Proactive Interhemispheric Disinhibition Supports Response Preparation during Selective Stopping.

Response inhibition is essential for terminating inappropriate actions. A substantial response delay may occur in the nonstopped effector when only part of a multieffector action is terminated. This stopping-interference effect has been attributed to nonselective response inhibition processes and can be reduced with proactive cuing. This study aimed to elucidate the role of interhemispheric primary motor cortex (M1-M1) influences during selective stopping with proactive cuing. We hypothesized that stopping-interference would be reduced as stopping certainty increased because of proactive recruitment of interhemispheric facilitation or inhibition when cued to respond or stop, respectively. Twenty-three healthy human participants of either sex performed a bimanual anticipatory response inhibition paradigm with cues signaling the likelihood of a stop-signal occurring. Dual-coil transcranial magnetic stimulation was used to determine corticomotor excitability (CME), interhemispheric inhibition (IHI), and interhemispheric facilitation (IHF) in the left hand at rest and during response preparation. Response times slowed and stopping-interference decreased with increased stopping certainty. Proactive response inhibition was marked by a reduced rate of rise and faster cancel time in electromyographical bursts during stopping. There was a nonselective release of IHI but not CME from rest to in-task response preparation, whereas IHF was not observed in either context. An effector-specific reduction in CME but no reinstatement of IHI was observed when the left hand was cued to stop. These findings indicate that stopping speed and selectivity are better with proactive cueing and that interhemispheric M1-M1 channels modulate inhibitory tone during response preparation to support going but not proactive response inhibition.SIGNIFICANCE STATEMENT Response inhibition is essential for terminating inappropriate actions and, in some cases, may be required for only part of a multieffector action. The present study examined interhemispheric influences between the primary motor cortices during selective stopping with proactive cuing. Stopping selectivity was greater with increased stopping certainty and was marked by proactive adjustments to the hand cued to stop and hand cued to respond separately. Inhibitory interhemispheric influences were released during response preparation but were not directly involved in proactive response inhibition. These findings indicate that between-hand stopping can be selective with proactive cuing, but cue-related improvements are unlikely to reflect the advance engagement of interhemispheric influences between primary motor cortices.

Corticomotor pathway function and recovery after stroke: a look back and a way forward.

Stroke is a leading cause of adult disability that results in motor deficits and reduced independence. Regaining independence relies on motor recovery, particularly regaining function of the hand and arm. This review presents evidence from human studies that have used transcranial magnetic stimulation (TMS) to identify neurophysiological mechanisms underlying upper limb motor recovery early after stroke. TMS studies undertaken at the subacute stage after stroke have identified several neurophysiological factors that can drive motor impairment, including membrane excitability, the recruitment of corticomotor neurons, and glutamatergic and GABAergic neurotransmission. However, the inherent variability and subsequent poor reliability of measures derived from motor evoked potentials (MEPs) limit the use of TMS for prognosis at the individual patient level. Currently, prediction tools that provide the most accurate information about upper limb motor outcomes for individual patients early after stroke combine clinical measures with a simple neurophysiological biomarker based on MEP presence or absence, i.e. MEP status. Here, we propose a new compositional framework to examine MEPs across several upper limb muscles within a threshold matrix. The matrix can provide a more comprehensive view of corticomotor function and recovery after stroke by quantifying the evolution of subthreshold and suprathreshold MEPs through compositional analyses. Our contention is that subthreshold responses might be the most sensitive to reduced output of corticomotor neurons, desynchronized firing of the remaining neurons, and myelination processes that occur early after stroke. Quantifying subthreshold responses might provide new insights into post-stroke neurophysiology and improve the accuracy of prediction of upper limb motor outcomes.

The excitability of ipsilateral motor evoked potentials is not task-specific and spatially distinct from the contralateral motor hotspot.

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.

A global pause generates nonselective response inhibition during selective stopping.

Selective response inhibition may be required when stopping a part of a multicomponent action. A persistent response delay (stopping-interference effect) indicates nonselective response inhibition during selective stopping. This study aimed to elucidate whether nonselective response inhibition is the consequence of a global pause process during attentional capture or specific to a nonselective cancel process during selective stopping. Twenty healthy human participants performed a bimanual anticipatory response inhibition paradigm with selective stop and ignore signals. Frontocentral and sensorimotor beta-bursts were recorded with electroencephalography. Corticomotor excitability and short-interval intracortical inhibition in primary motor cortex were recorded with transcranial magnetic stimulation. Behaviorally, responses in the non-signaled hand were delayed during selective ignore and stop trials. The response delay was largest during selective stop trials and indicated that stopping-interference could not be attributed entirely to attentional capture. A stimulus-nonselective increase in frontocentral beta-bursts occurred during stop and ignore trials. Sensorimotor response inhibition was reflected in maintenance of beta-bursts and short-interval intracortical inhibition relative to disinhibition observed during go trials. Response inhibition signatures were not associated with the magnitude of stopping-interference. Therefore, nonselective response inhibition during selective stopping results primarily from a nonselective pause process but does not entirely account for the stopping-interference effect.

Stopping Interference in Response Inhibition: Behavioral and Neural Signatures of Selective Stopping.

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.

Comparing anticipatory and stop-signal response inhibition with a novel, open-source selective stopping toolbox.

Response inhibition is essential for terminating inappropriate actions and, in some cases, may be required selectively. Selective stopping can be investigated with multicomponent anticipatory or stop-signal response inhibition paradigms. Here we provide a freely available open-source Selective Stopping Toolbox (SeleST) to investigate selective stopping using either anticipatory or stop-signal task variants. This study aimed to evaluate selective stopping between the anticipatory and stop-signal variants using SeleST and provide guidance to researchers for future use. Forty healthy human participants performed bimanual anticipatory response inhibition and stop-signal tasks in SeleST. Responses were more variable and slowed to a greater extent during the stop-signal than in the anticipatory paradigm. However, the stop-signal paradigm better conformed to the assumption of the independent race model of response inhibition. The expected response delay during selective stop trials was present in both variants. These findings indicate that selective stopping can successfully be investigated with either anticipatory or stop-signal paradigms in SeleST. We propose that the anticipatory paradigm should be used when strict control of response times is desired, while the stop-signal paradigm should be used when it is desired to estimate stop-signal reaction time with the independent race model. Importantly, the dual functionality of SeleST allows researchers flexibility in paradigm selection when investigating selective stopping.

Reliability of a TMS-derived threshold matrix of corticomotor function.

Transcranial magnetic stimulation (TMS) studies typically focus on suprathreshold motor evoked potentials (MEPs), overlooking small MEPs representing subthreshold corticomotor pathway activation. Assessing subthreshold excitability could provide insights into corticomotor pathway integrity and function, particularly in neurological conditions like stroke. The aim of the study was to examine the test-retest reliability of metrics derived from a novel compositional analysis of MEP data from older adults. The study also compared the composition between the dominant (D) and non-dominant (ND) sides and explored the association between subthreshold responses and resting motor threshold. In this proof-of-concept study, 23 healthy older adults participated in two identical experimental sessions. Stimulus-response (S-R) curves and threshold matrices were constructed using single-pulse TMS across intensities to obtain MEPs in four upper limb muscles. S-R curves had reliable slopes for every muscle (Intraclass Correlation Coefficient range = 0.58-0.88). Subliminal and suprathreshold elements of the threshold matrix showed good-excellent reliability (D subliminal ICC = 0.83; ND subliminal ICC = 0.79; D suprathreshold ICC = 0.92; ND suprathreshold ICC = 0.94). By contrast, subthreshold elements of the matrix showed poor reliability, presumably due to a floor effect (D subthreshold ICC = 0.39; ND subthreshold ICC = 0.05). No composition differences were found between D and ND sides (suprathreshold BF01 = 3.85; subthreshold BF01 = 1.68; subliminal BF01 = 3.49). The threshold matrix reliably assesses subliminal and suprathreshold MEPs in older adults. Further studies are warranted to evaluate the utility of compositional analyses for assessing recovery of corticomotor pathway function after neurological injury.

Muscle synergies are associated with intermuscular coherence and cortico-synergy coherence in an isometric upper limb task.

To elucidate the underlying physiological mechanisms of muscle synergies, we investigated long-range functional connectivity by cortico-muscular (CMC), intermuscular (IMC) and cortico-synergy (CSC) coherence. Fourteen healthy participants executed an isometric upper limb task in synergy-tuned directions. Cortical activity was recorded using 32-channel electroencephalography (EEG) and muscle activity using 16-channel electromyography (EMG). Using non-negative matrix factorisation (NMF), we calculated muscle synergies from two different tasks. A preliminary multidirectional task was used to identify synergy-preferred directions (PDs). A subsequent coherence task, consisting of generating forces isometrically in the synergy PDs, was used to assess the functional connectivity properties of synergies. Overall, we were able to identify four different synergies from the multidirectional task. A significant alpha band IMC was consistently present in all extracted synergies. Moreover, IMC alpha band was higher between muscles with higher weights within a synergy. Interestingly, CSC alpha band was also significantly higher across muscles with higher weights within a synergy. In contrast, no significant CMC was found between the motor cortex area and synergy muscles. The presence of a shared input onto synergistic muscles within a synergy supports the idea of neurally derived muscle synergies that build human movement. Our findings suggest cortical modulation of some of the synergies and the consequential existence of shared input between muscles within cortically modulated synergies.

Fast Outcome Categorization of the Upper Limb After Stroke.

BACKGROUND AND PURPOSE: The ARAT (Action Research Arm Test) has been used to classify upper limb motor outcome after stroke in 1 of 3, 4, or 5 categories. The COVID-19 pandemic has encouraged the development of assessments that can be performed quickly and remotely. The aim of this study was to derive and internally validate decision trees for categorizing upper limb motor outcomes at the late subacute and chronic stages of stroke using a subset of ARAT tasks. METHODS: This study retrospectively analyzed ARAT scores obtained in-person at 3 months poststroke from 333 patients. In-person ARAT scores were used to categorize patients' 3-month upper limb outcome using classification systems with 3, 4, and 5 outcome categories. Individual task scores from in-person assessments were then used in classification and regression tree analyses to determine subsets of tasks that could accurately categorize upper limb outcome for each of the 3 classification systems. The decision trees developed using 3-month ARAT data were also applied to in-person ARAT data obtained from 157 patients at 6 months poststroke. RESULTS: The classification and regression tree analyses produced decision trees requiring 2 to 4 ARAT tasks. The overall accuracy of the cross-validated decision trees ranged from 87.7% (SE, 1.0%) to 96.7% (SE, 2.0%). Accuracy was highest when classifying patients into one of 3 outcome categories and lowest for 5 categories. The decision trees are referred to as FOCUS (Fast Outcome Categorization of the Upper Limb After Stroke) assessments and they remained accurate for 6-month poststroke ARAT scores (overall accuracy range 83.4%-91.7%). CONCLUSIONS: A subset of ARAT tasks can accurately categorize upper limb motor outcomes after stroke. Future studies could investigate the feasibility and accuracy of categorizing outcomes using the FOCUS assessments remotely via video call.

Decoupling countermands nonselective response inhibition during selective stopping.

Response inhibition is essential for goal-directed behavior within dynamic environments. Selective stopping is a complex form of response inhibition where only part of a multieffector response must be cancelled. A substantial response delay emerges on unstopped effectors when a cued effector is successfully stopped. This stopping-interference effect is indicative of nonselective response inhibition during selective stopping, which may, in part, be a consequence of functional coupling. The present study examined selective stopping of (de)coupled bimanual responses in healthy human participants of either sex. Participants performed synchronous and asynchronous versions of an anticipatory stop-signal paradigm across two sessions while mu (µ) and beta (ß) rhythms were measured with electroencephalography. Results showed that responses were behaviorally decoupled during asynchronous go trials and the extent of response asynchrony was associated with lateralized sensorimotor µ- and ß-desynchronization during response preparation. Selective stopping produced a stopping-interference effect and was marked by a nonselective increase and subsequent rebound in prefrontal and sensorimotor ß. In support of the coupling account, stopping-interference was smaller during selective stopping of asynchronous responses and negatively associated with the magnitude of decoupling. However, the increase in sensorimotor ß during selective stopping was equivalent between the stopped and unstopped hand irrespective of response synchrony. Overall, the findings demonstrate that decoupling facilitates selective stopping after a global pause process and emphasizes the importance of considering the influence of both the go and stop context when investigating response inhibition.NEW & NOTEWORTHY Humans rely on their ability to stop preplanned or ongoing movements. The present study identified neural signatures of response preparation and inhibition from electroencephalography during selective stopping of coupled and decoupled bimanual responses. Stopping was more selective for decoupled compared with coupled responses and supported by lateralization of sensorimotor mu and beta power during response preparation. These findings demonstrate that decoupling may have functional significance for understanding cognitive control in the form of selective stopping.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Intracortical facilitation and inhibition in human primary motor cortex during motor skill acquisition.

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.

The role of interhemispheric communication during complete and partial cancellation of bimanual responses.

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.

The modulation of short and long-latency interhemispheric inhibition during bimanually coordinated movements.

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.

Neurochemical balance and inhibition at the subacute stage after stroke.

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.

Primary motor cortex function and motor skill acquisition: insights from threshold-hunting TMS.

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.

Between-hand coupling during response inhibition.

Response inhibition reflects the process of terminating inappropriate preplanned or ongoing movements. When one hand is cued to stop after preparing a bimanual response (Partial trial), there is a substantial delay on the responding side. This delay is termed the interference effect and identifies a constraint that limits selective response inhibition. γ-Aminobutyric acid (GABA)-mediated networks within primary motor cortex (M1) may have distinct roles during response inhibition. In this study we examined whether the interference effect is the consequence of between-hand "coupling" into a unitary response and whether this is reflected in GABAergic intracortical inhibition within M1. Eighteen healthy right-handed participants performed a bimanual synchronous and asynchronous anticipatory response inhibition task. Electromyographic recordings were obtained from the first dorsal interosseous muscle bilaterally. Motor evoked potentials were elicited by single- and paired-pulse transcranial magnetic stimulation over right M1. As expected, Go trial performance was better with the synchronous compared with the asynchronous version of the task. Paradoxically, response delays during Partial trials were longer with the synchronous compared with the asynchronous task. Although task difficulty did not modulate GABAergic intracortical inhibition, there was a trend for between-hand coupling on asynchronous trials to be associated with greater GABAB receptor-mediated inhibition and lesser recruitment of GABAA receptor-mediated inhibition. The novel findings indicate that the interference effect is in part a consequence of between-hand coupling into a unitary response during movement preparation. The ability to respond independently with the two hands may rely on modulation of distinct inhibitory processes.NEW & NOTEWORTHY The temporal dynamics of an anticipated response task were manipulated to effect the difficulty of behavioral stopping and the underlying effects on motor neurophysiology. There were large response delays during trials where a subcomponent of an upcoming bimanual response was cued to stop in conditions where the anticipated action of the hands were synchronous, but not when asynchronous. Response delays reflected the integration of actions of both hands into a unitary response.

Neurophysiological mechanisms underlying motor skill learning in young and older adults.

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.

Effects of arm weight support on neuromuscular activation during reaching in chronic stroke patients.

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.

Response inhibition activates distinct motor cortical inhibitory processes.

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 GABAB- and GABAA-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 GABAB-receptor-mediated pathway may set a default inhibitory tone according to task context, whereas the GABAA-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 GABAB inhibition was released during the task regardless of cue type, whereas GABAA inhibition was reduced when responding was highly probable or known compared with rest. GABAB-receptor-mediated inhibition may set a default inhibitory tone, whereas GABAA circuits may be modulated proactively according to response certainty.