Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications.

INTRODUCTION: MRI-guided focused ultrasound (FUS) is an incisionless thermo-ablative procedure that may be used to treat medication-refractory movement disorders, with a growing number of potential anatomic targets and clinical applications. As of this article's publication, the only US Food and Drug Administration (FDA)-approved uses of FUS for movement disorders are thalamotomy for essential tremor (ET) and tremor-dominant Parkinson's Disease (PD), and pallidotomy for other cardinal symptoms of PD. We present a state-of-the-art review on all non-FDA approved indications of FUS for movement disorders, beyond the most well-described indications of ET and PD. Our objective was to summarize the safety and efficacy of FUS in this setting and provide a roadmap for future directions of FUS for movement disorders. METHODS: A state-of-the-art review was conducted on use of FUS for non-FDA approved movement disorders. All movement disorders excluding FDA-approved uses for ET and PD were included. RESULTS: A total of 25 studies on 172 patients were included. In patients with tremor plus dystonia syndromes (n = 6), ventralis intermediate nucleus of the thalamus (VIM)-FUS gave >50% tremor reduction, with no improvement in dystonia and worsened dystonia in 2/6 patients. Ventral-oralis complex (VO)-FUS gave >50% improvement for focal hand dystonia (n = 6) and 100% return to musical performance in musician's dystonia (n = 6). In patients with multiple sclerosis (MS) and tremor (n = 3), improvement in tremor was seen in 2 patients with a favorable skull density ratio; no MS disease change was noted after VIM-FUS. In patients with tremor and comorbid ataxia syndromes (n = 3), none were found to have worsened ataxia after VIM-FUS; all had clinically significant tremor improvement. Subthalamic nucleus (STN)-FUS for PD (n = 49) gave approximately 50% improvement in PD motor symptoms, with dystonia and mild dyskinesias as possible adverse effects. Cerebellothalamic tract (CTT-FUS) for ET (n = 42) gave 55-90% tremor improvement, with gait dysfunction as a rare persistent adverse effect. Pallidothalamic tract (PTT-FUS) for PD (n = 50) gave approximately 50% improvement in motor symptoms, with mild speech dysfunction as a possible adverse effect. CONCLUSION: VIM-FUS appeared safe and effective for heterogenous tremor etiologies, and VO-FUS appeared most effective for isolated segmental dystonia. STN-FUS was effective for PD symptom reduction; postoperative dystonia and mild on-medication dyskinesias required medical management. Tractography-based targeting with CTT-FUS for ET and PTT-FUS for PD demonstrated promising early results. Larger prospective trials with long-term follow-up are needed to the evaluate the safety and efficacy non-FDA approved indications for FUS.

Subthalamic nucleus deep brain stimulation in primary Meige syndrome: motor and non-motor outcomes.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) has emerged as a promising treatment for movement disorders. This prospective study aims to evaluate the effects of bilateral subthalamic nucleus DBS (STN-DBS) on motor and non-motor symptoms in patients with primary Meige syndrome. METHODS: Thirty patients who underwent bilateral STN-DBS between April 2017 and June 2020 were included. Standardized and validated scales were utilized to assess the severity of dystonia, health-related quality of life, sleep, cognitive function and mental status at baseline and at 1 year and 3 years after neurostimulation. RESULTS: The Burke-Fahn-Marsden Dystonia Rating Scale movement scores showed a mean improvement of 63.0% and 66.8% at 1 year and 3 years, respectively, after neurostimulation. Similarly, the Burke-Fahn-Marsden Dystonia Rating Scale disability scores improved by 60.8% and 63.3% at the same time points. Postoperative quality of life demonstrated a significant and sustained improvement throughout the follow-up period. However, cognitive function, mental status, sleep quality and other neuropsychological functions did not change after 3 years of neurostimulation. Eight adverse events occurred in six patients, but no deaths or permanent sequelae were reported. CONCLUSIONS: Bilateral STN-DBS is a safe and effective alternative treatment for primary Meige syndrome, leading to improvements in motor function and quality of life. Nevertheless, it did not yield significant amelioration in cognitive, mental, sleep status and other neuropsychological functions after 3 years of neurostimulation.

Botulinum toxin and conservative treatment strategies in people with cervical dystonia: an online survey.

Isolated cervical dystonia is a focal, idiopathic dystonia affecting the neck muscles. Treatment usually consists of botulinum neurotoxin (BoNT) injections into the dystonic muscles. Our aim is to investigate the use of BoNT treatment and conservative treatments by people living with cervical dystonia. An online survey in English was conducted between June and August 2022. Participants were eligible to participate if they were living with cervical dystonia, were over 18 years old and could read and understand English. The survey consisted of demographic questions, characteristics of dystonia, questions relating to BoNT use and the perceived utility of conservative treatments. The data were analysed descriptively, and open-ended questions were grouped into similar topics represented by direct quotes. We received 128 responses from people with cervical dystonia, with an average age of 59 years and 77% women. Most participants (52%) described their cervical dystonia as mild to moderate with an average pain score of 5/10. Eighty-two (64%) participants were having regular BoNT injections, with overall positive perceived effects. Common activities reported to improve the symptoms were the use of heat packs, massage, relaxation, physiotherapy and participation in general exercise. Common coping strategies reported were getting sufficient rest, having the support of friends and family, and remaining engaged in enjoyable hobbies. We found that most participants received regular BoNT injections and that heat packs, exercise, massage, physiotherapy and relaxation were mostly perceived as effective in reducing the symptoms of cervical dystonia.

Experimental pharmacology: Targeting metabolic pathways.

Since the discovery of the treatment for Wilson disease a growing number of treatable inherited dystonias have been identified and their search and treatment have progressively been implemented in the clinics of patients with dystonia. While waiting for gene therapy to be more widely and adequately translated into the clinical setting, the efforts to divert the natural course of dystonia reside in unveiling its pathogenesis. Specific metabolic treatments can rewrite the natural history of the disease by preventing neurotoxic metabolite accumulation or interfering with the cell accumulation of damaging metabolites, restoring energetic cell fuel, supplementing defective metabolites, and supplementing the defective enzyme. A metabolic derangement of cell homeostasis is part of the progression of many non-metabolic genetic lesions and could be the target for possible metabolic approaches. In this chapter, we provided an update on treatment strategies for treatable inherited dystonias and an overview of genetic dystonias with new experimental therapeutic approaches available or close to clinical translation.

Secondary dystonia following parenchymal brain tumors.

BACKGROUND: Secondary dystonia has been associated with diverse etiologies. Dystonia associated with brain tumors has not been well characterized. OBJECTIVES: To characterize dystonia and relationship with parenchymal brain tumors. METHODS: We present six patients (1.03%) with dystonia related to parenchymal brain tumors, among 580 screened cases. RESULTS: Contralateral hemidystonia was observed in four cases, followed by focal limb (n = 1) and cervical dystonia (n = 1). Dystonia presented during the phase of tumor growth in four cases, and following tumor treatment in two, one case had re-emergent dystonia. Tumors were low-grade (WHO I or II) and located in the basal ganglia (n = 3), cortical areas (n = 2), thalamus (n = 1) and cerebral peduncle (n = 1). CONCLUSIONS: Secondary dystonia may be caused by brain tumors in diverse locations including basal ganglia, cortex and thalamus. It may be the presenting symptom of brain tumor or follow surgical resection combined with ancillary therapy.

Hemidystonia secondary to pediatric thalamic glioblastoma: a case report.

INTRODUCTION: Thalamic tumors are rare and uncommonly manifest as movement disorders, including hemidystonia. Despite this association, little is known about the evolution of hemidystonia. CASE DESCRIPTION: We report on a 11-year-old boy who complained of hypaesthesia and fine motor problems in the left hand. A magnetic resonance imaging showed a large mass in the right thalamus. Stereotactic biopsy revealed a WHO grade 4 astrocytoma, and the patient underwent normofractioned radiochemotherapy with proton-beam radiation and temozolomide. Three months later, a spastic hemiparesis developed on the left side, which progressed over months. Over the following months, the hemiparesis slowly improved, but hemidystonia in the same side developed. This was accompanied with radiological evidence of tumor regression, showing a persistent lesion in the ventral posterolateral and the intralaminar thalamus. CONCLUSION: This case illustrates the unusual and complex temporal course of appearance and disappearance of hemidystonia along with the regression and growth in glioblastoma involving the thalamus.

Dystonia-like Movement Disorders Ameliorated by Shear Force and Pressure Stimulation after Small Infarction in the Left Posterolateral Thalamus.

Focal dystonia (FD) can develop after thalamic lesions. Abnormal somatic sensations were argued to be responsible for FD. Our patient experienced FD-like movement disorders, agraphesthesia, and a reduced sense of shear force on the skin and pressure to deep tissues of the right upper limb following a small infarction in the left posterolateral thalamus. FD-like symptoms improved while the skin was being pulled or the deep tissue was being pushed in a manner proportional to the strength of muscle contractions. Therefore, the lack of these sensations was suggested to be related to FD-like symptoms.

Episodic ataxia type 2 (EA2) with interictal myokymia and focal dystonia.

Episodic ataxia type 1 and 2 (EA1 and EA2) are the most well-described of the episodic ataxias. They are autosomal dominantly inherited early-onset diseases characterized by attacks of cerebellar dysfunction. EA1 is clinically characterized by short episodes of ataxia with interictal myokymia, whereas EA2 is characterized by longer-lasting recurrent ataxia, slurred speech, and interictal nystagmus. We report on a patient with EA2 with interictal focal dystonia and also interictal myokymia, which is hitherto not reported as an interictal feature associated to EA2. The patient carries a previously described heterozygous pathogenic de novo frameshift variant in the CACNA1A gene, establishing the diagnosis of EA2. She had symptom onset at age 13 and from age 48 she developed interictal myokymia and focal dystonia as illustrated in Supplemental Movie S1. We conclude that interictal myokymia and focal dystonia may be interictal features associated to EA2 caused by the cerebellar pathophysiology of EA2. Episodes of ataxia were successfully treated with acetazolamide in low dose, whereas the interictal features were unresponsive to acetazolamide.

Harnessing cognitive strategy use for functional problems and proposed underlying mechanisms in childhood-onset dystonia.

BACKGROUND: There is a significant gap in knowledge about rehabilitation techniques and strategies that can help children and young people with hyperkinetic movement disorders (HMD) including dystonia to successfully perform daily activities and improve overall participation. A promising approach to support skill acquisition is the Cognitive Orientation to daily Occupational Performance (CO-OP) intervention. CO-OP uses cognitive strategies to help patients generate their own solutions to overcome self-identified problems encountered in everyday living. PURPOSE: 1. To identify and categorize strategies used by children with HMD to support skill acquisition during CO-OP; 2. To review the possible underlying mechanisms that might contribute to the cognitive strategies, in order to facilitate further studies for developing focused rehabilitation approaches. METHODS: A secondary analysis was performed on video-recorded data from a previous study exploring the efficacy of CO-OP for childhood onset HMD, in which CO-OP therapy sessions were delivered by a single occupational therapist. For the purpose of this study, we reviewed a total of 40 randomly selected hours of video footage of CO-OP sessions delivered to six participants (age 6-19 years) over ten intervention sessions. An observational recording sheet was applied to identify systematically the participants' or therapist's verbalizations of cognitive strategies during the therapy. The strategies were classified into six categories in line with published literature. RESULTS: Strategies used by HMD participants included distraction, externally focussed attention, internally focussed attention, emotion self-regulation, motor imagery and mental self-guidance. We postulate different underlying working mechanisms for these strategies, which have implications for the therapeutic management of children and young people with HMD including dystonia. CONCLUSIONS: Cognitive strategy training can fundamentally change and improve motor performance. On-going work will address both the underlying neural mechanisms of therapeutic change and the mediators and moderators that influence how change unfolds.

Musicians Focal Dystonia: The Practitioner's Perspective on Psychological, Psychosocial, and Behavioural Risk Factors and Non-motor Symptoms.

Musician's focal dystonia (MFD) is a painless, task-specific neurological movement disorder that impairs fine motor control when playing an instrument. The pathophysiology is not fully understood, and while the available treatment strategies can help with improving motor control, they are rarely able to fully and reliably rehabilitate playing skills. Recent studies suggest that apart from genetic factors, maladaptive neuroplasticity, and the repetitive nature of the instrumental technique, psychosocial, psychological, and behavioural factors might also play a role in the onset of MFD. However, the presence of some of these risk factors is supported primarily by anecdotal evidence, with only a few aspects examined empirically. To explore this area further, 14 semi-structured interviews were conducted with a convenience sample of practitioners (8 medical professionals and 6 musician-coaches) who frequently treated MFD sufferers. Throughout their career, these participants are estimated to have interacted with more than 2,000 musicians with MFD, creating a large, indirect sample. A detailed patient profile emerged from the data with three main components: 1) the negative impact of social environments, including traumatic experiences and low quality of instrumental teaching; 2) a perfectionist, anxious, overly sensitive, and acquiescent personality type; and 3) obsessive, controlling, and inadequate practice behaviours. Participants stated MFD needs to be treated holistically and that neglecting these aspects during treatment could jeopardise rehabilitation. Further objective, controlled research trials are needed to describe these factors in detail, quantify their potential impact as risk factors, and understand how they might hinder therapy.

A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.

Dystonia, chorea, hemiballismus and other dyskinesias.

Hyperkinesias are heterogeneous involuntary movements that significantly differ in terms of clinical and semeiological manifestations, including rhythm, regularity, speed, duration, and other factors that determine their appearance or suppression. Hyperkinesias are due to complex, variable, and largely undefined pathophysiological mechanisms that may involve different brain areas. In this chapter, we specifically focus on dystonia, chorea and hemiballismus, and other dyskinesias, specifically, levodopa-induced, tardive, and cranial dyskinesia. We address the role of neurophysiological studies aimed at explaining the pathophysiology of these conditions. We mainly refer to human studies using surface and invasive in-depth recordings, as well as spinal, brainstem, and transcortical reflexology and non-invasive brain stimulation techniques. We discuss the extent to which the neurophysiological abnormalities observed in hyperkinesias may be explained by pathophysiological models. We highlight the most relevant issues that deserve future research efforts. The potential role of neurophysiological assessment in the clinical context of hyperkinesia is also discussed.

Functional abnormalities in the cerebello-thalamic pathways in a mouse model of DYT25 dystonia.

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (Gnal+/-) mice carry a heterozygous knockout mutation of the Gnal gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, Gnal+/- mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.

Bilateral subthalamic nucleus deep brain stimulation for refractory isolated cervical dystonia.

Subthalamic nucleus (STN) deep brain stimulation (DBS) has been proven to be an alternative target choice for refractory isolated cervical dystonia (CD). However, assessments of its short and long-term safety, efficacy, and sustained effectiveness have been limited to few reports. Here, we evaluated nine consecutive refractory isolated CD patients who underwent bilateral STN DBS and accepted to short and long-term follow-up in this retrospective study. Seven time points were used to see the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores (pre-operation [baseline], 1, 3, 6, 12, 24 months post-operation and last follow-up) to assess improvement of dystonic symptoms. The 36-item Short-Form General Health Survey (SF-36) scores obtained at pre-operation and last follow-up to assess the changes in quality of life. All patients tolerated surgery well and acquired observable clinical benefits from STN DBS therapy. All patients achieved a considerable improvement in quality of life at the last follow-up. The hardware-related adverse events can be tolerated and the stimulation-related adverse events can be ameliorated by programming. Our data support the idea that bilateral STN DBS is a safety and effective method for the treatment of refractory isolated CD, with persistent and remarkable improvement in both movement and quality of life.

Vim-Thalamic Deep Brain Stimulation for Cervical Dystonia and Upper-Limb Tremor: Quantification by Markerless-3D Kinematics and Accelerometry.

Background: Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry. Methods: Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature. Results: Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing. Discussion: In this case, Vim DBS treated both cervical dystonic tremor and dystonic posturing. Markerless-3D-kinematics should be further studied as a method of quantifying and characterizing tremor and dystonia.

Thalamic structural connectivity profiles in blepharospam/Meige's syndrome.

BACKGROUND: Blepharospasm is a debilitating focal dystonia characterized by involuntary eyelid spasms that can be accompanied by oromandibular muscle involvement (Meige's syndrome). Frequently observed abnormality in functional neuroimaging hints at an important position of the thalamus, that relays involved cortico-basal ganglia-cortical and cortico-cerebello-cortical circuits, within the abnormal network in blepharospasm. OBJECTIVE: To characterize abnormal cortico-thalamic structural/streamline connectivity (SC) patterns in the disease, as well as their potential co-occurrence with abnormal subcortico-thalamo-cortical projections using diffusion tractography. METHODS: Diffusion imaging was obtained in 17 patients with blepharospasm (5 with mild lower facial involvement) and 17 healthy controls. Probabilistic tractography was used for quantification of SC between six cortical regions and thalamus, and voxel-level thalamic SC mapping as well as evaluation of the thalamic SC distributions' topography by center-of-gravity analysis was performed. Post-hoc, correlations of SC with clinical parameters were evaluated. Further, white matter integrity was investigated within representative segments of the dentato-thalamo-cortical and pallido-thalamo-cortical tract. RESULTS: Connectivity mapping showed significant reduction of right (pre)motor- and left occipital-thalamic SC, as well as a topographic shift of the left occipital-thalamic SC distribution in patients. Significant positive correlation of occipital-thalamic SC with disease severity was found. Post-hoc analysis revealed significantly reduced mean fractional anisotropy in patients within the dentato-thalamo-cortical trajectory connecting to right (pre)motor and left occipital cortex. CONCLUSION: Abnormal occipital/motor SC provides evidence for dysfunction of the thalamus-relayed visual and motor network as a key aspect in the disease. Concurrent impairment of microstructural integrity within the dentato-thalamic trajectories targeting those cortices hints at cerebellar contribution.

Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.