Re-emergence of hand-muscle representations in human motor cortex after hand allograft.
ABSTRACT: The human primary motor cortex (M1) undergoes considerable reorganization in response to traumatic upper limb amputation. The representations of the preserved arm muscles expand, invading portions of M1 previously dedicated to the hand, suggesting that former hand neurons are reassigned 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 amputation, to longitudinally track both the emergence of intrinsic (from the donor) 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 acquired 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 show that newly transplanted muscles can be recognized and integrated into the patient's motor cortex.
Project description:Amputation induces substantial reorganization of the body part somatotopy in primary sensory cortex (S1 complex, hereafter S1) [1, 2], and these effects of deafferentiation increase with time . Determining whether these changes are reversible is critical for understanding the potential to recover from deafferenting injuries. Earlier BOLD fMRI data demonstrate increased S1 activity in response to stimulation of an allogenically transplanted hand . Here, we report the first evidence that the representation of a transplanted hand can actually recapture the pre-amputation S1 hand territory. A 54-year-old male received a unilateral hand transplant 35 years after traumatic amputation of his right hand. Despite limited sensation, palmar tactile stimulation delivered 4 months post-transplant evoked contralateral S1 responses that were indistinguishable in location and amplitude from those detected in healthy matched controls. We find no evidence for persistent intrusion of representations of the face within the representation of the transplanted hand, although such intrusions are commonly reported in amputees [5, 6]. Our results suggest that even decades after complete deafferentiation, restoring afferent input to S1 leads to re-establishment of the gross hand representation within its original territory. Unexpectedly, large ipsilateral S1 responses accompanied sensory stimulation of the patient's intact hand. These may reflect a change in interhemispheric inhibition that could contribute to maintaining latent hand representations during the period of amputation.
Project description:Despite their disabilities, top Paralympic athletes have better motor skills than able-bodied athletes. However, the neural underpinnings of these better motor skills remain unclear. We investigated the reorganization of the primary motor cortex (M1) in a Paralympic athlete with congenital amputation of both arms who holds the world record for the farthest accurate shot in archery (Amputee Archer: AA). We recorded brain activity during contraction of right toe, ankle, knee, and hip joint muscles in the AA and 12 able-bodied control subjects using functional magnetic resonance imaging. The results revealed that M1 activation was more widespread in the AA compared with control subjects during all tasks, and shifted towards the lateral part of the M1 during contraction of toe and knee muscles. We also conducted a motor mapping experiment using navigated transcranial magnetic stimulation. The M1 area receiving stimulation elicited motor-evoked potentials from the toe, lower-leg, and thigh muscles, which were larger in the AA compared with 12 control subjects. Furthermore, the AA's motor maps were shifted towards the lateral side of M1. These results suggest an expansion of lower-limb M1 representation towards the lateral side of M1, including the trunk and upper-limb representations, and an expansion of the area of corticomotor neurons innervating the lower limb muscles in the AA. This unique M1 reorganization could underpin the AA's excellent archery performance in the absence of upper limbs. The current results suggest that Paralympic athletes may exhibit extreme M1 plasticity, which could arise through a combination of rigorous long-term motor training and compensatory M1 reorganization for missing body parts.
Project description:Little is known about whether and how multimodal representations of the body (BRs) and of the space around the body (Peripersonal Space, PPS) adapt to amputation and prosthesis implantation. In order to investigate this issue, we tested BR in a group of upper limb amputees by means of a tactile distance perception task and PPS by means of an audio-tactile interaction task. Subjects performed the tasks with stimulation either on the healthy limb or the stump of the amputated limb, while wearing or not wearing their prosthesis. When patients performed the tasks on the amputated limb, without the prosthesis, the perception of arm length shrank, with a concurrent shift of PPS boundaries towards the stump. Conversely, wearing the prosthesis increased the perceived length of the stump and extended the PPS boundaries so as to include the prosthetic hand, such that the prosthesis partially replaced the missing limb.
Project description:Leprosy is an endemic infectious disease caused by Mycobacterium leprae that predominantly attacks the skin and peripheral nerves, leading to progressive impairment of motor, sensory and autonomic function. Little is known about how this peripheral neuropathy affects corticospinal excitability of handgrip muscles. Our purpose was to explore the motor cortex organization after progressive peripheral nerve injury and upper-limb dysfunction induced by leprosy using noninvasive transcranial magnetic stimulation (TMS).In a cross-sectional study design, we mapped bilaterally in the primary motor cortex (M1) the representations of the hand flexor digitorum superficialis (FDS), as well as of the intrinsic hand muscles abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM). All participants underwent clinical assessment, handgrip dynamometry and motor and sensory nerve conduction exams 30 days before mapping. Wilcoxon signed rank and Mann-Whitney tests were performed with an alpha-value of p<0.05.Dynamometry performance of the patients' most affected hand (MAH), was worse than that of the less affected hand (LAH) and of healthy controls participants (p = 0.031), confirming handgrip impairment. Motor threshold (MT) of the FDS muscle was higher in both hemispheres in patients as compared to controls, and lower in the hemisphere contralateral to the MAH when compared to that of the LAH. Moreover, motor evoked potential (MEP) amplitudes collected in the FDS of the MAH were higher in comparison to those of controls. Strikingly, MEPs in the intrinsic hand muscle FDI had lower amplitudes in the hemisphere contralateral to MAH as compared to those of the LAH and the control group. Taken together, these results are suggestive of a more robust representation of an extrinsic hand flexor and impaired intrinsic hand muscle function in the hemisphere contralateral to the MAH due to leprosy.Decreased sensory-motor function induced by leprosy affects handgrip muscle representation in M1.
Project description:The BDNF Val66Met polymorphism is associated with impaired short-term plasticity in the motor cortex, short-term motor learning, and intermanual transfer of a procedural motor skill. Here, we investigated the impact of the Val66Met polymorphism on the modulation of cortical excitability and interhemispheric inhibition through sensorimotor practice of simple dynamic skills with the right and left first dorsal interosseous (FDI) muscles. To that end, we compared motor evoked potentials (MEP) amplitudes and short-interval intracortical inhibition (SICI) in the bilateral representations of the FDI muscle in the primary motor cortex (M1), and interhemispheric inhibition (IHI) from the left to right M1, before and after right and left FDI muscle training in an alternated sequence. Val66Met participants did not differ from their Val66Val counterparts on motor performance at baseline and following motor training, or on measures of MEP amplitude and IHI. However, while the Val66Val group displayed significant SICI reduction in the bilateral M1 in response to motor training, SICI remained unchanged in the Val66Met group. Further, Val66Val group's SICI decrease in the left M1, which was also observed following unimanual training with the right hand in the Control Right group, was correlated with motor improvement with the left hand. The potential interaction between left and right M1 activity during bimanual training and the implications of altered activity-dependent cortical excitability on short-term motor learning in Val66Met carriers are discussed.
Project description:Reaching and grasping typically are considered to be spatially separate processes that proceed concurrently in the arm and the hand, respectively. The proximal representation in the primary motor cortex (M1) controls the arm for reaching, while the distal representation controls the hand for grasping. Many studies of M1 activity therefore have focused either on reaching to various locations without grasping different objects, or else on grasping different objects all at the same location. Here, we recorded M1 neurons in the anterior bank and lip of the central sulcus as monkeys performed more naturalistic movements, reaching toward, grasping, and manipulating four different objects in up to eight different locations. We quantified the extent to which variation in firing rates depended on location, on object, and on their interaction-all as a function of time. Activity proceeded largely in two sequential phases: the first related predominantly to the location to which the upper extremity reached, and the second related to the object about to be grasped. Both phases involved activity distributed widely throughout the sampled territory, spanning both the proximal and the distal upper extremity representation in caudal M1. Our findings indicate that naturalistic reaching and grasping, rather than being spatially segregated processes that proceed concurrently, each are spatially distributed processes controlled by caudal M1 in large part sequentially. Rather than neuromuscular processes separated in space but not time, reaching and grasping are separated more in time than in space.Reaching and grasping typically are viewed as processes that proceed concurrently in the arm and hand, respectively. The arm region in the primary motor cortex (M1) is assumed to control reaching, while the hand region controls grasping. During naturalistic reach-grasp-manipulate movements, we found, however, that neuron activity proceeds largely in two sequential phases, each spanning both arm and hand representations in M1. The first phase is related predominantly to the reach location, and the second is related to the object about to be grasped. Our findings indicate that reaching and grasping are successive aspects of a single movement. Initially the arm and the hand both are projected toward the object's location, and later both are shaped to grasp and manipulate.
Project description:Converging evidence suggest that motor training is associated with early and late changes of the cortical motor system. Transcranial magnetic stimulation (TMS) offers the possibility to study plastic rearrangements of the motor system in physiological and pathological conditions. We used TMS to characterize long-term changes in upper limb motor cortical representation and interhemispheric inhibition associated with bimanual skill training in pianists who started playing in an early age. Ipsilateral silent period (iSP) and cortical TMS mapping of hand muscles were obtained from 30 strictly right-handed subjects (16 pianists, 14 naïve controls), together with electromyographic recording of mirror movements (MMs) to voluntary hand movements. In controls, motor cortical representation of hand muscles was larger on the dominant (DH) than on the non-dominant hemisphere (NDH). On the contrary, pianists showed symmetric cortical output maps, being their DH less represented than in controls. In naïve subjects, the iSP was smaller on the right vs left abductor pollicis brevis (APB) indicating a weaker inhibition from the NDH to the DH. In pianists, interhemispheric inhibition was more symmetric as their DH was better inhibited than in controls. Electromyographic MMs were observed only in naïve subjects (7/14) and only to voluntary movement of the non-dominant hand. Subjects with MM had a lower iSP area on the right APB compared with all the others. Our findings suggest a more symmetrical motor cortex organization in pianists, both in terms of muscle cortical representation and interhemispheric inhibition. Although we cannot disentangle training-related from preexisting conditions, it is possible that long-term bimanual practice may reshape motor cortical representation and rebalance interhemispheric interactions, which in naïve right-handed subjects would both tend to favour the dominant hemisphere.
Project description:This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.
Project description:BACKGROUND Correctly diagnosing a staple-line mass after pulmonary resection for lung malignant tumor can be difficult. Differential diagnoses of recurrence, infectious mass, granuloma, and so on must be considered, despite their rarity. We report two cases of pulmonary staple-stump granuloma after segmentectomy for lung cancer. CASE REPORT Case 1 involved a 70-year-old man with small nodule in the left upper lobe identified on computed tomography (CT). Video-assisted thoracoscopic (VATS) left upper division segmentectomy was performed. Histopathological examination revealed squamous carcinoma. Follow-up CT 1 year postoperatively showed a shadow at the staple-stump, with growth evident later. CT-guided biopsy found no malignancy. However, complete left upper lobectomy was performed because of the gradually enlarging lesion. Histopathological examination revealed epithelioid granuloma. Case 2 involved a 60-year-old with suspected lung cancer in the right upper lobe. VATS right upper division segmentectomy (S2) was performed. CT at 30 months postoperatively showed a shadow at the staple line, with subsequent growth. VATS right upper lobectomy was performed. Intraoperative rapid diagnosis revealed epithelioid granuloma. These two cases were compared with five cases of staple-stump recurrence in our institution. All cases of recurrence grew concentrically or radially from the staple line with the mass surrounding the staple line. On the other hand, cases of granuloma extended along the long axis of the staple line, and 3-dimensional CT (3DCT) may help to understand the morphology. CONCLUSIONS Although preoperative differentiation of staple-line granuloma is difficult and pathological diagnosis is important, characteristic radiologic features and 3DCT may facilitate diagnosis.
Project description:Human motor development is thought to result from a complex interaction between genes and experience. The well-known somatotopic organization of the primate primary motor cortex (M1) emerges postnatally. Although adaptive changes in response to learning and use occur throughout life, somatotopy is maintained as reorganization is restricted to modifications within major body part representations. We report of a unique opportunity to evaluate the influence of experience on the genetically determined somatotopic organization of motor cortex in humans. We examined the motor "foot" representation in subjects with congenitally compromised hand function and compensatory skillful foot use. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) of M1 revealed that the foot was represented in the classical medial foot area of M1 and was several centimetres away in nonadjacent cortex in the vicinity of the lateral "hand" area. Both areas had direct output to the spinal motor neurons innervating foot muscles and were behaviorally relevant because experimental disruption of either area by TMS altered reaction times. We demonstrate a unique, nonsomatotopically organized M1 in humans, which emerged as a function of grossly altered motor behavior from the earliest stages of development. Our results imply that during early motor development experience may play a more critical role in the shaping of genetically determined neural networks than previously assumed.