John C Rothwell

• MA PhD
• Professor at University College London

Background Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high‐frequency repetitive somatosensory stimulation (RSS; HF‐RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low‐frequency RSS (LF‐RSS) increases them. However,...

Background Essential tremor (ET) is a common debilitating condition, yet current treatments often fail to provide satisfactory relief. Transcutaneous spinal cord electrical stimulation (tSCS) has emerged as a potential noninvasive neuromodulation technique capable of disrupting the oscillatory activity underlying tremors. Objective This study aime...

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) is a novel technique to investigate cortical physiology in health and disease. The cerebellum has recently gained attention as a possible new hotspot in the field of TMS-EEG, with several reports published recently. However, EEG responses obtained by cerebellar stimulat...

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) allows for the study of brain dynamics in health and disease. Cranial muscle activation can decrease the interpretability of TMS-EEG signals by masking genuine EEG responses and increasing the reliance on preprocessing methods but can be at least partly prevented by coi...

HIGHLIGHTS. We developed a novel dual-site TMS setup to stimulate two adjacent brain regions. It is subject to fewer technical and spatial limitations than previous attempts. This enables more accurate and repeatable targeting of brain regions. ABSTRACT. Objective: Using dual-site transcranial magnetic stimulation (dsTMS), the effective conne...

Previous research on movement preparation identified a period of corticospinal suppression about 200 ms prior to movement initiation. This phenomenon has been observed for different types of motor tasks typically used to investigate movement preparation (e.g., reaction time, self-initiated, and anticipatory actions). However, we recently discovered...

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes...

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we del...

Transcranial magnetic stimulation (TMS) is a non‐invasive technique that is increasingly used to study the human brain. One of the principal outcome measures is the motor‐evoked potential (MEP) elicited in a muscle following TMS over the primary motor cortex (M1), where it is used to estimate changes in corticospinal excitability. However, multiple...

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...

Background Connections between the cerebellum and the cortex play a critical role in learning and executing complex behaviours. Dual-coil transcranial magnetic stimulation (TMS) can be used non-invasively to probe connectivity changes between the lateral cerebellum and motor cortex (M1) using the motor evoked potential as an outcome measure (cerebe...

Although rigidity is a cardinal motor sign in patients with Parkinson’s disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and its pathophysiological underpinning remains still unclear. Further advances in the field would require innovative methodological approaches able to measure parkinsonian rigidity objec...

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...

Botulinum toxin (BT) therapy may be blocked by antibodies (BT-AB) resulting in BT-AB induced therapy failure (ABF). BT-AB may be detected by the mouse lethality assay (MLA), the mouse diaphragm assay (MDA) and the sternocleidomastoid test (SCMT). For the first time, we wanted to compare all three BT-AB tests and correlate them to subjective complai...

The analysis of single motor unit (SMU) activity provides the foundation from which information about the neural strategies underlying the control of muscle force can be identified, due to the one-to-one association between the action potentials generated by an alpha motor neuron and those received by the innervated muscle fibers. Such a powerful a...

Studies using transcranial magnetic stimulation (TMS) have demonstrated the importance of direction and intensity of the applied current when the primary motor cortex (M1) is targeted. By varying these, it is possible to stimulate different subsets of neural elements, as demonstrated by modulation of motor evoked potentials (MEPs) and motor behavio...

Objective Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation. Y.Z. Huang et al. developed the first neuromodulation model to explain the bidirectional effects of theta-burst stimulation (TBS) based on the postsynaptic intracellular calcium concentration elevation. Ho...

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 individual...

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 line...

Objective. Motor-evoked potentials (MEPs) are among the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller respon...

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field an...

Understanding cerebellar–cortical physiological interactions is of fundamental importance to advance the efficacy of neurorehabilitation strategies for patients with cerebellar damage. Previous works have aimed to modulate this pathway by applying transcranial electrical or magnetic stimulation (TMS) over the cerebellum and probing the resulting ch...

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 mod...

Transcranial alternating current stimulation (TACS) is commonly used to synchronise the output of a cortical area to other parts of the nervous system, but evidence for this based on brain recordings in humans is challenging. The brain transmits beta oscillations ( ~ 21Hz) to tonically contracted limb muscles linearly and through the fastest cortic...

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 electroencep...

Background: Motor-evoked potentials (MEP) are one of the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller...

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum...

Background Pulses of transcranial magnetic stimulation (TMS) with a predominantly anterior-posterior (AP) or posterior-anterior (PA) current direction over the primary motor cortex appear to activate distinct excitatory inputs to corticospinal neurons. In contrast, very few reports have examined whether the inhibitory neurons responsible for short-...

Aberrant neural oscillations hallmark the pathophysiology of numerous neurological and psychiatric disorders. Here, we first report a method to accurately track the phase of neural oscillations in real-time by a Hilbert transform that avoids the characteristic Gibbs distortion at the end of the signal, aka endpoint-corrected Hilbert transform (ecHT...

Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia. However, the results from individual studies are conflicting and underpowered. This collaborative project collated all published data and systematically re-examined the contribution of the predictors dystonia and its subtypes within a statisti...

Background. Upper-limb impairment in patients with chronic stroke appears to be partly attributable to an upregulated reticulospinal tract (RST). Here, we assessed whether the impact of corticospinal (CST) and RST connectivity on motor impairment and skill-acquisition differs in sub-acute stroke, using transcranial magnetic stimulation (TMS)–based...

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 pathophysiolo...

Although a general age-related decline in neural plasticity is evident, the effects of age on neural plasticity after motor practice are inconclusive. Inconsistencies in the literature may be related to between-study differences in task difficulty. Therefore, we aimed to determine the effects of age and task difficulty on motor learning and associa...

Motor cortex (M1) paired-pulse TMS (ppTMS) probes excitatory and inhibitory intracor-tical dynamics by measurement of motor-evoked potentials (MEPs). However, MEPs reflect cortical and spinal excitabilities and therefore cannot isolate cortical function. Concurrent TMS-EEG has the ability to measure cortical function, while limiting peripheral conf...

The ability of repetitive transcranial magnetic stimulation (rTMS) to non-invasively induce neuroplasticity in the human cortex has opened exciting possibilities for its application in both basic and clinical research. Changes in the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation has so far pr...

Background: In preclinical models, behavioral training early after stroke produces larger gains compared with delayed training. The effects are thought to be mediated by increased and widespread reorganization of synaptic connections in the brain. It is viewed as a period of spontaneous biological recovery during which synaptic plasticity is incre...

This handbook is currently in development, with individual articles publishing online in advance of print publication. At this time, we cannot add information about unpublished articles in this handbook, however the table of contents will continue to grow as additional articles pass through the review process and are added to the site. Please note...

Introduction: Transcranial magnetic stimulation (TMS) is widely employed 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 ques...

Background The cerebellum is recognised to bilaterally modulate sensorimotor function and has recently been shown to play a role in swallowing. Indeed, we have previously shown that unilateral cerebellar repetitive trans-cranial magnetic stimulation (rTMS) can excite corticobulbar motor pathways to the pharynx. However, the comparative effects of b...

In everyday life, risky decision-making relies on multiple cognitive processes including sensitivity to reinforcers, exploration, learning, and forgetting. Neuroimaging evidence suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in exploration and risky decision-making, but the nature of its computations and its causal role remain...

Successful models of movement should encompass the flexibility of the human motor system to execute movements under different contexts. One such context-dependent modulation is proactive inhibition, a type of behavioural inhibition concerned with responding with restraint. Whilst movement has classically been modelled as a rise-to-threshold process...

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET)...

The process of learning and playing a musical instrument modulates the structural and functional organization of cortical motor networks. In the present study the excitability and short-term functional plasticity of face and hand areas of primary motor cortex (M1) were compared in woodwind musicians (WM), string musicians (SM) and non-musicians to...

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 p...

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 sti...

As the field of noninvasive brain stimulation (NIBS) expands there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three differ...

Digital assessments of motor severity could improve the sensitivity of clinical trials and personalise treatment in Parkinson’s disease (PD) but have yet to be widely adopted. Their ability to capture individual change across the heterogeneous motor presentations typical of PD remains inadequately tested against current clinical reference standards...

We investigate if rTMS has a therapeutic role in the treatment of dysphagia in patients with Parkinson’s disease (PD). Material and Methods. Thirty-three patients with PD and dysphagia were randomly classified with ratio 1:2 to receive sham or real rTMS (2000 pulses; 20 Hz; 90% resting motor threshold; 10 trains of 10 seconds with 25 seconds betwee...

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 rep...

Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation t...

Background the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute...

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical setti...

While the difficulty of a motor task can act as a stimulus for learning in younger adults, it is unknown how task difficulty interacts with age-related reductions in motor performance and altered brain activation. We examined the effects of task difficulty on motor performance and used electroencephalography (EEG) to probe task-related brain activa...

We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral...

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 s...

The cerebellum is recognised to bilaterally modulate sensorimotor function and has recently been shown to play a role in swallowing. Unilateral cerebellar repetitive trans-cranial magnetic stimulation (rTMS) excites corticobulbar motor pathways to the pharynx but the effects of bilateral versus unilateral cerebellar rTMS on these pathways are unkno...

Response inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of...

Key points We explored the large variability in motor skill acquisition‐related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual variance or the type of motor task investigated. We compared different motor‐learning tasks, i.e. model‐free vs. model‐based learning tasks, and their poss...

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET)...

Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinica...

Response inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of...

Anterior-posterior (AP) and posterior-anterior (PA) pulses of transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) appear to activate distinct interneuron networks that contribute differently to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). The AP network is thought to be more sensitive t...

Although facial muscles are heavily involved in emotional expressions, there is still a lack of evidence about the role of face primary motor cortex (face M1) in the processing of facial recognition and expression. This work investigated the effects of the passive viewing of different facial expressions on face M1 and compared data with those obtai...

The defining character of tics is that they can be transiently suppressed by volitional effort of will, and at a behavioural level this has led to the concept that tics result from a failure of inhibition. However, this logic conflates the mechanism responsible for the production of tics with that used in suppressing them. Volitional inhibition of...

Background Transcranial Magnetic stimulation (TMS) is a non-invasive cortical stimulation method that has been widely employed to explore cortical physiology in health and a range of diseases. At the core of many TMS protocols is the measurement of evoked muscle contractions using surface electromyography (sEMG). While sEMG is appropriate for many...

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 wa...

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 effe...

Background: Poststroke dysphagia is common, associated with a poor outcome and has no definitive treatments. Repetitive transcranial magnetic stimulation (rTMS) targeting the cerebellum is a noninvasive technique requiring minimal physical or cognitive input from the patient, and has been shown to induce positive swallow-related brain changes in p...

Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain. Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke. Methods. A total...

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 transcr...

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...

Background: Short-latency intracortical inhibition (SICI) is extensively used to probe GABAergic inhibitory mechanisms in M1. Task-related changes in SICI are presumed to reflect changes in the central excitability of GABAergic pathways. Usually, the level of SICI is evaluated using a single intensity of conditioning stimulus so that inhibition ca...

Background: Unilateral or very asymmetric upper limb tremors with a jerky appearance are poorly investigated. Their clinical classification is an unsolved problem because their classification as essential tremor versus dystonic tremor is uncertain. To avoid misclassification as essential tremor or premature classification as dystonic tremor, the t...

Objective A sensorimotor network structural phenotype predicted motor task performance in a previous study in Huntington’s disease (HD) gene carriers. We investigated in the visual network whether structure – function – behaviour relationship patterns, and the effects of the HD mutation, extended beyond the sensorimotor network. Methods We used mul...

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on involvement of both upper (UMN) lower motor neurons (LMN). Yet, there remains no objective marker of UMN involvement, limiting early diagnosis of ALS. This study establishes whether TMS combined with EEG can be used to measure short-interval intracortical inhibition (SICI) via TMS evoke...

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...