Showing papers by "Mark Hallett published in 2008"

Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review) Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Abstract: Objective: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I–IV). Results: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians’ practice may suggest stronger recommendations in some of these indications, evidencebased conclusions are limited by the availability of data. Neurology ® 2008;70:1699–1706

Motor Planning, Imagery, and Execution in the Distributed Motor Network: A Time-Course Study with Functional MRI

Abstract: Activation of motor-related areas has consistently been found during various motor imagery tasks and is regarded as the central mechanism generating motor imagery. However, the extent to which motor execution and imagery share neural substrates remains controversial. We examined brain activity during preparation for and execution of physical or mental finger tapping. During a functional magnetic resonance imaging at 3 T, 13 healthy volunteers performed an instructed delay finger-tapping task either in a physical mode or mental mode. Number stimuli instructed subjects about a finger-tapping sequence. After an instructed delay period, cue stimuli prompted them either to execute the tapping movement or to imagine it. Two types of planning/preparatory activity common for movement and imagery were found: instruction stimulus-related activity represented widely in multiple motor-related areas and delay period activity in the medial frontal areas. Although brain activity during movement execution and imagery was largely shared in the distributed motor network, imagery-related activity was in general more closely related to instruction-related activity than to the motor execution-related activity. Specifically, activity in the medial superior frontal gyrus, anterior cingulate cortex, precentral sulcus, supramarginal gyrus, fusiform gyrus, and posterolateral cerebellum likely reflects willed generation of virtual motor commands and analysis of virtual sensory signals.

The pathophysiological basis of dystonias

Abstract: Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.

Neural correlates of dual task performance in patients with Parkinson's disease

Abstract: Background: Patients with Parkinson’s disease (PD) have great difficulty in performing two tasks simultaneously, but the neural contribution to this problem has not been identified. In the current study, we investigated the pathophysiology of dual task performance in PD. Methods: We studied 15 patients with PD and 14 healthy controls. Functional MRIs were obtained before and after practicing dual tasks with different complexities. Results: After practice, 12 normal subjects performed all dual tasks correctly. Twelve patients performed the simpler dual tasks correctly. However, only 3 patients could perform the more complex dual task correctly. Dual tasks activated similar brain regions in both groups. The bilateral precuneus was additionally activated during performance of dual tasks compared with the component tasks in both groups. Patients had greater activity in the cerebellum, premotor area, parietal cortex, precuneus and prefrontal cortex compared with normal subjects. Conclusions: Difficulty in performing two tasks simultaneously in patients with PD is probably due to limited attentional resources, defective central executive function and less automaticity in performing the tasks. Practice can diminish dual task interference and improve performance in patients with PD.

The Spectrum of Parkinsonian Manifestations Associated With Glucocerebrosidase Mutations

Abstract: In Parkinson disease (PD) and related syndromes, the degeneration of dopaminergic neurons and the formation of Lewy bodies (LBs) manifest clinically as motor dysfunction that includes bradykinesia, resting tremor, and rigidity. Early non-motor signs associated with PD may include olfactory dysfunction, mood and behavioral disturbances, and subtle neurocognitive changes.1 Although genetic alterations have been identified in some with familial PD, in most sporadic cases the cause of neurodegeneration remains unknown. In recent years, multiple loci and mutations have been implicated in the etiology of rare Mendelian forms of PD, with a spectrum of phenotypes encountered.2 Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) (OMIM 606463) result in the autosomal recessive disorder Gaucher disease (GD), which affects the skeletal, hematologic, and nervous systems with varying severity.3 Different lines of evidence suggest that mutant glucocerebrosidase may be a risk factor for parkinsonism. Parkinsonian manifestations have been noted in a subset of patients with GD,4,5 and GBA mutations have been observed with increased frequency in different series of patients with parkinsonism, first in 57 brain bank samples, where 14% had GBA mutations,6 and then in 99 Israeli patients with PD, where 2 GBA mutations were present in 31.3%.7 An increase in GBA mutations subsequently was demonstrated in patients of different ethnicities with PD.8–10 The carrier frequency for GBA mutations is cited as being less than 1% in the general population and 6% to 7% in Ashkenazi Jews.3 Furthermore, a family history of parkinsonism is often reported in probands with GD.11 Although initial studies noted that patients with GD and parkinsonism had early-onset, levodopa-unresponsive disease, recent studies demonstrated that the pathologic entities associated with GBA mutations include a variety of synucle-inopathies,12 and, hence, the clinical phenotype might also be diverse. The present study details the clinical and neurologic spectrum of the parkinsonian phenotype in 10 patients carrying GBA mutations and is the first documentation, to our knowledge, of olfactory dysfunction in glucocerebrosidase-associated parkinsonism.

Short Intracortical and Surround Inhibition Are Selectively Reduced during Movement Initiation in Focal Hand Dystonia

Abstract: In patients with focal hand dystonia (FHD), pathological overflow activation occurs in muscles not involved in the movement. Surround inhibition is a neural mechanism that can sharpen desired movement by inhibiting unwanted movement in adjacent muscles. To further establish the phenomenon of surround inhibition and to determine whether short intracortical inhibition (SICI) reflecting inhibition from the local interneurons in primary motor cortex (M1), might play a role in its genesis, single- and paired-pulse transcranial magnetic stimulation (TMS), and Hoffmann reflex testing were applied to evaluate the excitability of the relaxed abductor pollicis brevis muscle (APB) at various intervals during a movement of the index finger in 16 patients with FHD and 20 controls. Whereas controls showed inhibition of APB motor-evoked potential (MEP) size during movement initiation and facilitation of APB MEP size during the maintenance phase, FHD patients did not modulate APB MEP size. In contrast, SICI remained constant in controls, but FHD patients showed reduced SICI during movement initiation. The H(max)/M(max) ratio in control subjects increased during movement initiation. The results provide additional evidence for the presence of surround inhibition in M1, where it occurs only during movement initiation, indicating that different mechanisms underlie movement initiation and maintenance. Thus, surround inhibition is sculpted both in time and space and may be an important neural mechanism during movement initiation to counteract increased spinal excitability. SICI may contribute to its generation, because in patients with FHD, the lack of depression of APB MEP size is accompanied by a reduction in SICI.

Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET.

Abstract: Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimer9s disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. Methods: A total of 8 patients with AD with an average (±SD) Mini-Mental State Examination score of 14.7 ± 8.4 (mean age, 71.7 ± 11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7 ± 5.6 y) were studied. Each subject received a 15O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-11C-AA scan of regional K* for AA. Results: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P

A high performance sensorimotor beta rhythm-based brain–computer interface associated with human natural motor behavior

Abstract: To explore the reliability of a high performance brain–computer interface (BCI) using non-invasive EEG signals associated with human natural motor behavior does not require extensive training. We propose a new BCI method, where users perform either sustaining or stopping a motor task with time locking to a predefined time window. Nine healthy volunteers, one stroke survivor with right-sided hemiparesis and one patient with amyotrophic lateral sclerosis (ALS) participated in this study. Subjects did not receive BCI training before participating in this study. We investigated tasks of both physical movement and motor imagery. The surface Laplacian derivation was used for enhancing EEG spatial resolution. A model-free threshold setting method was used for the classification of motor intentions. The performance of the proposed BCI was validated by an online sequential binary-cursor-control game for two-dimensional cursor movement. Event-related desynchronization and synchronization were observed when subjects sustained or stopped either motor execution or motor imagery. Feature analysis showed that EEG beta band activity over sensorimotor area provided the largest discrimination. With simple model-free classification of beta band EEG activity from a single electrode (with surface Laplacian derivation), the online classifications of the EEG activity with motor execution/motor imagery were: >90%/∼80% for six healthy volunteers, >80%/∼80% for the stroke patient and ∼90%/∼80% for the ALS patient. The EEG activities of the other three healthy volunteers were not classifiable. The sensorimotor beta rhythm of EEG associated with human natural motor behavior can be used for a reliable and high performance BCI for both healthy subjects and patients with neurological disorders. Significance: The proposed new non-invasive BCI method highlights a practical BCI for clinical applications, where the user does not require extensive training. M This article features online multimedia enhancements (Some figures in this article are in colour only in the electronic version)

Update on blepharospasm: report from the BEBRF International Workshop.

Abstract: This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Topics covered include clinical aspects, pathology, pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and treatment. Blepharospasm should be differentiated from apraxia of eyelid opening. New insights into pathology and pathophysiology are derived from different types of imaging, including magnetic resonance studies. Physiologic studies indicate increased plasticity and trigeminal sensitization. While botulinum neurotoxin injections are the mainstay of therapy, other therapies are on the horizon.

Research priorities in spasmodic dysphonia.

Abstract: Objective To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia. Study Design and Setting A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities. Results Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study. Conclusions The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials. Significance This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

Overview of Human Tremor Physiology

Abstract: The physiology differs in the many forms of human tremor. Tremors may derive from mechanical oscillations, mechanical reflex oscillations, normal central oscillators, and pathologic central oscillators. Methods of studying tremor include accelerometry and electromyography (EMG). An excellent method consists of accelerometry and EMG combined with spectral analysis and weighting of the body part, which allows separation of tremors coming from mechanical reflex and central oscillators. Physiologic tremor is a mechanical tremor with a possible contribution of the normal 8-12 Hz central oscillator; exaggerated physiologic tremor is a mechanical reflex tremor. Essential tremor (ET) comes from a central oscillator that can be easily influenced with sensory input. The classic rest tremor of Parkinson's disease (PD) comes from a central oscillator that seems less easily influenced with sensory input but can be affected by transcranial magnetic stimulation. Other tremors with central oscillators are palatal tremor and orthostatic tremor. Other tremors whose physiology involves central loops includes cerebellar tremor and cortical tremor. Neuropathic tremors may be a result of delays in peripheral loops, but central oscillators play a role in some.

The timing of the conscious intention to move

Abstract: The foundation of modern neuroscience and psychology about intention for action was laid by B. Libet et al. [(1983) Brain 106, 623-642]. They reported the time of awareness of wanting to move to be about 0.2 s before voluntary movement onset. However, despite repeated confirmation of the result, their method has been criticised for its dependence on self-reported timing and subjective memory, and the interpretation has been widely debated without general consensus. Here, we show that the mean time of the conscious intention to move was 1.42 s before movement, estimated based on the subject's real-time decision of whether or not there was a thought to move when a tone occurred. This event is after the onset of the bereitschaftspotential, an electroencephalographic activity preceding voluntary movement, but about 1 s earlier than the timing of intention reported previously based on the subject's recall. Our result solves some problems of the conventional method, thus giving a clearer answer to the controversies. The difference between the conventional result and our result suggests that the perception of intention rises through multiple levels of awareness, starting just after the brain initiates movement.

Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study

Abstract: Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.

The intrinsic and extrinsic aspects of freezing of gait.

Abstract: Freezing of gait appears to result from a number of fundamental problems in patients with Parkinson disease. Automaticity is impaired, putting more stress on voluntary mechanisms. Internal drivers of movement are impaired, likely because of deficient basal ganglia function. Deficiency of internal forces to initiate movement is a major factor in freezing. This deficiency gives a greater influence to external or sensory factors. The sensory factors can both help or hinder freezing. Analogous to the problem with set-shifting, there is also some difficulty in regulation of internal versus external factors and in regulation of different external factors.

Pre- and post-synaptic dopamine imaging and its relation with frontostriatal cognitive function in Parkinson disease: PET studies with [11C]NNC 112 and [18F]FDOPA

Abstract: Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD Fifteen non-demented PD patients and 14 healthy controls underwent [(18)F]FDOPA (for dopamine synthesis) and [(11)C]NNC 112 (for D(1) receptors) PET scans and cognitive testing Parametric images of [(18)F]FDOPA uptake (K(i)) and [(11)C]NNC 112 binding potential (BP(ND)) were calculated using reference tissue models Group differences in K(i) and BP(ND) were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests Measurement of [(18)F]FDOPA uptake in cerebral cortex was questionable because of higher K(i) values in white than adjacent gray matter These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [(18)F]FDOPA uptake in PD difficult We found no regional differences in D(1) receptor density between controls and PD, and no overall differences in frontostriatal performance Although D(1) receptor density did not relate to frontostriatal cognition, K(i) decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD

Modifications of the interactions in the motor networks when a movement becomes automatic

Abstract: A crucial feature of the motor system is the ability to control some movements automatically. We have previously shown that all parts of the motor networks reduce their activity with automaticity, and, while this change may indicate increased efficiency in terms of neural processing, it is not clear how motor skill can be maintained after a reduction of neural activity. In the current study, we used functional MRI (fMRI) to investigate influences on the effective connectivity of the brain motor networks when movements become automatic. Subjects practiced a sequential movement until they could execute it automatically, and task-related brain fMRI activation was measured before and after they achieved automaticity. Using the psychophysiological interaction (PPI) method, we found that the cerebellum, cingulate motor area, supplementary motor area, and putamen had significantly greater connectivity, whereas the precuneus had less connectivity in the motor networks at the automatic stage. Our findings demonstrate that the importance of the attention networks decrease when movements become automatic. Moreover, the process of automaticity is accompanied by a strengthened interaction of central motor networks even though the magnitude of the activation is decreased. We speculate that this increase in connectivity reflects more efficient neural coding of movement at the automatic stage.

Treatment of limb apraxia: moving forward to improved action.

Abstract: Limb apraxia is a common disorder of skilled, purposive movement that is frequently associated with stroke and degenerative diseases such as Alzheimer disease. Despite evidence that several types of limb apraxia significantly impact functional abilities, surprisingly few studies have focused on development of treatment paradigms. Additionally, although the most disabling types of apraxia reflect damage to gesture and/or object memory systems, existing treatments have not fully taken advantage of principles of experience known to affect learning and neural plasticity. We review the current state of the art in the rehabilitation of limb apraxia, indicate possible points of contact with the learning literature, and generate suggestions for how translational principles might be applied to the development of future research on treatment of this disabling disorder.

Impaired intracortical inhibition in the primary somatosensory cortex in focal hand dystonia

Abstract: Somesthetic temporal discrimination (STD) is impaired in focal hand dystonia (FHD). We explored the electrophysiological correlate of the STD deficit to assess whether this is due to dysfunction of temporal inhibition in the somatosensory inhibitory pathway or due to dysfunction in structures responsible for nonmodality-specific timing integration. Eleven FHD patients and 11 healthy volunteers were studied. STD threshold was investigated as the time interval required for perceiving a pair of stimuli as two separate stimuli in time. We also examined the somatosensory-evoked potential (SEP) in a paired-pulse paradigm. We compared STD threshold and recovery function of SEP between the groups. STD thresholds were significantly greater in FHD than in healthy volunteers. The amount of P27 suppression in the 5 ms-ISI condition was significantly less in FHD. It was also found that the STD threshold and P27 suppression were significantly correlated: the greater the STD threshold, the less the P27 suppression. Significantly less suppression of P27 with a lack of significant change in N20 indicates that the impairment of somatosensory information processing in the time domain is due to dysfunction within the primary somatosensory cortex, suggesting that that the STD deficit in FHD is more attributable to dysfunction in the somatosensory pathway.

The representation of blinking movement in cingulate motor areas: a functional magnetic resonance imaging study.

Abstract: Recent anatomical evidence from nonhuman primates indicates that cingulate motor areas (CMAs) play a substantial role in the cortical control of upper facial movement. Using event-related functional magnetic resonance imaging in 10 healthy subjects, we examined brain activity associated with volitional eye closure involving primarily the bilateral orbicularis oculi. The findings were compared with those from bimanual tapping, which should identify medial frontal areas nonsomatotopically or somatotopically related to bilateral movements. In a group-level analysis, the blinking task was associated with rostral cingulate activity more strongly than the bimanual tapping task. By contrast, the bimanual task activated the caudal cingulate zone plus supplementary motor areas. An individual-level analysis indicated that 2 foci of blinking-specific activity were situated in the cingulate or paracingulate sulcus: one close to the genu of the corpus callosum (anterior part of rostral cingulate zone) and the posterior part of rostral cingulate zone. The present data support the notion that direct cortical innervation of the facial subnuclei from the CMAs might control upper face movement in humans, as previously implied in nonhuman primates. The CMAs may contribute to the sparing of upper facial muscles after a stroke involving the lateral precentral motor regions.

Motor re-training does not need to be task specific to improve writer's cramp.

Abstract: Previous studies showed a beneficial effect of motor re-training in task-specific hand dystonia. Here we examined whether re-training needs to specifically focus on the task affected by dystonia. 21 patients with writer's cramp were randomly assigned to two types of re-training: One group of patients trained drawing and writing movements using a pen attached to the bottom of a finger splint. The second group used therapeutic putty to train finger movements without exercises of drawing and writing movements. Training lasted for 8 weeks. Before re-training, affected hand and forearm were immobilized for 4 weeks to facilitate the responsiveness to re-training. Dystonia was assessed during handwriting using the Writer's Cramp Rating Scale. Although no clinical improvement was observed immediately after immobilization, 8 weeks of re-training improved task-specific dystonia relative to baseline (P = 0.005). Both training modalities were equally effective. More severely affected patients benefited most. There was no correlation between disease duration and the individual treatment response. Re-training also improved hand function as indexed by the Arm Dystonia Disability Scale (P = 0.008). Kinematic handwriting analysis showed that re-training lowered vertical force level and enhanced the fluency of handwriting. We conclude that re-training does not need to specifically focus on the task affected by dystonia to be clinically effective.

Changes in short afferent inhibition during phasic movement in focal dystonia.

Abstract: Impaired surround inhibition could account for the abnormal motor control seen in patients with focal hand dystonia, but the neural mechanisms underlying surround inhibition in the motor system are not known. We sought to determine whether an abnormality of the influence of sensory input at short latency could contribute to the deficit of surround inhibition in patients with focal hand dystonia (FHD). To measure digital short afferent inhibition (dSAI), subjects received electrical stimulation at the digit followed after 23 ms by transcranial magnetic stimulation (TMS). Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) during rest and during voluntary phasic flexion of the second digit. F-waves were also recorded. We studied 13 FHD patients and 17 healthy volunteers. FHD patients had increased homotopic dSAI in ADM during flexion of the second digit, suggesting that this process acts to diminish overflow during movement; this might be a compensatory mechanism. No group differences were observed in first dorsal interosseous. Further, no differences were seen in the F-waves between groups, suggesting that the changes in dSAI are mediated at the cortical level rather than at the spinal cord. Understanding the role of these inhibitory circuits in dystonia may lead to development of therapeutic agents aimed at restoring inhibition.

Double-blind, placebo-controlled, pilot trial of botulinum toxin A in restless legs syndrome.

Abstract: The hallmarks of restless legs syndrome (RLS) are a desire to move the limbs due to sensory discomfort, motor restlessness, and worsening of symptoms during rest or at night.1 Sensory symptoms cause the greatest discomfort,2 and are commonly localized to muscle. Sensory and motor symptoms can be improved with dopaminergic medications, some anticonvulsants, opioids, and to a lesser extent with GABA-active hypnotics. Botulinum toxin has been suggested as a potential therapy for refractory RLS, based on its ability to reduce peripheral and central sensitization to pain.3 In an unblinded observational study by Rotenberg and colleagues, IM injections of 70–320 mouse units (mU) of botulinum toxin type A (BTX-A; Botox, Irvine, CA) were injected into the legs of three patients with RLS and demonstrated symptom improvement, reduced medication use, and a reduction in daytime sleepiness.4 Based on these findings, we conducted a randomized, placebo-controlled, double-blind, crossover study. ### Methods. #### Patients. We enrolled six patients from June to July 2007 who were age 18 or older, had a diagnosis of primary RLS based on International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria,1 had a minimum score of 11 (at least moderate severity) on the IRLSSG rating scale (IRLS),5 and were stable on medications for greater than 6 weeks prior to enrollment. Patients were excluded for an abnormal neurologic examination, abnormal laboratory test results, a dermatologic disorder precluding leg injections, pregnancy/lactation, incapacity for informed consent, taking medications which could interact with BTX-A, …