months,Z = 5.9; cluster size, 28). Across the four examinations, the centerof gravity (COG) of hand activations progressively shifted 10 mmfor the right hand and 6 mm for the left hand from the lateral tothe central part of the M1 hand region (Fig. 1b, Table 1).Elbow movement activation temporally evolved in parallelwith the hand motor representation. Before surgery, movementsabFig. 1. Activation maps in M1 obtained in the hand movement condition.The surface of both the right and the left central sulcus was manuallyextracted from the subject using high-resolution T1-MRI. The boundariesof M1 areas were defined within a space of 6 mm in front of the central sulcus.Activated voxels within this defined space were considered as M1 activationsand subsequently projected onto the three-dimensional surface onthe nearest point. The schematic location of the hand area on Penfield’s 6motor homunculus matches the ‘hand knob’ region as described previously5 , whereas the other body parts were scaled proportionally to thelength of the precentral sulcus. (a) Reconstructed coronal view of bothright and left precentral sulci. Activations were obtained in the examsbefore surgery (red) and six months afterward (blue), and their overlap(green) was projected onto Talairach’s coordinate system (x in abscissa;z in ordinate). (b) Spatial displacement of COG of activations in the differentscanning sessions. The COG of each M1 activation was calculatedusing the Z-score of each activated voxel as a weighting parameter.(c) Activation obtained in the statistical comparisons (before surgeryminus six months after surgery; six months after surgery minus beforesurgery) superimposed on C.D.’s MRI template. L, left; R, right.cnature neuroscience • volume 4 no 7 • july 2001 691

ief communications© 2001 Nature Publishing Group http://neurosci.nature.com© 2001 Nature Publishing Group http://neurosci.nature.comTable 1. Time course of the center of gravity of M1 activations for the hand and elbow, for the different exams.Movement Before surgery 2 months 4 months 6 months Change in distance (before surgeryx y z x y z x y z x y z versus 6 months afterward)Right hand –42 –22 40 –40 –25 46 –39 –25 45 –39 –27 48 10 mmLeft hand 36 –18 46 33 –23 49 38 –21 48 33 –22 49 6 mmRight elbow –34 –29 49 –26 –33 54 –30 –31 52 –28 –32 54 8 mmLeft elbow 31 –23 47 29 –28 51 30 –26 52 30 –26 54 7 mmValues are in Talairach coordinates.of either elbow activated a contralateral central region of M1 thatcorresponds to the hand motor map (Fig. 2a). Six months afterward,elbow activations migrated toward the upper part of thelimb representation, classically defined as the arm region 6 . DifferentM1 cortical maps were observed before and six monthsafter surgery: before the graft, a central region, and afterward, anew superior medial area (Fig. 2c). As for hand movements, thenew superior locus of activation was apparent at two months (versusbefore surgery; Z > 10; cluster size, 236) for right elbow movements.The signal strength had increased significantly at 4 months(versus 2 months; Z = 5.2; cluster size, 26) but did not increasefurther at 6 months. For left elbow movements, the most significantsignal changes occurred between 4 and 6 months (Z = 6.9;cluster size, 67). The COGs along the four examinations underwenta progressive shift from the central to the superior part ofM1 (right elbow, 8 mm; left elbow, 7 mm; Fig. 2b; Table 1).The changes observed within the motor cortex for hand andelbow representations seemed to be strongly correlated in bothabtime and space. Across the different examinations, the distancebetween COGs remained fairly constant for the two types ofmovements (Table 1). Hand and elbow activations showed a highdegree of overlap, the extent of which increased from beforesurgery through the examinations after surgery.Parallel changes were also recorded in somatosensory cortex.Hand and elbow movements activated S1 in all four examinationsand their pattern was similar to that of the motor cortex activations.These results show that grafted hands come to be recognizedand activated normally by sensorimotor cortex. The displacementof the cortical activity from lateral to medial along the precentralgyrus is remarkably similar for hand and elbowmovements. These cortical maps covered in the same amount oftime a similar distance, as revealed by the trajectory of the activationCOGs. This suggests that new peripheral inputs alloweda global remodeling of the limb cortical map and reversed thefunctional reorganization induced by the amputation. The spatialtrajectory of these activations in time further indicates that thecortical rearrangement occurs in an orderly manner; the handand arm representations tend to return to their original corticallocus. Hence, brain plasticity is accomplished with reference toa previous pre-amputation somatotopic body representation.What are the mechanisms underlying this cortical reversibility?In monkeys with amputated segments, severed efferentmotoneurons preserve their functional efficacy by targeting newmuscles 7 . As efferent and afferent central pathway neurons surviveafter they are cut, the sensorimotor circuit may be functionallyready after the graft; this could explain why activity shifts areobserved as early as two months after surgery. The intrinsicchanges within M1 may result from a shift in the strengths of activationsamong existing connections. If we assume that hand andelbow had preexisting connections, the elbow activation in thephase before surgery may emerge as a change in the weight ofthese connections; that is, the elbow connection may be enhancedat the expense of the deprived hand region. The hand transplantmay have restored the efficacy of the original connections at theexpense, this time, of the elbow representation, thus allowing typicalfeatures of cortical organization to reappear in the motor map.cACKNOWLEDGEMENTSThis work was supported by a CNRS grant to A.S.RECEIVED 5 FEBRUARY; ACCEPTED 30 APRIL 2001Fig. 2. Activation maps in M1 obtained in the elbow movement condition.(a–c) Same as in Fig.1.1. Kaas, J. H. in The Organization of the Cerebral Cortex (eds. Schmitt, F. O.,Worden, F. G., Adelman, G. & Dennis, S. G.) 223–236 (MIT Press,Cambridge, Massachusetts, 1981).2. Roricht S., Meyer, B. U., Niehaus, L. & Brandt, S. A. Neurology 53, 106–111(1999).3. Dubernard J. M. et al. Lancet 353, 1315–1320 (1999).4. Ramachandran, V. S., Rogers-Ramachandran, D. & Stewart, M. Science 258,1159–1160 (1992).5. Yousry, T. A. et al. Brain 120, 141–157 (1997).6. Penfield W. The Cerebral Cortex of the Man (MacMillan, New York, 1950).7. Wu, C. W. & Kaas, J. H. Neuron 28, 967–978 (2000).692 nature neuroscience • volume 4 no 7 • july 2001