Reorganization Of Primary Motor Cortex Research Articles

Optogenetics stimulates nerve reorganization in the contralesional anterolateral primary motor cortex in a mouse model of ischemic stroke.

The anterolateral motor cortex of rodents is an important motor auxiliary area, and its function is similar to that of the premotor area in humans. Activation and inhibition of the contralesional anterolateral motor cortex (cALM) have been shown to have direct effects on motor behavior. However, the significance of cALM activation and inhibition in the treatment of stroke remains unclear. This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke. The results showed that 21-day optogenetic cALM inhibition, but not activation, improved neurological function. In addition, optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity, as optogenetic cALM inhibition resulted in increased dendritic length, number of dendritic spines, and number of perforated synapses, whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections. Furthermore, RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition, and that several immediate-early genes (including cFOS, Erg1, and Sema3f) were expressed at higher levels after optogenetic inhibition than after optogenetic activation. These results were confirmed by quantitative reverse transcription-polymerase chain reaction. Finally, immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition. Taken together, these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere, and that optogenetic cALM inhibition and activation have different effects on neural plasticity. The study was approved by the Experimental Animal Ethics Committee of Fudan University (approval No. 201802173S) on March 3, 2018.

Segmental reorganization of the leg primary motor area

Reorganization of eloquent cortex due to neighboring stressors, like tumors and epilepsy, has been previously documented. Here we report reorganization of a subregion of the primary motor cortex due to a slow-growing primary brain tumor. We report the case of a 22-year-old, right-handed male with long-standing focal partial epilepsy involving the right leg who, on imaging, had a small contrast enhancing lesion within the left leg primary motor area. He underwent resective surgery with awake motor mapping. During mapping, a specific subregion of the primary leg motor area subserving proximal leg muscles was found on a gyrus posterior to the precentral gyrus. In addition, the foot/toe area had relocated supero-medially, but remained within the pre-central gyrus. The remainder of the motor homunculus was appropriately mapped on the same gyrus. To our knowledge, this is the first report of segmental reorganization of primary motor cortex subserving an isolated muscle group. Pre-operative functional imaging does not substitute for intra-operative real-time mapping with direct electrical stimulation. This case highlights the importance of careful mapping in order to achieve gross total resection of tumors within the primary motor cortex.

Grasping with a new hand: Improved performance and normalized grasp-selective brain responses despite persistent functional changes in primary motor cortex and low-level sensory and motor impairments

Hand loss can now be reversed through surgical transplantation years or decades after amputation. Remarkably, these patients come to use their new hand to skilfully grasp and manipulate objects. The brain mechanisms that make this possible are unknown. Here we test the hypothesis that the anterior intraparietal cortex (aIPC) – a multimodal region implicated in hand preshaping and error correction during grasping – plays a key role in this compensatory grasp control. Motion capture and fMRI are used to characterize hand kinematics and brain responses during visually guided grasping with a transplanted hand at 26 and 41 months post-transplant in patient DR, a former hand amputee of 13 years. Compared with matched controls, DR shows increasingly normal grasp kinematics paralleled by increasingly robust grasp-selective fMRI responses within the very same brain areas that show grasp-selectivity in controls, including the aIPC, premotor and cerebellar cortices. Paradoxically, over this same time DR exhibits significant limitations in basic sensory and motor functions, and persistent amputation-related functional reorganization of primary motor cortex. Movements of the non-transplanted hand positively activate the ipsilateral primary motor hand area – a functional marker of persistent interhemispheric amputation-related reorganization. Our data demonstrate for the first time that even after more than a decade of living as an amputee the normative functional brain organization governing the control of grasping can be restored. We propose that the aIPC and interconnected premotor and cerebellar cortices enable grasp normalization by compensating for the functional impact of reorganizational changes in primary sensorimotor cortex and targeting errors in regenerating peripheral nerves.

P293 Assessment of primary motor cortex plastic changes following the use of a new prosthetic system able to provide somatosensory feedback from the missing hand in an amputee patient: A TMS study

Introduction The cortical representation of a muscle can be significantly modified by plastic reorganization following a limb amputation. These plastic changes are not immutable and can be further modified restoring by the use of prosthesis like new bionic anthropomorphic prosthesis connected to the peripheral nervous system via bidirectional neural interfaces. Transcranial magnetic stimulation (TMS) is a non-invasive technique commonly used to assess topographical reorganization of motor brain areas. Objective The aim of this study is to evaluate the motor cortical reorganization of primary motor cortex with the TMS mapping technique in a left trans-radial amputee patient following the use of a novel prosthetic system able to provide somatosensory feed-back from the lost hand of the user. Materials and methods Cortical motor output was mapped via TMS (intensity 10% above standardized excitability motor Threshold) for each hemisphere at the beginning, after 1 month and 2 month of training with the new prosthetic system. Peripheral responses were recorded from forearm flexor and extensor carpi ulnaris muscles of both limbs. Resting and Active motor threshold were also collected during separate mapping of right and left hemispheres. Results No significant differences were found in the motor thresholds between the two hemispheres before and after implantation. Pre-surgical TMS motor maps showed a slight abnormal interhemispheric asymmetry of motor cortex topography, resulted in a smaller area of representation of muscles governing the stump compared to the area for the intact limb. Following training, post-surgical maps, showed a reduction and a partial reversal of this asymmetry because of an enlargement of the excitable area on the right hemisphere contralateral to the stump, leading towards a more symmetrical muscle representation in the two hemispheres, as in control subjects. Conclusions Our experiment provides a direct and unique evidence of brain plasticity changes occurring in the motor cortex following the use of a prosthetic system able to restore a somatosensory feedback from the missing limb after amputation. Figure options Download full-size image Download high-quality image (378 K) Download as PowerPoint slide Figure options Download full-size image Download high-quality image (399 K) Download as PowerPoint slide

Motor Cortex Reorganization and Repetitive Transcranial Magnetic Stimulation for Pain—A Methodological Study

Somatotopic reorganization of primary motor cortex (M1) has been described in several neurological conditions associated with chronic pain. We hypothesized that such reorganization impacts on the mechanisms of M1 stimulation induced analgesia and may either compromise the treatment effect of or provide an alternative target site for repetitive transcranial magnetic stimulation (rTMS). The aim of the study was to compare pain relief following rTMS of the standard motor "hotspot" with that of the reorganized area. We used TMS motor mapping in 30 patients to establish the location of the standard motor "hotspot" (site A) and an alternative site located in the reorganized area (site B), both within M1. Where TMS mapping was not possible (N = 8) we determined the location of the two sites using task-related fMRI. We compared the analgesic effect on neuropathic pain of 5 sessions of navigated rTMS applied over (i) site A, (ii) site B, and (iii) occipital fissure (SHAM stimulation site). Total Pain Relief (TOTPAR) was determined as the difference in average weekly pain scores between baseline and following each rTMS cycle, over three weeks. Data from 27 patients was analyzed. rTMS of sites A and B resulted in greater TOTPAR than that of SHAM. No difference was seen between sites A and B. Responders (≥15% pain relief) were seen in both groups, with partial overlap only. Addition of stimulation over site B improved the responder rate by 58% compared with site A. In an open-label extension study of five sessions of rTMS aimed at the optimized target site, 8/11 responders and 1/12 nonresponders reported pain relief. Cortical reorganization may provide a more effective stimulation target for rTMS in some individuals with neuropathic pain.

Intracortical inhibition is modulated by phase of prosthetic rehabilitation in transtibial amputees.

Reorganization of primary motor cortex (M1) is well-described in long-term lower limb amputees. In contrast cortical reorganization during the rehabilitation period after amputation is poorly understood. Thirteen transtibial amputees and 13 gender matched control participants of similar age were recruited. Transcranial magnetic stimulation was used to assess corticomotor and intracortical excitability of M1 bilaterally. Neurophysiological assessments were conducted at admission, prosthetic casting, first walk and discharge. Gait variability at discharge was assessed as a functional measure. Compared to controls, amputees had reduced short-latency intracortical inhibition (SICI) for the ipsilateral M1 at admission (p = 0.01). Analysis across rehabilitation revealed SICI was reduced for the contralateral M1 at first walk compared to discharge (p = 0.003). For the ipsilateral M1 both short and long-latency intracortical inhibition were reduced at admission (p < 0.05) and prosthetic casting (p < 0.02). Analysis of the neurophysiology and gait function revealed several interesting relationships. For the contralateral M1, reduced inhibition at admission (p = 0.04) and first walk (p = 0.05) was associated with better gait function. For the ipsilateral M1, reduced inhibition at discharge (p = 0.05) was associated with poor gait function. This study characterized intracortical excitability in rehabilitating amputees. A dichotomous relationship between reduced intracortical inhibition for each M1 and gait function was observed at different times. Intracortical inhibition may be an appropriate cortical biomarker of gait function in lower limb amputees during rehabilitation, but requires further investigation. Understanding M1 intracortical excitability of amputees undertaking prosthetic rehabilitation provides insight into brain reorganization in the sub-acute post-amputation period and may guide future studies seeking to improve rehabilitation outcomes.

Peripheral Neurostimulation and Specific Motor Training of Deep Abdominal Muscles Improve Posturomotor Control in Chronic Low Back Pain

Chronic low back pain (CLBP) is associated with an impaired control of transversus abdominis/internal oblique muscle (TrA/IO), volitionally and during anticipatory postural adjustment (delay) along with maladaptive reorganization of primary motor cortex (M1). Specific training of deep trunk muscles and repetitive peripheral magnetic stimulation (RPMS) improve motor control. We thus tested whether RPMS over TrA/IO combined with training could promote TrA/IO motor control and decrease pain beyond the gains already reached in CLBP. Thirteen CLBP patients, randomly allocated to RPMS and sham groups and compared with 9 pain-free controls, were tested in 1 session before/after (stimulation alone) and after (stimulation+TrA/IO training) combination. TrA/IO motor patterns were recorded during ballistic shoulder flexion using surface electromyography. Transcranial magnetic stimulation tested M1 excitability and short-interval intracortical inhibition. A blinded physical therapist assessed pain, disability, and kinesiophobia. The missing short-interval intracortical inhibition in CLBP was restored by RPMS alone then reduced after combination of RPMS with training. This combination also normalized the (at-first delayed) anticipatory activation of iTrA/IO (ipsilateral to arm raised) and the (at-first shortened) TrA/IO coactivation duration. Sham did not influence. Pain was reduced in both groups but kinesiophobia was decreased only in RPMS 2 weeks later. This study supports that peripheral neurostimulation (adjuvant to training) could improve TrA/IO motor learning and pain in CLBP associated with motor impairment. Testing of enlarged samples over several sessions should question the long-term influence of this new approach in CLBP.

Reversal of Cortical Reorganization in Human Primary Motor Cortex Following Thumb Reconstruction

Deafferentation such as the amputation of a body part causes cortical reorganization in the primary motor cortex (M1). We investigated whether this reorganization is reversible after reconstruction of the lost body part. We tested two patients who had long-standing thumb amputations followed by thumb reconstruction with toe-to-thumb transfer 9 to 10 mo later and one patient who underwent thumb replantation immediately following traumatic amputation. Using transcranial magnetic stimulation, we measured the motor evoked potential (MEP) threshold, latency, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) at different time points in the course of recovery in abductor pollicis brevis muscle. For the two patients who underwent late toe-to-thumb transfer, the rest motor threshold was lower on the injured side than that on the intact side before surgery and it increased with time after reconstruction, whereas the active motor threshold remained unchanged. The rest and active MEP latencies were similar on the injured side before and < or =15 wk after surgery and followed by restoration of expected latency differences. SICI was reduced before surgery and progressively normalized with the time after surgery. ICF did not change with time. These physiological measures correlated with the recovery of motor and sensory functions. All the measurements on the intact side of the toe-to-thumb transfer patients and in the patient with thumb replantation immediately following traumatic amputation remained stable over time. We conclude that chronic reorganization occurring in the M1 after amputation can be reversed by reconstruction of the lost body part.

Connections of neurons in the lumbar ventral horn of spinal cord are altered after long-standing limb loss in a macaque monkey

Explanations for the massive reorganization in primary motor cortex, M1, after limb amputation typically focus on processes that occur in cortex. Few have investigated whether changes in more peripheral parts of the pathway might also play a role in the reorganization. In the present study, we examined the integrity and connectivity of the spinal cord motoneurons in a macaque monkey (Macaca mulatta) that lost a hindlimb as a result of accidental injury more than 3.5 years earlier. To label motoneurons, multiple small injections of a neuroanatomical tracer were placed in the muscles of the hip just adjacent to the stump of the amputated leg, and in matched locations in the opposite side for control purposes. Injections of a second tracer were made in the intact foot. In the ventral horn that related to the intact hindlimb, motoneurons labeled by the hip injections were concentrated rostral and ventromedial to those labeled by the foot injections. Hip injections on the side of the amputation labeled neurons that were located well beyond the normal territory for motoneurons related to the hip and into the zone normally occupied by neurons projecting to the foot. Labeled motoneurons innervating the intact limb were significantly larger than neurons on the side of the amputation (x = 2410 and 2061 µm2, respectively). The findings suggest that many neurons survived the long-standing amputation, and made new connections with remaining intact muscles. These new patterns of connectivity likely contribute to the reorganization of motor cortex in amputees, and perhaps to abnormal behaviors like those reported by human amputees.

Spinal Cord Atrophy and Reorganization of Motoneuron Connections Following Long-Standing Limb Loss in Primates

Primates with long-standing therapeutic amputations of a limb at a young age were used to investigate the possibility that deefferented motor nerves sprout to new muscle targets. Injections of anatomical tracers into the muscles proximal to the amputated stump labeled a larger extent of motoneurons than matched injections on the intact side or in normal animals, including motoneurons that would normally supply only the missing limb muscles. Although the total numbers of distal limb motoneurons remained normal, some distal limb motoneurons on the amputated side were smaller in size and simpler in form. These results suggest that deprived motoneurons survive and retain function by reinnervating new muscle targets. The sprouted motor efferents may account for some of the reorganization of primary motor cortex that follows long-standing amputation.

Reorganization of primary motor cortex in adult macaque monkeys with long-standing amputations.

The organization of primary motor cortex (M1) of adult macaque monkeys was examined years after therapeutic amputation of part of a limb or digits. For each case, a large number of sites in M1 were electrically stimulated with a penetrating microelectrode, and the evoked movements and levels of current needed to evoke the movements were recorded. Results from four monkeys with the loss of a forelimb near or above the elbow show that extensive regions of cortex formerly devoted to the missing hand evoked movements of the stump and the adjoining shoulder. Threshold current levels for stump movements were comparable to those for normal arm movements. Few or no sites in the estimated former territory of the hand evoked face movements. Similar patterns of reorganization were observed in all four cases, which included two monkeys injured as adults, one as a juvenile, and one as an infant. In a single monkey with a hindlimb amputation at the knee as an infant, stimulation of cortex in the region normally devoted to the foot moved the leg stump, again at thresholds in the range for normal movements. Finally, in a monkey that had lost digit 5 and the distal phalanges of digits 2-4 at 2 yr of age, much of the hand portion of M1 was devoted to movements of the digit stumps.

Reorganization in Primary Motor Cortex of Primates with Long-Standing Therapeutic Amputations

Intracortical microstimulation was used to investigate the organization of primate primary motor cortex (M1) in three squirrel monkeys and two galagos years after the therapeutic amputation of an injured forelimb or hindlimb. In two squirrel monkeys with forelimb amputation, physiological results were correlated with the distribution of corticospinal neurons after injections of tracers into the lower cervical segments of the spinal cord. Distributions of labeled corticospinal neurons helped identify the locations of the former forelimb cortex in M1. Evoked movements from M1 ipsilateral to the missing limb were not obviously different from M1 of normal controls. Stimulation in the deefferented part of M1 contralateral to the missing limb elicited movements of the remaining proximal muscles as well as movements from adjacent body representations in all cases. Stimulation in the deefferented forelimb cortex evoked shoulder stump, trunk, and orofacial movements, whereas stimulation in the deefferented hindlimb cortex evoked hip stump, trunk, and tail movements. Movements were evoked from all sites in the deprived cortex, so that there were no unresponsive zones. Minimal levels of current necessary to evoke these movements varied from those in the normal range to those of much higher levels, with the average threshold higher than normal. Finally, multiunit recording from the two galagos revealed that the deprived portions of S1 were responsive to touch or taps on the stump and neighboring body parts.