Biomedical subjects

John C Rothwell

Publications and source records attributed to John C Rothwell.

At least 37 records · Page 2Linked to original sources

PubMed2006

Temporal discrimination of two passive movements in writer's cramp.

Although movement abnormalities are predominant symptoms of dystonia, patients also have alterations in temporal as well as spatial discrimination of cutaneous inputs. Here, we use a recently described method to test whether deficits also exist in temporal discrimination of proprioceptive inputs. Percutaneous electrical stimulation of the motor point of the first dorsal interosseous (FDI) muscle, and of the flexor carpii radialis (FCR) muscle separately, was used to produce a nonpainful contraction of the muscles that caused index finger abduction and wrist flexion, respectively. In 10 patients with writer's cramp and in 10 healthy subjects, pairs of stimuli separated by different time intervals were given and subjects were asked to report whether they perceived a single or a double index finger abduction movement or wrist flexion. The threshold value was the shortest interval at which the subjects reported two separated movements (temporal discrimination motor threshold [TDMT]). In both writer's cramp patients and controls, TDMTs were higher for FCR than for FDI. But in contrast to the reduced temporal discrimination reported for cutaneous sensation, there was no significant difference in either muscle between TDMT in patients and normal subjects. We conclude that temporal processing of muscle and cutaneous afferents is differentially affected in focal hand dystonia.

Adult↗

PubMed2006

Changes in blink reflex excitability after globus pallidus internus stimulation for dystonia.

A pathophysiological feature of dystonia is reduced inhibition at various levels of the nervous system, which may be detected in clinically unaffected body parts. Chronic deep brain stimulation (DBS) of the globus pallidus internus (GPi) has emerged as an effective treatment for primary torsion dystonia (PTD), although its mechanism of action and impact on inhibitory abnormalities in dystonia are unknown. We sought to understand the effect of GPi DBS on brainstem excitability in patients with PTD. We measured the blink reflex from orbicularis oculi in response to paired electrical stimulation of the supraorbital nerve at interstimulus intervals of 500 and 1,000 milliseconds in 10 patients with PTD before and at intervals of 1, 3, and 6 months after bilateral GPi DBS and in 10 healthy subjects. Patients were clinically evaluated using the Burke-Fahn-Marsden dystonia rating scale. We found R2 inhibition was significantly decreased in PTD patients compared with control subjects and progressively increased after GPi DBS, which correlated with clinical improvement in dystonia. We conclude that GPi DBS for PTD results in functional reorganization of the nervous system, which includes a long-term increase in brainstem inhibition.

Adult↗

PubMed2006

Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson's disease.

Previous studies in patients with Parkinson's disease have reported that a single session of repetitive transcranial magnetic stimulation (rTMS) can improve some or all of the motor symptoms for 30 to 60 minutes. A recent study suggested that repeated sessions of rTMS lead to effects that can last for at least 1 month. Here we report data that both confirm and extend this work. Fifty-five unmedicated PD patients were classified into four groups: two groups (early and late PD) received 25 Hz rTMS bilaterally on the motor arm and leg areas; other groups acted as control for frequency (10 Hz) and for site of stimulation (occipital stimulation). All patients received six consecutive daily sessions (3,000 pulses for each session). The first two groups then received a further three booster sessions (3 consecutive days of rTMS) after 1, 2, and 3 months, while the third group had only one additional session after the first month. Unified Parkinson's Disease Rating Scale (UPDRS), walking time, key-tapping speed, and self-assessment scale were measured for each patient before and after each rTMS session and before and after the monthly sessions. Compared to occipital stimulation, 25 Hz rTMS over motor areas improved all measures in both early and late groups; the group that received 10 Hz rTMS improved more than the occipital group but less than the 25 Hz groups. The effect built up gradually during the sessions and was maintained for 1 month after, with a slight reduction in efficacy. Interestingly, the effect was restored and maintained for the next month by the booster sessions. We conclude that 25 Hz rTMS can lead to cumulative and long-lasting effects on motor performance.

Adult↗

PubMed2006

Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers.

A mutation in the DYT1 gene causes dominantly inherited childhood-onset primary dystonia, but intriguingly, only 30 to 40% of those who carry the mutation ever develop symptoms. We have used the unique model provided by this group of patients to investigate the hypothesis that abnormalities in brain plasticity underlie the pathophysiology of primary dystonia. We recruited 8 DYT1 gene carriers with dystonia, 6 DYT1 gene carriers without dystonia, 6 patients with sporadic primary dystonia (torticollis), and 10 healthy control subjects. Groups were age-matched. We compared the effect in these groups of subjects of repetitive transcranial magnetic stimulation (rTMS) delivered to the motor cortex, by assessing changes in corticospinal excitability following rTMS. rTMS was given in the form of theta burst stimulation (TBS) using the inhibitory protocol "cTBS" (total of 300 pulses in 50-Hz bursts given every 5Hz). DYT1 gene carriers with dystonia and subjects with torticollis had a significantly prolonged response to rTMS in comparison with healthy subjects. In contrast, DYT1 gene carriers without dystonia had no significant response to rTMS. These data demonstrate an excessive response to an experimental "plasticity probing protocol" in subjects with dystonia, but a lack of response in genetically susceptible individuals who have not developed dystonia. These preliminary data suggest that the propensity to undergo plastic change may affect the development of symptoms in genetically susceptible individuals and that this may be an important mechanism in the pathogenesis of primary dystonia in general.

Adult↗

PubMed2006

Differences between the effects of three plasticity inducing protocols on the organization of the human motor cortex.

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.

Adult↗

PubMed2006

No evidence for a substantial involvement of primary motor hand area in handedness judgements: a transcranial magnetic stimulation study.

Twelve right-handed volunteers were asked to judge the laterality of a hand stimulus by pressing a button with one of their toes. Judgements were based on two-dimensional drawings of the back or palm of a right or left hand at various orientations. Suprathreshold single-pulse transcranial magnetic stimulation (TMS) was given to the left primary motor hand area (M1-HAND) at 0, 200, 400, 600, 800 or 1000 ms after stimulus onset to probe the functional involvement of the dominant left M1 at various stages of handedness recognition. We found that mean reaction times and error rates increased with angle of rotation depending on the actual biomechanical constraints of the hand but suprathreshold TMS had no influence on task performance regardless of the timing of TMS. However, the excitability of the corticomotor output from the left M1-HAND was modulated during the reaction. Judging left hand drawings was associated with an attenuation of motor-evoked potentials 300-100 ms before the response, whereas judging right hand drawings facilitated the motor-evoked potentials only immediately before the response. These effects were the same for pictures of backs and palms and were independent of the angle of rotation. The failure of TMS to affect task performance suggests that there is no time window during which the M1-HAND makes a critical contribution to mental rotation of the hand. The modulation of motor-evoked potentials according to the laterality of the stimulus indicates a secondary effect of the task on corticomotor excitability that is not directly related to mental rotation itself.

Adult↗

PubMed2005

Age reduces cortical reciprocal inhibition in humans.

Age alters the control of voluntary movement. A widely observed age-related adaptation is the heightened activation of the antagonist muscles during voluntary movements. We examined the possibility that age also modifies cortical reciprocal inhibition. In young (age 27, n = 6) and old (age 73, n = 6) adults a mild conditioning electrical stimulus was delivered to the median nerve at the elbow. The test stimulus, delivered by transcranial magnetic stimulation (TMS) at 1-ms increments between 11 and 24 ms after the electrical conditioning stimulus, evoked motor potentials (MEP) in the extensor carpi radialis (ECR) and flexor carpi radialis (FCR). The absolute TMS intensity, expressed as the percent of stimulator output, used to produce 1-mV control MEPs in the ECR was similar in young (mean 58.5, standard deviation +/-12.8%) and old adults (60.3+/-20.3%, P = 0.855). The size of the control MEP in the ECR was also similar in young (0.98+/-0.10 mV) and old subjects (0.90+/-0.14 mV, P = 0.686). The age by conditioning interval interaction (P = 0.001) showed that the MEPs in the ECR were significantly depressed at 14, 15, 16, 17, 18, and 19 ms (range 55.5--65.9% of control, all P < 0.05) compared with control value of 100% and with old adults who showed no depression. The MEPs remained at control level in the FCR and were also unaffected in the first dorsal interosseus. These data confirm the existence of cortical reciprocal inhibition reported previously in young humans and show that age reduces this inhibition similarly to the previously reported reduction of spinal reciprocal inhibition reported in old adults. Activation of agonist and antagonist muscle pairs are most likely organized around a dual system of cortically and spinally mediated reciprocal inhibition that is altered by age. The data also indicate the need to use age-matched control subjects when comparing individuals with abnormalities resulting from disorders that occur at an old age.

Adult↗

PubMed2005

Spatial attention affects sensorimotor reorganisation in human motor cortex.

It is well known that the somatotopic representation of sensory and motor cortices reorganises in response to sustained changes in sensory input. It is also clear that the extent of the effect depends on whether or not subjects pay attention during the procedure. Here we show that the pattern of reorganisation produced by sustained sensory input depends not only on the subjects' attention but also on the spatial focus of their attention on the body surface. Maximal effects are observed only when subjects pay attention to the site of the input; if they attend to an adjacent body part then the effects are reduced. These results may be relevant to rehabilitation procedures commonly used in patients after stroke.

Adult↗

PubMed2005

Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke.

Repetitive transcranial magnetic stimulation (rTMS) or sham stimulation was given over the motor cortex daily for 10 days to two randomly assigned groups of 26 patients with acute ischemic stroke. Patients otherwise continued their normal treatment. Disability scales measured before rTMS, at the end of the last rTMS session, and 10 days later showed that real rTMS improved patients' scores more than sham.

Brain Ischemia↗

PubMed2005

The role of dorsal premotor area in reaction task: comparing the "virtual lesion" effect of paired pulse or theta burst transcranial magnetic stimulation.

We compared the effect on reaction times of transient interference with function of the dorsal premotor cortex (PMd) using a pair (25-ms interval) of transcranial magnetic stimulation (TMS) pulses with long-term interference produced by a new repetitive TMS paradigm known as "theta burst stimulation" (TBS). Pairs of TMS pulses over left PMd increased choice but not simple reaction times of the right hand if given at the onset of the reaction interval. There was no effect of stimulation over right PMd or at a midline parietal control site (Pz). In contrast, TBS over either left or right PMd increased choice RTs of both hands for at least 5-10 min after the end of TBS. Pairs of TMS pulses over left PMd also increased error rates whereas TBS had no effect on error rates despite the effect on RTs. We suggest that TBS leads to widespread changes in activity and more complex effects on behaviour than expected from the paired pulse TMS and conclude that transient and long-term forms of interference with function may influence behavioural tasks in subtly different ways.

Adult↗

PubMed2005

Temporal discrimination of two passive movements in humans: a new psychophysical approach to assessing kinaesthesia.

Percutaneous electrical stimulation of the motor point of the first dorsal interosseous muscle (FDI) was used to produce a non-painful contraction of the FDI muscle that caused index finger abduction movement but no radiating cutaneous paraesthesias or sharp sensations localized to joints. Pairs of stimuli separated by different time intervals were given and subjects were asked to report whether they perceived a single or a double index finger abduction movement. The threshold value was the shortest interval for which the subjects reported two separate index finger abduction movements. Temporal discrimination movement thresholds (TDMT) were measured for both right and left hand. To assess the possible role of muscle and cutaneous afferents in temporal discrimination, we investigated the effects of high-frequency (20 Hz) electrical stimulation of the right ulnar and radial nerves on TDMT. In humans, muscle afferents from FDI are supplied by the ulnar nerve whereas the cutaneous territory overlying the muscle and joint is supplied by the radial and median nerves. Threshold values were not significantly different for right (75.1 ms) and left (75.6 ms) hands. During ulnar and to a lesser extent during radial nerve stimulation, TDMT values were significantly increased (119.2 and 93.5 ms, respectively) compared with baseline conditions (78.0 ms) whereas no changes were observed during median nerve stimulation (80.5 ms). These results suggest that muscle, and in part cutaneous, afferents contribute to temporal discrimination of a dual movement. The technique may provide a useful way of measuring temporal discrimination of kinaesthetic inputs in humans.

Adult↗

PubMed2005

Spatial consequences of bridging the saccadic gap.

We report six experiments suggesting that conscious perception is actively redrafted to take account of events both before and after the event that is reported. When observers saccade to a stationary object they overestimate its duration, as if the brain were filling in the saccadic gap with the post-saccadic image. We first demonstrate that this illusion holds for moving objects, implying that the perception of time, velocity, and distance traveled become discrepant. We then show that this discrepancy is partially resolved up to 500 ms after a saccade: the perceived offset position of a post-saccadic moving stimulus shows a greater forward mislocalization when pursued after a saccade than during pursuit alone. These data are consistent with the idea that the temporal bias is resolved by the subsequent spatial adjustment to provide a percept that is coherent in its gist but inconsistent in its detail.

Adult↗

PubMed2005

BOLD MRI responses to repetitive TMS over human dorsal premotor cortex.

Functional magnetic resonance imaging (fMRI) studies in humans have hitherto failed to demonstrate activity changes in the direct vicinity of transcranial magnetic stimulation (TMS) that cannot be attributed to re-afferent somatosensory feedback or a spread of excitation. In order to investigate the underlying activity changes at the site of stimulation as well as in remote connected regions, we applied short trains of high-intensity (110% of resting motor threshold) and low-intensity (90% of active motor threshold) repetitive TMS (rTMS; 3 Hz, 10 s duration) over the presumed location of the left dorsal premotor cortex (PMd) during fMRI. Signal increases in the direct vicinity of the stimulated PMd were observed during rTMS at 110% RMT. However, positive BOLD MRI responses were observed with rTMS at both 90% and 110% RMT in connected brain regions such as right PMd, bilateral PMv, supplementary motor area, somatosensory cortex, cingulate motor area, left posterior temporal lobe, cerebellum, and caudate nucleus. Responses were generally smaller during low-intensity rTMS. The results indicate that short trains of TMS can modify local hemodynamics in the absence of overt motor responses. In addition, premotor rTMS cannot only effectively stimulate cortico-cortical but also cortico-subcortical connections even at low stimulation intensities.

Adult↗

PubMed2005

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308-5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning.

Adult↗

PubMed2005

Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia.

The excitability of inhibitory circuits in patients with writer's cramp is reduced at multiple levels within the sensorimotor system, including the primary motor hand area (M1). Although this may play a major role in the pathophysiology of writer's cramp, it is still unclear what factors may cause the imbalance between inhibition and excitation to arise. One possibility is that homeostatic mechanisms that keep cortical excitability within a normal physiological range are impaired. In eight patients with writer's cramp and eight healthy age-matched controls, we combined low-frequency repetitive transcranial magnetic stimulation (rTMS) with transcranial direct current stimulation (TDCS) to probe regional homeostatic plasticity of the left M1. Confirming our previous study (Siebner et al., J Neurosci 2004; 24: 3379-85), 'facilitatory' preconditioning of the M1 with anodal TDCS enhanced the inhibitory effect of subsequent 1 Hz rTMS on corticospinal excitability. Conversely, 'inhibitory' preconditioning with cathodal TDCS reversed the after effect of 1 Hz rTMS, producing an increase in corticospinal excitability. The results were quite different in patients with writer's cramp. Following preconditioning with TDCS, 1 Hz rTMS induced no consistent changes in corticospinal excitability, indicating a loss of the normal 'homeostatic' response pattern. In addition, the normal inhibitory effect of preconditioning with cathodal TDCS was absent. The present data suggest that homeostatic mechanisms that stabilize excitability levels within a useful dynamic range are impaired in patients with writer's cramp. We propose that a faulty homeostatic response to acute increases in corticospinal excitability favours maladaptive motor plasticity. The role of homeostatic-like plasticity in the pathophysiology of task-specific dystonias warrants further study.

Adult↗

PubMed2005

Pathophysiological differences between musician's dystonia and writer's cramp.

Focal hand dystonia (FHD) has been suggested to be a maladaptive response of the brain to repetitive performance of stereotyped and attentionally demanding hand movements. However, not all patients with FHD have a strict history of excessive hand use; for example, patients with musician's dystonia (MD) spend many hours per day with their attention focused on instrumental practice, whereas many patients with writer's cramp (WC) have a history of average hand use. The present experiments test whether seven MD and six WC patients have different pathophysiological deficits by examining the spatial pattern of sensorimotor organization in the motor cortex. Two control groups were used, eight healthy non-musicians and eight healthy musicians. The latter served to control for physiological adaptation of the brain to musical training. We used focal vibration of a single hand muscle to produce sensory input whilst the excitability of corticospinal outputs to the vibrated and other hand muscles was evaluated with transcranial magnetic stimulation. In healthy non-musicians, vibration increases the amplitude of motor-evoked potentials and decreases the short-latency intracortical inhibition (SICI) in the vibrated muscle, whilst having the opposite effect on the non-vibrated hand muscles. The pattern of sensorimotor interaction was abnormal in both patient groups. However, the nature of the deficit differed between them. While vibration had little effect on cortical excitability in WC, it strongly reduced SICI in all hand muscles irrespective of spatial organization in MD. In the healthy musicians we found an organization intermediate between that of healthy non-musicians and MD. The data are consistent with a model in which musical practice in healthy musicians leads to beneficial changes in organization of the motor cortex, but in MD these progress too far and begin to interfere with movement rather than assist it. The fact that sensory input had no effect on motor output in patients with WC suggests that sensory information from the hand may play a smaller role in provoking pathological changes in WC than in MD.

Adult↗

PubMed2005

Theta burst stimulation of the human motor cortex.

It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

Adult↗

PubMed2005

The beneficial effects of subthalamic nucleus stimulation on manipulative finger force control in Parkinson's disease.

We investigated the differential effects of levodopa medication and STN stimulation on finger force control in Parkinson subjects grasping to lift an object and performing vertical point-to-point movements of a hand-held object. The experiments were conducted in four treatment conditions: off-drug/off-stimulation, off-drug/on-stimulation, on-drug/off-stimulation and on-drug/on-stimulation. We found that the bradykinesia in Parkinsonian subjects improved by both levodopa medication and STN stimulation. As compared to healthy subjects, excessive grip force was observed in all Parkinson subjects, regardless of the treatment condition. This force excess was most pronounced in the on-drug condition and ameliorated by STN stimulation. We observed reliable correlations between the amount of force overflow and the severity of levodopa-induced dyskinesias in the on-drug condition. Despite some similarities regarding therapeutic effects on bradykinesia, our findings contrast with earlier observations with respect to the differential effects of levodopa and STN stimulation on the scaling of fingertip forces in Parkinson's disease. While levodopa causes an overshoot of fingertip forces, STN stimulation appears to be sufficient to alleviate, but not normalise the force excess. STN stimulation enables Parkinson subjects to scale grip force more accurately to the loads arising from voluntary manipulation of hand-held objects.

Adult↗