Showing papers by "Mark Hallett published in 2017"

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

Abstract: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

Abstract: A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

Blepharospasm 40 years later.

Abstract: Forty years ago, C.D. Marsden proposed that blepharospasm should be considered a form of adult-onset focal dystonia. In the present paper, we provide a comprehensive overview of the findings regarding blepharospasm reported in the past 40 years. Although prolonged spasms of the orbicularis oculi muscles remain the clinical hallmark of blepharospasm, patients with blepharospasm may be characterized by various types of involuntary activation of periocular muscles. In addition to motor features, blepharospasm patients may also have nonmotor manifestations, including psychiatric, mild cognitive, and sensory disturbances. The various motor and nonmotor symptoms are not present in all patients, suggesting that blepharospasm is phenomenologically a heterogeneous condition. This emphasizes the need for tools for severity assessment that take into account both motor and nonmotor manifestations. The cause of blepharospasm remains elusive, but several lines of evidence indicate that blepharospasm is a multifactorial condition in which one, or several, as yet unknown genes together with epigenetic and environmental factors combine to reach the threshold of the disease. Although blepharospasm was originally believed to be solely a basal ganglia disorder, neurophysiological and neuroimaging evidence point to anatomical and functional involvement of several brain regions. The contribution of multiple areas has led to the hypothesis that blepharospasm should be considered as a network disorder, and this might reflect the varying occurrence of motor and nonmotor manifestations in blepharospasm patients. Despite advances in the aetiology and pathophysiology, treatment remains symptomatic. © 2017 International Parkinson and Movement Disorder Society.

Neurobiology of the Premonitory Urge in Tourette’s Syndrome: Pathophysiology and Treatment Implications

Abstract: Motor and vocal tics are relatively common motor manifestations identified as the core features of Tourette's syndrome (TS). Although traditional descriptions have focused on objective phenomenological observations, such as anatomical location, number and frequency of tics, patients' first-person accounts have consistently reported characteristic subjective correlates. These sensory phenomena are often described as a feeling of mounting inner tension or urge to move ("premonitory urge"), which is transiently relieved by tic expression. This article reviews the existing literature on the clinical and neurobiological aspects of the premonitory urge in patients with TS, with focus on its pathophysiology and possible treatment implications.

Impaired sense of agency in functional movement disorders: An fMRI study.

Abstract: The sense of agency (SA) is an established framework that refers to our ability to exert and perceive control over our own actions. Having an intact SA provides the basis for the human perception of voluntariness, while impairments in SA are hypothesized to lead to the perception of movements being involuntary that may be seen many neurological or psychiatric disorders. Individuals with functional movement disorders (FMD) experience a lack of control over their movements, yet these movements appear voluntary by physiology. We used fMRI to explore whether alterations in SA in an FMD population could explain why these patients feel their movements are involuntary. We compared the FMD group to a control group that was previously collected using an ecologically valid, virtual-reality movement paradigm that could modulate SA. We found selective dysfunction of the SA neural network, whereby the dorsolateral prefrontal cortex and pre-supplementary motor area on the right did not respond differentially to the loss of movement control. These findings provide some of the strongest evidence to date for a physiological basis underlying these disabling disorders.

The direct basal ganglia pathway is hyperfunctional in focal dystonia

Abstract: See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

Photophobia in neurologic disorders

Abstract: Photophobia is a common symptom seen in many neurologic disorders, however, its pathophysiology remains unclear. Even the term is ambiguous. In this paper, we review the epidemiology and clinical manifestations of photophobia in neurological disorders, including primary headache, blepharospasm, progressive supranuclear palsy, and traumatic brain injury, discuss the definition, etiology and pathogenesis, and summarize practical methods of diagnosis and treatment.

The cerebellum in dual-task performance in Parkinson’s disease

Abstract: Parkinson's disease (PD) patients have difficulty in performing a dual-task. It has been suggested that the cerebellum is important in dual-tasking. We used functional MRI to investigate the role of the cerebellum in performing a dual motor and cognitive task in PD patients. We have examined whether there are any areas additionally activated for dual-task performance, and compared the neural activity and functional connectivity pattern in the cerebellum between PD patients and healthy controls. We found that the right cerebellar vermis and left lobule V of cerebellar anterior lobe were additionally activated for dual-task performance in healthy controls and for motor task in PD patients. We didn't find any cerebellar regions additionally activated while performing dual-task in PD patients. In addition, the right cerebellar vermis had enhanced connectivity with motor and cognitive associated networks in PD patients. PD patients have limited cerebellar resources that are already utilized for single tasks and, for dual tasks, cannot augment as necessary in order to integrate motor and cognitive networks.

Research priorities in limb and task-specific dystonias

Abstract: Dystonia, which causes intermittent or sustained abnormal postures and movements, can present in a focal or a generalized manner. In the limbs, focal dystonia can occur in either the upper or lower limbs and may be task-specific causing abnormal motor performance for only a specific task, such as in writer’s cramp, runner’s dystonia or musician’s dystonia. Focal limb dystonia can be non-task-specific and may, in some circumstances, be associated with parkinsonian disorders. The true prevalence of focal limb dystonia is not known and is likely currently under-estimated, leaving a knowledge gap and an opportunity for future research. The pathophysiology of focal limb dystonia shares some commonalities with other dystonias with a loss of inhibition in the central nervous system and a loss of the normal regulation of plasticity, called homeostatic plasticity. Functional imaging studies revealed abnormalities in several anatomical networks that involve the cortex, basal ganglia and cerebellum. Further studies should focus on distinguishing cause from effect in both physiology and imaging studies to permit focus on most relevant biological correlates of dystonia. There is no specific therapy for the treatment of limb dystonia given the variability in presentation, but off-label botulinum toxin therapy is often applied to focal limb and task-specific dystonia. Various rehabilitation techniques have been applied and rehabilitation interventions may improve outcomes, but small sample size and lack of direct comparisons between methods to evaluate comparative efficacy limits conclusions. Finally, noninvasive and invasive therapeutic modalities have been explored in small studies with design limitations that do not yet clearly provide direction for larger clinical trials that could support new clinical therapies. Given these gaps in our clinical, pathophysiologic and therapeutic knowledge, we have identified priorities for future research including: the development of diagnostic criteria for limb dystonia, more precise phenotypic characterization and innovative clinical trial design that considers clinical heterogeneity and limited available number of participants.

Increased blinking may be a precursor of blepharospasm: a longitudinal study.

Abstract: Objective The aim of this five-year longitudinal study was to investigate whether patients with increased blinking develop orbicularis oculi muscle spasms. Methods Eleven patients who initially manifested increased blinking alone were clinically and neurophysiologically re-evaluated five years later. Results By the five-year follow-up assessment, nine of the 11 patients had developed orbicularis oculi muscle spasms. The blink reflex recovery cycle became abnormal whereas somatosensory temporal discrimination, already abnormal at the first evaluation, did not significantly change. Conclusions Our longitudinal study demonstrates that increased blinking may precede blepharospasm and that an abnormal blink reflex recovery cycle reflects the development of orbicularis oculi muscle spasms. This article is protected by copyright. All rights reserved.

The Phenomenology of Parkinson's Disease.

Abstract: The motor symptoms of Parkinson's disease are not limited to the cardinal symptoms of bradykinesia, rigidity, and resting tremor, but also include a variety of interrelated motor phenomena such as deficits in spatiotemporal planning and movement sequencing, scaling and timing of movements, and intermuscular coordination that can be clinically observed Although many of these phenomena overlap, a review of the full breadth of the motor phenomenon can aid in the diagnosis and monitoring of disease progression

A Common Function of Basal Ganglia-Cortical Circuits Subserving Speed in Both Motor and Cognitive Domains.

Abstract: Distinct regions of the frontal cortex connect with their basal ganglia and thalamic counterparts, constituting largely segregated basal ganglia-thalamo-cortical (BTC) circuits. However, any common role of the BTC circuits in different behavioral domains remains unclear. Indeed, whether dysfunctional motor and cognitive BTC circuits are responsible for motor slowing and cognitive slowing, respectively, in Parkinson's disease (PD) is a matter of debate. Here, we used an effortful behavioral paradigm in which the effects of task rate on accuracy were tested in movement, imagery, and calculation tasks in humans. Using nonlinear fitting, we separated baseline accuracy (Abase ) and "agility" (ability to function quickly) components of performance in healthy participants and then confirmed reduced agility and preserved Abase for the three tasks in PD. Using functional magnetic resonance imaging (fMRI) and diffusion tractography, we explored the neural substrates underlying speeded performance of the three tasks in healthy participants, suggesting the involvement of distinct BTC circuits in cognitive and motor agility. Language and motor BTC circuits were specifically active during speeded performance of the calculation and movement tasks, respectively, whereas premotor BTC circuits revealed activity for speeded performance of all tasks. Finally, PD showed reduced task rate-correlated activity in the language BTC circuits for speeded calculation, in the premotor BTC circuit for speeded imagery, and in the motor BTC circuits for speeded movement, as compared with controls. The present study casts light on the anatomo-functional organization of the BTC circuits and their parallel roles in invigorating movement and cognition through a function of dopamine.

The third-stimulus temporal discrimination threshold: focusing on the temporal processing of sensory input within primary somatosensory cortex.

Abstract: To investigate whether the time interval required to discriminate between stimuli varies according to changes in the stimulation pattern, we used the third-stimulus temporal discrimination threshol...

Lack of efficacy of levetiracetam in oromandibular and cranial dystonia.

Abstract: Objective To determine the efficacy of levetiracetam in oromandibular or cranial dystonia. Methods We recruited seven subjects with oromandibular or cranial dystonia. Five completed the study, median age was 71 years (range 42-79 years), median disease duration was 12 years (range 2-30 years). Participants were randomized to receive levetiracetam or placebo and were then crossed over. They titrated up to a total daily dose of 4000 mg or the maximum tolerated dose over 3 weeks and maintained that dose for another 3 weeks. The primary endpoint was the percent change of the eyes, mouth, speech, and swallowing Burke–Fahn–Marsden (BFM) subscores from baseline to weeks 6 and 14. Additional endpoints included the BFM subscore at weeks 3 and 11, and the global dystonia severity (GDS) subscore at weeks 3, 6, 11, and 14, as well as all adverse side effects. Results The mean percent increase in the BFM subscore (placebo: 31.25%, levetiracetam: 12.16%) was not significantly different between the two arms according to the Friedman analysis. The Wilcoxon signed-rank test showed that these percent changes were not significant, indicating that there was no statistical clinical worsening in either arm. The mean percent change of the BFM subscore at weeks 3 and 11 and the mean percent change of the GDS subscore at weeks 3, 6, 11, and 14 were not significantly different between the two arms, and the Wilcoxon signed-rank test did not show statistical significance. Conclusion Levetiracetam does not appear to be efficacious in patients with oromandibular or cranial dystonia.

Hearing Safety From Single- and Double-Pulse Transcranial Magnetic Stimulation in Children and Young Adults.

Abstract: Purpose Concerns regarding hearing safety have limited the number of studies using transcranial magnetic stimulation (TMS) in children and young adults. The objective of this study was to examine the safety of TMS with regards to hearing in a group of 16 children and young adults (17.3 ± 4.9 years) with and without brain injury. Methods Pure-tone hearing thresholds and distortion-product otoacoustic emissions were measured before and after exposure to single- and paired-pulse TMS (1-2 sessions of 149-446 TMS pulses at a median of 49%-100% maximum stimulator output over a 2.2 hours period). Results No mean change in hearing outcomes was noted. In addition, no clinically significant change in hearing threshold was observed in any participant, and participants did not experience a subjective change in hearing after TMS exposure. Conclusions Single- and double-pulse TMS administered within the parameters used in this study, which included hearing protection, can be used in children and young adults without impacting hearing. This study provides further evidence for hearing safety after TMS exposure in children and young adults.

Positional Tremor and its Treatment.

Abstract: Background Positional tremors arise when a patient's tremor is brought on during specific positioning of the involved body part. They can be distinguished from postural tremor, wherein a patient's tremor is elicited in any posture, and from task-specific tremor, wherein a patient's tremor occurs only during a certain task. Cases We describe two cases of positional tremor that are markedly improved with botulinum toxin injection. Discussion The term “positional” is a valuable descriptor for tremors. In patients with positional tremor, botulinum toxin may be beneficial for treatment. Lidocaine injection provides a transient way to test for the appropriateness of botulinum toxin injection in these patients. This article is protected by copyright. All rights reserved.

Sensory Tricks for Cervical Levodopa-induced Dyskinesia in Patients with Parkinson's Disease.

Abstract: Choreiform or dystonic movement in the craniocervical region can occur as levodopa-induced dyskinesia (LID). "Sensory tricks" are various alleviating maneuvers for the relief of abnormal postures in patients who have idiopathic focal dystonia, particularly those who have cervical dystonia. The authors report on three men with Parkinson's disease who had been receiving levodopa for more than 3 years and presented with involuntary neck movements during the drug on period. In all three patients, cervical LIDs appeared during the drug on period and completely disappeared during the drug off period. The effects of using sensory tricks to markedly improve the symptoms of cervical LID were studied. In all patients, the cervical LIDs improved more efficiently when sensory tricks were performed on the patient by another person (passive tricks) than by the patient himself (self-sensory tricks). The unique features of the sensory tricks for cervical LID in the current patients may be important clinical evidence of abnormal sensorimotor integration in patients who have PD with LID.

Multifocal Myoclonus as a Manifestation of Acute Cerebral Infarction Recovered by Carotid Arterial Stenting

Abstract: cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. JMD Dear Editor, Many types of hyperkinetic movement disorders, including tremor, myoclonus and dystonia, can occur both in the acute and chronic stages of stroke. 1 Among the various movement disorders, myoclonus is rare and occurs after recovery from the acute stage of stroke. 1 We describe a patient who presented with the abrupt onset of myoclonus as a manifestation of contralateral cortical infarction. This patient' s symptoms resolved after carotid artery stenting. A 71-year-old man was admitted due to the abrupt onset of twitching movement of his left hand and face for 7 days and paralysis of his right hand for 3 days. His previous medical history included coronary artery stenting due to acute myocardial infarction 10 years earlier, as well as hypertension and diabetes. The initial neurological examination showed brief, rhythmic and shock-like twitching movements in his left arm and face. The muscle power of his left hand and face was normal. The muscle power in his right hand had decreased to grade IV. Diffusion weighted brain MRI showed high signal intensity in the left basal ganglia including the caudate nucleus and the puta-men, bilateral centrum semiovale and frontal cortices (Figure 1A). Brain CT angiography showed severe stenosis of both proximal internal carotid arteries (Figure 1B). Valproic acid and levetiracetam were administered with antiplatelet medications for the relief of myoclonus. Despite marked improvements, involuntary movements persisted. Transfemoral percutaneous arteriography showed 88% and 83% stenosis in his right and left internal carotid arterys (ICAs), respectively (Figure 1C). Carotid artery stenting was performed on the patient's left internal carotid artery the day after admission (Figure 1D). Stent-ing of the right ICA was conducted two days after the procedure on the left ICA (Figure 1D). Beginning the day after the procedure , myoclonus disappeared in the left arm and face. The weakness in the patient's right arm gradually improved over the next month. The involuntary movements in our patient were continuous, rhythmic and jerky twitching confined to his left arm and face. This muscle twitching was not synchronous but occurred independently in the arm and face. It was neither focal nor generalized. Therefore, the movements might be defined as multi-focal myoclonus, which could …