Cardiac activity impacts cortical motor excitability.

Human cognition and action can be influenced by internal bodily processes such as heartbeats. For instance, somatosensory perception is impaired both during the systolic phase of the cardiac cycle and when heartbeats evoke stronger cortical responses. Here, we test whether these cardiac effects originate from overall changes in cortical excitability. Cortical and corticospinal excitability were assessed using electroencephalographic and electromyographic responses to transcranial magnetic stimulation while concurrently monitoring cardiac activity with electrocardiography. Cortical and corticospinal excitability were found to be highest during systole and following stronger neural responses to heartbeats. Furthermore, in a motor task, hand-muscle activity and the associated desynchronization of sensorimotor oscillations were stronger during systole. These results suggest that systolic cardiac signals have a facilitatory effect on motor excitability-in contrast to sensory attenuation that was previously reported for somatosensory perception. Thus, it is possible that distinct time windows exist across the cardiac cycle, optimizing either perception or action.

Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity.

Humans and other animals are able to adjust their speed-accuracy trade-off (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. A total of 50 participants performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in 2 contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation (TMS) on multiple motor representations, eliciting motor-evoked potentials (MEPs) in 9 finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while participants were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, although this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.

The pathobiology of psychomotor slowing in psychosis: altered cortical excitability and connectivity.

Psychomotor slowing is a frequent symptom of schizophrenia. Short-interval intracortical inhibition assessed by transcranial magnetic stimulation demonstrated inhibitory dysfunction in schizophrenia. The inhibitory deficit results from additional noise during information processing in the motor system in psychosis. Here, we tested whether cortical inhibitory dysfunction was linked to psychomotor slowing and motor network alterations. In this cross-sectional study, we included 60 patients with schizophrenia and psychomotor slowing determined by the Salpêtrière Retardation Rating Scale, 23 patients without slowing and 40 healthy control participants. We acquired single and double-pulse transcranial magnetic stimulation effects from the left primary motor cortex, resting-state functional connectivity and diffusion imaging on the same day. Groups were compared on resting motor threshold, amplitude of the motor evoked potentials, as well as short-interval intracortical inhibition. Regression analyses calculated the association between motor evoked potential amplitudes or cortical inhibition with seed-based resting-state functional connectivity from the left primary motor cortex and fractional anisotropy at whole brain level and within major motor tracts. In patients with schizophrenia and psychomotor slowing, we observed lower amplitudes of motor evoked potentials, while the short-interval intracortical inhibition/motor evoked potentials amplitude ratio was higher than in healthy controls, suggesting lower cortical inhibition in these patients. Patients without slowing also had lower amplitudes of motor evoked potentials. Across the combined patient sample, cortical inhibition deficits were linked to more motor coordination impairments. In patients with schizophrenia and psychomotor slowing, lower amplitudes of motor evoked potentials were associated with lower fractional anisotropy in motor tracts. Moreover, resting-state functional connectivity between the primary motor cortex, the anterior cingulate cortex and the cerebellum increased with stronger cortical inhibition. In contrast, in healthy controls and patients without slowing, stronger cortical inhibition was linked to lower resting-state functional connectivity between the left primary motor cortex and premotor or parietal cortices. Psychomotor slowing in psychosis is linked to less cortical inhibition and aberrant functional connectivity of the primary motor cortex. Higher neural noise in the motor system may drive psychomotor slowing and thus may become a treatment target.

Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Beta rebound reduces subsequent movement preparation time by modulating of GABAA inhibition.

Post-movement beta synchronization is an increase of beta power relative to baseline, which commonly used to represent the status quo of the motor system. However, its functional role to the subsequent voluntary motor output and potential electrophysiological significance remain largely unknown. Here, we examined the reaction time of a Go/No-Go task of index finger tapping which performed at the phases of power baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds (ballistic/self-paced) in 13 healthy subjects. We found a correlation between the post-movement beta synchronization and reaction time that larger post-movement beta synchronization prolonged the reaction time during Go trials. To probe the electrophysiological significance of post-movement beta synchronization, we assessed intracortical inhibitory measures probably involving GABAB (long-interval intracortical inhibition) and GABAA (short-interval intracortical inhibition) receptors in beta baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds. We found that short-interval intracortical inhibition but not long-interval intracortical inhibition increased in post-movement beta synchronization peak compared with that in the power baseline, and was negatively correlated with the change of post-movement beta synchronization peak value. These novel findings indicate that the post-movement beta synchronization is related to forward model updating, with high beta rebound predicting longer time for the preparation of subsequent movement by inhibitory neural pathways of GABAA.

Motor cortex activation during visuomotor transformations: evoked potentials during overt and imagined movements.

Despite the prevalence of visuomotor transformations in our motor skills, their mechanisms remain incompletely understood, especially when imagery actions are considered such as mentally picking up a cup or pressing a button. Here, we used a stimulus-response task to directly compare the visuomotor transformation underlying overt and imagined button presses. Electroencephalographic activity was recorded while participants responded to highlights of the target button while ignoring the second, non-target button. Movement-related potentials (MRPs) and event-related desynchronization occurred for both overt movements and motor imagery (MI), with responses present even for non-target stimuli. Consistent with the activity accumulation model where visual stimuli are evaluated and transformed into the eventual motor response, the timing of MRPs matched the response time on individual trials. Activity-accumulation patterns were observed for MI, as well. Yet, unlike overt movements, MI-related MRPs were not lateralized, which appears to be a neural marker for the distinction between generating a mental image and transforming it into an overt action. Top-down response strategies governing this hemispheric specificity should be accounted for in future research on MI, including basic studies and medical practice.

Ultra-early navigated transcranial magnetic stimulation for perioperative stroke: anatomo-functional report.

Navigated repetitive transmagnetic stimulation is a non-invasive and safe brain activity modulation technique. When combined with the classical rehabilitation process in stroke patients it has the potential to enhance the overall neurologic recovery. We present a case of a peri-operative stroke, treated with ultra-early low frequency navigated repetitive transmagnetic stimulation over the contralesional hemisphere. The patient received low frequency navigated repetitive transmagnetic stimulation within 12 hours of stroke onset for seven consecutive days and a significant improvement in his right sided weakness was noticed and he was discharge with normal power. This was accompanied by an increase in the number of positive responses evoked by navigated repetitive transmagnetic stimulation and a decrease of the resting motor thresholds at a cortical level. Subcortically, a decrease in the radial, axial, and mean diffusivity were recorded in the ipsilateral corticospinal tract and an increase in fractional anisotropy, axial diffusivity, and mean diffusivity was observed in the interhemispheric fibers of the corpus callosum responsible for the interhemispheric connectivity between motor areas. Our case demonstrates clearly that ultra-early low frequency navigated repetitive transmagnetic stimulation applied to the contralateral motor cortex can lead to significant clinical motor improvement in patients with subcortical stroke.

Cortically Evoked Movement in Humans Reflects History of Prior Executions, Not Plan for Upcoming Movement.

Human motor behavior involves planning and execution of actions, some more frequently. Manipulating probability distribution of a movement through intensive direction-specific repetition causes physiological bias toward that direction, which can be cortically evoked by transcranial magnetic stimulation (TMS). However, because evoked movement has not been used to distinguish movement execution and plan histories to date, it is unclear whether the bias is because of frequently executed movements or recent planning of movement. Here, in a cohort of 40 participants (22 female), we separately manipulate the recent history of movement plans and execution and probe the resulting effects on physiological biases using TMS and on the default plan for goal-directed actions using a timed-response task. Baseline physiological biases shared similar low-level kinematic properties (direction) to a default plan for upcoming movement. However, manipulation of recent execution history via repetitions toward a specific direction significantly affected physiological biases, but not plan-based goal-directed movement. To further determine whether physiological biases reflect ongoing motor planning, we biased plan history by increasing the likelihood of a specific target location and found a significant effect on the default plan for goal-directed movements. However, TMS-evoked movement during preparation did not become biased toward the most frequent plan. This suggests that physiological biases may either provide a readout of the default state of primary motor cortex population activity in the movement-related space, but not ongoing neural activation in the planning-related space, or that practice induces sensitization of neurons involved in the practiced movement, calling into question the relevance of cortically evoked physiological biases to voluntary movements.SIGNIFICANCE STATEMENT Human motor performance depends not only on ability to make movements relevant to the environment/body's current state, but also on recent action history. One emerging approach to study recent movement history effects on the brain is via physiological biases in cortically-evoked involuntary movements. However, because prior movement execution and plan histories were indistinguishable to date, to what extent physiological biases are due to pure execution-dependent history, or to prior planning of the most probable action, remains unclear. Here, we show that physiological biases are profoundly affected by recent movement execution history, but not ongoing movement planning. Evoked movement, therefore, provides a readout of the default state within the movement space, but not of ongoing activation related to voluntary movement planning.

Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.

Pairing Transcranial Magnetic Stimulation and Loud Sounds Produces Plastic Changes in Motor Output.

Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50 ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30 min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms.SIGNIFICANCE STATEMENT Induction of plasticity by neurostimulation protocols may be promising to enhance functional recovery after damage such as following stroke, but current protocols mainly target cortical circuits. In this study, we developed a novel paradigm which may generate long-term changes in connections between cortex and brainstem. This could provide an additional tool to modulate and improve recovery.

Personalized depth-specific neuromodulation of the human primary motor cortex via ultrasound.

Non-invasive brain stimulation has the potential to boost neuronal plasticity in the primary motor cortex (M1), but it remains unclear whether the stimulation of both superficial and deep layers of the human motor cortex can effectively promote M1 plasticity. Here, we leveraged transcranial ultrasound stimulation (TUS) to precisely target M1 circuits at depths of approximately 5 mm and 16 mm from the cortical surface. Initially, we generated computed tomography images from each participant's individual anatomical magnetic resonance images (MRI), which allowed for the generation of accurate acoustic simulations. This process ensured that personalized TUS was administered exactly to the targeted depths within M1 for each participant. Using long-term depression and long-term potentiation (LTD/LTP) theta-burst stimulation paradigms, we examined whether TUS over distinct depths of M1 could induce LTD/LTP plasticity. Our findings indicated that continuous theta-burst TUS-induced LTD-like plasticity with both superficial and deep M1 stimulation, persisting for at least 30 min. In comparison, sham TUS did not significantly alter M1 excitability. Moreover, intermittent theta-burst TUS did not result in the induction of LTP- or LTD-like plasticity with either superficial or deep M1 stimulation. These findings suggest that the induction of M1 plasticity can be achieved with ultrasound stimulation targeting distinct depths of M1, which is contingent on the characteristics of TUS. KEY POINTS: The study integrated personalized transcranial ultrasound stimulation (TUS) with electrophysiology to determine whether TUS targeting superficial and deep layers of the human motor cortex (M1) could elicit long-term depression (LTD) or long-term potentiation (LTP) plastic changes. Utilizing acoustic simulations derived from individualized pseudo-computed tomography scans, we ensured the precision of TUS delivery to the intended M1 depths for each participant. Continuous theta-burst TUS targeting both the superficial and deep layers of M1 resulted in the emergence of LTD-like plasticity, lasting for at least 30 min. Administering intermittent theta-burst TUS to both the superficial and deep layers of M1 did not lead to the induction of LTP- or LTD-like plastic changes. We suggest that theta-burst TUS targeting distinct depths of M1 can induce plasticity, but this effect is dependent on specific TUS parameters.

Scale-invariant changes in corticospinal excitability reflect multiplexed oscillations in the motor output.

In the absence of disease, humans produce smooth and accurate movement trajectories. Despite such 'macroscopic' aspect, the 'microscopic' structure of movements reveals recurrent (quasi-rhythmic) discontinuities. To date, it is unclear how the sensorimotor system contributes to the macroscopic and microscopic architecture of movement. Here, we investigated how corticospinal excitability changes in relation to microscopic fluctuations that are naturally embedded within larger macroscopic variations in motor output. Participants performed a visuomotor tracking task. In addition to the 0.25 Hz modulation that is required for task fulfilment (macroscopic scale), the motor output shows tiny but systematic fluctuations at ∼2 and 8 Hz (microscopic scales). We show that motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) during task performance are consistently modulated at all (time) scales. Surprisingly, MEP modulation covers a similar range at both micro- and macroscopic scales, even though the motor output differs by several orders of magnitude. Thus, corticospinal excitability finely maps the multiscale temporal patterning of the motor output, but it does so according to a principle of scale invariance. These results suggest that corticospinal excitability indexes a relatively abstract level of movement encoding that may reflect the hierarchical organisation of sensorimotor processes. KEY POINTS: Motor behaviour is organised on multiple (time)scales. Small but systematic ('microscopic') fluctuations are engrained in larger and slower ('macroscopic') variations in motor output, which are instrumental in deploying the desired motor plan. Corticospinal excitability is modulated in relation to motor fluctuations on both macroscopic and microscopic (time)scales. Corticospinal excitability obeys a principle of scale invariance, that is, it is modulated similarly at all (time)scales, possibly reflecting hierarchical mechanisms that optimise motor encoding.

Associative Visuomotor Learning Using Transcranial Magnetic Stimulation Induces Stimulus-Response Interference.

Classical conditioning states that the systematic co-occurrence of a neutral stimulus with an unconditioned stimulus can cause the neutral stimulus to, over time, evoke the same response as the unconditioned stimulus. On a neural level, Hebbian learning suggests that this type of learning occurs through changes in synaptic plasticity when two neurons are simultaneously active, resulting in increased connectivity between them. Inspired by associative learning theories, we here investigated whether the mere co-activation of visual stimuli and stimulation of the primary motor cortex using TMS would result in stimulus-response associations that can impact future behavior. During a learning phase, we repeatedly paired the presentation of a specific color (but not other colors) with a TMS pulse over the motor cortex. Next, participants performed a two-alternative forced-choice task where they had to categorize simple shapes and we studied whether the shapes' task-irrelevant color (and its potentially associated involuntary motor activity) affected the required motor response. Participants showed more errors on incongruent trials for stimuli that were previously paired with high intensity TMS pulses, but only when tested on the same day. Using a drift diffusion model for conflict tasks, we further demonstrate that this interference occurred early, and gradually increased as a function of associated TMS intensity. Taken together, our findings show that the human brain can learn stimulus-response associations using externally induced motor cortex stimulation. Although we were inspired by the Hebbian learning literature, future studies should investigate whether Hebbian or other learning processes were also what brought about this effect.

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

BACKGROUND: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. METHODS: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. RESULTS: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. CONCLUSIONS: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

Contextual expectations shape the motor coding of movement kinematics during the prediction of observed actions: A TMS study.

Contextual information may shape motor resonance and support intention understanding during observation of incomplete, ambiguous actions. It is unclear, however, whether this effect is contingent upon kinematics ambiguity or contextual information is continuously integrated with kinematics to predict the overarching action intention. Moreover, a differentiation between the motor mapping of the intention suggested by context or kinematics has not been clearly demonstrated. In a first action execution phase, 29 participants were asked to perform reaching-to-grasp movements towards big or small food objects with the intention to eat or to move; electromyography from the First Dorsal Interosseous (FDI) and Abductor Digiti Minimi (ADM) was recorded. Depending on object size, the intentions to eat or to move were differently implemented by a whole-hand or a precision grip kinematics, thus qualifying an action-muscle dissociation. Then, in a following action prediction task, the same participants were asked to observe an actor performing the same actions and to predict his/her intention while motor resonance was assessed for the same muscles. Of note, videos were interrupted at early or late action phases, and actions were embedded in contexts pointing toward an eating or a moving intention, congruently or incongruently with kinematics. We found greater involvement of the FDI or ADM in the execution of precision or whole-hand grips, respectively. Crucially, this pattern of activation was mirrored during observation of the same actions in congruent contexts, but it was cancelled out or reversed in the incongruent ones, either when videos were interrupted at either early or long phases of action deployment. Our results extend previous evidence by showing that contextual information shapes motor resonance not only under conditions of perceptual uncertainty but also when more informative kinematics is available.

Local vibration induces changes in spinal and corticospinal excitability in vibrated and antagonist muscles.

Local vibration (LV) applied over the muscle tendon constitutes a powerful stimulus to activate the muscle spindle primary (Ia) afferents that project to the spinal level and are conveyed to the cortical level. This study aimed to identify the neuromuscular changes induced by a 30-min LV-inducing illusions of hand extension on the vibrated flexor carpi radialis (FCR) and the antagonist extensor carpi radialis (ECR) muscles. We studied the change of the maximal voluntary isometric contraction (MVIC, experiment 1) for carpal flexion and extension, motor-evoked potentials (MEPs, experiment 2), cervicomedullary motor-evoked potentials (CMEPs, experiment 2), and Hoffmann's reflex (H-reflex, experiment 3) for both muscles at rest. Measurements were performed before (PRE) and at 0, 30, and 60 min after LV protocol. A lasting decrease in strength was only observed for the vibrated muscle. The reduction in CMEPs observed for both muscles seems to support a decrease in alpha motoneurons excitability. In contrast, a slight decrease in MEPs responses was observed only for the vibrated muscle. The MEP/CMEP ratio increase suggested greater cortical excitability after LV for both muscles. In addition, the H-reflex largely decreased for the vibrated and the antagonist muscles. The decrease in the H/CMEP ratio for the vibrated muscle supported both pre- and postsynaptic causes of the decrease in the H-reflex. Finally, LV-inducing illusions of movement reduced alpha motoneurons excitability for both muscles with a concomitant increase in cortical excitability.NEW & NOTEWORTHY Spinal disturbances confound the interpretation of excitability changes in motor areas and compromise the conclusions reached by previous studies using only a corticospinal marker for both vibrated and antagonist muscles. The time course recovery suggests that the H-reflex perturbations for the vibrated muscle do not only depend on changes in alpha motoneurons excitability. Local vibration induces neuromuscular changes in both vibrated and antagonist muscles at the spinal and cortical levels.

The paired-pulse TMS paradigm of short intracortical inhibition is mediated by a reduction of repetitive motor neuron discharges.

Transcranial magnetic stimulation (TMS) causes repetitive spinal motoneuron discharges (repMNDs), but the effects of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) on repMNDs remain unknown. Triple stimulation technique (TST) and the extended TST-protocols that include a fourth and fifth stimulation, the Quadruple (QuadS) and Quintuple (QuintS) stimulation, respectively, offer a precise estimate of cortical and spinal motor neuron discharges, including repMNDs. The objective of our study was to explore the effects of SICI and ICF on repMNDs. We explored conventional paired-pulse TMS protocols of SICI and ICF with the TMS, TST, the QuadS, and the QuintS protocols, in a randomized study design in 20 healthy volunteers. We found significantly less repMNDs in the SICI paradigm compared with a single-pulse TMS (SP-TMS). No significant difference was observed in the ICF paradigm. There was a significant inter- and intrasubject variability in both SICI and ICF. We demonstrate a significant reduction of repMNDs in SICI, which may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no increase in repMNDs in ICF suggesting another mechanism underlying facilitation. This study provides the proof that a reduction of repMNDs mediates the inhibition seen in SICI.NEW & NOTEWORTHY Significant reduction of repetitive motor neuron discharges (repMNDs) in short-interval intracortical inhibition (SICI) may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no change in the number of repMNDs in intracortical facilitation (ICF). There was a significant variability in SICI and ICF in healthy subjects.

Different descending pathways mediate early and late portions of lower limb responses to transcranial magnetic stimulation.

Although recent studies in nonhuman primates have provided evidence that transcranial magnetic stimulation (TMS) activates cells within the reticular formation, it remains unclear whether descending brain stem projections contribute to the generation of TMS-induced motor evoked potentials (MEPs) in skeletal muscles. We compared MEPs in muscles with extensive direct corticomotoneuronal input (first dorsal interosseous) versus a prominent role in postural control (gastrocnemius) to determine whether the amplitudes of early and late MEPs were differentially modulated by cortical suppression. Suprathreshold TMS was applied with and without a preceding suprathreshold TMS pulse at two interstimulus intervals (50 and 80 ms). H reflexes in target muscles were also tested with and without TMS conditioning. Early and late gastrocnemius MEPs were differentially modulated by cortical inhibition, the amplitude of the early MEP being significantly reduced by cortical suppression and the late MEP facilitated. The amplitude of H reflexes in the gastrocnemius was reduced within the cortical silent period. Early MEPs in the first dorsal interosseous were also reduced during the silent period, but late MEPs were unaffected. Independent modulation of early and late MEPs in the gastrocnemius muscle supports the idea that the MEP is generated by multiple descending pathways. Suppression of the early MEP is consistent with transmission along the fast-conducting corticospinal tract, whereas facilitation of the late MEP suggests transmission along a corticofugal, potentially cortico-reticulospinal, pathway. Accordingly, differences in late MEP modulation between the first dorsal interosseous and gastrocnemius reflect an increased role of corticofugal pathways in the control of postural muscles.NEW & NOTEWORTHY Early and late portions of the response to transcranial magnetic stimulation (TMS) in a lower limb postural muscle are modulated independently by cortical suppression, late motor evoked potentials (MEPs) being facilitated during cortical inhibition. These results suggest a cortico-brain stem transmission pathway for late portions of the TMS-induced MEP.