The effects of transcutaneous spinal cord stimulation delivered with and without high-frequency modulation on spinal and corticospinal excitability.

Transcutaneous spinal cord stimulation (TSCS) has been shown to improve motor recovery in people with spinal cord injury (SCI). Some groups deliver TSCS modulated with a kHz-frequency (TSCS-kHz); the intensity used for TSCS-kHz is usually set based on the motor threshold for TSCS, even though TSCS-kHz threshold is considerably higher than TSCS. As a result, TSCS-kHz interventions tend to be delivered at low intensities with respect to the motor threshold (~40%). In this study, we compared the effects of sub-threshold TSCS and TSCS-kHz, when delivered at similar intensity relative to their own motor threshold. Experiment I compared the after-effects of 20 min of sub-threshold (40% threshold) TSCS and TSCS-kHz on spinal and corticospinal excitability in able-bodied participants. Experiment II assessed the dose-response relationship of delivering short (10-pulse) trains of TSCS and TSCS-kHz at three different current intensities relative to the threshold (40%, 60%, and 80%). Experiment I found that 20 min of TSCS-kHz at a 40% threshold decreased posterior root reflex amplitude (p < 0.05), whereas TSCS did not. In experiment II, motor-evoked potential (MEP) amplitude increased following short trains of TSCS and TSCS-kHz of increasing intensity. MEP amplitude was significantly greater for TSCS-kHz compared with TSCS when delivered at 80% of the threshold (p < 0.05). These results suggest that TSCS and TSCS-kHz have different effects when delivered at similar intensity relative to their own threshold; both for immediate effects on corticospinal excitability and following prolonged stimulation on spinal excitability. These different effects may be utilized for optimal rehabilitation in people with SCI.

Failing to attend versus failing to stop: Single-trial decomposition of action-stopping in the stop signal task.

The capacity to stop impending or ongoing actions contributes to executive control over behavior. Action-stopping, however, is difficult to directly quantify. It is therefore assayed via computational modeling of behavior in the stop signal task to estimate the latency of stopping (stop signal reaction time, SSRT) and, more recently, the reliability of stopping in terms of the distribution of SSRTs (standard deviation, SD-SSRT) and the frequency with which one outright fails to react to a stop signal (trigger failures, TF). Critically, the validity of computational estimates remains unknown because we currently have no direct readouts of behavior against which to compare them. Here, we developed a method for providing single-trial behavioral readouts of SSRT and trigger failures. The method relies on an adaptation of the stop signal task in which participants respond by moving a computer mouse. In two online experiments, we used movement kinematics to quantify stopping performance (SSRT, SD-SSRT, and TF), and then applied the standard Race Model and recent BEESTS model in order to examine the convergent validity of the methods. Overall, we demonstrate good correspondence between kinematics- and model-based estimates of stopping performance at the group and individual level. We conclude that the new method provides valid estimates of stopping performance that, unlike model-based estimates, can be read out at the level of single trials. Our approach might therefore be useful for interrogating single-trial neurophysiological correlates of stopping and for large-scale, online studies of behavioral stopping.

Motor cortex oscillates at its intrinsic post-movement beta rhythm following real (but not sham) single pulse, rhythmic and arrhythmic transcranial magnetic stimulation.

We aimed to test the idea that rhythmic transcranial magnetic stimulation (TMS) entrains cortical oscillations. To do this, we examined oscillatory responses in the electroencephalogram (EEG) to TMS over primary motor cortex. In particular, we contrasted responses to real TMS with those to sham TMS in order to dissociate the contributions of direct (transcranial) activation and indirect activation (via auditory/sensory input) of the brain. We first showed that real single pulse TMS elicited a brief (∼200 ms) increase in sensorimotor beta power whose frequency closely matched that of each individual's post-movement beta rebound (PMBR, ∼18 Hz). Sham TMS triggered minimal oscillatory activity. Together this implies that real TMS interacts with endogenous oscillations via direct brain activation. We then showed that although trains of real rhythmic TMS delivered at each individuals PMBR frequency produced a brief increase in beta power at the same frequency, real arrhythmic TMS also elicited an equivalent increase in beta. The implication is that the oscillatory response is independent of the rhythm of stimulation. By contrast, sham stimulation elicited minimal activity in the beta band, and the responses to rhythmic and arrhythmic sham TMS were broadly similar, showing that sham rhythmic stimulation did not produce entrainment via sensory rhythms. Together, the data demonstrate that the beta oscillatory response of M1 to real TMS predominantly reflects direct activation of the underlying cortex. However, the data do not support the notion of rhythmic TMS enhancing oscillatory activity via entrainment-like mechanisms, at least within the constraints of the current experimental set-up.

The Immediate and Short-Term Effects of Transcutaneous Spinal Cord Stimulation and Peripheral Nerve Stimulation on Corticospinal Excitability.

Rehabilitative interventions involving electrical stimulation show promise for neuroplastic recovery in people living with Spinal Cord Injury (SCI). However, the understanding of how stimulation interacts with descending and spinal excitability remain unclear. In this study we compared the immediate and short-term (within a few minutes) effects of pairing Transcranial Magnetic Stimulation (TMS) with transcutaneous Spinal Cord stimulation (tSCS) and Peripheral Nerve Stimulation (PNS) on Corticospinal excitability in healthy subjects. Three separate experimental conditions were assessed. In Experiment I, paired associative stimulation (PAS) was applied, involving repeated pairing of single pulses of TMS and tSCS, either arriving simultaneously at the spinal motoneurones (PAS0ms) or slightly delayed (PAS5ms). Corticospinal and spinal excitability, and motor performance, were assessed before and after the PAS interventions in 24 subjects. Experiment II compared the immediate effects of tSCS and PNS on corticospinal excitability in 20 subjects. Experiment III compared the immediate effects of tSCS with tSCS delivered at the same stimulation amplitude but modulated with a carrier frequency (in the kHz range) on corticospinal excitability in 10 subjects. Electromyography (EMG) electrodes were placed over the Tibialis Anterior (TA) soleus (SOL) and vastus medialis (VM) muscles and stimulation electrodes (cathodes) were placed on the lumbar spine (tSCS) and lateral to the popliteal fossa (PNS). TMS over the primary motor cortex (M1) was paired with tSCS or PNS to produce Motor Evoked Potentials (MEPs) in the TA and SOL muscles. Simultaneous delivery of repetitive PAS (PAS0ms) increased corticospinal excitability and H-reflex amplitude at least 5 min after the intervention, and dorsiflexion force was increased in a force-matching task. When comparing effects on descending excitability between tSCS and PNS, a subsequent facilitation in MEPs was observed following tSCS at 30-50 ms which was not present following PNS. To a lesser extent this facilitatory effect was also observed with HF- tSCS at subthreshold currents. Here we have shown that repeated pairing of TMS and tSCS can increase corticospinal excitability when timed to arrive simultaneously at the alpha-motoneurone and can influence functional motor output. These results may be useful in optimizing stimulation parameters for neuroplasticity in people living with SCI.

Two forms of short-interval intracortical inhibition in human motor cortex.

BACKGROUND: Pulses of transcranial magnetic stimulation (TMS) with a predominantly anterior-posterior (AP) or posterior-anterior (PA) current direction over the primary motor cortex appear to activate distinct excitatory inputs to corticospinal neurons. In contrast, very few reports have examined whether the inhibitory neurons responsible for short-interval intracortical inhibition (SICI) are sensitive to TMS current direction. OBJECTIVES: To investigate whether SICI evaluated with AP and PA conditioning stimuli (CSPA and CSAP) activate different inhibitory pathways. SICI was always assessed using a PA-oriented test stimulus (TSPA). METHODS: Using two superimposed TMS coils, CSPA and CSAP were applied at interstimulus intervals (ISI) of 1-5 ms before a TSPA, and at a range of different intensities. Using a triple stimulation design, we then tested whether SICI at ISI of 3 ms using opposite directions of CS (SICICSPA3 and SICICSAP3) interacted differently with three other forms of inhibition, including SICI at ISI of 2 ms (SICICSPA2), cerebellum-motor cortex inhibition (CBI 5 ms) and short-latency afferent inhibition (SAI 22 ms). Finally, we compared the effect of tonic and phasic voluntary contraction on SICICSPA3 and SICICSAP3. RESULTS: CSAP produced little SICI at ISIs = 1 and 2 ms. However, at ISI = 3 ms, both CSAP and CSPA were equally effective at the same percent of maximum stimulator output. Despite this apparent similarity, combining SICICSPA3 or SICICSAP3 with other forms of inhibition led to quite different results: SICICSPA3 interacted in complex ways with CBI, SAI and SICICSPA2, whereas the effect of SICICSAP3 appeared to be quite independent of them. Although SICICSPA and SICICSAP were both reduced by the same amount during voluntary tonic contraction compared with rest, in a simple reaction time task SICICSAP was disinhibited much earlier following the imperative signal than SICICSPA. CONCLUSIONS: SICICSPA appears to activate a different inhibitory pathway to that activated by SICICSAP. The difference is behaviourally relevant since the pathways are controlled differently during volitional contraction. The results may explain some previous pathological data and open the possibility of testing whether these pathways are differentially recruited in a range of tasks.

Comparative Study of a Continuous Train of Theta-Burst Stimulation for a Duration of 20 s (cTBS 300) versus a Duration of 40 s (cTBS 600) in a Pre-Stimulation Relaxed Condition in Healthy Volunteers.

As variable after effects have been observed following phasic muscle contraction prior to continuous theta-burst stimulation (cTBS), we here investigated two cTBS protocols (cTBS300 and cTBS600) in 20 healthy participants employing a pre-relaxed muscle condition including visual feedback on idle peripheral surface EMG activity. Furthermore, we assessed corticospinal excitability measures also from a pre-relaxed state to better understand the potential impact of these proposed contributors to TBS. Motor-evoked potential (MEP) magnitude changes were assessed for 30 min. The linear model computed across both experimental paradigms (cTBS300 and cTBS600) revealed a main effect of TIME COURSE (p = 0.044). Separate exploratory analysis for cTBS300 revealed a main effect of TIME COURSE (p = 0.031), which did not maintain significance after Greenhouse-Geisser correction (p = 0.073). For cTBS600, no main effects were observed. An exploratory analysis revealed a correlation between relative SICF at 2.0 ms (p = 0.006) and after effects (relative mean change) of cTBS600, which did not survive correction for multiple testing. Our findings thereby do not support the hypothesis of a specific excitability modulating effect of cTBS applied to the human motor-cortex in setups with pre-relaxed muscle conditions.

Towards real-world generalizability of a circuit for action-stopping.

Two decades of cross-species neuroscience research on rapid action-stopping in the laboratory has provided motivation for an underlying prefrontal-basal ganglia circuit. Here we provide an update of key studies from the past few years. We conclude that this basic neural circuit is on increasingly firm ground, and we move on to consider whether the action-stopping function implemented by this circuit applies beyond the simple laboratory stop signal task. We advance through a series of studies of increasing 'real-worldness', starting with laboratory tests of stopping of speech, gait and bodily functions, and then going beyond the laboratory to consider neural recordings and stimulation during moments of control presumably required in everyday activities such as walking and driving. We end by asking whether stopping research has clinical relevance, focusing on movement disorders such as stuttering, tics and freezing of gait. Overall, we conclude there are hints that the prefrontal-basal ganglia action-stopping circuit that is engaged by the basic stop signal task is recruited in myriad scenarios; however, truly proving this for real-world scenarios requires a new generation of studies that will need to overcome substantial technical and inferential challenges.

Reliability of transcranial magnetic stimulation measurements of maximum activation of the knee extensors in young adult males.

PURPOSE: METHODS: RESULTS: CONCLUSION.

Corticospinal excitability and motor representation after long-term resistance training.

It is poorly understood how the central nervous system adapts to resistance training, especially after years of exposure. We compared corticospinal excitability and motor representation assessed with transcranial magnetic stimulation (TMS) between long-term resistance trained (LRT, ≥3 years) versus untrained (UNT) males (n = 15/group). Motor-evoked potentials (MEPs) were obtained from the biceps brachii during isometric elbow flexion. Stimulus-response curves were created at the hotspot during 10% maximum voluntary torque (MVT) contractions. Maximum peak-to-peak MEP amplitude (MEPmax) was acquired with 100% stimulator output intensity, whilst 25%-100% MVT was produced. Maps were created during 10% MVT contractions, with an individualised TMS intensity eliciting 20% MEPmax at the hotspot. LRT had a 48% lower stimulus-response curve slope than UNT (p < .05). LRT also had a 66% larger absolute map size, although TMS intensity used for mapping was greater in LRT versus UNT (48% vs. 26% above active motor threshold) to achieve a target 20% MEPmax at the hotspot, due to the lower slope of LRT. Map size was strongly correlated with the TMS intensity used for mapping (r = 0.776, p < .001). Once map size was normalised to TMS intensity, there was no difference between the groups (p = .683). We conclude that LRT had a lower stimulus-response curve slope/excitability, suggesting higher neural efficiency. TMS map size was overwhelmingly determined by TMS intensity, even when the MEP response at the hotspot was matched among individuals, likely due to larger current spread with higher intensities. Motor representation appears similar between LRT and UNT given no difference in the normalised map size.

Reduced differentiation of emotion-associated bodily sensations in autism.

LAY ABSTRACT: More research has been conducted on how autistic people understand and interpret other people's emotions, than on how autistic people experience their own emotions. The experience of emotion is important however, because it can relate to difficulties like anxiety and depression, which are common in autism. In neurotypical adults and children, different emotions have been associated with unique maps of activity patterns in the body. Whether these maps of emotion are comparable in autism is currently unknown. Here, we asked 100 children and adolescents, 45 of whom were autistic, to color in outlines of the body to indicate how they experienced seven emotions. Autistic adults and children sometimes report differences in how they experience their internal bodily states, termed interoception, and so we also investigated how this related to the bodily maps of emotion. In this study, the autistic children and adolescents had comparable interoception to the non-autistic children and adolescents, but there was less variability in their maps of emotion. In other words, they showed more similar patterns of activity across the different emotions. This was not related to interoception, however. This work suggests that there are differences in how autistic people experience emotion that are not explained by differences in interoception. In neurotypical people, less variability in emotional experiences is linked to anxiety and depression, and future work should seek to understand if this is a contributing factor to the increased prevalence of these difficulties in autism.

Corticospinal excitability modulation by pairing peripheral nerve stimulation with cortical states of movement initiation.

KEY POINTS: We compare the effects on corticospinal excitability of repeatedly delivering peripheral nerve stimulation at three time points (-30 ms, 0 ms, +50 ms) relative to muscle onset in a cue-guided task. Plastic changes in excitability are only observed when stimuli are delivered immediately before the time when muscles activate, while stimuli delivered at muscle onset or shortly later (0, +50 ms) have no effect. Plastic effects are abolished if there is ongoing volitional electromyogram activity in the muscles prior to the onset of the phasic contraction. The plastic effects induced by timing peripheral stimulation relative to electromyographic markers of muscle activation are as effective as those that occur if stimulation is timed relative to electroencephalographic markers of motor cortical activation. We provide a simple alternative protocol to induce plasticity in people in whom electroencephalogram recording is difficult. ABSTRACT: Plastic changes in corticospinal excitability (CSE) and motor function can be induced in a targeted and long-term manner if afferent volleys evoked by peripheral nerve stimulation are repeatedly associated with the peak of premovement brain activity assessed with an electroencephalogram (EEG). The present study investigated whether other factors might also characterize this optimal brain state for plasticity induction. In healthy human volunteers (n = 24), we found that the same reliable changes in CSE can be induced by timing peripheral afferent stimulation relative to the onset of electromyogram (EMG) activity rather than using the EEG peak. Specifically, we observed an increase in CSE when peripheral stimulation activated the cortex just before movement initiation. By contrast, there was no effect on CSE if the afferent input reached the cortex at the same time or after EMG onset, consistent with the idea that the temporal order of synaptic activation from afferent input and voluntary movement is important for production of plasticity. Finally, in 14 volunteers, we found that background voluntary muscle activity prior to movement also abolished the effect on CSE. One possible explanation is that the intervention strengthens synapses that are inactive at rest but change their activity in anticipation of movement, and that the intervention fails when the synapses are tonically active during background EMG activity. Overall, we demonstrate that, in individuals with voluntary control of muscles targeted by our intervention, EMG signals are a suitable alternative to an EEG for inducing plasticity by coupling movement-related brain states with peripheral afferent input.

Temporally-precise disruption of prefrontal cortex informed by the timing of beta bursts impairs human action-stopping.

Human action-stopping is thought to rely on a prefronto-basal ganglia-thalamocortical network, with right inferior frontal cortex (rIFC) posited to play a critical role in the early stage of implementation. Here we sought causal evidence for this idea in experiments involving healthy human participants. We first show that action-stopping is preceded by bursts of electroencephalographic activity in the beta band over prefrontal electrodes, putatively rIFC, and that the timing of these bursts correlates with the latency of stopping at a single-trial level: earlier bursts are associated with faster stopping. From this we reasoned that the integrity of rIFC at the time of beta bursts might be critical to successful stopping. We then used fMRI-guided transcranial magnetic stimulation (TMS) to disrupt rIFC at the approximate time of beta bursting. Stimulation prolonged stopping latencies and, moreover, the prolongation was most pronounced in individuals for whom the pulse appeared closer to the presumed time of beta bursting. These results help validate a model of the neural architecture and temporal dynamics of action-stopping. They also highlight the usefulness of prefrontal beta bursts to index an apparently important sub-process of stopping, the timing of which might help explain within- and between-individual variation in impulse control.

Transcranial magnetic stimulation: a non-invasive window into the excitatory circuits involved in human motor behavior.

Transcranial magnetic stimulation (TMS) is one of the most popular non-invasive tools for investigating the cortical circuits involved in human movement. Stimulation of the primary motor cortex elicits motor evoked potentials in peripheral muscles, the amplitude of which reflects the net excitability of circuits in the cortex and spinal cord. A number of methods exist to help broadly distinguish between excitatory and inhibitory influences on corticospinal output, allowing us to probe changes in the respective cortical circuits before and during movement. Something that has rarely been considered in human TMS studies, however, is the idea that specific populations of excitatory neurons might underlie different aspects of motor behavior. The current article provides a brief review of recent TMS studies which suggest that it is possible to selectively probe distinct excitatory inputs to corticospinal neurons during a range of movement-related states, from the preparation and execution of movements, to the suppression of unwanted movements. Together with recent advancements in computational modelling of the mechanisms of TMS and the capacity to record single-cell responses to TMS in behaving non-human primates, this avenue of research has the potential to shed light on the motor circuits underlying the repertoire of human motor behaviors, as well as their pathophysiology in diseases of the motor system.

Temporal cascade of frontal, motor and muscle processes underlying human action-stopping.

Action-stopping is a canonical executive function thought to involve top-down control over the motor system. Here we aimed to validate this stopping system using high temporal resolution methods in humans. We show that, following the requirement to stop, there was an increase of right frontal beta (~13 to 30 Hz) at ~120 ms, likely a proxy of right inferior frontal gyrus; then, at 140 ms, there was a broad skeletomotor suppression, likely reflecting the impact of the subthalamic nucleus on basal ganglia output; then, at ~160 ms, suppression was detected in the muscle, and, finally, the behavioral time of stopping was ~220 ms. This temporal cascade supports a physiological model of action-stopping, and partitions it into subprocesses that are isolable to different nodes and are more precise than the behavioral latency of stopping. Variation in these subprocesses, including at the single-trial level, could better explain individual differences in impulse control.

Temporal discrimination is altered in patients with isolated asymmetric and jerky upper limb tremor.

BACKGROUND: Unilateral or very asymmetric upper limb tremors with a jerky appearance are poorly investigated. Their clinical classification is an unsolved problem because their classification as essential tremor versus dystonic tremor is uncertain. To avoid misclassification as essential tremor or premature classification as dystonic tremor, the term indeterminate tremor was suggested. OBJECTIVES: The aim of this study was to characterize this tremor subgroup electrophysiologically and evaluate whether diagnostically meaningful electrophysiological differences exist compared to patients with essential tremor and dystonic tremor. METHODS: We enrolled 29 healthy subjects and 64 patients with tremor: 26 with dystonic tremor, 23 with essential tremor, and 15 patients with upper limb tremor resembling essential tremor but was unusually asymmetric and jerky (indeterminate tremor). We investigated the somatosensory temporal discrimination threshold, the short-interval intracortical inhibition, and the cortical plasticity by paired associative stimulation. RESULTS: Somatosensory temporal discrimination threshold was significantly increased in patients with dystonic tremor and indeterminate tremor, but it was normal in the essential tremor patients and healthy controls. Significant differences in short-interval intracortical inhibition and paired associative stimulation were not found among the three patient groups and controls. CONCLUSION: These results indicate that indeterminate tremor, as defined in this study, shares electrophysiological similarities with dystonic tremor rather than essential tremor. Therefore, we propose that indeterminate tremor should be considered as a separate clinical entity from essential tremor and that it might be dystonic in nature. Somatosensory temporal discrimination appears to be a useful tool in tremor classification. © 2019 International Parkinson and Movement Disorder Society.

The effect of frontoparietal paired associative stimulation on decision-making and working memory.

Previous single-site neurostimulation experiments have unsuccessfully attempted to shift decision-making away from habitual control, a fast, inflexible cognitive strategy, towards goal-directed control, a flexible, though computationally expensive strategy. We employed a dual-target neurostimulation approach in 30 healthy participants, using cortico-cortical paired associative stimulation (ccPAS) to target two key nodes: lateral prefrontal cortex (LPFC) and intraparietal sulcus (IPS), to test whether decision-making can be artificially shifted from habitual toward goal-directed control. Participants received three active stimulations, delivered at least six days apart (each involving 100 paired pulses over the IPS and LPFC, varying the interstimulus interval): two interventional, time-relevant ccPAS (10 msec interval) and one control, non-time-relevant ccPAS (100 msec interval). Following stimulation, participants completed a sequential learning task, measuring goal-directed/habitual control, and a working memory task. IPS→LPFC ccPAS (stimulating IPS, then LPFC with a 10 msec interval) shifted decision-making from habitual toward goal-directed control, compared to control ccPAS. There was no effect of LPFC→IPS ccPAS, nor an effect of any PAS condition on working memory. Previous studies have shown ccPAS effects outside the motor domain targeting prefrontal regions on response inhibition, attentional bias, and alpha asymmetry. The present study measures the behavioural effects of parietal-prefrontal PAS, focusing on a highly complex decision-making task and working memory. If confirmed in larger studies, this would be the first instance of neurostimulation successfully shifting decision-making from habitual to goal-directed control, putatively via inducing long-term potentiation between the IPS and LPFC. However, we found no effect in the other direction (LPFC→IPS ccPAS), and no effect on working memory overall. PAS is a relatively new neuromodulatory technique in the cognitive arsenal, and this study could help guide future approaches in healthy and disordered decision-making.

Direction of TDCS current flow in human sensorimotor cortex influences behavioural learning.

BACKGROUND: Recent studies have shown that neurophysiological outcomes of transcranial direct current stimulation (TDCS) are influenced by current flow in brain regions between the electrodes, and in particular the orientation of current flow relative to the cortical surface. OBJECTIVE: We asked whether the directional effects of TDCS on physiological measures in the motor system would also be observed on motor behaviours. METHODS: We applied TDCS during the practice of a ballistic movement task to test whether it affected learning or the retention of learning 48 h later. TDCS electrodes were oriented perpendicular to the central sulcus and two current orientations were used (posterior-anterior, TDCSPA; and anterior-posterior, TDCSAP). Transcranial magnetic stimulation (TMS) was used to assess whether changes in corticospinal excitability reflected any behavioural changes. RESULTS: Directional TDCSAP impaired the retention of learning on the ballistic movement task compared to TDCSPA and a sham condition. Although TDCSPA had no effect on learning or retention, it blocked the typical increase in corticospinal excitability after a period of motor practice. CONCLUSIONS: Our results extend on previous reports of TDCS producing directionally specific changes in neurophysiological outcomes by showing that current direction through a cortical target also impacts upon behavioural outcomes. In addition, changes in corticospinal excitability after a period of motor practice are not causally linked to behavioural learning.