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The ability to perform intricate movements is crucial for human motor function. The neural mechanisms underlying precision and power grips are incompletely understood. Corticospinal output from M1 is thought to be modulated by GABA A -ergic intracortical networks within M1. The objective of our study was to investigate the contribution of M1 intracortical inhibition to fine motor control using adaptive threshold hunting (ATH) with paired-pulse TMS during pinch and grasp. We hypothesized that short-interval intracortical inhibition (SICI) could be assessed during voluntary activation and that corticomotor excitability and SICI modulation would be greater during pinch than grasp, reflecting corticospinal control. Seventeen healthy participants performed gradual pinch and grasp tasks. Using ATH, paired-pulse TMS was applied in the anterior-posterior current direction to measure MEP latencies, corticomotor excitability, and SICI. MEP latencies indicated that the procedure preferentially targeted late I-waves. In terms of corticomotor excitability, there was no difference in the TMS intensity required to reach the MEP target during pinch and grasp. Greater inhibition was found during pinch than during grasp. ATH with paired-pulse TMS permits investigation of intracortical inhibitory networks and their modulation during the performance of dexterous motor tasks revealing a greater modulation of GABA A -ergic inhibition contributing to SICI during pinch compared with grasp. NEW & NOTEWORTHY Primary motor cortex intracortical inhibition was investigated during dexterous manual task performance using adaptive threshold hunting. Motor cortex intracortical inhibition was uniquely modulated during pinching versus grasping tasks.

Objective: The role of ipsilateral descending motor pathways in voluntary movement of humans is still a matter of debate, with partly contradictory results. The aim of our study therefore was to examine the excitability of ipsilateral motor evoked potentials (iMEPs) regarding site and the specificity for unilateral and bilateral elbow flexion extension tasks., Methods: MR-navigated transcranial magnetic stimulation mapping of the dominant hemisphere was performed in twenty healthy participants during tonic unilateral (iBB), bilateral homologous (bBB) or bilateral antagonistic elbow flexion-extension (iBB-cAE), the map center of gravity (CoG) and iMEP area from BB were obtained., Results: The map CoG of the ipsilateral BB was located more anterior-laterally than the hotspot of the contralateral BB within the primary motor cortex, with a significant difference in CoG in iBB and iBB-cAE, but not bBB compared to the hotspot for the contralateral BB (each p < 0.05). However, different tasks had no effect on the size of the iMEPs., Conclusion: Our data demonstrated that excitability of ipsilateral and contralateral MEP differ spatially in a task-specific manner suggesting the involvement of different motor networks within the motor cortex., (© 2024. The Author(s).)

The primary motor cortex (M1) is critical for movement execution, but its role in motor skill acquisition remains elusive. Here, we examine the role of M1 intracortical circuits during skill acquisition. Paired-pulse transcranial magnetic stimulation (TMS) paradigms of short-interval intracortical facilitation (SICF) and inhibition (SICI) were used to assess excitatory and inhibitory circuits, respectively. We hypothesised that intracortical facilitation and inhibition circuits in M1 would be modulated to support acquisition of a novel visuomotor skill. Twenty-two young, neurologically healthy adults trained with their nondominant hand on a skilled and non-skilled sequential visuomotor isometric finger abduction task. Electromyographic recordings were obtained from the nondominant first dorsal interosseous (FDI) muscle. Corticomotor excitability, SICF, and SICI were examined before, at the midway point, and after the 10-block motor training. SICI was assessed using adaptive threshold-hunting procedures. Task performance improved after the skilled, but not non-skilled, task training, which likely reflected the increase in movement speed during training. The amplitudes of late SICF peaks were modulated with skilled task training. There was no modulation of the early SICF peak, SICI, and corticomotor excitability with either task training. There was also no association between skill acquisition and SICF or SICI. The findings indicate that excitatory circuitries responsible for the generation of late SICF peaks, but not the early SICF peak, are modulated in motor skill acquisition for a sequential visuomotor isometric finger abduction task., (© 2022. The Author(s).)

Response inhibition is an essential aspect of cognitive control that is necessary for terminating inappropriate preplanned or ongoing responses. Response-selective stopping represents a complex form of response inhibition where only a subcomponent of a multicomponent action must be terminated. In this context, a substantial response delay emerges on unstopped effectors after the cued effector is successfully stopped. This response delay has been termed the stopping interference effect. Converging lines of evidence indicate that this effect results from a global response inhibition mechanism that is recruited regardless of the stopping context. However, behavioral observations reveal that the stopping interference effect may not always occur during selective stopping. This review summarizes the behavioral and neural signatures of response inhibition during selective stopping. An overview of selective stopping contexts and the stopping interference effect is provided. A "restart" model of selective stopping is expanded on in light of recent neurophysiological evidence of selective and nonselective response inhibition. Factors beyond overt action cancellation that contribute to the stopping interference effect are discussed. Finally, a pause-then-cancel model of action stopping is presented as a candidate framework to understand stopping interference during response-selective stopping. The extant literature indicates that stopping interference may result from both selective and nonselective response inhibition processes, which can be amplified or attenuated by response conflict, task familiarity, and functional coupling., (Copyright © 2022 the authors.)

Bimanual coordination is essential for the performance of many everyday tasks. There are several types of bimanually coordinated movements, classified according to whether the arms are acting to achieve a single goal (cooperative) or separate goals (independent), and whether the arms are moving symmetrically or asymmetrically. Symmetric bimanual movements are thought to facilitate corticomotor excitability (CME), while asymmetric bimanual movements are thought to recruit interhemispheric inhibition to reduce functional coupling between the motor cortices. The influences of movement symmetry and goal conceptualisation on interhemispheric interactions have not been studied together, and not during bimanually active dynamic tasks. The present study used transcranial magnetic stimulation (TMS) to investigate the modulation of CME and short- and long-latency interhemispheric inhibition (SIHI and LIHI, respectively) during bimanually active dynamic tasks requiring different types of bimanual coordination. Twenty healthy right-handed adults performed four bimanual tasks in which they held a dumbbell in each hand (independent) or a custom device between both hands (cooperative) while rhythmically flexing and extending their wrists symmetrically or asymmetrically. Motor-evoked potentials were recorded from the right extensor carpi ulnaris. We found CME was greater during asymmetric tasks than symmetric tasks, and movement symmetry did not modulate SIHI or LIHI. There was no effect of goal conceptualisation nor any interaction with movement symmetry for CME, SIHI or LIHI. Based on these results, movement symmetry and goal conceptualisation may not modulate interhemispheric inhibition during dynamic bimanual tasks. These findings contradict prevailing thinking about the roles of CME and interhemispheric inhibition in bimanual coordination.

Precise control of upper limb movements in response to external stimuli is vital to effectively interact with the environment. Accurate execution of bimanual movement is known to rely on finely orchestrated interhemispheric communication between the primary motor cortices (M1s). However, relatively little is known about the role of interhemispheric communication during sudden cancellation of prepared bimanual movement. The current study investigated the role of interhemispheric interactions during complete and partial cancellation of bimanual movement. In two experiments, healthy young human participants received transcranial magnetic stimulation to both M1s during a bimanual response inhibition task. The increased corticomotor excitability in anticipation of bimanual movement was accompanied by a release of inhibition from both M1s. After a stop cue, inhibition was reengaged onto both hemispheres to successfully cancel the complete bimanual response. However, when the stop cue signaled partial cancellation (stopping of one digit only), inhibition was reengaged with regard to the cancelled digit, but the responding digit representation was facilitated. This bifurcation in interhemispheric communication between M1s occurred 75 ms later in the more difficult condition when the nondominant, as opposed to dominant, hand was still responding. Our results demonstrate that interhemispheric communication is integral to response inhibition once a bimanual response has been prepared. Interestingly, M1-M1 interhemispheric circuitry does not appear to be responsible for the nonselective suppression of all movement components that has been observed during partial cancellation. Instead such interhemispheric communication enables uncoupling of bimanual response components and facilitates the selective initiation of just the required unimanual movement. NEW & NOTEWORTHY We provide the first evidence that interhemispheric communication plays an important role during sudden movement cancellation of two-handed responses. Simultaneously increased inhibition onto both hemispheres assists with two-handed movement cancellation. However, this network is not responsible for the widespread suppression of motor activity observed when only one of the two hands is cancelled. Instead, communication between hemispheres enables the separation of motor activity for the two hands and helps to execute the required one-handed response.

Modulation of GABA-mediated inhibition in primary motor cortex (M1) is important for the induction of training-induced plasticity. The downregulation of inhibition during acquisition may promote cortical reorganization, whereas an upregulation once performance has plateaued may promote consolidation of the newly acquired skill. GABA-related inhibition in human M1 is routinely assessed using the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI). However, modulation of SICI with motor skill learning is not a consistent finding and may be influenced by TMS parameters. The aim of this study was to compare the modulation of SICI by motor skill learning between conventional and adaptive threshold-hunting techniques with an anterior-posterior and posterior-anterior induced current. Sixteen participants (21-33 years) trained with their dominant (right) hand on a sequential visual isometric pinch task. Electromyographic recordings were obtained from the right first dorsal interosseous muscle. Corticomotor excitability and SICI were examined before and immediately after 12 blocks of training. Skill increased throughout the training, with performance plateauing before completion. Corticomotor excitability increased after motor training for both current directions. The amount of SICI was greater with anterior-posterior stimulation than posterior-anterior for both conventional and adaptive threshold-hunting techniques. SICI increased after motor training, but only for adaptive threshold-hunting with an anterior-posterior-induced current. The increased GABA-mediated inhibition evident after motor skill learning may promote consolidation of the newly acquired skill. The findings also support the notion that adaptive threshold-hunting SICI using an anterior-posterior current provides an effective assessment in interventional studies.

Motor imagery (MI) is the mental simulation of an action without any apparent muscular contraction. By means of transcranial magnetic stimulation (TMS), few studies revealed a decrease of short-interval intracortical inhibition (SICI) within the primary motor cortex. However, this decrease is ambiguous, as one would expect greater inhibition during MI to prevent overt motor output. The current study investigated the extent of SICI modulation during MI through a methodological and a conceptual reconsideration of (i) the importance of parameters to assess SICI (Exp.1) and (ii) the inhibitory process within the primary motor cortex as an inherent feature of MI (Exp.2). Participants performed two tasks: (1) rest and (2) imagery of isometric abduction of the right index finger. Using TMS, motor evoked potentials were elicited in the right first dorsal interosseous (FDI) muscle. An adaptive threshold-hunting paradigm was used, where the stimulus intensity required to maintain a fixed motor evoked potential amplitude was quantified. To test SICI, we conditioned the test stimulus with a conditioning stimulus (CS) of different intensities. Results revealed an Intensity by Task interaction showing that SICI decreased during MI as compared to rest only for the higher CS intensity (Exp.1). At the lowest CS intensities, a Task main effect revealed that SICI increased during MI (Exp.2). SICI modulation during MI depends critically on the CS intensity. By optimising CS intensity, we have shown that SICI circuits may increase during MI, revealing a potential mechanism to prevent the production of a movement while the motor system is activated., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Stroke is a leading cause of death and disability worldwide with many people left with impaired motor function. Evidence from experimental animal models of stroke indicates that reducing motor cortex inhibition may facilitate neural plasticity and motor recovery. This study compared primary motor cortex (M1) inhibition measures over the first 12 wk after stroke with a cohort of age-similar healthy controls. The excitation-inhibition ratio and gamma-aminobutyric acid (GABA) neurotransmission within M1 were assessed using magnetic resonance spectroscopy and threshold hunting paired-pulse transcranial magnetic stimulation respectively. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Patients with a functional corticospinal pathway had motor-evoked potentials on the paretic side and exhibited better recovery from upper limb impairment and recovery of function than patients without a functional corticospinal pathway. Compared with age-similar controls, the neurochemical balance in terms of the excitation-inhibition ratio was greater within contralesional M1 in patients with a functional corticospinal pathway. There was evidence for elevated long-interval inhibition in both ipsilesional and contralesional M1 compared with controls. Short-interval inhibition measures differed between the first and second phases, with evidence for elevation of the former only in ipsilesional M1 and no evidence of disinhibition for the latter. Overall, findings from transcranial magnetic stimulation indicate an upregulation of GABA-mediated tonic inhibition in M1 early after stroke. Therapeutic approaches that aim to normalize inhibitory tone during the subacute period warrant further investigation. NEW & NOTEWORTHY Magnetic resonance spectroscopy indicated higher excitation-inhibition ratios within motor cortex during subacute recovery than age-similar healthy controls. Measures obtained from adaptive threshold hunting paired-pulse transcranial magnetic stimulation indicated greater tonic inhibition in patients compared with controls. Therapeutic approaches that aim to normalize motor cortex inhibition during the subacute stage of recovery should be explored.

To better understand how arm weight support (WS) can be used to alleviate upper limb impairment after stroke, we investigated the effects of WS on muscle activity, muscle synergy expression, and corticomotor excitability (CME) in 13 chronic stroke patients and 6 age-similar healthy controls. For patients, lesion location and corticospinal tract integrity were assessed using magnetic resonance imaging. Upper limb impairment was assessed using the Fugl-Meyer upper extremity assessment with patients categorised as either mild or moderate-severe. Three levels of WS were examined: low = 0, medium = 50 and high = 100% of full support. Surface EMG was recorded from 8 upper limb muscles, and muscle synergies were decomposed using non-negative matrix factorisation from data obtained during reaching movements to an array of 14 targets using the paretic or dominant arm. Interactions between impairment level and WS were found for the number of targets hit, and EMG measures. Overall, greater WS resulted in lower EMG levels, although the degree of modulation between WS levels was less for patients with moderate-severe compared to mild impairment. Healthy controls expressed more synergies than patients with moderate-severe impairment. Healthy controls and patients with mild impairment showed more synergies with high compared to low weight support. Transcranial magnetic stimulation was used to elicit motor-evoked potentials (MEPs) to which stimulus-response curves were fitted as a measure of corticomotor excitability (CME). The effect of WS on CME varied between muscles and across impairment level. These preliminary findings demonstrate that WS has direct and indirect effects on muscle activity, synergies, and CME and warrants further study in order to reduce upper limb impairment after stroke.

The ability to acquire and retain novel motor skills is preserved with advancing age. However, the neurophysiological mechanisms underlying skill acquisition in older adults have received little systematic investigation. The aim of the present study was to assess the modulation of primary motor cortex excitability and inhibition after skill acquisition in young and older adults. Sixteen young and sixteen older adults trained on a sequential visual isometric wrist extension task. Anodal or sham transcranial direct current stimulation was applied during training in a pseudorandomized crossover design. Skill was quantified before, immediately after, 24 h and 7 days post-training. Transcranial magnetic stimulation protocols were used to examine corticomotor excitability and intracortical inhibition pre- and post-training. Corticomotor excitability increased and intracortical inhibition decreased after skill acquisition in both age groups. Anodal transcranial direct current stimulation did not enhance skill acquisition or the modulation of neurophysiological variables. These findings indicate potential neurophysiological mechanisms relevant for motor learning in neurorehabilitation contexts involving older adults, such as after stroke.

Background: Non-invasive neuromodulation may provide treatment strategies for neurological deficits affecting movement, such as stroke. For example, weak electrical stimulation applied to the hand by wearing a "mesh glove" (MGS) can transiently increase primary motor cortex (M1) excitability. Conversely, transcranial direct current stimulation with the cathode over M1 (c-tDCS) can decrease corticomotor excitability., Objective/hypothesis: We applied M1 c-tDCS as a priming adjuvant to MGS and hypothesised metaplastic effects would be apparent in improved motor performance and modulation of M1 inhibitory and facilitatory circuits., Methods: Sixteen right-handed neurologically healthy individuals participated in a repeated measures cross-over study; nine minutes of sham- or c-tDCS followed by 30 min of suprasensory threshold MGS. Dexterity of the non-dominant (left) hand was assessed using the grooved pegboard task, and measures of corticomotor excitability, intracortical facilitation, short-latency afferent inhibition (SAI), short-interval intracortical inhibition (SICI), and SAI in the presence of SICI (SAIxSICI), were obtained at baseline, post-tDCS, and 0, 30 and 60 min post-MGS., Results: There was a greater improvement in grooved pegboard completion times with c-tDCS primed MGS than sham + MGS. There was also more pronounced disinhibition of SAI. However, disinhibition of SAI in the presence of SICI was less and rest motor threshold higher compared to sham + MGS., Conclusions: The results indicate a metaplastic modulation of corticomotor excitability with c-tDCS primed MGS. Further studies are warranted to determine how various stimulation approaches can induce metaplastic effects on M1 neuronal circuits to boost functional gains obtained with motor practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Stroke is a leading cause of adult disability owing largely to motor impairment and loss of function. After stroke, there may be abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory function within primary motor cortex (M1), which may have implications for residual motor impairment and the potential for functional improvements at the chronic stage., Objective: To quantify GABA neurotransmission and concentration within ipsilesional and contralesional M1 and determine if they relate to upper limb impairment and function at the chronic stage of stroke., Methods: Twelve chronic stroke patients and 16 age-similar controls were recruited for the study. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Threshold tracking paired-pulse transcranial magnetic stimulation protocols were used to examine short- and long-interval intracortical inhibition and late cortical disinhibition. Magnetic resonance spectroscopy was used to evaluate GABA concentration., Results: Short-interval intracortical inhibition was similar between patients and controls ( P = .10). Long-interval intracortical inhibition was greater in ipsilesional M1 compared with controls ( P < .001). Patients who did not exhibit late cortical disinhibition in ipsilesional M1 were those with greater upper limb impairment and worse function ( P = .002 and P = .017). GABA concentration was lower within ipsilesional ( P = .009) and contralesional ( P = .021) M1 compared with controls, resulting in an elevated excitation-inhibition ratio for patients., Conclusion: These findings indicate that ipsilesional and contralesional M1 GABAergic inhibition are altered in this small cohort of chronic stroke patients. Further study is warranted to determine how M1 inhibitory networks might be targeted to improve motor function.

Background: In human primary motor cortex (M1), the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI) can be expressed conventionally as a percent change in the relative amplitude of a conditioned motor evoked potential to non-conditioned; or adaptive threshold-hunting a target motor evoked potential amplitude in the absence or presence of a conditioning stimulus, and noting the relative change in stimulation intensity. The suitability of each approach may depend on the induced current direction, which probe separate M1 interneuronal populations., Objective: To examine the influence of conditioning stimulus intensity, interstimulus interval (ISI) and current direction for adaptive threshold-hunting and conventional SICI using equivalent TMS intensities., Methods: In 16 participants (21-32 years), SICI was examined using adaptive threshold-hunting and conventional paired-pulse TMS with posterior-anterior and anterior-posterior stimulation, ISIs of 2 and 3 ms, and a range of conditioning intensities., Results: Inhibition with adaptive threshold-hunting was greater for anterior-posterior stimulation with an ISI of 3 ms (23.6 ± 9.0%) compared with 2 ms (7.5 ± 7.8%, P < 0.001) and posterior-anterior stimulation at both ISIs (2 ms 8.6 ± 8.7%, 3 ms 5.9 ± 4.8%; P < 0.001). There was an association between inhibition obtained with conventional and adaptive threshold-hunting for posterior-anterior but not anterior-posterior stimulation (2 ms only, r = 0.68, P = 0.03)., Conclusions: More inhibition was evident with anterior-posterior than posterior-anterior current for both adaptive threshold-hunting and conventional paired-pulse TMS. Assessment of SICI with anterior-posterior stimulation was not directly comparable between the two approaches. However, the amount of inhibition was dependent on conditioning stimulus intensity and ISI for both SICI techniques., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Interhemispheric inhibition between bilateral motor cortices is important for the performance of unimanual activities and may be compromised with advancing age. Conventionally, interhemispheric inhibition is assessed using paired-pulse transcranial magnetic stimulation (TMS) with constant conditioning and test stimulation parameters. Adaptive threshold hunting TMS, whereby a target motor-evoked potential amplitude is maintained in the presence of the conditioning, may provide an alternative means of assessment. Furthermore, interhemispheric inhibition may suppress late indirect-waves more so than early indirect-waves which can be preferentially elicited using anterior-posterior (AP) and posterior-anterior (PA) induced currents, respectively. The aim of this study was to assess age-related effects on interhemispheric inhibition using both conventional and threshold hunting techniques with PA- and AP-induced current. In 15 young and 15 older adults, short (10 ms) and long (40 ms) interval interhemispheric inhibition was examined in the nondominant extensor carpi radialis muscle at rest and during voluntary extension of the contralateral wrist. With the conventional technique, there were no age-related differences in short-interval interhemispheric inhibition. With threshold hunting and AP-induced current, young adults exhibited greater short-interval interhemispheric inhibition during contralateral activation compared with rest and compared with older adults. Furthermore, long-interval interhemispheric inhibition was greater in older adults compared with young for both conventional and threshold hunting techniques. Age-related differences in interhemispheric inhibition are evident with threshold hunting using PA- and AP-induced current., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA)-mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior-anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior-posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 ± 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICI AP was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICI AP and LICI AP modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after-effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA-mediated inhibitory circuits.

We routinely cancel preplanned movements that are no longer required. If stopping is forewarned, proactive processes are engaged to selectively decrease motor cortex excitability. However, without advance information there is a nonselective reduction in motor cortical excitability. In this study we examined modulation of human primary motor cortex inhibitory networks during response inhibition tasks with informative and uninformative cues using paired-pulse transcranial magnetic stimulation. Long- (LICI) and short-interval intracortical inhibition (SICI), indicative of GABA B - and GABA A -receptor mediated inhibition, respectively, were examined from motor evoked potentials obtained in task-relevant and task-irrelevant hand muscles when response inhibition was preceded by informative and uninformative cues. When the participants (10 men and 8 women) were cued to stop only a subcomponent of the bimanual response, the remaining response was delayed, and the extent of delay was greatest in the more reactive context, when cues were uninformative. For LICI, inhibition was reduced in both muscles during all types of response inhibition trials compared with the pre-task resting baseline. When cues were uninformative and left-hand responses were suddenly canceled, task-relevant LICI positively correlated with response times of the responding right hand. In trials where left-hand responding was highly probable or known (informative cues), task-relevant SICI was reduced compared with that when cued to rest, revealing a motor set indicative of responding. These novel findings indicate that the GABA B -receptor-mediated pathway may set a default inhibitory tone according to task context, whereas the GABA A -receptor-mediated pathways are recruited proactively with response certainty. NEW & NOTEWORTHY We examined how informative and uninformative cues that trigger both proactive and reactive processes modulate GABAergic inhibitory networks within human primary motor cortex. We show that GABA B inhibition was released during the task regardless of cue type, whereas GABA A inhibition was reduced when responding was highly probable or known compared with rest. GABA B -receptor-mediated inhibition may set a default inhibitory tone, whereas GABA A circuits may be modulated proactively according to response certainty.

Objective: Cervical propriospinal premotoneurons (PN) relay descending motor commands and integrate peripheral afferent feedback. Effects of anodal transcranial direct current stimulation (a-tDCS) on propriospinal excitability in the upper limbs are unknown., Methods: Healthy right-handed adults received a-tDCS or sham tDCS over primary motor cortex (M1) at 1mA (Experiment 1, n=18) or 2mA current intensity (Experiment 2, n=15). Propriospinal excitability was assessed by suppression of background electromyography (EMG) in extensor carpi radialis (ECR) from electrical stimulation of the superficial radial nerve during bilateral (Experiment 1 and 2) or unilateral (Experiment 2 only) activation of the left and/or right ECR. EMG suppression could be attributed to an early propriospinal component and late cortical component. Motor evoked potentials (MEP) were obtained as a manipulation check., Results: Before tDCS, propriospinal-mediated cutaneous-induced suppression was present in each arm for early and late components. ECR MEP amplitude increased after 1mA, but not 2mA, a-tDCS. Neither 1mA nor 2mA a-tDCS modulated either component of ipsilateral or contralateral propriospinal excitability during bilateral or unilateral tasks., Conclusions: Propriospinal-mediated cutaneous-induced suppression was not modulated by a-tDCS in healthy adults., Significance: Reporting non-significant findings is paramount for the development of clinically-relevant tDCS protocols., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The effects of healthy aging on γ-aminobutyric acid (GABA) within primary motor cortex (M1) remain poorly understood. Studies have reported contrasting results, potentially due to limitations with the common assessment technique. The aim of the present study was to investigate the effect of healthy aging on M1 GABA concentration and neurotransmission using a multimodal approach. Fifteen young and sixteen older adults participated in this study. Magnetic resonance spectroscopy (MRS) was used to measure M1 GABA concentration. Single-pulse and threshold-tracking paired-pulse transcranial magnetic stimulation (TMS) protocols were used to examine cortical silent period duration, short- and long-interval intracortical inhibition (SICI and LICI), and late cortical disinhibition (LCD). The reliability of TMS measures was examined with intraclass correlation coefficient analyses. SICI at 1 ms was reduced in older adults (15.13 ± 2.59%) compared with young (25.66 ± 1.44%; P = 0.002). However, there was no age-related effect for cortical silent period duration, SICI at 3 ms, LICI, or LCD (all P > 0.66). The intersession reliability of threshold-tracking measures was good to excellent for both young (range 0.75-0.96) and older adults (range 0.88-0.93). Our findings indicate that extrasynaptic inhibition may be reduced with advancing age, whereas GABA concentration and synaptic inhibition are maintained. Furthermore, MRS and threshold-tracking TMS provide valid and reliable assessment of M1 GABA concentration and neurotransmission, respectively, in young and older adults. NEW & NOTEWORTHY γ-Aminobutyric acid (GABA) in primary motor cortex was assessed in young and older adults using magnetic resonance spectroscopy and threshold-tracking paired-pulse transcranial magnetic stimulation. Older adults exhibited reduced extrasynaptic inhibition (short-interval intracortical inhibition at 1 ms) compared with young, whereas GABA concentration and synaptic inhibition were similar between age groups. We demonstrate that magnetic resonance spectroscopy and threshold-tracking provide valid and reliable assessments of primary motor cortex GABA concentration and neurotransmission, respectively., (Copyright © 2017 the American Physiological Society.)

Reactive response inhibition (RI) is the cancellation of a prepared response when it is no longer appropriate. Selectivity of RI can be examined by cueing the cancellation of one component of a prepared multi-component response. This substantially delays execution of other components. There is debate regarding whether this response delay is due to a selective neural mechanism. Here we propose a computational activation threshold model (ATM) and test it against a classical "horse-race" model using behavioural and neurophysiological data from partial RI experiments. The models comprise both facilitatory and inhibitory processes that compete upstream of motor output regions. Summary statistics (means and standard deviations) of predicted muscular and neurophysiological data were fit in both models to equivalent experimental measures by minimizing a Pearson Chi-square statistic. The ATM best captured behavioural and neurophysiological dynamics of partial RI. The ATM demonstrated that the observed modulation of corticomotor excitability during partial RI can be explained by nonselective inhibition of the prepared response. The inhibition raised the activation threshold to a level that could not be reached by the original response. This was necessarily followed by an additional phase of facilitation representing a secondary activation process in order to reach the new inhibition threshold and initiate the executed component of the response. The ATM offers a mechanistic description of the neural events underlying RI, in which partial movement cancellation results from a nonselective inhibitory event followed by subsequent initiation of a new response. The ATM provides a framework for considering and exploring the neuroanatomical constraints that underlie RI., Competing Interests: The authors have declared that no competing interests exist.

The use of arm weight support (WS) to optimize movement quality may be an avenue for improved upper limb stroke rehabilitation; however, the underlying neurophysiological effects of WS are not well understood. Rehabilitation exercises may be performed when sitting or standing, but the interaction of posture with WS has not been examined until now. We explored the effect of posture with WS on corticomotor excitability (CME) in healthy adults. Thirteen participants performed static shoulder abduction in two postures (sitting and standing) at three levels of WS (0, 45, and 90 % of full support). Transcranial magnetic stimulation of primary motor cortex was used to elicit motor-evoked potentials (MEPs) in eight upper limb muscles. Stimulus-response (SR) curves were fitted to the MEP data using nonlinear regression. Whole-body posture interacted with WS to influence tonic activity and CME in all muscles examined. SR curve parameters revealed greater CME when standing compared to sitting for upper arm muscles, but lower CME to the shoulder, forearm, and hand. Distal to the shoulder, tonic activity and CME were modulated independent of any explicit differences in task requirements. Overall, these results support a model of integrated upper limb control influenced by whole-body posture and WS. These findings have implications for the application of WS in settings such as upper limb rehabilitation after stroke.

Aerobic exercise can enhance neuroplasticity although presently the neural mechanisms underpinning these benefits remain unclear. One possible mechanism is through effects on primary motor cortex (M1) function via down-regulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The aim of the present study was to examine how corticomotor excitability (CME) and M1 intracortical inhibition are modulated in response to a single bout of moderate intensity aerobic exercise. Ten healthy right-handed adults were participants. Single- and paired-pulse transcranial magnetic stimulation was applied over left M1 to obtain motor-evoked potentials in the right flexor pollicis brevis. We examined CME, cortical silent period (SP) duration, short- and long-interval intracortical inhibition (SICI, LICI), and late cortical disinhibition (LCD), before and after acute aerobic exercise (exercise session) or an equivalent duration without exercise (control session). Aerobic exercise was performed on a cycle ergometer for 30 min at a workload equivalent to 60 % of maximal cardiorespiratory fitness (VO 2 peak; heart rate reserve = 75 ± 3 %, perceived exertion = 13.5 ± 0.7). LICI was reduced at 10 (52 ± 17 %, P = 0.03) and 20 min (27 ± 8 %, P = 0.03) post-exercise compared to baseline (13 ± 4 %). No significant changes in CME, SP duration, SICI or LCD were observed. The present study shows that GABA B -mediated intracortical inhibition may be down-regulated after acute aerobic exercise. The potential effects this may have on M1 plasticity remain to be determined.

Paired-pulse transcranial magnetic stimulation (TMS) can be used to probe inhibitory activity in primary motor cortex (M1). Recruitment of descending volleys with TMS depends on the induced current direction in M1. Anterior-posterior (AP) stimulation preferentially activates late indirect- (I-) waves that are most susceptible to paired-pulse TMS. Threshold tracking TMS can assess intracortical inhibition; however, previous studies have only used a current direction that preferentially recruits early I-waves [posterior-anterior (PA)]. Our objective was to examine intracortical inhibition with threshold tracking TMS designed to preferentially recruit early vs. late I-waves with PA and AP stimulation respectively. Electromyographic recordings were obtained from the right first dorsal interosseous muscle of 15 participants (21-50 years). Motor evoked potentials elicited by TMS over left M1 were recorded for PA, AP and lateromedial (LM) induced currents, with I-wave recruitment calculated as the onset latency difference between PA-LM and AP-LM. Short- and long-interval intracortical inhibition (SICI and LICI) were examined across a range of conditioning stimulus intensities and interstimulus intervals (3 and 100-260 ms) with threshold tracking TMS for PA and AP stimulation. SICI and LICI were greater for AP compared with PA current direction using threshold tracking. In addition, the efficacy of late I-wave recruitment was associated with the extent of SICI for AP but not PA stimulation, and was not associated with LICI. These findings indicate that threshold tracking with an AP-induced current provides a more robust and sensitive measure of M1 intracortical inhibition than PA., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Dual-hemisphere transcranial direct current stimulation over the primary motor cortex (M1-M1 tDCS) is assumed to modulate neural excitability in a polarity-dependent manner and improve motor performance of the hand. In the proximal upper limb, the neurophysiological and behavioural after-effects of M1-M1 tDCS are not well known. This study investigated the after-effects of M1-M1 tDCS on contralateral, ipsilateral and transcallosal excitability to the proximal upper limb muscle biceps brachii (BB). Circle tracing was used to assess motor performance before and after tDCS as this task requires coordination of proximal and distal musculature. Sixteen healthy right-handed adults participated in the study, each receiving M1-M1 tDCS (1 mA, 15 min) or sham tDCS in separate sessions. The anode was positioned over right M1 and cathode over left M1. M1-M1 tDCS suppressed transcallosal inhibition from the M1 under the cathode (P < 0.045). No other neurophysiologic or behavioural effects were observed (P > 0.6). The study provides important information regarding inconsistent neurophysiological and behavioural changes following tDCS that have implications for future tDCS research on the motor system.

Background: Recovery of upper limb function is important for regaining independence after stroke., Objective: To test the effects of priming upper limb physical therapy with intermittent theta burst stimulation (iTBS), a form of noninvasive brain stimulation., Methods: Eighteen adults with first-ever chronic monohemispheric subcortical stroke participated in this randomized, controlled, triple-blinded trial. Intervention consisted of priming with real or sham iTBS to the ipsilesional primary motor cortex immediately before 45 minutes of upper limb physical therapy, daily for 10 days. Changes in upper limb function (Action Research Arm Test [ARAT]), upper limb impairment (Fugl-Meyer Scale), and corticomotor excitability, were assessed before, during, and immediately, 1 month and 3 months after the intervention. Functional magnetic resonance images were acquired before and at one month after the intervention., Results: Improvements in ARAT were observed after the intervention period when therapy was primed with real iTBS, but not sham, and were maintained at 1 month. These improvements were not apparent halfway through the intervention, indicating a dose effect. Improvements in ARAT at 1 month were related to balancing of corticomotor excitability and an increase in ipsilesional premotor cortex activation during paretic hand grip., Conclusions: Two weeks of iTBS-primed therapy improves upper limb function at the chronic stage of stroke, for at least 1 month postintervention, whereas therapy alone may not be sufficient to alter function. This indicates a potential role for iTBS as an adjuvant to therapy delivered at the chronic stage., (© The Author(s) 2015.)

Background: Anodal transcranial direct current stimulation (a-tDCS) can facilitate primary motor cortex (M1), but the modulation of motor evoked potentials (MEPs) by a-tDCS varies between participants, and may depend on the balance between early versus late I-wave recruitment, as assessed by the difference in MEP latency between latero-medial and anterior-posterior cortical currents induced by transcranial magnetic stimulation (TMS)., Objective: To date, the dependence of tDCS after-effects on I-wave recruitment has only been investigated in intrinsic hand muscles. In order to better understand the effects of tDCS across the upper limb, the present study examined I-wave recruitment and MEP modulation by a-tDCS or dual-hemisphere tDCS in muscles of the forearm (Extensor Carpi Radialis; ECR) and proximal upper limb (Biceps Brachii; BB)., Methods: We conducted a randomized double-blind study with 18 healthy adults. Each received anodal, dual-hemisphere, or sham tDCS over M1 in separate sessions (tDCS, 1 mA for 15 min)., Results: Linear regression analyzes showed a-tDCS modulated MEP size dependent on the latency difference in the ECR (P = 0.01) but not BB (P = 0.28). Individuals with small MEP latency differences showed the expected facilitation of ECR MEPs after a-tDCS, whereas those with large MEP latency differences had suppressed ECR MEPs after a-tDCS. This relationship was not present after dual-hemisphere or sham tDCS in either muscle (all P > 0.32)., Conclusions: I-wave recruitment can predict the after-effects of a-tDCS in the distal but not proximal upper limb. These findings provide further insight into the variability of tDCS after-effects, and the relationship between I-wave recruitment and putative mechanisms of tDCS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Non-invasive brain stimulation techniques may be useful adjuvants to promote recovery after stroke. They are typically used to facilitate ipsilesional cortical excitability directly, or indirectly by suppressing contralesional cortical excitability and reducing interhemispheric inhibition from the contralesional to ipsilesional hemisphere. However, most of the evidence for this approach comes from studies of patients at the chronic stage of recovery., Hypothesis: We hypothesized that corticomotor excitability and interhemispheric inhibition would initially be asymmetric, with greater interhemispheric inhibition from contralesional to ipsilesional M1. We also hypothesized that balancing of corticomotor excitability and interhemispheric inhibition would be associated with greater improvements in paretic upper-limb impairment and function., Methods: We conducted a retrospective analysis of longitudinal data collected from 46 patients during the first six months after stroke. Transcranial magnetic stimulation was used to measure rest motor threshold, stimulus-response curves, and ipsilateral silent periods from the extensor carpi radialis muscles of both upper limbs. Analyses of variance and linear regression modeling were used to evaluate the effect of time on corticomotor excitability and interhemispheric inhibition in both hemispheres, and associations between these effects and improvements in paretic upper-limb impairment and function., Results: All participants had subcortical damage and only two had motor cortex involvement. As expected, ipsilesional corticomotor excitability was initially suppressed and increased over time, and this increase was associated with improved upper-limb impairment and function. However, interhemispheric inhibition was symmetrical and stable over time, and there was no evidence for a decrease in contralesional corticomotor excitability., Conclusions: Neuromodulation interventions applied during spontaneous recovery may be more beneficial if they facilitate ipsilesional corticomotor excitability directly., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Impairment or interruption of oxygen supply compromises brain function and plays a role in neurological and neurodegenerative conditions. Creatine is a naturally occurring compound involved in the buffering, transport, and regulation of cellular energy, with the potential to replenish cellular adenosine triphosphate without oxygen. Creatine is also neuroprotective in vitro against anoxic/hypoxic damage. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Here we investigate, for the first time in humans, the utility of creatine as a dietary supplement to protect against energetic insult. The aim of this study was to assess the influence of oral creatine supplementation on the neurophysiological and neuropsychological function of healthy young adults during acute oxygen deprivation. Fifteen healthy adults were supplemented with creatine and placebo treatments for 7 d, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 min, causing global oxygen deficit and impairing a range of neuropsychological processes. Hypoxia-induced decrements in cognitive performance, specifically attentional capacity, were restored when participants were creatine supplemented, and corticomotor excitability increased. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contributing factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials. Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents the decline in attention that occurs during severe oxygen deficit. This is the first demonstration of creatine's utility as a neuroprotective supplement when cellular energy provision is compromised., (Copyright © 2015 the authors 0270-6474/15/351773-08$15.00/0.)

Motor learning requires practice over a period of time and depends on brain plasticity, yet even for relatively simple movements, there are multiple practice strategies that can be used for skill acquisition. We investigated the role of intracortical inhibition in the primary motor cortex (M1) during motor skill learning. Event-related transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability and inhibition thought to involve synaptic and extrasynaptic γ-aminobutyric acid (GABA). Short intracortical inhibition (SICI) was assessed using 1- and 2.5-ms interstimulus intervals (ISIs). Participants learned a novel, sequential pinch-grip task on a computer in either a repetitive or interleaved practice structure. Both practice structures showed equivalent levels of motor performance at the end of acquisition and at retention 1 wk later. There was a novel task-related modulation of 1-ms SICI. Repetitive practice elicited a greater reduction of 1- and 2.5-ms SICI, i.e., disinhibition, between rest and task acquisition, compared with interleaved practice. These novel findings support the use of a repetitive practice structure for motor learning because the associated effects within M1 have relevance for motor rehabilitation., (Copyright © 2014 the American Physiological Society.)

Hand and foot movements are made more reliably when both limbs move in the same direction at the same time (isodirectional) compared with when they are made in opposite directions (anisodirectional). We hypothesized that M1 intracortical facilitation may subserve hand-foot coordination and reveal correlates that explain the preference for hand-foot movements to be performed in an isodirectional pattern. To test our hypothesis we investigated behavioral kinematics of hand-foot coordination (experiment 1) and neurophysiological measures of corticomotor excitability and intracortical facilitation (experiment 2) in 17 healthy young adults. As expected, coordination became unstable in the anisodirectional pattern but not the isodirectional pattern, as confirmed in measures of wrist and ankle relative phase error and stability (both P < 0.001). Short-latency paired-pulse TMS was used to elicit motor evoked potentials (MEPs) and produce short-latency intracortical facilitation (sICF) in right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) in the presence and absence of right ankle plantarflexion/dorsiflexion (P < 0.015). An isodirectional preference was confirmed by facilitation of FCR MEPs and TMS-induced wrist flexion during ankle plantarflexion (both P < 0.025) but no evidence of modulation of any particular "I wave" during foot movement compared with rest. A novel finding was the association between loss of stability of the anisodirectional pattern (experiment 1) and the modulation of corticomotor excitability in support of the isodirectional pattern (experiment 2) (P < 0.05). The preference for isodirectional hand-foot movements appears not to depend on M1 intracortical facilitation.

Background: The relationship between structural and functional integrity of descending motor pathways can predict the potential for motor recovery after stroke. The authors examine the relationship between brain imaging biomarkers within contralesional and ipsilesional hemispheres and hand function in well-recovered patients after subcortical stroke at the level of the internal capsule., Measures: of functional activation and integrity of the ipsilesional corticospinal tract might predict paretic hand function., Methods: A total of 14 patients in the chronic stable phase of motor recovery after subcortical stroke and 24 healthy age-matched individuals participated in the study. Functional MRI was used to examine BOLD contrast during passive wrist flexion-extension and paced or maximum-velocity active fist clenching. Functional integrity of the corticospinal pathway was assessed by transcranial magnetic stimulation to obtain motor-evoked potentials (MEPs) in the first dorsal interosseus muscle of the paretic and nonparetic hands. Fractional anisotropy and the proportion of traces between hemispheres in the posterior limb of both internal capsules were quantified using diffusion-weighted MRI., Results: Patients with smaller MEPs had a weaker paretic hand and more primary motor cortex activation in their affected hemisphere. Asymmetry between white matter tracts of either hemisphere was associated with reduced precision grip strength and increased BOLD activation within the contralesional dorsal premotor cortex for demanding hand tasks., Conclusion: There may be beneficial reorganization in contralesional secondary motor areas with increasing damage to the corticospinal tract after subcortical stroke. Associations between clinical, functional, and structural integrity measures in chronic stroke may lead to a better understanding of motor recovery processes.

Motor imagery (MI) increases corticomotor excitability and modulates intracortical inhibition. This study aimed to relate these neurophysiological mechanisms to imagery quality. Twenty-three healthy adults participated. First, the ability to vividly and accurately imagine performing a finger-to-thumb opposition task was evaluated by calculating a MI index (MII) based on psychological, behavioural and psychophysiological measurements. These scores were used to distinguish good from poor imagers. Transcranial magnetic stimulation was then used to assess modulation of corticomotor excitability, short-interval intracortical inhibition (sICI) and short-interval intracortical facilitation (sICF). Participants imagined abduction of their right thumb paced by a 1-Hz metronome. Single and paired magnetic stimuli were delivered at rest, while listening to the metronome, and during or between imagined movements. Corticomotor excitability was facilitated in the right opponens pollicis for good and poor imagers during MI, and this was positively correlated to the MII score. Poor imagers also facilitated corticomotor excitability of the right abductor digiti minimi, which was not involved in the movement. No interactions were found with sICI and sICF for good imagers, whereas poor imagers recruited intracortical facilitation while imagining. Accurate MI performance was characterised by muscle-specific temporal modulation of corticomotor excitability., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Both mental rotation (MR) and motor imagery (MI) involve an internalization of movement within motor and parietal cortex. Transcranial magnetic stimulation (TMS) techniques allow for a task-dependent investigation of the interhemispheric interaction between these areas. We used image-guided dual-coil TMS to investigate interactions between right inferior parietal lobe (rIPL) and left primary motor cortex (M1) in 11 healthy participants. They performed MI (right index-thumb pinching in time with a 1 Hz metronome) or hand MR tasks, while motor evoked potentials (MEPs) were recorded from right first dorsal interosseous. At rest, rIPL conditioning 6 ms prior to M1 stimulation facilitated MEPs in all participants, whereas this facilitation was abolished during MR. While rIPL conditioning 12 ms prior to M1 stimulation had no effect on MEPs at rest, it suppressed corticomotor excitability during MI. These results support the idea that rIPL forms part of a distinct inhibitory network that may prevent unwanted movement during imagery tasks.

Objective: To evaluate use-dependent plasticity (UDP) before and after training under metronome-paced and self-paced conditions., Methods: Twelve healthy adults were recruited to this cross-over, pseudo-randomized, repeated measures study. Participants performed wrist extension training that was either self-paced, or externally-paced to an auditory metronome at their preferred movement frequency or at a more demanding frequency. Motor evoked potentials from transcranial magnetic stimulation of left primary motor cortex were recorded in right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) to assess corticomotor excitability. The direction and velocity of TMS-evoked wrist movement (stimulus-evoked velocity, SEV) were measured before and after training to evaluate UDP., Results: The most persistent UDP occurred when training was metronome-paced at the participant's preferred movement frequency. This training protocol produced spatially selective modulation of resting ECR and FCR corticomotor excitability and directional tuning of TMS-evoked wrist movement toward the trained direction. Metronome-paced training at a more demanding frequency resulted in nonspecific facilitation of resting corticomotor excitability, and did not alter TMS-evoked wrist movement., Conclusions: These novel findings indicate that externally-paced training at the individual's preferred frequency facilitates UDP., Significance: UDP underpins motor recovery after stroke. Externally-paced training may be a useful adjunct to movement rehabilitation therapy., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Proximal upper limb muscles are represented bilaterally in primary motor cortex. Goal-directed upper limb movement requires precise control of proximal and distal agonist and antagonist muscles. Failure to suppress antagonist muscles can lead to abnormal movement patterns, such as those commonly experienced in the proximal upper limb after stroke. We examined whether noninvasive brain stimulation of primary motor cortex could be used to improve selective control of the ipsilateral proximal upper limb. Thirteen healthy participants performed isometric left elbow flexion by contracting biceps brachii (BB; agonist) and left forearm pronation (BB antagonist) before and after 20 min of cathodal transcranial direct current stimulation (c-tDCS) or sham tDCS of left M1. During the tasks, motor evoked potentials (MEPs) in left BB were acquired using single-pulse transcranial magnetic stimulation of right M1 150-270 ms before muscle contraction. As expected, left BB MEPs were facilitated before flexion and suppressed before pronation. After c-tDCS, left BB MEP amplitudes were reduced compared with sham stimulation, before pronation but not flexion, indicating that c-tDCS enhanced selective muscle activation of the ipsilateral BB in a task-specific manner. The potential for c-tDCS to improve BB antagonist control correlated with BB MEP amplitude for pronation relative to flexion, expressed as a selectivity ratio. This is the first demonstration that selective muscle activation in the proximal upper limb can be improved after c-tDCS of ipsilateral M1 and that the benefits of c-tDCS for selective muscle activation may be most effective in cases where activation strategies are already suboptimal. These findings may have relevance for the use of tDCS in rehabilitation after stroke.

This study investigated whether cathodal transcranial direct current stimulation (c-tDCS) of left primary motor cortex (M1) modulates excitability of ipsilateral propriospinal premotoneurons (PNs) in healthy humans. Transcranial magnetic stimulation (TMS) of the right motor cortex was used to obtain motor evoked potentials (MEPs) from the left biceps brachii (BB) while participants maintained contraction of the left BB. To examine presumed PN excitability, left BB MEPs were compared with those conditioned by median nerve stimulation (MNS) at the left elbow. Interstimulus intervals between TMS and MNS were set to produce summation at the C3-C4 level of the spinal cord. MNS facilitated BB MEPs elicited at TMS intensities near active motor threshold but inhibited BB MEPs at slightly higher intensities, indicative of putative PN modulation. c-tDCS suppressed the facilitatory and inhibitory effects of MNS. Sham tDCS did not alter either component. There was no effect of c-tDCS and sham tDCS on nonconditioned left BB MEPs or on the ipsilateral silent period of left BB. Right first dorsal interosseous MEPs were suppressed by c-tDCS. These results indicate that M1 c-tDCS can be used to modulate excitability of ipsilateral projections to presumed PNs controlling the proximal arm muscle BB. This technique may hold promise for promoting motor recovery of proximal upper limb function after stroke.

This study investigated whether repetitive transcranial magnetic stimulation (TMS) delivered as continuous theta burst stimulation (cTBS) to left M1 degraded selective muscle activation in the contralateral and ipsilateral upper limb in healthy participants. Contralateral motor-evoked potentials (cMEPs) were elicited in left and right biceps brachii (BB) before either elbow flexion or forearm pronation. A neurophysiological index, the excitability ratio (ER), was computed from the relative size of BB cMEPs before each type of movement. Short interval intracortical inhibition (SICI) was assessed in cMEPs of right BB with paired-pulse TMS of left M1. Ipsilateral MEPs (iMEPs) and silent periods (iSPs) were measured in left BB with single-pulse TMS of left M1. Low-intensity cTBS was expected to suppress corticospinal output from left M1. A sham condition was also included. Real but not sham cTBS caused increases in BB ER bilaterally. In the right arm, ER increased because BB cMEPs before flexion were less facilitated, whereas cMEPs in the pronation task were unaffected. This was accompanied by an increase in left M1 SICI. In the left arm, ER increased because BB cMEPs before pronation were facilitated but were unaffected in the flexion task. There was also facilitation of left BB iMEPs. These changes in the left arm are consistent with inappropriate facilitation of left BB α-motoneurons (αMNs) before pronation. This is the first demonstration that cTBS of M1 can alter excitability of neurons controlling ipsilateral proximal musculature and degrade ipsilateral upper limb motor control, providing evidence that ipsilateral and contralateral M1 shape the spatial and temporal characteristics of proximal muscle activation appropriate for the task at hand.

The presence of carbohydrate in the mouth can immediately improve physical performance. How this occurs is not well understood. Here we used transcranial magnetic stimulation of primary motor cortex (M1) to investigate the effects of non-sweet carbohydrate on corticomotor excitability and voluntary force production. In Experiment 1, 16 participants performed a fatiguing isometric elbow flexion exercise for 30 min, and Motor evoked potentials (MEPs) were recorded from the biceps brachii during maximal voluntary force (MVF) produced every 2 min. After 11 min participants drank a carbohydrate solution (CHO) or an energy-free placebo solution (PLA), in a double-blind, cross-over protocol. MEP amplitude increased by 30%, and MVF increased by 2%, immediately after carbohydrate ingestion. There was no relationship between the facilitation of MEP amplitude and plasma glucose or magnitude of fatigue. In a control experiment, 17 participants alternately mouth-rinsed CHO and PLA, in a randomized, double-blind protocol. MEPs were recorded from right first dorsal interosseous at rest or during isometric contraction. MEP amplitude increased by 9% with CHO, when the muscle was voluntarily activated. In both experiments, there were no effects on silent period duration, indicating that MEP facilitation was not due to reduced inhibition within M1. This is the first demonstration that carbohydrate in the mouth immediately increases the excitability of the corticomotor pathway, prior to its ingestion. Afference from oral receptors is integrated with descending motor output, perhaps via nuclei in the brainstem. This novel form of sensorimotor integration facilitates corticomotor output to both fatigued and fresh muscle., (2010 Elsevier B.V. All rights reserved.)

Cathodal transcranial DC stimulation (c-tDCS) suppresses excitability of primary motor cortex (M1) controlling contralateral hand muscles. This study assessed whether c-tDCS would have similar effects on ipsi- and contralateral M1 projections to a proximal upper limb muscle. Transcranial magnetic stimulation (TMS) of left M1 was used to elicit motor evoked potentials (MEPs) in the left and right infraspinatus (INF) muscle immediately before and after c-tDCS of left M1, and at 20 and 40 min, post-c-tDCS. TMS was delivered as participants preactivated each INF in isolation (left, right) or both INF together (bilateral). After c-tDCS, ipsilateral MEPs in left INF and contralateral MEPs in right INF were suppressed in the left task but not in the bilateral or right tasks, indicative of task-dependent modulation. Ipsilateral silent period duration in the left INF was reduced after c-tDCS, indicative of altered transcallosal inhibition. These findings may have implications for the use of tDCS as an adjunct to therapy for the proximal upper limb after stroke.

Task-specific focal dystonia is thought to have a neurological basis where stereotypical synchronous inputs and maladaptive plasticity play a role. As afferent input is a powerful driver of cortical reorganization, we propose that a period of asynchronous afferent stimulation may reverse maladaptive cortical changes and alleviate symptoms. Using transcranial magnetic stimulation (TMS), 3 hand muscles were mapped in 10 dystonics and 10 healthy controls. Mapping occurred before and after 1 h of nonassociative stimulation (NAS) to first dorsal interosseous (FDI) and abductor pollicis brevis (APB). Participants performed grip lift, handwriting, and cyclic drawing before and after NAS. Prior to NAS, dystonics had larger maps, and the centers of gravity (CoGs) of the FDI and APB maps were closer together. Dystonics demonstrated impairments in grip-lift, handwriting, and cyclic drawing tasks. Following NAS, map size was reduced in all muscles in dystonic participants and FDI and APB CoGs moved further apart. Among dystonics, NAS produced a reduction in movement variability during cyclic drawing. Thus, 1 h of NAS can reduce the magnitude, and increase the separation, of TMS representational maps. We suggest that these changes reflect some normalization of the representational abnormalities seen in focal dystonia and provide initial, limited evidence that such changes are associated with improvements in circle drawing.

Background: Repetitive transcranial magnetic stimulation can be used to explore functional connectivity between cortical areas., Objective: To determine the effects of two theta burst stimulation (TBS) patterns (intermittent, iTBS; and continuous, cTBS) of left dorsal premotor cortex (PMd)., Methods: Left PMd was identified in 11 participants using functional magnetic resonance imaging (fMRI), during performance of complex sequential finger movements. Each participant received iTBS, cTBS, or sham TBS of left PMd in three separate sessions within a randomized, single-blind design. The speed and accuracy of simple and complex sequential reaction time (RT) task performance was measured before and after TBS. The excitability of primary motor cortex (M1) bilaterally, and interhemispheric facilitation from left PMd to right M1, were also measured before and after TBS., Results: iTBS sped up the preparation of complex sequences performed with the right hand, with no detectable changes in M1 excitability. RT performance was maintained after cTBS, in the presence of increased left M1 excitability and suppressed right M1 excitability., Conclusions: Facilitatory and inhibitory TBS protocols applied to left PMd differentially alter corticomotor excitability and behavior, which suggests that these protocols affect different neuronal populations.

Processes that engage frontal cortex and the basal ganglia are responsible for the prevention of planned movements. Here, we review the role of primary motor cortex (M1) in this function. M1 receives and integrates input from a range of cortical and subcortical sites. It is also the final cortical processing site for voluntary motor commands, before they descend to the spinal cord. Inhibitory networks within M1 may be an important mechanism for the prevention or suppression of movement. Transcranial magnetic stimulation (TMS) has been used to evaluate corticospinal excitability and intracortical inhibition in humans, during the performance of a range of movement selection and prevention tasks. This review explores how M1 intracortical inhibition is selectively reduced to initiate desired voluntary movements, while movement prevention is associated with rapid, non-selective recruitment of inhibition within M1. The relationship between deficient intracortical inhibition and behavioural inhibition is also explored. Examples of neuropathology are reviewed, including focal dystonia, attention deficit hyperactivity disorder and Tourette syndrome. The strengths and limitations of TMS in the study of movement prevention are also discussed. While the precise functional links between M1 neuronal populations and the fronto-basal-ganglia network activated by movement prevention have yet to be elucidated, it is clear that M1 plays a critical role in the final processing stage of response inhibition.

Noninvasive transcranial stimulation is being increasingly used by clinicians and neuroscientists to alter deliberately the status of the human brain. Important applications are the induction of virtual lesions (for example, transient dysfunction) to identify the importance of the stimulated brain network for a certain sensorimotor or cognitive task, and the induction of changes in neuronal excitability, synaptic plasticity or behavioral function outlasting the stimulation, for example, for therapeutic purposes. The aim of this article is to review critically the properties of the different currently used stimulation protocols, including a focus on their particular strengths and weaknesses, to facilitate their appropriate and conscientious application.

After stroke, the function of primary motor cortex (M1) between the hemispheres may become unbalanced. Techniques that promote a re-balancing of M1 excitability may prime the brain to be more responsive to rehabilitation therapies and lead to improved functional outcomes. The present study examined the effects of Active-Passive Bilateral Therapy (APBT), a putative movement-based priming strategy designed to reduce intracortical inhibition and increase excitability within the ipsilesional M1. Thirty-two patients with upper limb weakness at least 6 months after stroke were randomized to a 1-month intervention of self-directed motor practice with their affected upper limb (control group) or to APBT for 10-15 min prior to the same motor practice (APBT group). A blinded clinical rater assessed upper limb function at baseline, and immediately and 1 month after the intervention. Transcranial magnetic stimulation was used to assess M1 excitability. Immediately after the intervention, motor function of the affected upper limb improved in both groups (P < 0.005). One month after the intervention, the APBT group had better upper limb motor function than control patients (P < 0.05). The APBT group had increased ipsilesional M1 excitability (P < 0.025), increased transcallosal inhibition from ipsilesional to contralesional M1 (P < 0.01) and increased intracortical inhibition within contralesional M1 (P < 0.005). None of these changes were found in the control group. APBT produced sustained improvements in upper limb motor function in chronic stroke patients and induced specific and sustained changes in motor cortex inhibitory function. We speculate that APBT may have facilitated plastic reorganization in the brain in response to motor therapy. The utility of APBT as an adjuvant to physical therapy warrants further consideration.

Objective: Motor imagery may activate the primary motor cortex (M1) and promote functional recovery following stroke. We investigated whether the hemisphere affected by stroke affects performance and M1 activity during motor imagery., Methods: Twelve stroke patients (6 left, 6 right hemisphere) and eight healthy age-matched adults participated. Experiment 1 assessed the speed and ease of actual and imagined motor performance. Experiment 2 measured corticomotor excitability during imagined movement of each hand separately, and both hands together, using transcranial magnetic stimulation., Results: For control participants, imagined movements were performed more slowly than actual movements, and right-hand MEPs were facilitated when they imagined moving their right hand or both hands together. Patients reported being able to imagine movements with either hand, despite no measurable facilitation of MEPs in the stroke-affected hand. In left hemisphere patients, MEPs were facilitated in the left hand during imagery of the right hand and both hands together. In right hemisphere patients, motor imagery did not facilitate MEPs in either hand., Conclusions: Motor imagery does not appear to facilitate the ipsilesional M1 following stroke., Significance: Motor imagery may play a role in rehabilitating movement planning, but its role in directly facilitating corticomotor output appears limited.

Objective: To evaluate the role of coordination mode on the generation of use-dependent plasticity (UDP) within the primary motor cortex (M1)., Methods: Ten healthy volunteers performed brisk repetitive thumb movements for 30 min in the opposite direction to those evoked by transcranial magnetic stimulation (TMS) prior to training. This practice was synchronized or syncopated with a 1 Hz auditory metronome in two separate sessions. Motor evoked potentials (MEPs) were recorded from 3 intrinsic thumb muscles, to assess changes in corticomotor excitability., Results: Both synchronized and syncopated motor practice induced changes in the direction of TMS-evoked thumb movements, away from the baseline direction toward the trained direction. MEP amplitude increased following synchronized, but not syncopated, motor practice. Changes in movement direction and corticomotor excitability lasted for at least 30 minutes., Conclusions: UDP can be elicited in the presence or absence of changes in corticomotor excitability., Significance: Motor practice that is synchronized with external pacing may promote UDP and facilitate corticomotor excitability in patient populations with reduced corticomotor output, such as stroke. Training that is syncopated with external pacing may promote UDP without increasing corticomotor excitability. This could be relevant for individuals with disorders characterized by maladaptive plasticity.

Coincident hand and foot movements are more reliably performed in the same direction than in opposite directions. Using transcranial magnetic stimulation (TMS) to assess motor cortex function, we examined the physiological basis of these movements across three novel experiments. Experiment 1 demonstrated that upper limb corticomotor excitability changed in a way that facilitated isodirectional movements of the hand and foot, during phasic and isometric muscle activation conditions. Experiment 2 demonstrated that motor cortex inhibition was modified with active, but not passive, foot movement in a manner that facilitated hand movement in the direction of foot movement. Together, these findings demonstrate that the coupling between motor representations within motor cortex is activity dependent. Because there are no known connections between hand and foot areas within primary motor cortex, experiment 3 used a dual-coil paired-pulse TMS protocol to examine functional connectivity between secondary and primary motor areas during active ankle dorsiflexion and plantarflexion. Dorsal premotor cortex (PMd) and supplementary motor area (SMA) conditioning, but not ventral premotor cortex (PMv) conditioning, produced distinct phases of task-dependent modulation of excitability of forearm representations within primary motor cortex (M1). Networks involving PMd-M1 facilitate isodirectional movements of hand and foot, whereas networks involving SMA-M1 facilitate corticomotor pathways nonspecifically, which may help to stabilize posture during interlimb coordination. These results may have implications for targeted neurorehabilitation after stroke.

Volitional inhibition is the voluntary prevention of a prepared movement. Here we ask whether primary motor cortex (M1) is a site of convergence of cortical activity associated with movement preparation and volitional inhibition. Volitional inhibition was studied by presenting a stop signal before execution of an anticipated response that requires a key lift to intercept a revolving dial. Motor evoked potentials (MEPs) were elicited in intrinsic hand muscles by transcranial magnetic stimulation (TMS) to assess corticomotor excitability and short interval intracortical inhibition (sICI) during task performance. The closer the stop cue was presented to the anticipated response, the harder it was for subjects to inhibit their response. Corticomotor pathway excitability was temporally modulated during volitional inhibition. Using subthreshold TMS, corticomotor excitability was reduced for Stop trials relative to Go trials from 140 ms after the cue. sICI was significantly greater for Stop trials compared with Go trials at a time that preceded the onset of muscle activity associated with the anticipated response. These results provide evidence that volitional inhibition is exerted at a cortical level and that inhibitory networks within M1 contribute to volitional inhibition of prepared action.

Fourteen neurologically healthy, right-handed subjects performed a choice-hand reaction time (RT) task, which involved wrist flexion or extension of either the left or right hand to one of three fixed target locations corresponding to 45 degrees flexion, 20 degrees flexion, or 20 degrees extension from the starting position. In each trial, a pre-cue provided information regarding the forthcoming target location. The hand was specified by the imperative signal. Focal transcranial magnetic stimulation (TMS) was delivered over the hand motor area of either the right or left hemisphere at set times during the foreperiod, and at random intervals during the RT interval defined by electromyography onset. As expected, an increase in corticomotor excitability was observed in the agonist of the responding hand over the RT interval. When the cue appeared at a location that required flexion with either hand, an increase in excitability was observed following stimulation over the hemisphere ipsilateral to the responding hand, indicating activation of the homologous muscle. However, when the cue appeared at a location at which the response would require flexion with one hand and extension with the other, the modulation of excitability was also based on the direction of the response. This direction-specific effect was only observed for TMS delivered to the left hemisphere during the left-hand movement, and suggested goal-based preparation in the left hemisphere independent of whether the actual movement is made with the right or left hand. These results indicate that both the homologous-muscle and the directional-specific constraints affect the corticomotor excitability of the non-responding hand.