Showing papers by "Mark Hallett published in 2001"

Pathophysiology of bradykinesia in parkinson's disease

Abstract: Bradykinesia means slowness of movement and is one of the cardinal manifestations of Parkinson's disease. Weakness, tremor and rigidity may contribute to but do not fully explain bradykinesia. We argue that bradykinesia results from a failure of basal ganglia output to reinforce the cortical mechanisms that prepare and execute the commands to move. The cortical deficit is most apparent in midline motor areas. This leads to particular difficulty with self-paced movements, prolonged reaction times and abnormal pre-movement EEG activity. Movements are often performed with normally timed EMG bursts but the amount of EMG activity is underscaled relative to the desired movement parameters. There are also abnormalities in sensory scaling and sensorimotor integration. The brain appears to be able to compensate to some degree for the basal ganglia deficit. There is overactivity in the lateral premotor areas during task performance and movements can be speeded by giving sensory cues. Attention to movement is also beneficial. However, we propose that the engagement of compensatory processes may also lead to reduced performance in other tasks. For example, patients' problems in performing more than one task at the same time could result from lack of sufficient resources both to compensate for their basal ganglia deficit and to run two tasks simultaneously. Surgical therapies are unlikely to work solely by normalizing basal ganglia output to that seen in healthy individuals. It seems more plausible that surgery removes an interfering signal that allows more efficient compensation by other structures.

Modulation of practice-dependent plasticity in human motor cortex

Abstract: Motor practice may lead to expansion of trained representations in the motor cortex, but it is unknown whether this practice-dependent plasticity can be purposefully enhanced or depressed. Evidence, mainly based on animal experiments, indicates that the activity of GABA-related cortical inhibition is important in controlling the extent to which plasticity may occur. We tested the role of GABA in modulating practice-dependent plasticity in the human motor cortex. A decrease in GABA-related cortical inhibition was achieved by ischaemic nerve block (INB) in the hand by deafferentation/deefferentation and an increase was achieved by administration of the GABA(A) receptor agonist lorazepam. In Experiment 1, healthy subjects performed motor practice (MP), consisting of repeated ballistic contractions of the biceps muscle in the absence (MP alone) or presence of INB (MP+INB). Changes in the biceps motor cortex representation were assessed by transcranial magnetic stimulation (TMS). MP+INB resulted in a dramatic increase in the size of the motor evoked potential (MEP) and in paired-pulse excitability compared with mild or no changes in the MP-alone and INB-alone conditions. In Experiment 2, this dramatic increase in biceps representation induced by MP+INB was replicated when subjects were pretreated with placebo, but this increase was prevented or even switched to a decrease when subjects were pretreated with lorazepam. These findings indicate that a decrease in GABA-related inhibition facilitates practice-dependent plasticity in the human motor cortex, whereas an increase depresses it. In Experiment 3, practice-dependent plasticity (assessed by TMS, as in the first two experiments) was also tested at the behavioural level. The dramatic increase in biceps MEP size induced by MP+INB was paralleled by an increase in peak acceleration of the fastest elbow flexion movements. Similarly, the lack of change in MEP size in the MP-alone condition was paralleled by a lack of change in peak acceleration. We propose that changes in GABA activity may be instrumented to modulate plasticity purposefully; for instance, to enhance plastic change and recovery of function after a lesion in neurological patients.

Role of the human motor cortex in rapid motor learning

Abstract: Recent studies suggest that the human primary motor cortex (M1) is involved in motor learning, but the nature of that involvement is not clear Here, learning-related changes in M1 excitability were studied with transcranial magnetic stimulation (TMS) while naive subjects practiced either a ballistic or a ramp pinch task to the 05-Hz beat of a metronome Subjects rapidly learned to optimize ballistic contractions as indicated by a significant increase in peak pinch acceleration and peak force after the 60-min practice epoch The increase in force and acceleration was associated with an increase in motor evoked potential (MEP) amplitude in a muscle involved in the training (flexor policis brevis) but not in a muscle unrelated to the task (abductor digiti minimi) MEPs returned to their baseline amplitude after subjects had acquired the new skill, whereas no practice-induced changes in MEP amplitude were observed after subjects had overlearned the task, or after practicing slow ramp pinches Since the changes in MEP amplitude were observed only after TMS of M1 but not after direct stimulation of the corticospinal tract, these findings indicate task- and effector-specific involvement of human M1 in rapid motor learning

Neural Correlates of Auditory–Visual Stimulus Onset Asynchrony Detection

Abstract: Intersensory temporal synchrony is an ubiquitous sensory attribute that has proven to be critical for binding multisensory inputs, sometimes erroneously leading to dramatic perceptual illusions. However, little is known about how the brain detects temporal synchrony between multimodal sensory inputs. We used positron emission tomography to demonstrate that detecting auditory–visual stimulus onset asynchrony activates a large-scale neural network of insular, posterior parietal, prefrontal, and cerebellar areas with the highest and task-specific activity localized to the right insula. Interregional covariance analysis further showed significant task-related functional interactions between the insula, the posterior thalamus, and superior colliculus. Based on these results and the available electrophysiological and anatomical connectivity data in animals, we propose that the insula, via its known short-latency connections with the tectal system, mediates temporally defined auditory–visual interaction at an early stage of cortical processing permitting phenomena such as the ventriloquist and the McGurk illusions.

Transient Interhemispheric Neuronal Synchrony Correlates with Object Recognition

Abstract: Object recognition might be achieved by the recreation of a meaningful internal image from visual fragments. This recreation might be achieved by neuronal synchronization that has been proposed as a solution for the perceptual binding problem. In this study, we evaluated synchronization between the occipitotemporal regions bilaterally using electroencephalograms during several visual recognition tasks. Conscious recognition of familiar objects spanning the visual midline induced transient interhemispheric electroencephalographic coherence in the alpha band, which did not occur with meaningless objects or with passive viewing. Moreover, there was no interhemispheric coherence when midline objects were not recognized as meaningful or when familiar objects were presented in one visual hemifield. These data suggest a close link between site-specific interregional synchronization and object recognition.

Coherence between cortical and muscular activities after subcortical stroke.

Abstract: Background and Purpose — Functional connection between the motor cortex and muscle can be measured by electroencephalogram-electromyogram (EEG-EMG) coherence. To evaluate the functional connection to muscle between contralateral and ipsilateral motor cortices after pyramidal tract lesions, we investigated 6 patients with chronic subcortical stroke. Methods — High-resolution EEG and EMG of the hand, forearm, and biceps muscles were recorded during 3 tonic contraction tasks: (1) elbow flexion, (2) wrist extension, and (3) power grip. To evaluate the cortical control of EMG, EEG-EMG coherence was computed. Results — EEG-EMG coherence was localized over the contralateral sensorimotor area in all circumstances, and there was no significant coherence at the ipsilateral side. EEG-EMG coherence was significantly smaller on the affected side for the hand and forearm muscles but not for the biceps muscle. Conclusions — All direct functional connections to muscle after recovered subcortical stroke come from the contralateral motor cortex. The different effects of the lesion on the proximal and distal muscles appear to be associated with the strength of the corticospinal pathway.

Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy

Abstract: Objective: There is no effective treatment for progressive supranuclear palsy (PSP). Because results of immunochemical and pharmacologic studies suggest that the cholinergic system may play a role in the cognitive and motor features of PSP, the authors investigated the effects of donepezil (10 mg/day), an acetylcholinesterase inhibitor, in 21 patients with PSP (mean age ± SD; 65.7 ± 4.7 years) by a randomized, double-blind, placebo-controlled crossover trial. Methods: Donepezil and placebo were administered for 6 weeks each with a 1-month washout period. Patients were evaluated before and at the end of each treatment phase. Outcome measures evaluated neuropsychiatric, global cognitive, frontal, memory, motor, and activities of daily living (ADL) status. Results: Two patients withdrew during the washout phase because of unrelated medical problems. Donepezil-induced systemic side effects were transient and generally mild. Because of worsening of motor function, three patients received 5 mg/day of donepezil. All patients achieved blood and CSF therapeutic levels of donepezil. While the patients were taking donepezil, their Double Memory Test scores improved, whereas their ADL/mobility scores significantly worsened. Conclusion: The findings suggest that acetylcholinesterase inhibitors such as donepezil have at best selective, modest effects on cognition in patients with PSP. In light of its deleterious effects on ADL/mobility, donepezil is not recommended for this patient population.

Gluten sensitivity in sporadic and hereditary cerebellar ataxia.

Abstract: Gluten sensitivity, with or without classical celiac disease symptoms and intestinal pathology, has been suggested as a potentially treatable cause of sporadic cerebellar ataxia. Here, we investigated the prevalence of abnormally high serum immunoglobulin A (IgA) and IgG anti-gliadin antibody titers and typical human lymphocyte antigen (HLA) genotypes in 50 patients presenting with cerebellar ataxia who were tested for molecularly characterized hereditary ataxias. A high prevalence of gluten sensitivity was found in patients with sporadic (7/26; 27%) and autosomal dominant (9/24; 37%) ataxias, including patients with known ataxia genotypes indicating a hitherto unrecognized association between hereditary ataxias and gluten sensitivity. Further studies are needed to determine whether gluten sensitivity contributes to cerebellar degeneration in patients with hereditary cerebellar ataxia. Patients with hereditary ataxia (including asymptomatic patients with known ataxia genotype) should be considered for screening for gluten sensitivity and gluten-free diet trials.

Coil for magnetic stimulation and methods for using the same

Abstract: A magnetic stimulator (11), which may be used as a transcranial magnetic stimulation (TMS) device, and a method for its use are disclosed. The stimulator comprises a frame and an electrically conductive coil having a partially toroidal or ovate base (12) and an outwardly projecting extension portion (14). The frame may be a flexible or malleable material and may be non-conductive. The electrically conductive coil may comprise one or more windings of electrically conductive material (such as a wire) coupled to the frame. The coil is electrically connected to a power supply. The device (11) may be place adjacent to or in contact with the body of a subject, such as on the head (100) of a subject. The device may be used on humans for treating certain physiological conditions, such as cardiovascular or neurophysiological conditions, or for studying the physiology of the body. This device is useful in studying or treating neurophysiological conditions associated with the deep regions of the brain, such as drug addiction and depression.

Effect of levetiracetam on human corticospinal excitability.

Abstract: Objective: To investigate whether levetiracetam (LTC) alters corticospinal excitability in humans Background: Although the antiepileptic activity of LTC is well recognized, its mechanism of action has yet to be determined Transcranial magnetic stimulation (TMS) has been used to investigate the pharmacologic effects of various antiepileptic drugs on human corticospinal excitability Methods: The authors performed TMS before and after double-blind administration of 3000 mg LTC or placebo in six healthy volunteers TMS measurements included resting and active motor threshold (MT), recruitment curve of motor-evoked potential amplitudes, intracortical inhibition, and facilitation using the paired-pulse technique and silent period F-wave and compound muscle action potential (CMAP) were also measured Results: In recruitment curve measurements, motor-evoked potential amplitude was reduced for LTC with high stimulation intensity (130% and 140% of resting MT) compared with placebo ( p p Conclusion: These results suggest that LTC reduces the corticospinal neuronal response to magnetic stimulation, preferentially affecting less excitable neurons The lack of change in F-wave and CMAP suggests that this effect is mainly derived from the motor cortex

Analogous corticocortical inhibition and facilitation in ipsilateral and contralateral human motor cortex representations of the tongue.

Abstract: How the human brain controls activation of the ipsilateral part of midline muscles is unknown. We studied corticospinal and corticocortical network excitability of both ipsilateral and contralateral motor representations of the tongue to determine whether they are under analogous or disparate inhibitory and facilitatory corticocortical control. Motor evoked potentials (MEPs) to unilateral focal transcranial magnetic stimulation (TMS) of the tongue primary motor cortex were recorded simultaneously from the ipsilateral and contralateral lingual muscles. Single-pulse TMS was used to assess motor threshold (MT) and MEP recruitment. Paired-pulse TMS was used to study intracortical inhibition (ICI) and intracortical facilitation (ICF) at various interstimulus intervals (ISIs) between the conditioning stimulus (CS) and the test stimulus (TS), and at different CS and TS intensities, respectively. Focal TMS invariably produced MEPs in both ipsilateral and contralateral lingual muscles. MT was lower and MEP recruitment was steeper when recorded from the contralateral muscle group. ICI and ICF were identical in the ipsilateral and contralateral representations, with inhibition occurring at short ISIs (2 and 3 ms) and facilitation occurring at longer ISIs (10 and 15 ms). Moreover, changing one stimulus parameter regularly produced analogous changes in MEP size bilaterally, revealing strong linear correlations between ipsilateral and contralateral ICI and ICF (P < 0.0001). These findings indicate that the ipsilateral and contralateral representations of the tongue are under analogous inhibitory and facilitatory control, possibly by a common intracortical network.

Coil for magnetic stimulation

Abstract: A magnetic stimulator (11), which may be used as a transcranial magnetic stimulation (TMS) device, and a method for its use are disclosed. The stimulator comprises a frame and an electrically conductive coil having a partially toroidal or ovate base (12) and an outwardly projecting extension portion (14). The frame may be a flexible or malleable material and may be non-conductive. The electrically conductive coil may comprise one or more windings of electrically conductive material (such as a wire) coupled to the frame. The coil is electrically connected to a power supply. The device (11) may be place adjacent to or in contact with the body of a subject, such as on the head (100) of a subject. The device may be used on humans for treating certain physiological conditions, such as cardiovascular or neurophysiological conditions, or for studying the physiology of the body. This device is useful in studying or treating neurophysiological conditions associated with the deep regions of the brain, such as drug addiction and depression.

Time course of determination of movement direction in the reaction time task in humans.

Abstract: The primary motor cortex produces motor commands that include encoding the direction of movement. Excitability of the motor cortex in the reaction time (RT) task can be assessed using transcranial magnetic stimulation (TMS). To elucidate the timing of the increase in cortical excitability and of the determination of movement direction before movement onset, we asked six right-handed, healthy subjects to either abduct or extend their right thumb after a go-signal indicated the appropriate direction. Between the go-signal and movement onset, single TMS pulses were delivered to the contralateral motor cortex. We recorded the direction of the TMS-induced thumb movement and the amplitude of motor-evoked potentials (MEPs) from the abductor pollicis brevis and extensor pollicis brevis muscles. Facilitation of MEPs from the prime mover, as early as 200 ms before the end of the reaction time, preceded facilitation of MEPs from the nonprime mover, and both preceded measurable directional change. Compared with a control condition in which no voluntary movement was required, the direction of the TMS-induced thumb movement started to change in the direction of the intended movement as early as 90 ms before the end of the RT, and maximum changes were seen shortly before the end of reaction time. Movement acceleration also increased with maxima shortly before the end of the RT. We conclude that in concentric movements a change of the movement direction encoded in the primary motor cortex occurs in the 200 ms prior to movement onset, which is as early as increased excitability itself can be detected.

Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease

Abstract: The authors compared stretch-evoked somatosensory evoked potentials (SEP) of 18 type 3 Gaucher disease (GD3) patients (two with progressive myoclonus epilepsy [PME]) with 22 age-matched normal controls and six patients with type 1 (nonneuronopathic) Gaucher disease (GD1). The mean P1-N2 SEP amplitude in GD3 patients was significantly larger than the SEP in controls and in GD1 patients, and there was a significant negative correlation between SEP amplitude and the IQ of GD3 patients. The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit.

Pathophysiology of bradykinesia in Parkinson's

Abstract: Summary Bradykinesia means slowness of movement and is one of the cardinal manifestations of Parkinson’s disease. Weakness, tremor and rigidity may contribute to but do not fully explain bradykinesia. We argue that bradykinesia results from a failure of basal ganglia output to reinforce the cortical mechanisms that prepare and execute the commands to move. The cortical deficit is most apparent in midline motor areas. This leads to particular difficulty with self-paced movements, prolonged reaction times and abnormal pre-movement EEG activity. Movements are often performed with normally timed EMG bursts but the amount of EMG activity is underscaled relative to the desired movement parameters. There are also abnormalities in sensory scaling and sensorimotor integration. The brain appears

Impairment of eyeblink classical conditioning in progressive supranuclear palsy.

Abstract: In a previous study we showed that learning in eyeblink classical conditioning (EBCC) is normal in Parkinson's disease (PD) and that the serial reaction time task (SRTT) is only marginally impaired. Since pathological lesions are more widespread in the atypical parkinsonian disorder of progressive supranuclear palsy (PSP) than in PD, we hypothesized that PSP patients may show more profound deficits in the EBCC and SRTT learning tasks. We therefore investigated EBCC with a delay and two trace paradigms, an SRTT and the California Verbal Learning Test (CVLT) in eight patients with PSP and an age-matched control group. In all EBCC paradigms, we found a significant difference between groups with no significant learning in PSP patients. In the SRTT, implicit learning may have been impaired, but verbal and manual sequence recall were only marginally impaired. Verbal memory was significantly worse in PSP patients than in the control group. Our study shows a dissociated pattern of learning abilities in PSP, where the EBCC as a measure of implicit learning is impaired, the explicit sequence detection in the SRTT is relatively preserved, and the verbal memory impaired. We hypothesize that the PSP patients' deficits in EBCC learning may be due to lesions of deep cerebellar nuclei. There may be a clinical role for EBCC in distinguishing PD and PSP patients.

Immunotoxin (mAB-RICIN) for the treatment of focal movement disorders

Abstract: Compositions and methods for treatment of focal muscle spasms. Immunotoxin conjugates comprise a toxin conjugated to an antibody reactive to a muscle specific antigen.

Plasticity and Basal Ganglia Disorders

Abstract: One of the important facts about the physiology of the brain that has emerged in recent years is that, even in adult life, the brain remains capable of changes in many different ways. These changes permit the brain to learn as well as respond to injury, and may be adaptive or non-adaptive. The brain is not only capable of reorganizing, it is constantly doing so.

Reporting clinical trials: Full access to all the data

Abstract: Biomedical research is becoming more complex as a result of involvement by individual investigators, universities, commercial research units and industry. Financial conflicts of interest have been the subject of many editorials, and most peer-reviewed journals now require any conflicts to be identified and explained when authors submit manuscripts for publication. Clear statements of industry sponsored research and author participation in corporate activities are required for evaluation of a manuscript. Full disclosure of financial interests by authors is essential to retain public trust in biomedical research, the peer-review process and the integrity of the authors and of the universities.1 We already require that each author sign a statement of his or her financial arrangements with public, private and industry sources of support. These declarations alert the editor, reviewer and physician-reader to any potential bias in the interpretation and presentation of the data. Patients’ lives may depend on an accurate and complete understanding of how and …