elbow [18] and trunk [19] towards the hand has been found in ... Human Brain Plasticity after Bilateral Hand .... gests that hand transplantation resulted in glob-.
Section 9-h
Human Brain Plasticity after Bilateral Hand Allograft Antoine Aballéa, Pascal Giraux, Marc Schieber, Jean-Michel Dubernard, Angela Sirigu
Introduction Neuropsychological studies suggest that somatic perception and awareness of bodily movement emerge from the activation of multiple, coordinated, dynamic representations of the body at different levels of the central nervous system, commonly called the “body schema”. Among the regions involved in this process, the primary sensory and motor cortices contain the most detailed maps in the cerebral cortex. This body representation in the primary sensory (S1) and motor (M1) cortex were classically conceived as “somatotopic”. The concept of the “homunculus” (literally, “little man”), as described by Penfield and Rasmussen [1] refers to anatomically and functionally independent representations of body segments within the central sulcus. However, recent electrophysiological data in monkeys and functional neuroimaging results in humans converge to a more dynamic model of body representations in M1 and S1. Though the somatotopic organization of M1 clearly includes separate representations of the face, arm, and leg within each of these major representations, studies have shown considerable overlap and intermingling of representations of smaller body parts. In monkeys, a given neuron may be active during movements of distinct digits, and the cortical territories containing neurons active during movements of different digits show considerable overlap [2]. Functional magnetic resonance imaging (fMRI)
studies in normal subjects confirm the existence of spatial overlap in the motor cortex for movements that involve adjacent corporal segments, such as fingers, wrist, and elbow [3, 4]. Thus, although large body segments such as head, limb and trunk occupy distinct territories, there seems to be a mosaic-like representation of muscular groups [5]. In contrast to the classical somatotopically organised model, these data suggest that movement execution depends on a distributed network in the sensorimotor cortex, constituting an efficient way of coding multisegment motor synergies [6]. These representational maps could undergo considerable plastic reorganisation in response to behavioural use, for instance, or amputation of the peripheral sensory and motor apparatus. Reorganization of the sensorimotor cortex has previously been shown in animals and in humans after peripheral injuries, such as deafferentation, peripheral lesions, or amputation [7–12]. In the case of amputation, the absence of a limb may lead to strong phantom sensations accompanied in most cases by pain. The phenomenon of phantom limb, defined as the persistence of sensorimotor perceptions associated with the missing body part, has been interpreted as reflecting reorganisation in the sensorimotor cortex [13–16]. In parallel, an extension of the primary sensory representation of the face [17], elbow [18] and trunk [19] towards the hand has been found in S1. Some studies have shown that representation of unaffected muscles expands such that representation of the stump invades
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portions of M1 previously dedicated to the amputated segment [20–24]. Thus, after amputation, the cortical territory that has been deprived of its afferent sensory input, like its motor effectors, reorganises to represent remaining nearby body parts [25–27]. The human brain is able to reorganise and adapt to all new situations. But little is known about the reversibility of such plastic reorganisation months or years after amputation when neuronal degeneration and regrowth of peripheral axons to innervate aberrant targets have all had time to occur [28–32]. Thus, human subjects whose amputated body parts are replaced by transplantation have provided a new and unique opportunity to study that reversibility of neural plasticity after such long-term changes. Previous studies in unilateral transplant recipients indicated that reinnervations often remain incomplete, even after many years [33]. From animal studies, it has been established that regrowth of peripheral sensory nerves following a peripheral nerve cut is a very gradual and often quite imprecise process [34, 35]. Human subjects whose amputated body parts are replaced by
transplantation provide a unique opportunity to examine the reversal of long-standing, amputation-induced reorganisation in the motor cortex. In a recent study [36], we investigated directly the nature and time course of cortical rearrangement of body motor representation produced by hand allograft. We tested patient CD, who received in January 2000 a bilateral hand transplant in Lyon, France [37]. We performed six identical fMRI examinations, the first 6 months before the graft and then postoperatively 2, 4, 6, 12 and 18 months afterwards. The task required the subject to perform flexion/extension of the last four digits of the left or right hand and flexion/extension of the left or right elbow. Before surgery, we monitored flexion and extension of the missing fingers by palpating the corresponding extrinsic muscle contractions at the forearm level. In the presurgery exam, movements of both right and left hand activated the most lateral part of the hand area in M1. This activated region is close to the face representation. Six months after the graft, the hand representation expanded medially and reoccupied the normal hand region (Fig. 1).
Fig. 1. Activation maps in the primary motor cortex (M1) obtained for right-hand movement condition.The surface of both the right and the left central sulcus was manually extracted from the subject using high-resolution T1-weighted magnetic resonance imaging (MRI). Boundaries of 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 activations and subsequently projected onto the three-dimensional surface on the nearest point. The schematic location of the hand area on Penfield’s motor homunculus matches the “hand knob” region, as described previously, whereas the other body parts were scaled proportionally to the length of the precentral sulcus
Human Brain Plasticity after Bilateral Hand Allograft Direct statistical comparison between the first (preoperative) and 6-month examination indicated that lateral M1 sites that were active for hand movements prior to the graft were less active following the graft and that a medial site that was not active before became active after [36]. Interestingly, this medial M1 site corresponds to the anatomical “hand knob” within the central sulcus, which marks the functional sensorimotor hand representation in normal subjects performing a similar task [38]. Analysis of centre of gravity (COG) coordinates for hand activations showed a spatial displacement between the pre- and postoperative phases. Before graft, COGs were close to the face area but shifted towards the classical hand area after the graft. More important, hand movement COGs recorded at 18 months postsurgery were similar to those recorded 6 months earlier. This demonstrated that spatial displacement of hand activations was not accomplished randomly. Thus, it seems that once hand neurons have recognised their target (i.e. the hand area), between major representations (i.e., face and hand) decrease. This cortical stability is probably achieved thanks to major
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inputs (sensory but also visual) and outputs (potential movements) necessary to reactivate the hand representation (Fig. 2). Elbow movements produced a pattern of motor activations that evolved over time in parallel with hand motor representation. Before surgery, movements of either elbow triggered extensive activation in a contralateral central region of M1, corresponding to the normal location of hand motor representation. Left elbow movements, in addition, activated a more medial area. At 6 months postsurgery, elbow activations had migrated towards an area situated in the upper part of the limb representation and classically defined as the arm region [1]. Statistical comparison between the first (presurgery) and 6-month exam demonstrated that different M1 cortical maps were associated with the pre- and postoperative period, namely, a more lateral region before the graft and a more superior medial region 6 months after the graft. Thus, changes observed in motor cortex hand and elbow representations were strongly correlated. Interestingly, in the presurgery period, the COG coordinates for elbow activations were similar to
Fig. 2. Temporal displacement of the centres of gravity (COGs) for primary motor cortex (M1) hand activation from 2 to 18 months postgraft. Reconstructed coronal view of both right and left precentral sulci. Activations were obtained in the examinations before surgery (yellow round and green square) and 2, 4, 6, 12 and 18 months afterwards (yellow, orange and red squares)
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those for the COG of hand movement at 6 months, suggesting that during that amputation period, the elbow representation had occupied the hand region. It should also be noted that hand and elbow activations showed a high degree of overlap. The extent of this overlap increased longitudinally from preoperative through postoperative exams (Fig. 3). These results show that a bilateral hand allograft has a direct effect on hand and elbow representations in the sensorimotor cortex. The main finding is that the displacement of cortical activity from lateral to medial along the precentral gyrus is remarkably similar for both hand
and elbow movements. These changes in these cortical maps covered similar distances in the same amount of time, as revealed by the temporal trajectories of COG coordinates. This suggests that hand transplantation resulted in global remodelling of the limb cortical map, reversing functional reorganisation induced by the amputation. The spatial trajectory of these activations in time further indicates that cortical rearrangement takes place in an orderly manner: hand and arm representations tend to return to their original cortical locus. Therefore, brain plasticity seems to be accomplished with reference to a preamputation body representation.
Preoperative
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Fig. 3. Spatial overlap between hand and elbow activations. Increasing overlap between hand and elbow activations from presurgery to 6 months after the graft
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References 1.
Penfield W, Rasmussen T (1950) The cerebral cortex of man. MacMillan Press, New York 2. Schieber MH, Hibbard LS (1993) How somatotopic is the motor cortex hand area? Science 261:489 3. Lotze M, Erb M, Flor H et al (2000) fMRI evaluation of somatotopic representation in human primary motor cortex. Neuroimage 11:473–481 4. Sanes JN (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats II. Rapid reorganization following motor nerve lesions Exp. Brain Res. 79(3):479–491 5. Donoghue JP, Leibovic S, Sanes JN (1992) Organization of the forelimb area in the squirrel monkey motor cortex: representation of digit, wrist and elbow muscles. Exp Brain Res 89:1–19 6. Schieber MH (2001) Constraints on somatotopic organization in the primary motor cortex. J Neurophysiol 86:2125–2143 7. Merzenich MM, Recanzone G, Jenkins WM et al (1988) Cortical representational plasticity. In: Rakic P, Singer W (eds) Neurobiology of neocortex. John Wiley, Chichester, pp 41–67 8. Pleger B, Dinse HR, Ragert P et al (2001) Shifts in cortical representations predict human discrimination improvement. Proc Natl Acad Sci USA 98:12255–12260 9. Pons T, Garrahty PE, Ommaya AK et al (1991) Massive cortical reorganization after sensory deafferentation in adult macaques. Science 252:1857–1860 10. Sanes JN, Suner S, Donoghue JP (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp Brain Res 79:479–491 11. Sanes JN, Donoghue JP (2000) Plasticity and primary motor cortex. Annu Rev Neurosci 23:393 12. Wall JT, Huerta MF, Kaas JH (1992) Changes in the cortical map of the hand following postnatal median nerve injury in monkeys: modification of somatotopic aggregates. J Neurosci 12:3445–3455 13. Flor H, Elbert T, Knecht S et al (1995) Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375:482–484 14. Knecht S, Henningsen H, Hohling C et al (1998) Plasticity of plasticity? Changes in the pattern of perceptual correlates of reorganization after amputation. Brain 121:717 15. Ramachandran VS, Rogers-Ramachandran DC, Stewart M (1992) Perceptual correlates of massive cortical reorganization. Science 258:1159–1160 16. Yang TT, Gallen CC, Ramachandran VS et al (1994) Non invasive detection of cerebral plasticity in the adult human somatosensory cortex. Neuroreport 5:701–704 17. Borsook D, Becerra L, Fishman S et al (1998) Acute plasticity in the human somatosensory cortex following amputation. Neuroreport 9(6):1013–1017 18. Kew JJM, Halligan PW, Marshall JC et al (1997) Abnormal access of axial vibrotactile input to deafferented somatosensory cortex in human upper limb amputees. J Neurophysiol 77:2753–2764 19. Knecht S, Henningsen H, Elbert T et al (1996) Reorga-
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
nizational and perceptual changes after amputation. Brain 119:1213–1219 Cohen LG, Bandinelli S, Findley TW, Hallett M (1991) Motor reorganization after upper limb amputation in man. A study with focal magnetic stimulation. Brain 114:615–627 Dettmers C, Liepert J, Adler T et al (1999) Abnormal motor cortex organization contralateral to early upper limb amputation in humans. Neurosci Lett 263:41–44 Pascual-Leone A, Peris M, Tormos JM et al (1996) Reorganization of human cortical motor output maps following traumatic forearm amputation. Neuroreport 7:2068–2070 Röricht S, Meyer BU, Niehaus L, Brandt SA (1999) Longterm reorganization of motor cortex outputs after arm amputation. Neurology 53:106–111 Röricht S, Meyer BU (2000) Residual function in motor cortex contralateral to amputated hand. Neurology 54:984 Merzenich MM, Recanzone G, Jenkins WM et al (1988) Cortical representational plasticity. In: Rakic P, Singer W (eds) Neurobiology of Neocortex. John Wiley, Chichester, pp 41–67 Chen R, Corwell B, Yaseen Z et al (1998) Mechanisms of cortical reorganization in lower-limb amputees. J Neurosci 18:3443–3450 Karl A, Birbaumer N, Lutzenberger W (2001) Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci 21:3609–3618 Campbell AW (1905) Histological studies on the localisation of cerebral function. Cambridge University Press, Cambridge Florence SL, Taub HB, Kaas JH (1998) Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science 6:1117-1121 Florence SL, Kaas JH (1995) Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys. J Neurosci 15:8083–8095 Jain N, Florence SL, Qi HX, Kaas JH (2000) Growth of new brainstem connections in adult monkeys with massive sensory loss. Proc Natl Acad Sci USA 97:5546–5550 Wu CWH, Kaas JH (2000) Spinal cord atrophy and reorganization of motoneuron connections following long-standing limb loss in primates. Neuron 28:967–978 Röricht S, Machetanz J, Irlbacher K et al (2001) Reorganization of human motor cortex after hand replantation. Ann Neurol 50:240–249 Wall JT, Kaas JH (1986) Long-term cortical consequences of reinnervation errors after nerve regeneration in monkeys. Brain Res 7:400–404 Wall JT, Kaas JH, Sur M et al (1986) Functional reorganization in somatosensory cortical areas 3b and 1 of adult monkeys after median nerve repair: possible relationships to sensory recovery in humans. J Neurosci 6:218–233 Giraux P, Sirigu A, Schneider F, Dubernard JM (2001) Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci 4:1–2
346 37.
A. Aballéa, P. Giraux, M. Schieber et al. Dubernard JM ,Owen E, Herzberg G et al (1999) Human hand allograft: report on first 6 months. Lancet 353:1315
38.
Yousry TA, Schmid UD, Alkadhi H et al (1997) Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120:141
