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In patients with movement disorders, voluntary movements can sometimes be accompanied by unintentional muscle contractions in other body regions. In this review, we discuss clinical and pathophysiological aspects of several motor phenomena including mirror movements, dystonic overflow, synkinesia, entrainment and mirror dystonia, focusing on their similarities and differences. These phenomena share some common clinical and pathophysiological features, which often leads to confusion in their definition. However, they differ in several aspects, such as the body part showing the undesired movement, the type of this movement (identical or not to the intentional movement), the underlying neurological condition, and the role of primary motor areas, descending pathways and inhibitory circuits involved, suggesting that these are distinct phenomena. We summarize the main features of these fascinating clinical signs aiming to improve the clinical recognition and standardize the terminology in research studies. We also suggest that the term "mirror dystonia" may be not appropriate to describe this peculiar phenomenon which may be closer to dystonic overflow rather than to the classical mirror movements. [ABSTRACT FROM AUTHOR]

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]

Objective: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)–induced long‐interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short‐interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. Methods: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter‐stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. Results: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age‐ and sex‐matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p <.001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p <.001) and SICI (rho = 0.689; p =.006). Significance: Our results strengthen the finding of deranged γ‐aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease‐modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study. [ABSTRACT FROM AUTHOR]

Background: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. Objective: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. Methods: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age‐ and sex‐matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter‐rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. Results: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT‐TOR1A, DYT‐THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. Conclusions: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Motor impairment in Parkinson's disease (PD) reflects changes in the basal ganglia‐thalamocortical circuit converging on the primary motor cortex (M1) and supplementary motor area (SMA). Previous studies assessed M1 excitability in PD using transcranial magnetic stimulation (TMS)‐evoked electromyographic activity. TMS‐evoked electroencephalographic activity may unveil broader motor cortical network changes in PD. Objective: The aim was to assess motor cortical network excitability in PD. Methods: We compared TMS‐evoked cortical potentials (TEPs) from M1 and the pre‐SMA between 20 PD patients tested off and on medication and 19 healthy controls (HCs) and investigated possible correlations with bradykinesia. Results: Off PD patients compared to HCs had smaller P30 responses from the M1s contralateral (M1+) and ipsilateral (M1–) to the most bradykinetic side and increased pre‐SMA N40. Dopaminergic therapy normalized the amplitude of M1+ and M1– P30 as well as pre‐SMA N40. We found a positive correlation between M1+ P30 amplitude and bradykinesia in off PD patients. Conclusions: Changes in M1 P30 and pre‐SMA N40 in PD suggest that M1 excitability is reduced on both sides, whereas pre‐SMA excitability is increased. The effect of dopaminergic therapy and the clinical correlation suggest that these cortical changes may reflect abnormal basal ganglia‐thalamocortical activity. TMS electroencephalography provides novel insight into motor cortical network changes related to the pathophysiology of PD. © 2022 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: It has been debated for decades whether primary writing tremor is a form of dystonic tremor, a variant of essential tremor, or a separate entity. We wished to test the hypothesis that primary writing tremor and dystonia share a common pathophysiology. Objectives: The objective of the present study was to investigate the pathophysiological hallmarks of dystonia in patients affected by primary writing tremor. Methods: Ten patients with idiopathic dystonic tremor syndrome, 7 with primary writing tremor, 10 with essential tremor, and 10 healthy subjects were recruited. They underwent eyeblink classic conditioning, blink recovery cycle, and transcranial magnetic stimulation assessment, including motor‐evoked potentials and short‐ and long‐interval intracortical inhibition at baseline. Transcranial magnetic stimulation measures were also recorded after paired‐associative plasticity protocol. Results: Primary writing tremor and dystonic tremor syndrome had a similar pattern of electrophysiological abnormalities, consisting of reduced eyeblink classic conditioning learning, reduced blink recovery cycle inhibition, and a lack of effect of paired‐associative plasticity on long‐interval intracortical inhibition. The latter 2 differ from those obtained in essential tremor and healthy subjects. Although not significant, slightly reduced short‐interval intracortical inhibition and a larger effect of paired‐associative plasticity in primary writing tremor and dystonic tremor syndrome, compared with essential tremor and healthy subjects, was observed. Conclusions: Our initial hypothesis of a common pathophysiology between dystonia and primary writing tremor has been confirmed. Primary writing tremor might be considered a form of dystonic tremor. © 2021 International Parkinson and Movement Disorder Society [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]

Introduction: Transcranial magnetic stimulation (TMS) is widely used to explore cortical physiology in health and disease. Surface electromyography (sEMG) is appropriate for superficial muscles, but cannot be applied easily to less accessible muscles. Muscle ultrasound (mUS) may provide an elegant solution to this problem, but fundamental questions remain. We explore the relationship between TMS evoked muscle potentials and TMS evoked muscle contractions measured with mUS.Methods: In 10 participants, we performed a TMS recruitment curve, simultaneously measuring motor evoked potentials (MEPs) and mUS in biceps (BI), first dorsal interosseous (FDI), tibialis anterior (TA), and the tongue (TO).Results: Resting motor threshold (RMT) measurements and recruitment curves were found to be consistent across sEMG and mUS.Discussion: This work supports the use of TMS-US to study less accessible muscles. The implications are broad but could include the study of a new range of muscles in disorders such as amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Many brain regions exhibit rhythmical activity thought to reflect the summed behaviour of large populations of neurons. The endogenous alpha rhythm has been associated with phase‐dependent modulation of corticospinal excitability. However, whether exogenous alpha rhythm, induced using transcranial alternating current stimulation (tACS) also has a phase‐dependent effect on corticospinal excitability remains unknown. Here, we triggered transcranial magnetic stimuli (TMS) on the up‐ or down‐going phase of a tACS‐imposed alpha oscillation and measured motor evoked potential (MEP) amplitude and short‐interval intracortical inhibition (SICI). There was no significant difference in MEP amplitude or SICI when TMS was triggered on the up‐ or down‐going phase of the tACS‐imposed alpha oscillation. The current study provides no evidence of differences in corticospinal excitability or GABAergic inhibition when targeting the up‐going (peak) and down‐going (trough) phase of the tACS‐imposed oscillation. [ABSTRACT FROM AUTHOR]

Background: Dystonia may have different neuroanatomical substrates and pathophysiology. This is supported by studies on the motor system showing, for instance, that plasticity is abnormal in idiopathic dystonia, but not in dystonia secondary to basal ganglia lesions.Objective: The aim of this study was to test whether somatosensory inhibition and plasticity abnormalities reported in patients with idiopathic dystonia also occur in patients with dystonia caused by basal ganglia damage.Methods: Ten patients with acquired dystonia as a result of basal ganglia lesions and 12 healthy control subjects were recruited. They underwent electrophysiological testing at baseline and after a single 45-minute session of high-frequency repetitive somatosensory stimulation. Electrophysiological testing consisted of somatosensory temporal discrimination, somatosensory-evoked potentials (including measurement of early and late high-frequency oscillations and the spatial inhibition ratio of N20/25 and P14 components), the recovery cycle of paired-pulse somatosensory-evoked potentials, and primary motor cortex short-interval intracortical inhibition.Results: Unlike previous reports of patients with idiopathic dystonia, patients with acquired dystonia did not differ from healthy control subjects in any of the electrophysiological measures either before or after high-frequency repetitive somatosensory stimulation, except for short-interval intracortical inhibition, which was reduced at baseline in patients compared to control subjects.Conclusions: The data show that reduced somatosensory inhibition and enhanced cortical plasticity are not required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Patients with movement disorders experience fluctuations unrelated to disease progression or treatment. Extrinsic factors that contribute to the variable expression of movement disorders are environment related. They influence the expression of movement disorders through sensory–motor interactions and include somatosensory, visual, and auditory stimuli. Examples of somatosensory effects are stimulus sensitivity of myoclonus on touch and sensory amelioration in dystonia but also some less‐appreciated effects on parkinsonian tremor and gait. Changes in visual input may affect practically all types of movement disorders, either by loss of its compensatory role or by disease‐related alterations in the pathways subserving visuomotor integration. The interaction between auditory input and motor function is reflected in simple protective reflexes and in complex behaviors such as singing or dancing. Various expressions range from the effect of music on parkinsonian bradykinesia to tics. Changes in body position affect muscle tone and may result in marked fluctuations of rigidity or may affect dystonic manifestations. Factors intrinsic to the patient are related to their voluntary activity and cognitive, motivational, and emotional states. Depending on the situation or disease, they may improve or worsen movement disorders. We discuss various factors that can influence the phenotypic variability of movement disorders, highlighting the potential mechanisms underlying these manifestations. We also describe how motor fluctuations can be provoked during the clinical assessment to help reach the diagnosis and appreciated to understand complaints that seem discrepant with objective findings. We summarize advice and interventions based on the variability of movement disorders that may improve patients' functioning in everyday life. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Somatosensory temporal discrimination is abnormal in dystonia and reflects reduced somatosensory inhibition. In healthy individuals, both the latter are enhanced by high‐frequency repetitive somatosensory stimulation, whereas opposite effects are observed in patients with cervical dystonia. Objectives: We tested whether low‐frequency repetitive sensory stimulation, which in healthy individuals worsens discrimination, might have the opposite effect in patients with cervical dystonia at the physiological level and, in turn, improve their perceptual performance. Methods: Somatosensory temporal discrimination and several electrophysiological measures of sensorimotor inhibition were collected before and after 45 minutes of low‐frequency repetitive sensory stimulation. Results: As predicted, and opposite to what happened in controls, low‐frequency repetitive sensory stimulation in patients enhanced sensorimotor inhibition and normalized somatosensory temporal discrimination. Conclusions: Patients with cervical dystonia have an abnormal response to repetitive sensory stimulation, which we hypothesize is attributed to abnormally sensitive homeostatic mechanisms of inhibitory circuitry in both sensory and motor systems. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Advances in genetics may enable a deeper understanding of disease mechanisms and promote a shift to more personalised medicine in the epilepsies. At present, understanding of consequences of genetic variants mainly relies on preclinical functional work; tools for acquiring similar data from the living human brain are needed. Transcranial magnetic stimulation (TMS), in particular paired‐pulse TMS protocols which depend on the function of cortical GABAergic interneuron networks, has the potential to become such a tool. For this report, we identified and reviewed 23 publications on TMS studies of cortical excitability and inhibition in 15 different genes or conditions relevant to epilepsy. Reduced short‐interval intracortical inhibition (SICI) and reduced cortical silent period (CSP) duration were the most commonly reported findings, suggesting abnormal GABAA‐ (SICI) or GABABergic (CSP) signalling. For several conditions, these findings are plausible based on established evidence of involvement of the GABAergic system; for some others, they may inform future research around such mechanisms. Challenges of TMS include lack of complete understanding of the neural underpinnings of the measures used: hypotheses and analyses should be based on existing clinical and preclinical data. Further pitfalls include gathering sufficient numbers of participants, and the effect of confounding factors, especially medications. TMS‐EEG is a unique perturbational technique to study the intrinsic properties of the cortex with excellent temporal resolution; while it has the potential to provide further information of use in interpreting effects of genetic variants, currently the links between measures and neurophysiology are less established. Despite these challenges, TMS is a tool with potential for elucidating the system‐level in vivo functional consequences of genetic variants in people carrying genetic changes of interest, providing unique insights. [ABSTRACT FROM AUTHOR]

Background: Volitional control of involuntary movements has so far been considered a hallmark of tic disorders. However, modulation of involuntary movements can also be observed in other hyperkinesias. Cases Here, we present 6 patients with chorea able to suppress their involuntary movements, on demand. In 3 of them, surface electromyography was used to quantify degree of suppression and confirmed a reduction of muscle activity up to 68%, during volitional control. Conclusion: This observation represents a first step toward a description of a new clinical feature in choreic syndromes and an opportunity to redefine the role of volitional inhibition in hyperkinetic movement disorders. View Supplementary Video [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]

Background: Demographic and clinical studies imply that female sex may be protective for PD, but pathophysiological evidence to support these observations is missing. In early PD, functional changes may be detected in primary motor cortex using transcranial magnetic stimulation.Objective: We hypothesised that if pathophysiology differs between sexes in PD, this will be reflected in differences of motor cortex measurements.Methods: Forty-one newly diagnosed PD patients (22 males, 19 females) were clinically assessed using MDS-UPDRS part III, and various measures of cortical excitability and sensorimotor cortex plasticity were measured over both hemispheres, corresponding to the less and more affected side, using transcranial magnetic stimulation. Twenty-three healthy (10 men, 13 women) participants were studied for comparison.Results: Among patients, no significant differences between sexes were found in age, age of diagnosis, symptom duration, and total or lateralized motor score. However, male patients had disturbed interhemispheric balance of motor thresholds, caused by decreased resting and active motor thresholds in the more affected hemisphere. Short interval intracortical inhibition was more effective in female compared to male patients in both hemispheres. Female patients had a preserved physiological focal response to sensorimotor plasticity protocol, whereas male patients showed an abnormal spread of the protocol effect.Conclusion: The study provides one of the first neurophysiological evidences of sex differences in early PD. Female patients have a more favorable profile of transcranial magnetic stimulation measures, possibly reflecting a more successful cortical compensation or delayed maladaptive changes in the sensorimotor cortex. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The physiological landscape of dystonia has changed considerably over the past 10 years. Initial ideas that dystonic motor symptoms could be explained by a combination of loss of inhibition and increased plasticity, together with subtle deficits in sensory processing, have been questioned, whereas the possible role of the cerebellum has risen in importance. In addition, it has been recognized that symptoms affect more than just the motor and sensory systems and encompass independent cognitive and psychological changes. Finally, it has become clear that, despite similarities in symptoms, there may be pathophysiological differences between idiopathic, inherited, and acquired forms of dystonia. In other words, progress in the pathophysiology of dystonia has followed the usual pattern from an initial phase in which core deficits are readily explained by highly simplified models to a realization that within a highly interconnected network, effects are more nuanced with widespread changes that might either compensate or contribute to the clinical symptoms to different degrees in different individuals. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related myoclonus-dystonia, these conditions can be collectively classified as "myoclonus-dystonia syndromes." In the present article, we present myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: A large number of methods have been described that use transcranial magnetic stimulation to probe the physiology of the human motor cortex. Since the 1990s, hundreds of papers have used them to investigate neurophysiological signatures of different types of movement disorders. However, in recent years there has been increasing recognition of the interindividual variability of these measures and a focus on estimating their reliability and reproducibility. Although this work has been carried out in healthy individuals, it is highly relevant to movement disorders because it may impact the validity of some accepted ("canonical") neurophysiological biomarkers. The aim of this review is to reexamine the diagnostic usefulness of transcranial magnetic stimulation methods in movement disorders in the context of present knowledge of methodological variability.Methods: We conducted a search of the PubMed database for research and review articles on transcranial magnetic stimulation and its diagnostic utility in movement disorders (specifically Parkinson's disease and atypical parkinsonism, dystonia, Tourette syndrome and other chronic tic disorders, Huntington's disease, and essential tremor). We highlighted contradictions in the literature and common misconceptions with the aim of providing a clearer picture of the reliability of these measures in differential diagnosis of movement disorders.Conclusion: Although there is no doubt that these studies have provided useful insight into the pathophysiology of movement disorders, there is a clear disagreement among many studies that questions the validity of some of the so called "canonical" findings as diagnostic markers. However, useful findings remain and even those with higher variability can be used to support clinical diagnosis in selected cases. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Transcranial magnetic stimulation is a safe and painless non-invasive brain stimulation technique that has been largely used in the past 30 years to explore cortical function in healthy participants and, inter alia, the pathophysiology of movement disorders. During the years, its use has evolved from primarily research purposes to treatment of a large variety of neurological and psychiatric diseases. In this article, we illustrate the basic principles on which the therapeutic use of transcranial magnetic stimulation is based and review the clinical trials that have been performed in patients with movement disorders.Methods: A search of the PubMed database for research and review articles was performed on therapeutic applications of transcranial magnetic stimulation in movement disorders. The search included the following conditions: Parkinson's disease, dystonia, Tourette syndrome and other chronic tic disorders, Huntington's disease and choreas, and essential tremor. The results of the studies and possible mechanistic explanations for the relatively minor effects of transcranial magnetic stimulation are discussed. Possible ways to improve the methodology and achieve greater therapeutic efficacy are discussed.Conclusion: Despite the promising and robust rationales for the use of transcranial magnetic stimulations as a treatment tool in movement disorders, the results taken as a whole are not as successful as were initially expected. There is encouraging evidence that transcranial magnetic stimulation may improve motor symptoms and depression in Parkinson's disease, but the efficacy in other movement disorders is unclear. Possible improvements in methodology are on the horizon but have yet to be implemented in large clinical studies. © 2019 International Parkinson and Movement Disorder Society © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Despite its widespread use in cognitive studies, there is still limited understanding of whether and how transcranial direct current stimulation (tDCS) modulates brain network function. To clarify its physiological effects, we assessed brain network function using functional magnetic resonance imaging (fMRI) simultaneously acquired during tDCS stimulation. Cognitive state was manipulated by having subjects perform a Choice Reaction Task or being at "rest." A novel factorial design was used to assess the effects of brain state and polarity. Anodal and cathodal tDCS were applied to the right inferior frontal gyrus (rIFG), a region involved in controlling activity large‐scale intrinsic connectivity networks during switches of cognitive state. tDCS produced widespread modulation of brain activity in a polarity and brain state dependent manner. In the absence of task, the main effect of tDCS was to accentuate default mode network (DMN) activation and salience network (SN) deactivation. In contrast, during task performance, tDCS increased SN activation. In the absence of task, the main effect of anodal tDCS was more pronounced, whereas cathodal tDCS had a greater effect during task performance. Cathodal tDCS also accentuated the within‐DMN connectivity associated with task performance. There were minimal main effects of stimulation on network connectivity. These results demonstrate that rIFG tDCS can modulate the activity and functional connectivity of large‐scale brain networks involved in cognitive function, in a brain state and polarity dependent manner. This study provides an important insight into mechanisms by which tDCS may modulate cognitive function, and also has implications for the design of future stimulation studies. [ABSTRACT FROM AUTHOR]

Background: Recent research has highlighted the role of the cerebellum in the pathophysiology of myoclonus-dystonia syndrome as a result of mutations in the ɛ-sarcoglycan gene (DYT11). Specifically, a cerebellar-dependent saccadic adaptation task is dramatically impaired in this patient group.Objectives: The objective of this study was to investigate whether saccadic deficits coexist with impairments of limb adaptation to provide a potential mechanism linking cerebellar dysfunction to the movement disorder within symptomatic body regions.Methods: Limb adaptation to visuomotor (visual feedback rotated by 30°) and forcefield (force applied by robot to deviate arm) perturbations were examined in 5 patients with DYT11 and 10 aged-matched controls.Results: Patients with DYT11 successfully adapted to both types of perturbation. Modelled and averaged summary metrics that captured adaptation behaviors were equivalent to the control group across conditions.Conclusions: DYT11 is not characterized by a uniform deficit in adaptation. The previously observed large deficit in saccadic adaption is not reflected in an equivalent deficit in limb adaptation in symptomatic body regions. We suggest potential mechanisms at the root of this discordance and identify key research questions that need future study. © 2018 International Parkinson and Movement Disorder Society. [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]

Abstract: Intracortical facilitation (ICF) describes the facilitation of an EMG response (motor evoked potential) to a suprathreshold pulse (S2) of transcranial magnetic stimulation (TMS) by a preceding subthreshold pulse (S1) given 10–15 ms earlier. ICF is widely assumed to originate from intracortical mechanisms. In this study, we used spinal H‐reflexes to test whether subcortical mechanisms can also contribute to the facilitation. Measurements were performed in the upper limb muscle flexor carpi radialis in 17 healthy volunteers, and in the lower limb muscle soleus in 16 healthy volunteers. S2 given alone facilitated the H‐reflex. When S1 preceded S2 by 10 ms, the amount of facilitation increased, compatible with ICF. However, S1 given alone also facilitated the H‐reflex, suggesting that it had evoked descending activity even though its intensity was well below resting motor threshold. Across participants, the amount of H‐reflex facilitation from S1 alone was proportional to the degree of H‐reflex facilitation with combined S1–S2. These results indicate that subcortical mechanisms can contribute to ICF and potentially add to the variability of the ICF measure reported in previous studies. [ABSTRACT FROM AUTHOR]

Background: In Huntington's disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas.Objectives: The objective of this study was to explore the ability to synchronize activity in a motor network using transcranial magnetic stimulation and to relate this to timing of motor performance.Methods: We examined synchronization in oscillatory activity of cortical motor areas in response to an external input produced by a pulse of transcranial magnetic stimulation. We combined this with EEG to compare the response of 16 presymptomatic Huntington's disease participants with 16 age-matched healthy volunteers to test whether the strength of synchronization relates to the variability of motor performance at the following 2 tasks: a grip force task and a speeded-tapping task.Results: Phase synchronization in response to M1 stimulation was lower in Huntington's disease than healthy volunteers (P < .01), resulting in a reduced cortical activity at global (P < .02) and local levels (P < .01). Participants who showed better timed motor performance also showed stronger oscillatory synchronization (r = -0.356; P < .05) and higher cortical activity (r = -0.393; P < .05).Conclusions: Our data may model the ability of the motor command to respond to more subtle, physiological inputs from other brain areas. This novel insight indicates that impairments of the timing accuracy of synchronization and desynchronization could be a physiological basis for some key clinical features of Huntington's disease. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for Parkinson's disease (PD), but can have side effects caused by stimulus spread to structures outside the target volume such as the pyramidal tract.Objectives: To assess the relevance of pyramidal tract activation with STN-DBS in PD.Methods: In a multimodal, blinded study in 20 STN-DBS patients, we measured stimulation thresholds for evoking electromyographic activity in orbicularis oris and first dorsal interosseous muscles at each of 150 electrode sites. We also modeled the electric field spread and calculated its overlap with the estimated anatomical location of corticospinal and corticobulbar tracts from primary motor cortex using 3 Tesla MRI probabilistic tractography.Results: Mean resting motor thresholds were significantly lower for the contralateral orbicularis oris (3.5 ± 1.0 mA) compared with ipsilaterally (4.1 ± 1.1 mA) and with the contralateral first dorsal interosseous (4.0 ± 1.2 mA). The modeled volumes of corticobulbar and corticospinal tract activated correlated inversely with the resting motor threshold of the contralateral orbicularis oris and first dorsal interosseous, respectively. Active motor thresholds were significantly lower compared with resting motor thresholds by around 30% to 35% and correlated with the clinically used stimulation amplitude. Backward multiple regression in 12 individuals with a "lateral-type" speech showed that stimulation amplitude, levodopa equivalent dose reduction postsurgery, preoperative speech intelligibility, and first dorsal interosseous resting motor thresholds explained 79.9% of the variance in postoperative speech intelligibility.Conclusions: Direct pyramidal tract activation can occur at stimulation thresholds that are within the range used in clinical routine. This spread of current compromises increase in stimulation strengths and is related to the development of side effects such as speech disturbances with chronic stimulation. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Somatosensory temporal discrimination threshold is often prolonged in patients with dystonia. Previous evidence suggested that this might be caused by impaired somatosensory processing in the time domain. Here, we tested if other markers of reduced inhibition in the somatosensory system might also contribute to abnormal somatosensory temporal discrimination in dystonia.Methods: Somatosensory temporal discrimination threshold was measured in 19 patients with isolated cervical dystonia and 19 age-matched healthy controls. We evaluated temporal somatosensory inhibition using paired-pulse somatosensory evoked potentials, spatial somatosensory inhibition by measuring the somatosensory evoked potentials interaction between simultaneous stimulation of the digital nerves in thumb and index finger, and Gamma-aminobutyric acid-ergic (GABAergic) sensory inhibition using the early and late components of high-frequency oscillations in digital nerves somatosensory evoked potentials.Results: When compared with healthy controls, dystonic patients had longer somatosensory temporal discrimination thresholds, reduced suppression of cortical and subcortical paired-pulse somatosensory evoked potentials, less spatial inhibition of simultaneous somatosensory evoked potentials, and a smaller area of the early component of the high-frequency oscillations. A logistic regression analysis found that paired pulse suppression of the N20 component at an interstimulus interval of 5 milliseconds and the late component of the high-frequency oscillations were independently related to somatosensory temporal discrimination thresholds. "Dystonia group" was also a predictor of enhanced somatosensory temporal discrimination threshold, indicating a dystonia-specific effect that independently influences this threshold.Conclusions: Increased somatosensory temporal discrimination threshold in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Activation of neurons not only changes their membrane potential and firing rate but as a secondary action reduces membrane resistance. This loss of resistance, or increase of conductance, may be of central importance in non-invasive magnetic or electric stimulation of the human brain since electrical fields cause larger changes in transmembrane voltage in resting neurons with low membrane conductances than in active neurons with high conductance. This may explain why both the immediate effects and after-effects of brain stimulation are smaller or even reversed during voluntary activity compared with rest. Membrane conductance is also increased during shunting inhibition, which accompanies the classic GABAA IPSP. This short-circuits nearby EPSPs and is suggested here to contribute to the magnitude and time course of short-interval intracortical inhibition and intracortical facilitation. [ABSTRACT FROM AUTHOR]

Background: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.Objectives: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty.Methods: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor.Results: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%.Conclusion: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice. [ABSTRACT FROM AUTHOR]

Background The natural fluctuation of motor symptoms of Parkinson's disease ( PD) makes judgement of any change challenging and the use of clinical scales such as the International Parkinson and Movement Disorder Society ( MDS)- UPDRS imperative. Recently developed commodity mobile communication devices, such as smartphones, could possibly be used to assess motor symptoms in PD patients in a convenient way with low cost. We provide the first report on the development and testing of stand-alone software for mobile devices that could be used to assess both tremor and bradykinesia of PD patients. Methods We assessed motor symptoms with a custom-made smartphone application in 14 patients and compared the results with their MDS- UPDRS scores. Results We found significant correlation between five subscores of MDS- UPDRS (rest tremor, postural tremor, pronation-supination, leg agility, and finger tapping) and eight parameters of the data collected with the smartphone. Conclusions These results provide evidence as a proof of principle that smartphones could be a useful tool to objectively assess motor symptoms in PD in clinical and experimental settings. [ABSTRACT FROM AUTHOR]

Key points Neurostimulation is a rapidly emerging approach to swallowing rehabilitation, but cerebellar stimulation has not been explored as a treatment. Such proposed therapies for post-stroke dysphagia have required confirmation of physiological effects and optimisation of parameters in healthy humans prior to translational progression into patient groups., There is strong evidence for a role of the cerebellum in swallowing physiology, but this relationship has been under-explored., Recently, single pulses of cerebellar magnetic stimulation have been shown to directly evoke responses from pharyngeal musculature and produce short-term enhancement of cortico-pharyngeal motor evoked potentials, suggesting the feasibility of a cerebellar approach to neurostimulation in the swallowing system., We therefore examined multiple parameters of repetitive cerebellar magnetic stimulation and have described the optimal settings to provoke longer-lasting changes in swallowing neurophysiology. Based on evidence from the post-stroke dysphagia neurostimulation literature, these changes may have a therapeutic potential for swallowing rehabilitation., Abstract Brain neurostimulation has been shown to modulate cortical swallowing neurophysiology in post-stroke dysphagia with therapeutic effects which are critically dependent on the stimulation parameters. Cerebellar neurostimulation is, however, a novel, unexplored approach to modulation of swallowing pathways as a prelude to therapy for dysphagia. Here, we randomised healthy human subjects ( n = 17) to receive one of five cerebellar repetitive TMS (rTMS) interventions (Sham, 1 Hz, 5 Hz, 10 Hz and 20 Hz) on separate visits to our laboratory. Additionally, a subset of subjects randomly received each of three different durations (50, 250, 500 pulses) of optimal frequency versus sham cerebellar rTMS. Prior to interventions subjects underwent MRI-guided single-pulse transcranial magnetic stimulation (TMS) to co-localise pharyngeal and thenar representation in the cortex and cerebellum (midline and hemispheric) before acquisition of baseline motor evoked potential (MEP) recordings from each site as a measure of excitability. Post-interventional MEPs were recorded for an hour and compared to sham using repeated measures ANOVA. Only 10 Hz cerebellar rTMS increased cortico-pharyngeal MEP amplitudes (mean bilateral increase 52%, P = 0.007) with effects lasting 30 min post-intervention with an optimal train length of 250 pulses ( P = 0.019). These optimised parameters of cerebellar rTMS can produce sustained increases in corticobulbar excitability and may have clinical translation in future studies of neurogenic dysphagia. [ABSTRACT FROM AUTHOR]

Objective The photoparoxysmal response ( PPR) involves rapid spread of epileptic activity from visual to parietal and frontal areas. We used a transcranial magnetic stimulation ( TMS) technique to assess the physiologic connections between primary visual (V1) and motor (M1) areas in patients with idiopathic generalized epilepsy ( IGE). We hypothesized that in PPR-positive patients, M1 would respond excessively to inputs from V1. Methods Eleven photosensitive patients with IGE who had a PPR at the time of the study were compared with 10 similar patients without a PPR, and with 11 healthy subjects of similar age and sex. The connection between V1 and M1 was assessed in resting participants by delivering a conditioning stimulus ( CS) over the phosphene hotspot of the visual cortex (intensity 90% phosphene threshold, PT) followed at random interstimulus intervals ( ISIs; 15, 18, 21, 24, 27, 30, 35 and 40 msec) by a test stimulus ( TS) over the left motor cortex to elicit a motor evoked potential ( MEP) of ~1 mV from the right first dorsal interosseous muscle. Results In healthy subjects, a CS over V1 suppressed M1 at ISIs between 18 and 40 msec. Similar effects occurred in IGE patients without a PPR. This was not true in PPR-positive IGE patients, in whom this type of physiologic inhibition was significantly (p < 0.05) reduced. Significance IGE patients with a PPR have an overactive functional response of M1 to inputs traveling from V1. This may represent one core factor for the anterior spread of the PPR itself and for the origin of the abnormal epileptic motor phenomenon, such as myoclonus. [ABSTRACT FROM AUTHOR]

Background A number of neurophysiological abnormalities have been described in patients with Parkinson's disease, but very few longitudinal studies of how these change with disease progression have been reported. We describe measures of motor cortex inhibition and plasticity at 6 and 12 mo in 12 patients that we previously reported at initial diagnosis. Given the well-known interindividual variation in these measures, we were particularly concerned with the within-subject changes over time. Methods Patients were assessed clinically, and transcranial magnetic stimulation (TMS) was used to measure motor cortical excitability, inhibition (short interval intracortical inhibition, cortical silent period), and plasticity (response to excitatory paired associative stimulation protocol) in both hemispheres. All measurements were performed 6 mo and 12 mo after the baseline experiments. Results Asymmetry in clinical motor symptoms was reflected in asymmetry of plasticity and inhibition. In the group as a whole, little change was seen in any of the parameters over 12 mo. However, analysis of within-individual data showed clear correlations between changes in clinical asymmetry and asymmetry of response to paired associative stimulation protocol and cortical silent period. Conclusions Longitudinal changes in cortical silent period and response to paired associative stimulation protocol in Parkinson's disease reflect dynamic effects on motor cortex that are related to progression of motor signs. They are useful objective markers of early disease progression that could be used to detect effects of disease-modifying therapies. The decline in heightened plasticity that was present at disease onset may reflect failure of compensatory mechanisms that maintained function in the preclinical state. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Key points We studied the interaction between the primary visual cortex and the primary motor cortex using paired transcranial magnetic stimulation (TMS) with an interstimulus interval (ISI) in the range 12-40 ms., The connection is inhibitory at rest and possibly mediated by inhibitory interneurones in the motor cortex., The effect with an ISI of 40 ms reverses into facilitation during a visuomotor (but not audiomotor) reaction task. By contrast, there is no change in inhibition with an ISI of 18 ms, suggesting that separate pathways can be probed at different ISIs., We conclude that a physiologically relevant occipito-motor connection can be activated by means of TMS. It may contribute to visuomotor integration, as well as being involved in certain types of visual epilepsy. , Abstract The major link between the visual and motor systems is via the dorsal stream pathways from visual to parietal and frontal areas of the cortex. Although the pathway appears to be indirect, there is evidence that visual input can reach the motor cortex at relatively short latency. To shed some light on its neural basis, we studied the visuomotor interaction using paired transcranial magnetic stimulation (TMS). Motor-evoked potentials (MEPs) were recorded from the right first dorsal interosseous in sixteen healthy volunteers. A conditioning stimulus (CS) was applied over the phosphene hotspot of the visual cortex, followed by a test stimulus over the left primary motor cortex (M1) with a random interstimulus interval (ISI) in range 12-40 ms. The effects of paired stimulation were retested during visual and auditory reaction-time tasks (RT). Finally, we measured the effects of a CS on short-interval intracortical inhibition (SICI). At rest, a CS over the occiput significantly ( P < 0.001) suppressed test MEPs with an ISI in the range 18-40 ms. In the visual RT, inhibition with an ISI of 40 ms (but not 18 ms) was replaced by a time-specific facilitation ( P < 0.001), whereas, in the auditory RT, the CS no longer had any effect on MEPs. Finally, an occipital CS facilitated SICI with an ISI of 40 ms ( P < 0.01). We conclude that it is possible to study separate functional connections from visual to motor cortices using paired-TMS with an ISI in the range 18-40 ms. The connections are inhibitory at rest and possibly mediated by inhibitory interneurones in the motor cortex. The effect with an ISI of 40 ms reverses into facilitation during a visuomotor RT but not an audiomotor RT. This suggests that it plays a role in visuomotor integration. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Purpose The neurophysiological characteristics of motor cortex have been well characterized in patients with Huntington's disease. We present the first data on cortical excitability in patients with Sydenham's chorea. Methods Motor cortex excitability was examined using transcranial magnetic stimulation in 16 patients in the early clinical stages of Sydenham's chorea and in 17 age- and sex-matched control subjects. Investigations included resting and active motor threshold, motor evoked potential, input-output curves, contralateral silent period, and transcallosal inhibition. Results Resting and active motor threshold were significantly higher and motor evoked potentials were significantly smaller in patients in comparison with controls. The input-output curves were shallower in both hemispheres of patients with chorea compared with controls. No significant differences were seen in silent period or transcallosal inhibition duration. Conclusion Sydenham's chorea is characterized by reduced excitability of corticospinal output similar to that observed in Huntington's disease. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Surround inhibition is a physiological mechanism that is hypothesised to improve contrast between signals in the central nervous system. In the human motor system, motor surround inhibition (m SI) can be assessed using transcranial magnetic stimulation ( TMS). We evaluated whether it is possible to modulate m SI, using a paradigm able to induce plastic effects in primary motor cortex ( M1). Fifteen healthy volunteers participated in the experiments. To assess m SI, we delivered single pulses at rest and at the onset of a right thumb abduction. TMS pulses over abductor digiti minimi ( ADM; surround muscle) hotspot were delivered when EMG activity in right abductor pollicis brevis ( APB; active muscle) > 100 μV was detected. Paired associative stimulation ( PAS) was delivered using peripheral median nerve electric stimulation and TMS over APB M1 area at an interstimulus interval of 21.5 ms for the real PAS ( PAS21.5) and 100 ms for the sham PAS ( PAS100). To verify the effect of PAS21.5 on m SI we collected 20 MEPs from ADM at rest and during APB movements before ( T0) and 5 ( T1), 15 ( T2) and 30 ( T3) minutes after PAS21.5. mSI from APB to ADM was present at baseline. PAS21.5 increased the amount of m SI compared with baseline whereas there was no effect after PAS100. Our results suggest that m SI is an adaptable phenomenon depending on prior experience. [ABSTRACT FROM AUTHOR]

A number of methods have been developed recently that stimulate the human brain non-invasively through the intact scalp. The most common are transcranial magnetic stimulation (TMS), transcranial electric stimulation (TES) and transcranial direct current stimulation (TDCS). They are widely used to probe function and connectivity of brain areas as well as therapeutically in a variety of conditions such as depression or stroke. They are much less focal than conventional invasive methods which use small electrodes placed on or in the brain and are often thought to activate all classes of neurones in the stimulated area. However, this is not true. A large body of evidence from experiments on the motor cortex shows that non-invasive methods of brain stimulation can be surprisingly selective and that adjusting the intensity and direction of stimulation can activate different classes of inhibitory and excitatory inputs to the corticospinal output cells. Here we review data that have elucidated the action of TMS and TES, concentrating mainly on the most direct evidence available from spinal epidural recordings of the descending corticospinal volleys. The results show that it is potentially possible to test and condition specific neural circuits in motor cortex that could be affected differentially by disease, or be used in different forms of natural behaviour. However, there is substantial interindividual variability in the specificity of these protocols. Perhaps in the future it will be possible, with the advances currently being made to model the electrical fields induced in individual brains, to develop forms of stimulation that can reliably target more specific populations of neurones, and open up the internal circuitry of the motor cortex for study in behaving humans. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Primary dystonia is characterized neurophysiologically by reduced inhibitory mechanisms and abnormal regulation of plasticity responses. The potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool in writing dystonia was examined, after the observation that cerebellar stimulation reduces responses to an associative plasticity protocol in healthy subjects. Methods Ten patients with writing dystonia completed a two-part study (sham and anodal) in which cerebellar stimulation was given simultaneously with paired associative stimulation. Electrophysiological and clinical parameters were measured before and after stimulation. Results Clinical symptoms were unchanged by cerebellar stimulation. Patients exhibited much variability in the size and direction of their plasticity responses. Excessive or topographically abnormal plasticity responses were not observed. In the subgroup of patients with facilitatory responses to paired associative stimulation in the sham condition, anodal cerebellar stimulation retained its ability to reduce the magnitude of plasticity response. Conclusions Our limited understanding of intersubject variability of plasticity responses in writing dystonia currently undermines cerebellar stimulation as a novel treatment in this subset of dystonia. Cerebellar stimulation may be beneficial in other neurological disorders with consistently exaggerated plasticity. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

The link between basic physiology and its modulation by cognitive states, such as attention, is poorly understood. A significant association becomes apparent when patients with movement disorders describe experiences with changing their attention focus and the fundamental effect that this has on their motor symptoms. Moreover, frequently used mental strategies for treating such patients, e.g. with task-specific dystonia, widely lack laboratory-based knowledge about physiological mechanisms. In this largely unexplored field, we looked at how the locus of attention, when it changed between internal (locus hand) and external (visual target), influenced excitability in the primary motor cortex (M1) in healthy humans. Intriguingly, both internal and external attention had the capacity to change M1 excitability. Both led to a reduced stimulation-induced GABA-related inhibition and a change in motor evoked potential size, i.e. an overall increased M1 excitability. These previously unreported findings indicated: (i) that cognitive state differentially interacted with M1 physiology, (ii) that our view of distraction (attention locus shifted towards external or distant location), which is used as a prevention or management strategy for use-dependent motor disorders, is too simple and currently unsupported for clinical application, and (iii) the physiological state reached through attention modulation represents an alternative explanation for frequently reported electrophysiology findings in neuropsychiatric disorders, such as an aberrant inhibition. [ABSTRACT FROM AUTHOR]

Surround inhibition ( SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus ( FDI), abductor pollicis brevis (APB) and abductor digiti minimi ( ADM)] and electromyographic ( EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement ( P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively. [ABSTRACT FROM AUTHOR]

ABSTRACT Much attention has focused on the hypothesis that there is enhanced plasticity of sensorimotor circuits in patients with dystonia. A common experimental method to assess plasticity in dystonia research is paired associative stimulation (PAS). Excessive, nonfocal effects of PAS were observed in early studies of dystonia; however, these large effects have not been uniformly replicated. In this viewpoint, data from 15 patients with writing dystonia are presented. We suggest that, as in healthy individuals, the effects of PAS are highly variable. A review of previous studies examining PAS in writing dystonia highlights the range of results that have been observed. We conclude that current experimental evidence cannot be fully explained by the notion that PAS responses in writing dystonia are consistently excessive or nonspecific. The variability of PAS responses is such that enhanced plasticity should not be considered a dystonic fingerprint, because the direction of response can vary, and there is overlap between patient and healthy data. We also discuss evidence questioning the assumption that PAS responses are a clear correlate to levels of synaptic plasticity; we need to define more specifically what PAS responses signify in the dystonic brain. Our conclusions are limited to PAS in writing dystonia; however, much variation exists with other plasticity protocols. Large multicenter studies of both focal and generalized forms of dystonia, probing variability of individual neurophysiological profiles, are encouraged. This will reveal the true role of plasticity in the pathophysiology of dystonia and may expose subject-specific therapeutic interventions that are currently concealed. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Key points Sensory mismatch negativity is impaired in patients with cerebellar lesions, suggesting that the cerebellum may play an important role in this form of sensory processing., Anodal transcranial direct current stimulation over the right cerebellar hemisphere increased the amplitude of sensory mismatch negativity to stimuli delivered to the right hand while cathodal transcranial direct current stimulation reduced it., The cerebellum appears to be an important node in the network mediating sensory mismatch negativity, and tDCS is a useful method with which to manipulate sensory mismatch negativity for experimental studies., Abstract Appropriate orientation towards potentially salient novel environmental stimuli requires a system capable of detecting change in the sensorium. Mismatch negativity (MMN), an evoked potential calculated by subtracting the response to a standard repeated stimulus and a rare 'oddball' stimulus, is proposed as such a change detection mechanism. It is most widely studied in the auditory domain, but here we chose to explore the mechanism of somatosensory MMN, and specifically its dependence on the cerebellum. We recorded event-related potentials (ERPs) evoked in response to auditory and sensory stimuli from 10 healthy subjects before and after anodal, cathodal and sham transcranial direct current stimulation (tDCS) of the right cerebellar hemisphere. There was a significant increase in peak amplitude of somatosensory MMN after anodal tDCS ( F(1,9) = 8.98, P < 0.02, mean difference anodal pre-post: −1.02 μV) and a significant reduction in peak amplitude of somatosensory MMN after cathodal tDCS ( F(1,9) = 7.15, P < 0.03, mean difference cathodal pre-post: 0.65 μV). The amplitude of auditory MMN was unchanged by tDCS. These results reveal the capability of tDCS to cause bidirectional modulation of somatosensory MMN and the dependence of somatosensory MMN on the cerebellum. [ABSTRACT FROM AUTHOR]

Key points Cortical control of swallowing exhibits functional asymmetry with brain lesions involving the strongest projection being implicated in the pathophysiology of dysphagia after unilateral stroke., Swallowing recovery is associated with neuroplastic adaptation in the unlesioned hemisphere, a process which can be facilitated by excitatory neurostimulation techniques including transcranial direct current stimulation (tDCS)., Unilateral suppression of the strongest pharyngeal motor projection using 1 Hz repetitive transcranial magnetic stimulation (rTMS) can disrupt swallowing neurophysiology and behaviour making it a useful model for trialling novel neurostimulation interventions in healthy subjects., In this healthy participant study we examined the effects of tDCS after unilateral pre-conditioning with 1 Hz rTMS to determine its ability to restore swallowing neurophysiology and behaviour., We show that application of optimised parameters of tDCS (anodal stimulation, 1.5 mA, 10 min) over the unconditioned hemisphere reverses the brain and behavioural consequences of inhibitory pre-conditioning, supporting the use of tDCS in clinical trials., Abstract The human cortical swallowing system exhibits bilateral but functionally asymmetric representation in health and disease as evidenced by both focal cortical inhibition (pre-conditioning with 1 Hz repetitive transcranial magnetic stimulation; rTMS) and unilateral stroke, where disruption of the stronger (dominant) pharyngeal projection alters swallowing neurophysiology and behaviour. Moreover, excitatory neurostimulation protocols capable of reversing the disruptive effects of focal cortical inhibition have demonstrated therapeutic promise in post-stroke dysphagia when applied contralaterally. In healthy participants ( n = 15, 8 males, mean age (±SEM) 35 ± 9 years), optimal parameters of transcranial direct current stimulation (tDCS) (anodal, 1.5 mA, 10 min) were applied contralaterally after 1 Hz rTMS pre-conditioning to the strongest pharyngeal projection. Swallowing neurophysiology was assessed in both hemispheres by intraluminal recordings of pharyngeal motor-evoked responses (PMEPs) to single-pulse TMS as a measure of cortical excitability. Swallowing behaviour was examined using a pressure-based reaction time protocol. Measurements were made before and for up to 60 min post intervention. Subjects were randomised to active or sham tDCS after 1 Hz rTMS on separate days and data were compared using repeated measures ANOVA. Active tDCS increased PMEPs bilaterally ( F1,14 = 7.4, P = 0.017) reversing the inhibitory effects of 1 Hz rTMS in the pre-conditioned hemisphere ( F1,14 = 10.1, P = 0.007). Active tDCS also enhanced swallowing behaviour, increasing the number of correctly timed challenge swallows compared to sham ( F1,14 = 6.3, P = 0.025). Thus, tDCS to the contralateral pharyngeal motor cortex reverses the neurophysiological and behavioural effects of focal cortical inhibition on swallowing in healthy individuals and has therapeutic potential for dysphagia rehabilitation. [ABSTRACT FROM AUTHOR]

ABSTRACT Background We investigated whether clinical improvement observed after deep brain stimulation (DBS) of the globus pallidus internus (GPi) in cervical dystonia (CD) is paralleled by the normalisation of temporal discrimination thresholds (TDTs), a marker of abnormal sensory processing in CD. Methods TDT was tested in 11 patients with CD after they received DBS and was compared with TDT scores from 24 patients with CD and a group of 61 controls. Results A clear clinical response to GPi-DBS was demonstrated (total Toronto Western Spasmodic Torticollis Rating Scale scores fell from 50 to 18; P < 0.001). In contrast, TDT remained abnormal in the CD-DBS group ( P < 0.001) and was not significantly different from the abnormal TDT range observed in CD. Conclusions Underlying sensory abnormalities in temporal discrimination observed in dystonia do not seem to be corrected by successful GPi-DBS. This adds further data to the ongoing debate regarding which pathophysiological abnormalities observed in dystonia are likely to be causal in the genesis of the disease rather than epiphenomena observed secondary to abnormal motor activity. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Functional neurological symptoms are one of the most common conditions observed in neurological practice, but understanding of their underlying neurobiology is poor. Historic psychological models, based on the concept of conversion of emotional trauma into physical symptoms, have not been implemented neurobiologically, and are not generally supported by epidemiological studies. In contrast, there are robust clinical procedures that positively distinguish between organic and functional motor signs that rely primarily on distracting attention away from movement or accessing it covertly. We aimed to investigate the neurobiological principles underpinning these techniques and implications for understanding functional symptoms. We assessed 11 patients with functional motor symptoms and 11 healthy controls in three experimental set-ups, where voluntary movements were made either with full explicit control or could additionally be influenced automatically by factors of which participants were much less aware (one-back reaching, visuomotor transformation, and precued reaction time with variable predictive value of the precue). Patients specifically failed in those tasks where preplanning of movement could occur and under conditions of increasing certainty regarding the movement to be performed. However, they implicitly learned to adapt to a visuomotor transformation as well as healthy controls. We propose that when the movement to be performed can be preplanned or is highly predicted, patients with functional motor symptoms shift to an explicit attentive mode of processing that impairs kinematics of movement control, but movement becomes normal when such processes cannot be employed (e.g., during unexpected movement or implicit motor adaptation). © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]