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Increased use of epidural Spinal Cord Stimulation (eSCS) for the rehabilitation of spinal cord injury (SCI) has highlighted the need for a greater understanding of the properties of reflex circuits in the isolated spinal cord, particularly in response to repetitive stimulation. Here, we investigate the frequency-dependence of modulation of short- and long-latency EMG responses of lower limb muscles in patients with SCI at rest. Single stimuli could evoke short-latency responses as well as long-latency (likely polysynaptic) responses. The short-latency component was enhanced at low frequencies and declined at higher rates. In all muscles, the effects of eSCS were more complex if polysynaptic activity was elicited, making the motor output become an active process expressed either as suppression, tonic or rhythmical activity. The polysynaptic activity threshold is not constant and might vary with different stimulation frequencies, which speaks for its temporal dependency. Polysynaptic components can be observed as direct responses, neuromodulation of monosynaptic responses or driving the muscle activity by themselves, depending on the frequency level. We suggest that the presence of polysynaptic activity could be a potential predictor for appropriate stimulation conditions. This work studies the complex behaviour of spinal circuits deprived of voluntary motor control from the brain and in the absence of any other inputs. This is done by describing the monosynaptic responses, polysynaptic activity, and its interaction through its input–output interaction with sustain stimulation that, unlike single stimuli used to study the reflex pathway, can strongly influence the interneuron circuitry and reveal a broader spectrum of connectivity. [ABSTRACT FROM AUTHOR]

Objective: The mechanisms contributing to the pathogenesis of tremor and/or dysmetria in multiple sclerosis (MS) are poorly understood. Abnormal oscillations within the olivocerebello-thalamo-cortical networks are believed to play an important part in tremor aetiology, but could also contribute to intention dysmetria due to disruptions in motor timing. Conversely, delayed central motor conduction times are a common feature of ataxias, but could also contribute to the expression of dysmetria in MS. This study examined the roles of central conduction delays in the manifestation of tremor and/or dysmetria in MS. Methods: Twenty-three individuals with MS participated: 8 with no movement disorder, 6 with tremor, 4 with pure dysmetria and 5 with both tremor and dysmetria. Median nerve somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) over the motor cortex and cervical spine, stretch reflexes were used assess sensory and motor conduction times. Results: Central, but not peripheral, sensory conductions time were significantly delayed in participants with dysmetria, regardless of the presence of tremor. Similarly, the TMS evoked muscles responses and the long-latency component of stretch reflexes were significantly delayed in those with dysmetria, but not pure tremor. Conclusion: Dysmetria in MS is associated with delays in central conduction of sensory or motor pathways, or both, likely leading to disruption of muscle activation timing and terminal oscillations that contribute to dysmetria. Significance: The presence of dysmetria in MS is associated with decreased conduction velocities in central sensory and/or motor pathways likely reflects greater demyelination of these axons compared to those with no movement disorder or pure tremor. [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]

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]

• Evidence supporting the electrophysiological criteria of cortical myoclonus is not very solid. • Although they can be useful if properly used, the electrophysiological criteria of cortical myoclonus should be reviewed. • Combining more than one test, together with clinical features, may increase the diagnostic accuracy of cortical myoclonus. Cortical myoclonus is thought to result from abnormal electrical discharges arising in the sensorimotor cortex. Given the ease of recording of cortical discharges, electrophysiological features of cortical myoclonus have been better characterized than those of subcortical forms, and electrophysiological criteria for cortical myoclonus have been proposed. These include the presence of giant somatosensory evoked potentials, enhanced long-latency reflexes, electroencephalographic discharges time-locked to individual myoclonic jerks and significant cortico-muscular connectivity. Other features that are assumed to support the cortical origin of myoclonus are short-duration electromyographic bursts, the presence of both positive and negative myoclonus and cranial-caudal progression of the jerks. While these criteria are widely used in clinical practice and research settings, their application can be difficult in practice and, as a result, they are fulfilled only by a minority of patients. In this review we reappraise the evidence that led to the definition of the electrophysiological criteria of cortical myoclonus, highlighting possible methodological incongruencies and misconceptions. We believe that, at present, the diagnostic accuracy of cortical myoclonus can be increased only by combining observations from multiple tests, according to their pathophysiological rationale; nevertheless, larger studies are needed to standardise the methods, to resolve methodological issues, to establish the diagnostic criteria sensitivity and specificity and to develop further methods that might be useful to clarify the pathophysiology of myoclonus. [ABSTRACT FROM AUTHOR]

Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role. [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]

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: Alternating hemiplegia of childhood is a very rare and serious neurodevelopmental syndrome; its genetic basis has recently been established. Its characteristic features include typically-unprovoked episodes of hemiplegia and other transient or more persistent neurological abnormalities. Methods: We used transcranial magnetic stimulation to assess the effect of the condition on motor cortex neurophysiology both during and between attacks of hemiplegia. Nine people with alternating hemiplegia of childhood were recruited; eight were successfully tested using transcranial magnetic stimulation to study motor cortex excitability, using single and paired pulse paradigms. For comparison, data from ten people with epilepsy but not alternating hemiplegia, and ten healthy controls, were used. Results: One person with alternating hemiplegia tested during the onset of a hemiplegic attack showed progressively diminishing motor cortex excitability until no response could be evoked; a second person tested during a prolonged bilateral hemiplegic attack showed unusually low excitability. Three people tested between attacks showed asymptomatic variation in cortical excitability, not seen in controls. Paired pulse paradigms, which probe intracortical inhibitory and excitatory circuits, gave results similar to controls. Conclusions: We report symptomatic and asymptomatic fluctuations in motor cortex excitability in people with alternating hemiplegia of childhood, not seen in controls. We propose that such fluctuations underlie hemiplegic attacks, and speculate that the asymptomatic fluctuation we detected may be useful as a biomarker for disease activity. [ABSTRACT FROM AUTHOR]

Background: Evidence in animal stroke models suggests that neuroplasticity takes place maximally in a specific time window after an ischaemic lesion, which may coincide with the optimal time to intervene with rehabilitation. The aim of this study is to investigate neurophysiological evidence for a "critical window" of enhanced neuroplasticity in patients following ischaemic stroke, and establish its duration. We will also investigate changes in cortical inhibition following stroke, and the influence this has on functional recovery. Methods/Design: We will recruit participants recently admitted to the Stroke Unit of major metropolitan hospitals who have had a stroke and can provide informed consent. Participants will be excluded if they have any contraindications to Transcranial Magnetic Stimulation. We will compare neurophysiological outcomes in an age-matched healthy control group. We conservatively hypothesise a 5 % increase in neuroplasticity at the optimal timing following stroke, compared to control participants, and require 43 patients following stroke to detect a significant difference with 80 % power. The primary outcome is the change in the motor evoked potential (MEP) amplitude in a hand muscle, after the administration of a plasticity-inducing paradigm to the affected hemisphere. Secondary outcomes include measures of cortical excitability, intracortical inhibition and arm function. Discussion: The data from this trial will clarify whether there is a critical window for neuroplastic change in the brain following stroke. If so, intensive rehabilitation during this period could be more effective, reducing long-term disability and the cost burden of stroke. [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]

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]

Action selection describes the high-level process that selects between competing movements. In animals, behavioral variability is critical for the motor exploration required to select the action that optimizes reward and minimizes cost/punishment and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioral and neurophysiological variability on DA and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant's behavior but predetermined. Blocks highly biased toward punishment were associated with increased MA variability relative to blocks either with reward or without feedback. This increase in behavioral variability was positively correlated with neurophysiological variability, as measured by changes in corticospinal excitability with transcranial magnetic stimula-tion over the primary motor cortex. Following the administration of a DA antagonist, the variability associated with punishment dimin-ished and the correlation between behavioral and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a predetermined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioral variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcomes. [ABSTRACT FROM AUTHOR]

Paired-pulse transcranial magnetic stimulation ( TMS) is used to measure the excitability of interhemispheric inhibition ( IHI) between the hand areas of the two motor cortices. It varies from person to person, and is highly predictive of individual differences in callosal anatomy (fractional anisotropy) and even motor behaviour, e.g. the amount of involuntary electromyographic ( EMG) 'mirroring' in one hand during rapid contraction of the other. The present experiments tested whether it also predicts how well individuals can improve motor performance in a task involving the two hands. Healthy participants were given 100 trials to maximize the initial acceleration of a ballistic finger movement made with one hand while trying to maintain a tonic low level of EMG activity in the other hand. Initially, each movement was accompanied by additional unwanted EMG mirroring in the other hand. However, after practice, participants had on average increased acceleration by approximately one-third without changing the amount of EMG mirroring in the contralateral hand; indeed, in some individuals EMG mirroring activity declined. TMS measures showed that there was an increase in corticospinal excitability in the trained hemisphere, but there was no change in the excitability of short- or long-latency IHI from the trained to non-trained hemisphere. Nevertheless, in each individual, the baseline (pre-practice) excitability of short-latency IHI was highly predictive ( r = 0.65; P = 0.0019) of the change in EMG mirroring. The implication is that a physiological measure of brain excitability at rest can predict behaviour in response to training. [ABSTRACT FROM AUTHOR]

Preterm-born children commonly experience motor, cognitive, and learning difficulties that may be accompanied by altered brain microstructure, connectivity, and neurochemistry. However, the mechanisms linking the altered neurophysiology with the behavioral outcomes are unknown. Here we provide the first physiological evidence that human adolescents born preterm at or before 37 weeks of completed gestation have a significantly reduced capacity for cortical neuroplasticity, the key overall mechanism underlying learning and memory. We examined motor cortex neuroplasticity in three groups of adolescents who were born after gestations of 32 completed weeks (early preterm), 33-37 weeks (late preterm), and 38-41 weeks (term) using a noninvasive transcranial magnetic brain stimulation technique to induce long-term depression (LTD)-like neuroplasticity. Compared with term-born adolescents, both early and late preterm adolescents had reduced LTD-like neuroplasticity in response to brain stimulation that was also associated with low salivary Cortisol levels. We also compared neuroplasticity in term-born adolescents with that in term-born young adults, finding that the motor cortex retains a relatively enhanced neuroplastic capacity in adolescence. These findings provide a possible mechanistic link between the altered brain physiology of preterm birth and the subsequent associated behavioral deficits, particularly in learning and memory. They also suggest that altered hypothalamic-pituitary-adrenal axis function due to preterm birth may be a significant modulator of this altered neuroplasticity. This latter finding may offer options in the development of possible therapeutic interventions. [ABSTRACT FROM AUTHOR]

Long-term results show that benefits from chronic deep brain stimulation in dystonia are maintained for many years. Despite this, the neurophysiological long-term consequences of treatment and their relationship to clinical effects are not well understood. Previous studies have shown that transcranial magnetic stimulation measures of abnormal long-term potentiation-like plasticity (paired associative stimulation) and GABAa-ergic inhibition (short-interval intracortical inhibition), which are seen in dystonia, normalize after several months of deep brain stimulation. In the present study, we examine the same measures in a homogenous group of 10 DYT1 gene-positive patients after long-term deep brain stimulation treatment for at least 4.5 years. Recordings were made ‘on’ deep brain stimulation and after stopping deep brain stimulation for 2 days. The results show that: (i) on average, prior to discontinuing deep brain stimulation, the paired associative stimulation response was almost absent and short-interval intracortical inhibition was reduced compared with normal. This pattern differs from that in both healthy volunteers and from the typical pattern of enhanced plasticity and reduced inhibition seen in deep brain stimulation-naïve dystonia. It is similar to that seen in untreated Parkinson’s disease and may relate to thus far unexplained clinical phenomena like parkinsonian symptoms that have sometimes been observed in patients treated with deep brain stimulation. (ii) Overall, there was no change in average physiological or clinical status when deep brain stimulation was turned off for 2 days, suggesting that deep brain stimulation had produced long-term neural reorganization in the motor system. (iii) However, there was considerable variation between patients. Those who had higher levels of plasticity when deep brain stimulation was ‘on’, had the best retention of clinical benefit when deep brain stimulation was stopped and vice versa. This may indicate that better plasticity is required for longer term retention of normal movement when deep brain stimulation is off. (iv) Patients with the highest plasticity ‘on’ deep brain stimulation were those who had been receiving stimulation with the least current drain. This suggests that it might be possible to ‘shape’ deep brain stimulation of an individual patient to maximize beneficial neurophysiological patterns that have an impact on clinical status. The results are relevant for understanding long-term consequences and management of deep brain stimulation in dystonia. [ABSTRACT FROM AUTHOR]

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke. [ABSTRACT FROM AUTHOR]

Dystonia is an involuntary movement disorder characterized by muscle contractions causing abnormal postures and spasms, affecting part or all of the body. Dystonia may be primary where an abnormal gene, most commonly DYT1, may be identified, or secondary to structural brain lesions or heredodegenerative disorders. The underlying defect is believed to be abnormal basal ganglia modulation of cortical motor pathways, and various motor and sensory physiological abnormalities have been demonstrated. The failure of medical treatment in many patients with the more severe and generalized forms of dystonia has led to renewed interest in neurosurgical treatment approaches. In recent years, deep brain stimulation (DBS) of globus pallidus internus (GPi) has emerged as an effective treatment for dystonia, particularly patients with primary generalized dystonia, where remarkable improvement may occur. In contrast to Parkinson's disease, the beneficial effects of DBS in dystonia are not immediate but progressive over weeks to months. Physiological and imaging studies in dystonia patients with GPi DBS have demonstrated both short and long-term effects of GPi DBS on motor cortex and subcortical circuits including progressive normalization of spinal and brainstem excitability after GPi DBS which correlate with clinical improvement. These effects, in light of existing physiological data in dystonia, suggest that GPi DBS acts primarily by major modification of basal ganglia output to brainstem, thalamus, and cortex resulting in neural reorganization, which may explain the characteristic progressive improvement in dystonia after GPi DBS. [ABSTRACT FROM AUTHOR]

Musicians not only have extraordinary motor and sensory skills, but they also have an increased ability to learn new tasks compared with non-musicians. We examined how these features are expressed in neurophysiological parameters of excitability and plasticity in the motor system by comparing the results of 11 professional musicians and 8 age-matched non-musicians. Parameters of motor excitability were assessed using transcranial magnetic stimulation (TMS) to measure motor-evoked potentials (MEPs) together with recruitment of corticospinal projections [input- output curve (IOcurve)] and of short-latency intracortical inhibition (SICIcurve). Plasticity, here defined as change of synaptic effectiveness, was tested by measuring MEPs and IOcurves after paired associative stimulation (PAS), which consists of an electric median nerve stimulus repeatedly paired (200 times at 0.25Hz) with a TMS pulse over the hand motor area. Using an interstimulus interval of 25ms(PAS25) or 10ms(PAS10), this leads to long-term potentiation- or long-term depression-like plasticity, respectively. Musicians showed steeper recruitment of MEPs and SICI (IOcurve and SICIcurve). Additionally, PAS25 increased and PAS10 decreased the MEP amplitudes and the slope of the IOcurves significantly more in musicians than in non-musicians. This is consistent with a wider modification range of synaptic plasticity in musicians. Together with the steeper recruitment of corticospinal excitatory and intracortical inhibitory projections, this suggests that they regulate plasticity and excitability with a higher gain than normal. Because some of these changes depend on age at which instrumental playing commenced and on practice intensity, they may reflect an increase in number and modifiability of synapses within the motor area caused by long-term musical practice. [ABSTRACT FROM AUTHOR]

In healthy human subjects, the relative contribution of cortical regions to motor performance varies with the task parameters. Additionally, after stroke, recruitment of cortical areas during a simple motor task varies with corticospinal system integrity. We investigated whether the pattern of motor system recruitment in a task involving increasingly forceful hand grips is influenced by the degree of corticospinal system damage. Nine chronic subcortical stroke patients and nine age-matched controls underwent functional magnetic brain imaging whilst performing repetitive isometric hand grips. Target grip forces were varied between 15% and 45% of individual maximum grip force. Corticospinal system functional integrity was assessed with transcranial magnetic stimulation. Averaged across all forces, there was more task-related activation compared with rest in the secondary motor areas of patients with greater corticospinal system damage, confirming previous reports. However, here we were primarily interested in regional brain activation, which covaried with the amount of force generated, implying a prominent executive role in force production. We found that in control subjects and patients with lesser corticospinal system damage, signal change increased linearly with increasing force output in contralateral primary motor cortex, supplementary motor area and ipsilateral cerebellum. In contrast, in patients with greater corticospinal system damage, force-related signal changes were seen mainly in contralesional dorsolateral premotor cortex, bilateral ventrolateral premotor cortices and contralesional cerebellum, but not ipsilesional primary motor cortex. These findings suggest that the premotor cortices might play a new and functionally relevant role in controlling force production in patients with more severe corticospinal system disruption. [ABSTRACT FROM AUTHOR]

Fast ballistic flexion movements of the wrist are produced by a triphasic pattern of electromyographic (EMG) activity in flexor and extensor muscle. Whereas it is generally accepted that the primary motor cortex generates the first agonist burst (AG1), its contribution to the following antagonist burst (ANT) and second agonist burst (AG2) is unresolved. We applied single pulses of suprathreshold transcranial magnetic stimulation (TMS) at different times to the motor cortex ipsilateral to wrist flexion. This produced interhemispheric inhibition of the opposite motor cortex and a silent period in the ballistic EMG pattern that started about 30 ms after the stimulus and lasted for a further 30 ms. If the silence was timed to start within the first 30 ms of AG1, then timing of the subsequent ANT and AG2 bursts was delayed. However, if the silence began later, then the timing of the ANT burst was not changed. A similar effect on the onset latency of the AG2 was seen if the silence began in the first part of the ANT burst. The results are compatible with a model in which the triphasic pattern is not triggered as a single entity. Instead we suggest that each burst has its own trigger that occurs about 30–40 ms after the start of AG1 (or ANT). If AG1 (or ANT) is interrupted within this time period then this trigger, and hence later bursts, are delayed. If the interruption occurs after 30–40 ms it has no effect on the onset of later bursts since they have already been triggered. [ABSTRACT FROM AUTHOR]

Several experimental protocols induce lasting changes in the excitability of motor cortex. Some involve direct cortical stimulation, others activate the somatosensory system and some combine motor and sensory stimulation. The effects usually are measured as changes in amplitude of the motor-evoked-potential (MEP) or short-interval intracortical inhibition (SICI) elicited by a single or paired pulses of transcranial magnetic stimulation (TMS). Recent work has also tested sensorimotor organization within the motor cortex by recording MEPs and SICI during short periods of vibration applied to single intrinsic hand muscles. Here sensorimotor organization is focal: MEPs increase and SICI decreases in the vibrated muscle, whilst the opposite occurs in neighbouring muscles. In six volunteers we compared the after effects of three protocols that lead to lasting changes in cortical excitability: (i) paired associative stimulation (PAS) between a TMS pulse and an electrical stimulus to the median nerve; (ii) motor practice of rapid thumb abduction; and (iii) sensory input produced by semicontinuous muscle vibration, on MEPs and SICI at rest and on the sensorimotor organization. PAS increased MEP amplitudes, whereas vibration changed sensorimotor organization. Motor practice had a dual effect and increased MEPs as well as affecting sensorimotor organization. The implication is that different protocols target different sets of cortical circuits. We speculate that protocols that involve repeated activation of motor cortical output lead to lasting changes in efficacy of synaptic connections in output circuits, whereas protocols that emphasize sensory inputs affect the strength of sensory inputs to motor circuits. [ABSTRACT FROM AUTHOR]

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

Previous electrophysiological and neuroimaging studies have provided evidence that the supplementary motor area (SMA) has an important role in the control of bimanual coordination. The present experiment investigated the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the SMA region on kinematic variables during cyclical bimanual coordination, with a particular focus on the quality of coordination. Subjects performed metronome-paced trials of in-phase and anti-phase bimanual index-finger movements at near-maximal cycling frequency. During movement execution, rTMS (20 Hz, 0.5 s, 120% hand motor threshold) was applied over one of three positions in the sagittal midline 2.0, 4.0 and 6.0 cm anterior to the primary motor leg area. Sham rTMS was included as a control condition. After rTMS, the mean relative phase error between hands increased, but only in the anti-phase trials. The maximum increase in phase error occurred immediately after rather than during the rTMS train. The effect was largest after stimulation 4 or 6 cm anterior to the leg area of the primary motor cortex. We did not observe any changes in the variability of relative phase or in cycle duration or movement amplitude. Findings are discussed in light of recent functional models on the role of the SMA in bimanual movement control. [ABSTRACT FROM AUTHOR]

Task-specific dystonia is a movement disorder characterized by a painless loss of dexterity specific to a particular motor skill. This disorder is prevalent among writers, musicians, dancers and athletes. No current treatment is predictably effective, and the disorder generally ends the careers of affected individuals. Traditional disease models of dystonia have a number of limitations with regard to task-specific dystonia. We therefore discuss emerging evidence that the disorder has its origins within normal compensatory mechanisms of a healthy motor system in which the representation and reproduction of motor skill are disrupted. We describe how risk factors for task-specific dystonia can be stratified and translated into mechanisms of dysfunctional motor control. The proposed model aims to define new directions for experimental research and stimulate therapeutic advances for this highly disabling disorder. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The effects of theta burst stimulation (TBS) have been extensively investigated in primary motor cortex, where it leads to long-lasting LTP/LTD-like effects on synaptic plasticity. This study aimed to extend these observations to sensory cortex. Methods: Fourteen healthy subjects participated in the study. Conditioning 600-pulse intermittent TBS (iTBS) and continuous TBS (cTBS) were delivered to left somatosensory cortex (S1) with an intensity of 80% active motor threshold. Somatosensory evoked potentials (SEPs) were evoked by median nerve electrical stimulation at right wrist. High frequency oscillations (HFOs) were obtained by digital filtering of original SEPs and divided into early and late subcomponents, relative to N20peak latency. Results: Repeated-measures ANOVA showed that iTBS facilitated N20onset–N20peak at 15min and N20peak–P25 at 15 and 30min after conditioning, whereas cTBS did not. iTBS left the early and late HFOs unchanged. Conversely, cTBS facilitated the early HFOs, whereas it inhibited the late HFOs at 15min after conditioning. Conclusions: S1-iTBS facilitated SEPs without changes in HFOs whereas cTBS modulated early and late HFOs without changes in SEPs. Significance: S1-TBS produces lasting changes in the excitability of intracortical circuits generating SEPs and HFOs differentially through mechanisms of LTP/LTD-like synaptic plasticity. [ABSTRACT FROM AUTHOR]

Over the last decade, electrophysiological studies in parkinsonian animals have shown that there are abnormalities of synaptic plasticity in motor areas of cortex and basal ganglia. In humans with Parkinson's disease (PD), cortical plasticity has been widely investigated using transcranial magnetic stimulation. A number of studies have reported abnormal responses to several different conditioning protocols, but their relationship to altered basal ganglia output and dopaminergic loss is still not entirely clear. Thus in the near future it seems unlikely that measures of cortical plasticity could be used as a biomarker of disease severity and progression. In this review we provide an overview on current knowledge of abnormalities of plasticity in PD in the light of recent advances in parkinsonian animal models. Finally we will discuss the relevance of abnormalities of plasticity in the clinical context of PD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To test whether inhibitory continuous Theta Burst (cTBS) transcranial magnetic stimulation (TMS) can alter neural activity involved in planning and execution of a self-paced movement. Methods: In seven subjects, cTBS was applied over either the left or right primary motor cortex (left M1 and right M1) and the left dorsal premotor cortex (left PMd) in different experimental sessions. Motor evoked potentials (MEP) at rest were measured as well as the two main components of the movement related cortical potential (MRCP), the Bereitschaftspotential (BP) and the negative slope (NS’), prior to self-paced right thumb opposition. Results: cTBS suppressed contralateral MEPs when it was applied over left M1, right M1 and left PMd. In addition, cTBS over left M1, but not at any other location, reduced the amplitude of the NS’ and tended to shorten the BP onset without changing EMG activity associated with voluntary muscular output. There was a significant correlation between the percent suppression of the MEP and the reduction in amplitude of the total MRCP (BP+NS’). Conclusions: cTBS can produce long-lasting effects on brain activity involved in the preparation and execution of a volitional movement. Significance: The fact that movement was not compromised while brain activity changed suggests that the motor system of healthy subjects operates with a safety factor that can adjust patterns of activation to compensate for the partial disruption caused by cTBS. [Copyright &y& Elsevier]

Abstract: Objective: This study was designed to examine whether exhaustive grip exercise of the left hand affected intracortical excitability in ipsilateral motor cortex. Methods: Ten healthy male subjects (aged 21–24 years) participated in experiment 1 in which paired-pulse transcranial magnetic stimulation (TMS) was used to test corticospinal and corticocortical excitability in right (relaxed) first dorsal interosseous (FDI) muscle during the recovery period after exhaustive forceful grip exercise of the left hand. Seven of the same subjects participated in experiment 2, in which the intensity of the test stimulus was adjusted so that the amplitude of motor evoked potential (MEPTEST) was kept constant throughout the measurement. Results: In experiment 1, MEPTEST was slightly reduced from 5 to 15min after exercise whilst short interval intracortical inhibition (SICI) at interstimulus interval (ISI) of 2 and 3ms became less effective. Intracortical facilitation (ICF) was unchanged. In experiment 2 when the MEPTEST was maintained at a constant size there was again no change in ICF, and the reduction in SICI was still present at the same intervals. Conclusions: We conclude that unilateral exhaustive grip exercise reduced the excitability of the corticospinal output of the ipsilateral motor cortex whilst simultaneously reducing the excitability of SICI. These results would be compatible with the idea that fatigue increases the tonic level of interhemispheric inhibition from the fatigued to the non-fatigued cortex. Significance: Muscle fatigue to the point of exhaustion has lasting effects on the excitability of intracortical circuits in the non-exercised hemisphere, perhaps via changes in the tonic levels of activity in transcallosal pathways. [Copyright &y& Elsevier]