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Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS‐driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high‐density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. Key points: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions.It is challenging to find direct evidence supporting TACS‐driven neural entrainment due to the technical difficulties in recording brain activity during stimulation.Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment.Motor unit activity from human muscles does not support TACS‐driven corticospinal entrainment. [ABSTRACT FROM AUTHOR]

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. 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. 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 FROM AUTHOR]

Key points: Previous studies investigating the effects of somatosensory afferent inputs on cortical excitability and neural plasticity often used transcranial magnetic stimulation (TMS) of hand motor cortex (M1) as a model, but in this model it is difficult to separate out the relative contribution of cutaneous and muscle afferent input to each effect.In the face, cutaneous and muscle afferents are segregated in the trigeminal and facial nerves, respectively. We studied their relative contribution to corticobulbar excitability and neural plasticity in the depressor anguli oris M1.Stimulation of trigeminal afferents induced short‐latency (SAI) but not long‐latency (LAI) afferent inhibition of face M1, while facial nerve stimulation evoked LAI but not SAI. Plasticity induction was observed only after a paired associative stimulation protocol using the facial nerve.Physiological differences in effects of cutaneous and muscle afferent inputs on face M1 excitability suggest they play separate functional roles in behaviour. The lack of conventional muscle spindles in face muscles raises the question of how sensory input from the face is used to control muscle activation. In 16 healthy volunteers, we probed sensorimotor interactions in face motor cortex (fM1) using short‐afferent inhibition (SAI), long‐afferent inhibition (LAI) and LTP‐like plasticity following paired associative stimulation (PAS) in the depressor anguli oris muscle (DAO). Stimulation of low threshold afferents in the trigeminal nerve produced a clear SAI (P < 0.05) when the interval between trigeminal stimulation and transcranial magnetic stimulation (TMS) of fM1 was 15–30 ms. However, there was no evidence for LAI at longer intervals of 100–200 ms, nor was there any effect of PAS. In contrast, facial nerve stimulation produced significant LAI (P < 0.05) as well as significant facilitation 10–30 minutes after PAS (P < 0.05). Given that the facial nerve is a pure motor nerve, we presume that the afferent fibres responsible were those activated by the evoked muscle twitch. The F‐wave in DAO was unaffected during both LAI and SAI, consistent with their presumed cortical origin. We hypothesize that, in fM1, SAI is evoked by activity in low threshold, presumably cutaneous afferents, whereas LAI and PAS require activity in (higher threshold) afferents activated by the muscle twitch evoked by electrical stimulation of the facial nerve. Cutaneous inputs may exert a paucisynaptic inhibitory effect on fM1, while proprioceptive information is likely to target inhibitory and excitatory polysynaptic circuits involved in LAI and PAS. Such information may be relevant to the physiopathology of several disorders involving the cranio‐facial system. Key points: Previous studies investigating the effects of somatosensory afferent inputs on cortical excitability and neural plasticity often used transcranial magnetic stimulation (TMS) of hand motor cortex (M1) as a model, but in this model it is difficult to separate out the relative contribution of cutaneous and muscle afferent input to each effect.In the face, cutaneous and muscle afferents are segregated in the trigeminal and facial nerves, respectively. We studied their relative contribution to corticobulbar excitability and neural plasticity in the depressor anguli oris M1.Stimulation of trigeminal afferents induced short‐latency (SAI) but not long‐latency (LAI) afferent inhibition of face M1, while facial nerve stimulation evoked LAI but not SAI. Plasticity induction was observed only after a paired associative stimulation protocol using the facial nerve.Physiological differences in effects of cutaneous and muscle afferent inputs on face M1 excitability suggest they play separate functional roles in behaviour. [ABSTRACT FROM AUTHOR]

Key points: Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta‐burst stimulation (iTBS) remain poorly understood.Individual response to iTBS is associated with recruitment of late indirect wave (I‐wave) generating pathways that can be probed by the onset latency of transcranial magnetic stimulation applied to primary motor cortex (M1) at different coil orientations.We found an association between late I‐wave recruitment [reflected by anterior–posterior (AP)‐lateromedial (LM) latency; i.e. the excess latency of motor‐evoked potentials generated by transcranial magnetic stimulation with an AP orientation over the latency of motor‐evoked potentials evoked by direct activation of corticospinal axons using LM stimulation] and changes in cortical excitability following iTBS, confirming previous studies.AP‐LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS‐induced increase in cortical excitability across subjects.Plasticity in the motor network may in part derive from a modulation of excitability and the recruitment of late I‐wave generating cortical pathways. Plasticity‐induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I‐waves) can be probed by the excess latency of motor‐evoked potentials elicited by transcranial magnetic stimulation with an anterior–posterior (AP) orientation over the latency of motor‐evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the 'AP‐LM latency' difference. Importantly, AP‐LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I‐wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I‐wave recruitment as reflected by changes in the AP‐LM latency. As expected, we found that AP‐LM latencies before iTBS were associated with iTBS‐induced excitability changes. A novel finding was that iTBS reduced AP‐LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP‐LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity‐induction by iTBS may derive from the modulation of I‐wave generating pathways projecting onto M1, accounting for the predictive potential of I‐wave recruitment. The excitability of I‐wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols. Key points: Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta‐burst stimulation (iTBS) remain poorly understood.Individual response to iTBS is associated with recruitment of late indirect wave (I‐wave) generating pathways that can be probed by the onset latency of transcranial magnetic stimulation applied to primary motor cortex (M1) at different coil orientations.We found an association between late I‐wave recruitment [reflected by anterior–posterior (AP)‐lateromedial (LM) latency; i.e. the excess latency of motor‐evoked potentials generated by transcranial magnetic stimulation with an AP orientation over the latency of motor‐evoked potentials evoked by direct activation of corticospinal axons using LM stimulation] and changes in cortical excitability following iTBS, confirming previous studies.AP‐LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS‐induced increase in cortical excitability across subjects.Plasticity in the motor network may in part derive from a modulation of excitability and the recruitment of late I‐wave generating cortical pathways. [ABSTRACT FROM AUTHOR]

Key Points: Synaptic plasticity is involved in daily activities but abnormal plasticity may be deleterious. In this study, we found that motor plasticity could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Such changes in motor plasticity were associated with reduced learning of a simple motor task. We postulate that the premotor cortex adjusts the amount of motor plasticity to modulate motor learning through heterosynaptic metaplasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network, a concept that could be employed to intervene in diseases with abnormal plasticity. Abstract: Primary motor cortex (M1) plasticity is known to be influenced by the excitability and prior activation history of M1 itself. However, little is known about how its plasticity is influenced by other areas of the brain. In the present study on humans of either sex who were known to respond to theta burst stimulation from previous studies, we found plasticity of M1 could be modulated by suppressing the premotor cortex with the theta burst form of repetitive transcranial magnetic stimulation. Motor plasticity was distorted and disappeared 30 min and 120 min, respectively, after premotor excitability was suppressed. Further evaluation revealed that such changes in motor plasticity were associated with impaired learning of a simple motor task. We postulate that the premotor cortex modulates the amount of plasticity within M1 through heterosynaptic metaplasticity, and that this may impact on learning of a simple motor task previously shown to be directly affected by M1 plasticity. The present results provide an insight into how the brain physiologically coordinates two different areas to bring them into a functional network. Furthermore, such concepts could be translated into therapeutic approaches for diseases with aberrant plasticity. [ABSTRACT FROM AUTHOR]

We describe EMG responses recorded in active masseter muscles following unilateral and bilateral electrical vestibular stimulation (EVS, current pulses of 5 mA intensity, 2 ms duration, 3 Hz frequency). Averaged responses in unrectified masseter EMG induced by unilateral EVS were examined in 16 healthy subjects; effects induced by bilateral (transmastoid) stimulation were studied in 10 subjects. Results showed that unilateral as well as bilateral EVS induces bilaterally a clear biphasic response (onset latency ranging from 7.2 to 8.8 ms), that is of equal amplitude and latency contra- and ipsilateral to the stimulation site. In all subjects, unilateral cathodal stimulation induced a positive-negative response termed p11/n15 according to its mean peak latency; the anodal stimulation induced a response of opposite polarity (n11/p15) in 11/16 subjects. Cathodal responses were significantly larger than anodal responses. Bilateral stimulation induced a p11/n15 response significantly larger than that induced by the unilateral cathodal stimulation. Recordings from single motor units showed that responses to cathodal stimulation corresponded to a brief (2-4 ms) silent period in motor unit discharge rate. The magnitude of EVS-induced masseter response was linearly related to current intensity and scaled with the mean level of EMG activity. The size of the p11/n15 response was asymmetrically modulated when subjects were tilted on both sides; in contrast head rotation did not exert any influence. Control experiments excluded a possible role of cutaneous receptors in generating the masseter response. We conclude that transmastoid electrical stimulation evokes vestibulomasseteric reflexes in healthy humans at latencies consistent with a di-trisynaptic pathway. [ABSTRACT FROM AUTHOR]

Key points Face muscles are important in a variety of different functions, such as feeding, speech and communication of non‐verbal affective states, which require quite different patterns of activity from those of a typical hand muscle. We ask whether there are differences in their neurophysiological control that might reflect this. Fifteen healthy individuals were studied. Standard single‐ and paired‐pulse transcranial magnetic stimulation (TMS) methods were used to compare intracortical inhibitory (short interval intracortical inhibition (SICI); cortical silent period (CSP)) and excitatory circuitries (short interval intracortical facilitation (SICF)) in two typical muscles, the depressor anguli oris (DAO), a face muscle, and the first dorsal interosseous (FDI), a hand muscle. TMS threshold was higher in DAO than in FDI. Over a range of intensities, resting SICF was not different between DAO and FDI, while during muscle activation SICF was stronger in FDI than in DAO (P = 0.012). At rest, SICI was stronger in FDI than in DAO (P = 0.038) but during muscle contraction, SICI was weaker in FDI than in DAO (P = 0.034). We argue that although many of the difference in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting SICI in DAO, may reflect fundamental differences in the physiology of the two muscle groups. Transcranial magnetic stimulation (TMS) single‐ and paired‐pulse protocols were used to investigate and compare the activity of facilitatory and inhibitory intracortical circuits in a face (depressor anguli oris; DAO) and hand (first dorsal interosseous; FDI) muscles. Several TMS intensities and interstimulus intervals were tested with the target muscles at rest and when voluntarily activated. At rest, intracortical inhibitory activity was stronger in FDI than in DAO. In contrast, during muscle contraction inhibitory activity was stronger in DAO than in FDI. As many previous reports have found, the motor evoked potential threshold was higher in DAO than in FDI. Although many of the differences in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting short interval intracortical inhibition in DAO, may reflect fundamental differences in the physiology of the two muscle groups. [ABSTRACT FROM AUTHOR]