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Background and Purpose: Neuroplastic alterations of cortical excitability and activity represent the likely neurophysiological foundation of learning and memory formation. Beyond their induction, alterations of these processes by subsequent modification of cortical activity, termed metaplasticity, came into the focus of interest recently. Animal slice experiments demonstrated that neuroplastic excitability enhancements, or diminutions, can be abolished by consecutive subthreshold stimulation. These processes, termed de-potentiation, and de-depression, have so far not been explored in humans., Methods: We combined neuroplasticity induction by transcranial direct current stimulation (tDCS) applied to the hand area of primary motor cortex (M1), which can be used to induce long-lasting excitability enhancements or reductions, dependent on the polarity of stimulation, with short-lasting voluntary muscle contraction (VMC), which itself does not induce plastic cortical excitability changes. Corticospinal and intra-cortical M1 excitability were monitored by different transcranial magnetic stimulation (TMS) protocols., Results: VMC reduced or tended to reverse the anodal tDCS-driven motor cortical excitability enhancement and the cathodal tDCS-induced excitability diminution. Our findings thus demonstrate de-potentiation- and de-depression-like phenomena at the system level in the human motor cortex., Conclusion: This neurophysiological study may contribute to a better understanding of the balance between induction and reversal of plasticity associated with motor learning and rehabilitation processes.

Data derived from transcranial magnetic stimulation (TMS) studies suggest that transcallosal inhibition mechanisms between the primary motor cortex of both hemispheres may contribute to the reduced motor performance of stroke patients. We here investigated the potential of modulating pathological interactions between cortical motor areas by means of repetitive TMS using functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM). Eleven subacute stroke patients were scanned 1-3 months after symptom onset while performing whole hand fist closure movements. After a baseline scan, patients were stimulated with inhibitory 1-Hz rTMS applied over two different locations: (i) vertex (control stimulation) and (ii) primary motor cortex (M1) of the unaffected (contralesional) hemisphere. Changes in the endogenous and task-dependent effective connectivity were assessed by DCM of a bilateral network comprising M1, lateral premotor cortex, and the supplementary motor area (SMA). The results showed that rTMS applied over contralesional M1 significantly improved the motor performance of the paretic hand. The connectivity analysis revealed that the behavioral improvements were significantly correlated with a reduction of the negative influences originating from contralesional M1 during paretic hand movements. Concurrently, endogenous coupling between ipsilesional SMA and M1 was significantly enhanced only after rTMS applied over contralesional M1. Therefore, rTMS applied over contralesional M1 may be used to transiently remodel the disturbed functional network architecture of the motor system. The connectivity analyses suggest that both a reduction of pathological transcallosal influences (originating from contralesional M1) and a restitution of ipsilesional effective connectivity between SMA and M1 underlie improved motor performance., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

1 Hz rTMS applied over primary motor cortex (M1) reduces cortical excitability outlasting the stimulation period. Healthy right-handed subjects performed finger and hand tapping and a reach-to-grasp movement prior to (baseline) and after 1 Hz rTMS applied over (1) M1 of either the right or the left hemisphere, and (2) the vertex (control stimulation). 1 Hz rTMS applied over the left M1, but not over the vertex, improved movement kinematics of finger and hand tapping as well as grasping with the left hand. 1 Hz rTMS applied over the right M1, but not over the vertex, improved only the kinematics of hand tapping performed with the right hand. These data suggest that 1 Hz rTMS induced inhibition of ipsilateral M1 reduces transcallosal inhibition of contralateral M1 and thereby improves motor performance at the ipsilateral hand. The impact on motor performance of the ipsilateral hand is most pronounced after 1 Hz rTMS over the left M1.

Within the concept of interhemispheric competition we tested the effect of inhibitory 1 Hz repetitive transcranial magnetic stimulation (rTMS), applied over the primary motor cortex of the unaffected hemisphere, upon dexterity of the affected hand in subcortical stroke patients. Subjects grasped, lifted and held an instrumented object between the index finger and thumb with both the affected and unaffected hand prior to (baseline) and following 1 Hz rTMS applied over (i) the vertex (control stimulation) and (ii) the primary motor cortex of the unaffected hemisphere. Compared to baseline, 1 Hz rTMS applied over the unaffected primary motor cortex, but not the vertex, improved the efficiency and timing of grasping and lifting with the affected hand. Our data support the interhemispheric competition concept and furthermore reinforce current efforts to implement rTMS in novel approaches to stroke rehabilitation.

Background: Following the concept of interhemispheric competition, downregulation of the contralesional primary motor cortex (M1) may improve the dexterity of the affected hand after stroke., Objective: To determine the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) of the contralesional M1 on movement kinematics and neural activation within the motor system in the subacute phase after subcortical stroke., Design: Crossover investigation., Setting: A university hospital., Methods: Fifteen right-handed patients with impaired dexterity due to subcortical middle cerebral artery stroke received 1-Hz rTMS for 10 minutes applied to the vertex (control stimulation) and contralesional M1. For behavioral testing, patients performed finger and grasp movements with both hands at 2 baseline conditions, separated by 1 week, and following each rTMS application. For functional magnetic resonance imaging, patients performed hand grip movements with their affected or unaffected hand before and after each rTMS application., Results: Application of rTMS to the contralesional M1 improved the kinematics of finger and grasp movements in the affected hand. At the neural level, rTMS applied to the contralesional M1 reduced overactivity in the contralesional primary and nonprimary motor areas. There was no significant correlation between the rTMS-induced reduction in blood oxygen level-dependent responses within the contralesional M1 and the degree of behavioral improvement of the affected hand. Overactivity of the contralesional dorsal premotor cortex, contralesional parietal operculum, and ipsilesional mesial frontal cortex at baseline predicted improvement of movement kinematics with the affected hand after rTMS of the contralesional M1., Conclusion: The functional magnetic resonance imaging data suggest that rTMS of the contralesional M1 may normalize neural activation within the cortical motor network after subcortical stroke. Identifying patients suitable for rTMS intervention based on individual patterns of cortical activation may help to implement rTMS in motor rehabilitation after stroke.

In humans, transcranial direct current stimulation (tDCS) can be used to induce, depending on polarity, increases or decreases of cortical excitability by polarization of the underlying brain tissue. Cognitive enhancement as a result of tDCS has been reported. The purpose of this study was to test whether weak tDCS (current density, 57 microA/cm(2)) can be used to modify language processing. Fifteen healthy subjects performed a visual picture naming task before, during and after tDCS applied over the posterior perisylvian region (PPR), i.e. an area which includes Wernicke's area [BA 22]. Four different sessions were carried out: (1) anodal and (2) cathodal stimulation of left PPR and, for control, (3) anodal stimulation of the homologous region of the right hemisphere and (4) sham stimulation. We found that subjects responded significantly faster following anodal tDCS to the left PPR (p<0.01). No decreases in performance were detected. Our finding of a transient improvement in a language task following the application of tDCS together with previous studies which investigated the modulation of picture naming latency by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) suggest that tDCS applied to the left PPR (including Wernicke's area [BA 22]) can be used to enhance language processing in healthy subjects. Whether this safe, low cost, and easy to use brain stimulation technique can be used to ameliorate deficits of picture naming in aphasic patients needs further investigations.

Single pulse transcranial magnetic stimulation (TMS) was applied to the hand area of the left primary motor cortex or, as a control, to the vertex (STIMULATION: TMS(M1) vs. TMS(vertex)) while right-handed volunteers silently read verbs related to hand actions. We examined three different tasks and time points for stimulation within the same experiment: subjects indicated with their left foot when they (i) had finished reading, (ii) had judged whether the corresponding movement involved a hand rotation after simulating the hand movement, and (iii) had judged whether they would frequently encounter the action verb in a newspaper (TASK: silent reading, motor imagery, and frequency judgment). Response times were compared between TMS(M1) and TMS(vertex), both applied at different time points after stimulus onset (DELAY: 150, 300, 450, 600, and 750 ms). TMS(M1) differentially modulated task performance: there was a significant facilitatory effect of TMS(M1) for the imagery task only (about 88 ms), with subjects responding about 10% faster (compared to TMS(vertex)). In contrast, response times for silent reading and frequency judgments were unaffected by TMS(M1). No differential effect of the time point of TMS(M1) was observed. The differential effect of TMS(M1) when subjects performed a motor imagery task (relative to performing silent reading or frequency judgments with the same set of verbs) suggests that the primary motor cortex is critically involved in processing action verbs only when subjects are simulating the corresponding movement. This task-dependent effect of hand motor cortex TMS on the processing of hand-related action verbs is discussed with respect to the notion of embodied cognition and the associationist theory.

Abstract: Objective: The contribution of the human anterior intraparietal area and the dorsal premotor cortex to arbitrary visuo-motor mapping during grasping were tested. Methods: Trained right-handed subjects reached for and pincer-grasped a cube with the right hand in the absence of visual feedback after the cube location had been displayed for 200ms. During the reaching movements, the colour of the cube changed and visual feedback about the change of colour was provided for 100ms at 500ms after movement onset (at the time of peak grasp aperture). Depending on colour, subjects were instructed to either pincer-grasp the cube in a horizontal or vertical grasp position with the latter necessitating wrist rotation (experiment 1) or to pincer-grasp and transport the cube to either a left or right target position (experiment 2). Within two consecutive 200ms time windows (TMS 1 and 2) starting 500ms and 700ms after movement onset, respectively, double pulses of supra-threshold transcranial magnetic stimulation (inter-stimulus interval: 100ms) were delivered over (i) the left primary motor cortex (90° vertically angulated coil position, control stimulation), (ii) the left dorsal premotor cortex or (ii) the left anterior intraparietal area. Results: Compared to control stimulation, stimulation of the anterior intraparietal area, but not of the dorsal premotor cortex, at TMS 1 delayed the times to wrist rotation (experiment 1) and hand transport (experiment 2). Compared to control stimulation, stimulation of the dorsal premotor cortex, but not of the anterior intraparietal area, at TMS 2 delayed both wrist rotation (experiment 1) and hand transport (experiment 2). Conclusions: We contend that the anterior intraparietal area and the dorsal premotor cortex are both involved albeit at different phases during the mapping of arbitrary visual cues with goal directed grasp and transport movements. Significance: These data add to the current understanding of how human cortical areas work in concert during manual activities. [Copyright &y& Elsevier]

Abstract: When lifting objects of different mass but identical visual appearance, we apply grip forces that match the expected mass of the object. Here we study the role of the primary motor cortex (M1), the ventral premotor cortex (PMv) and the anterior intraparietal area (AIP) for predictive and reactive scaling of grip forces. Participants performed a precision grip between the index finger and thumb of the right hand to lift two different masses of identical visual appearance in random order. Neuronavigated single pulse transcranial magnetic stimulation (TMS) over (i) left M1, (ii) left PMv, (iii) left AIP and (iv) the vertex (for control) was applied at two time points of the grasping movement after an unexpected change in mass had occurred: (a) at the time of movement onset and (b) at the time of peak grasp aperture. TMS over the PMv, but not over the vertex, M1 or the AIP, interfered with the predictive scaling of grip forces according to the most recent lift when applied at the time of peak grasp aperture. In contrast, TMS over AIP, but not over the vertex, M1 or PMv, disrupted the reactive adjustment of grip force to the novel mass of the object at hand. The findings highlight the differential involvement of PMv in the predictive scaling of grip force and of AIP in the reactive online adjustment of grip force during object manipulation. [Copyright &y& Elsevier]