Showing papers by "Mark Hallett published in 2019"

Consensus Paper: Experimental Neurostimulation of the Cerebellum

Abstract: The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson’s disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

MDS evidence-based review of treatments for essential tremor

Abstract: Background Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor. Objectives To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society. Methods We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee. Results Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions. Conclusion Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales. © 2019 International Parkinson and Movement Disorder Society.

Compensation Strategies for Gait Impairments in Parkinson Disease: A Review.

Abstract: Importance Patients with Parkinson disease can use a wide variety of strategies to compensate for their gait impairments. Examples include walking while rhythmically bouncing a ball, crossing the legs when walking, or stepping over an inverted cane. An overview and classification of the many available compensation strategies may contribute to understanding their underlying mechanisms and developing focused rehabilitation techniques. Moreover, a comprehensive summary of compensation strategies may help patients by allowing them to select a strategy that best matches their needs and preferences and health care professionals by permitting them to incorporate these into their therapeutic arsenal. To create this overview, this narrative review discusses collected video recordings of patients who spontaneously informed clinicians about the use of self-invented tricks and aids to improve their mobility. Observations Fifty-nine unique compensation strategies were identified from approximately several hundred videos. Here, these observed strategies are classified into 7 main categories for elaboration on their possible underlying mechanisms. The overarching working mechanisms involve an allocation of attention to gait, the introduction of goal directedness, and the use of motor programs that are less automatized than those used for normal walking. Conclusions and Relevance Overall, these compensation strategies seem to appeal to processes that refer to earlier phases of the motor learning process rather than to a reliance on final consolidation. This review discusses the implications of the various compensation strategies for the management of gait impairment in Parkinson disease.

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

Abstract: OBJECTIVE To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002). CONCLUSION Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [18 F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.

The role of sensory information in the pathophysiology of focal dystonias

Abstract: Over the past few decades, abnormalities in sensory functions, such as tactile, proprioceptive and nociceptive processing, have been increasingly recognized in patients with focal dystonias. In this Review, we ask whether sensory system abnormalities are specific to particular types of dystonia, whether a causal link exists between sensory alterations and dystonic motor activity and how mechanisms underlying the sensory abnormalities fit in with the proposed ‘network model’ of dystonia. We suggest that alterations in the various sensory modalities participate at three different levels in the pathophysiological cascade that leads to dystonia: a background level that predisposes individuals to dystonia, a disease-related level that is evident only when dystonia becomes manifest and a causative level that triggers dystonia. We conclude that it is crucial to study sensory as well as motor pathophysiology to fully understand focal dystonias. Abnormalities in sensory functions, including tactile, proprioceptive and nociceptive processing, are increasingly recognized in patients with focal dystonias. The authors explore the link between sensory system abnormalities and dystonic motor activity in the context of the 'network model' of dystonia.

Lack of Target Engagement Following Low-Frequency Deep Transcranial Magnetic Stimulation of the Anterior Insula

Abstract: Objective To evaluate the safety and efficacy of low-frequency, inhibitory, deep rTMS with a novel H-coil specifically designed to stimulate the insula. Methods In a randomized, crossover order, 16 healthy volunteers underwent two sessions (sham; active) of 1 Hz repetitive TMS at an intensity of 120% of individual motor threshold, over the right anterior insular cortex localized using a neuronavigation system. Before, immediately after, and one hour after rTMS, subjects performed two tasks that have previously been shown in fMRI experiments to activate insular cortex: A blink suppression task and a forced-choice risk-taking task. Results No drop-outs or adverse events occurred. Active deep rTMS did not result in decreased urge to blink compared to sham. Similarly, no significant time × condition interaction on risk-taking behavior was found. Conclusions Low-frequency deep rTMS using a novel H8 coil was shown to be safe but did not affect any of the behavioral markers, also used to investigate modulation of insula activity. Our findings highlight the challenges of modulating the activity of deep brain regions with TMS. Further studies are necessary to identify effective stimulation parameters for deep targets, and to characterize the effects of deep TMS on overlying cortical regions.

Intracortical Inhibition and Surround Inhibition in the Motor Cortex: A TMS-EEG Study.

Abstract: Background: Short-latency intracortical inhibition (SICI) and motor surround inhibition (mSI) are cortical phenomena that have been investigated with Transcranial Magnetic Stimulation (TMS). mSI is believed to be necessary for the execution of fine finger movements, and SICI may participate in mSI genesis, however, the mechanisms underlying both mSI and SICI are not entirely clear. Objective: We explored the cortical physiology of SICI and mSI in healthy subjects by TMS-evoked cortical potentials (TEPs). Methods: Single (sp) and paired-pulse (pp) TMS were delivered on the ADM muscle cortical hotspot while recording EEG and EMG. Three conditions were tested: spTMS and ppTMS at rest, and spTMS at the onset of an index finger movement. SICI and mSI were calculated on the ADM motor evoked potential (MEP) and two groups were defined based on the presence of mSI. Average TEPs were calculated for each condition and for five regions of interest. Results: At movement onset we observed a widespread reduction of the inhibitory late component N100 suggesting cortical facilitation associated with motor performance. At motor cortex level, SICI and mSI are associated with similar modulation of TEPs consisting in a reduction of P30 and an increase of N45 amplitude. Conclusions: Our findings suggest that SICI and mSI modulate cortical excitability with shared inhibitory mechanisms.

Hiding in Plain Sight: Functional Neurological Disorders in the News.

Abstract: Objective:Functional movement and seizure disorders are still widely misunderstood and receive little public and academic attention. This is in stark contrast to their high prevalence and levels of...

Evidence From Parkinson's Disease That the Superior Colliculus Couples Action and Perception

Abstract: Background Action and perception should be coordinated for good visual-motor performance. The mechanism coupling action and perception may be a prominence map in the intermediate layer of the superior colliculus that modulates motor and attentional/perceptual processes. This coordination comes with a cost: the misperception that briefly overlapping stimuli are separated in time. Our model predicts that abnormal intermediate layer of the superior colliculus inhibition, such as that arising from increased basal ganglia output, would affect the action and perception coupling, and it would worsen the misperception. Objective To test the prominence map model by measuring reaction times and perceptions in human intermediate layer of the superior colliculus dysfunction. Methods We measured the saccadic and perceptual reaction time changes and the percept for different temporal asynchronies between fixation point offset and peripheral target onset in Parkinson's disease (PD). Results We found that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus prominence map disrupted the normal coupling of action and perception. With increasing temporal asynchronies, the PD perceptual reaction times increased approximately 3 times more than the increase of the saccadic reaction times. Also, PD subjects misperceive small overlaps as gaps for temporal asynchronies up to 3 times longer than controls. The results can be reproduced by an intermediate layer of the superior colliculus rostral-caudal gradient of inhibition. Conclusion These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus couples action and perception through modulation of attention. A dysfunction of this network quantifies abnormal basal ganglia output and could underlie visual deficits, including common, yet poorly understood, misperceptions and visual-motor deficits of PD. © 2019 International Parkinson and Movement Disorder Society.

Functional movement disorders: Is the crisis resolved?

Abstract: In 2006, I published an article titled, “Psychogenic movement disorders: a crisis for neurology.” I had an epiphany a few years before when I realized that 30% of the patients that I was seeing in my referral movement disorder clinic had a psychogenic disorder. I looked around for information and found very little. I wrote, “The nature of the crisis is that there are many patients, we don’t understand the pathophysiology, we often don’t know how to make the diagnosis, we don’t know how to treat the patients, the patients don’t want to hear that they have a psychiatric disorder and they go from doctor to doctor, psychiatrists don’t seem interested anyway, and the prognosis is terrible.” It was not that this was a new epidemic; functional disorders have been recognized for at least 2500 years. Hippocrates wrote about hysteria. Briquet, Charcot, Janet, and Freud made the subject popular in the 19th century, but then at least through the latter part of the 20th century, the disorder seems to have gone underground. The topic disappeared from textbooks, and neither neurologists or psychiatrists were trained in this area. Neurologists generally sent the patients away without any plan. A psychiatrist about that time told me that conversion disorders were a disorder of the 19th century and that there were no such patients any more. I decided that I should work on this topic, and, fortunately, others also became interested about this same time. The last decade has seen remarkable progress. I will consider the crises in the order I had listed them in the 2006 article. The pathophysiology of functional movement disorders has been largely dominated by Freudian concepts of conversion and, to a lesser extent, Janet’s concept of dissociation. Moreover, in clinicians’ thinking, patients with functional disorders were also mixed up with those with factitious disorder or malingering. So often, although primary and secondary gains might be recognized, neurologists would just tell the patients that nothing was wrong and that they should just get themselves better by trying harder to do so. The first step in improving understanding of pathophysiology was to clearly separate conversion and factitious/malingering, an involuntary disorder and the voluntary look-alikes, respectively. This was aided by an improved classification of psychiatric disorders in the Diagnostic and Statistical Manual (DSM) 5. A second step was the pathophysiological investigation of these patients with neuroimaging and clinical neurophysiology. Such studies show abnormalities of brain function and, more recently, even subtle abnormalities of brain structure. Patients with functional paralysis do not activate the primary motor cortex when attempting to move, but instead activate other areas such as limbic areas or frontal areas. The primary motor cortex is actually inhibited, as can be demonstrated by transcranial magnetic stimulation and functional MRI (fMRI). These findings suggest “top-down” interference with the initiation of motor control signals. Another element of disordered topdown control is likely to be abnormal attention to the body part with the involuntary movement. This is apparent clinically, and physiological evidence for this comes from abnormal modulation of beta desynchronization in a choice reaction time task. Patients with functional myoclonus show a Bereitschaftspotential (BP) prior to their involuntary jerks. The BP was originally described to precede voluntary movement and largely comes from activation of the premotor cortex and supplementary motor area. This shows that functional myoclonus uses the same final mechanism as voluntary movement. Moreover, stimulus-sensitive functional myoclonus behaves like voluntary reaction time movements. Functional tremor behaves in all ways like voluntary rhythmic movements. Indeed, if a patient is asked to make a voluntary rhythmic movement of another body part, the involuntary tremor entrains to the voluntary movement. Hence, *Correspondence to: Mark Hallett, MD, DrMed (hon), Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 7D37, 10 Center Drive, Bethesda, MD 20892-1428; E-mail: hallettm@ninds.nih.gov

How Do I Assess Tremor Using Novel Technology

Abstract: Transducers are defined as any sensor that converts a physiological signal of tremor into an electrical signal. Evolving technologies have utilized transducers to develop devices for tremor measurement that are more convenient, accurate, and capable of continuous recording. Transducer-based methods provide valuable diagnostic tools for the clinician that can distinguish between different tremor syndromes and differentiate tremor from other hyperkinetic movement disorders. Transducers are also used to objectively quantify and track tremor symptom severity over time and assess clinical response to intervention (e.g., pharmaceutical treatments or DBS). This video highlights the utility of transducer-based methods in characterizing and quantifying tremor and reviews the available technologies for measuring tremor. We provide case examples that demonstrate how different technology-based measures for tremor direct the approach to diagnosis and management of symptoms.

Prevalence of restless legs syndrome in functional movement disorders: a case-control study from the Czech Republic.

Abstract: Objectives The prevalence of restless legs syndrome (RLS) in functional movement disorders (FMD) is not known. Patients with FMD often present with multiple motor and sensory symptoms. Some of these symptoms might be due to comorbid RLS. Therefore, our objective was to evaluate possible association between FMD and RLS. Design Case–control study. Setting Movement Disorders Center, 1st Faculty of Medicine and General University Hospital in Prague, Czech Republic. Participants 96 consecutive patients with clinically established FMD (80 females, mean age (SD) 45.0 (13) years), and 76 matched controls. Primary and secondary outcome measures The primary outcome measure was prevalence of RLS based on updated International RLS Study Group criteria. Secondary outcome measures included prevalence of periodic limb movements (PLM) using actigraphy; pain, motor and sensory symptoms in lower limbs; organic comorbidities and medication affecting RLS. Results RLS criteria were fulfilled in 43.8% of patients (95% CI 34 to 54) and in 7.9% of controls (95% CI 3 to 17, p Conclusions We found an increased prevalence of RLS in patients with FMD. Clinical diagnosis of RLS was supported by actigraphic measurement of clinically relevant PLM in a significant proportion of patients with FMD. Although functional motor and sensory symptoms may mimic RLS, RLS may be unrecognised in patients with FMD. This finding may have clinical implications in management of FMD, and it raises the possibility of common pathophysiological mechanisms of FMD and RLS/PLM.

Focal Leg Dystonia Associated with Cerebellar Infarction and Application of Low-Frequency Cerebellar Transcranial Magnetic Stimulation: Evidence of Topographically Specific Cerebellar Contribution to Dystonia Development.

Abstract: The cerebellum has recently been highlighted as a key neural substrate responsible for dystonia. A 57-year-old female presented with isolated focal leg dystonia that developed 8 years after acute cerebellar infarction. Brain magnetic resonance imaging showed an old cerebellar infarct in the right anterior cerebellum. Low-frequency cerebellar repetitive transcranial magnetic stimulation on the right cerebellum partially improved dystonia in this patient. This case provides valuable evidence on cerebellar mechanisms related to the development of dystonia in a topographically specific manner. Cerebellar brain stimulation can be a potential therapeutic strategy for patients with dystonia.

Dual-hemispheric transcranial direct current stimulation (tDCS) over primary motor cortex does not affect movement selection.

Abstract: Volition and sense of agency are two primary components of a voluntary or internally generated movement. It has been shown that movement selection cannot be altered without interfering with the sense of volition using single pulse transcranial magnetic stimulation over the primary motor cortex. In the current study, we aimed at examining whether modulating the cortical excitability of the final effector in the voluntary motor pathway-the primary motor cortex, using transcranial direct current stimulation (tDCS) would alter movement selection. Our hypothesis was that anodal tDCS would increase motor cortical excitability and thereby decrease the threshold for movement execution, which could favor selection of the contralateral hand. We recruited 13 healthy adults to perform a movement selection task involving free-choice and externally-cued trials while applying real/sham tDCS in a C3-C4 dual-hemispheric electrode montage. Contrary to our hypothesis, we did not observe any effect of tDCS on movement selection either at the individual or group level. However, our data confirms the strong preference of right-handed individuals for the dominant right hand. We also found higher reaction time for internally generated movement compared to externally triggered movement. We therefore conclude that movement selection cannot be influenced at the level of primary motor cortex and that brain areas upstream of the primary motor cortex in the voluntary motor pathway may be possible targets for influencing movement selection.

Characteristics of oscillatory activity in the globus pallidus internus in patients with Parkinson’s disease (P1.8-028)

Abstract: Objective: The aim of this study was to quantify the characteristics of oscillatory neurons in the globus pallidus internus (GPi) in patients with Parkinson’s disease (PD). Background: The pathophysiology underlying parkinsonian motor deficits remain unclear. Tremor frequency neurons in the basal ganglia have been predicted to be involved in tremor genesis. Design/Methods: Six patients with PD (4 males, 2 females; age: 58.67±6.15 years) who underwent electrode implantation for GPi deep brain stimulation or pallidotomy were studied. Microelectrode recordings of the GPi neuronal activity were obtained during surgery for PD. EMG on the contralateral limbs was performed. The interspike intervals were assessed. Spectral analysis was used to evaluate neuronal oscillatory activity. Coherence was calculated. Mean firing rates and proportions of patterns of GPi oscillatory neurons were identified. Coherence analysis was used to study relationship between oscillatory activity and limb symptoms. Results: Of 55 GPi oscillatory neurons identified, 58.2% (n=32) were tremor frequency (at mean frequency of 4.67±0.71Hz) oscillatory neurons, 16.4% (n=9) were β frequency oscillatory neurons (at mean frequency of 15.84 ±8.33 Hz) and 25.4% (n=14) were non-oscillatory neurons. Of these tremor frequency oscillatory neurons, 50% neurons were significantly coherent with limb tremor (coherence magnitude range of 0.52–0.85, mean: 0.72± 0.14). The mean firing rate of all neurons was 81.46±7.44 Hz. Conclusions: Consistent with previous the findings, there were three types of oscillatory neurons: tremor frequency, β frequency and non-oscillatory neurons in the GPi. The presence of high proportion of tremor related oscillatory neurons in the GPi and their strong coherence, supports a role of the globus pallidus in the production of rest tremor in PD patients. Disclosure: Dr. Zhuang has nothing to disclose. Dr. Hallett has received personal compensation in an editorial capacity for Elsevier. Dr. Hallett has received royalty, license fees, or contractual rights payments from Brainsway via the NIH. Dr. Hallett has received research support from Allergan, Medtronic, Inc., and CALA Health. Dr. Meng has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Li has nothing to disclose.