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Introduction Pallidal DBS is an established treatment for severe isolated dystonia. However, its use in disabling and treatment-refractory tardive syndromes (TS) including tardive dyskinesia and tardive dystonia (TD) is less well investigated and long-term data remain sparse. This observational study evaluates long-term effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with medically refractory TS. Methods We retrospectively analyzed a cohort of seven TD patients with bilateral GPi-DBS. Involuntary movements, dystonia and disability were rated at long-term follow-up (LT-FU) after a mean of 122 ± 33.2 SD months (range 63–171 months) and compared to baseline (BL), short-term (ST-FU; mean 6 ± 2.0 SD months) and 4-year follow-up (4y-FU; mean 45 ± 12.3 SD months) using the Abnormal Involuntary Movement Scale (AIMS) and the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), respectively. Quality of life and mood were evaluated using the SF36 and Beck Depression Index (BDI) questionnaires, respectively. Results At LT-FU patients had improved by 73% ± 14.2 SD in involuntary movements and 90% ± 1.0 SD in dystonia. Mood had improved significantly whereas quality of life remained unchanged compared to baseline. No serious long-lasting stimulation-related adverse events (AEs) were observed. Three patients of this cohort presented without active stimulation and ongoing symptom relief at long-term follow-up after 3–10 years of continuous DBS. Conclusion Pallidal DBS is a safe and effective long-term TD treatment. Even more interesting, three of our patients could stop stimulation after several years of DBS without serious relapse. Larger studies need to explore the phenomenon of ongoing symptom relief after DBS cessation.

ObjectiveWith a growing appreciation for interindividual anatomical variability and patient-specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice.MethodsUsing fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity we retrospectively analyzed 65 patients (26 female, mean age: 69.1±12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity’s ability to predict clinical outcome using stimulation volume modeling and voxel-wise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient-specific level.ResultsAnatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentato-rubro-thalamic tract. Overlap between DBS stimulation volumes and the hypointensity in common space significantly correlated with tremor improvement (R2=0.16, p=0.017) and distance to hotspots previously reported in the literature (R2=0.49, p=7.9e-4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R2=0.37, p=0.002).InterpretationOur findings introduce and validate a novel imaging-based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor.

ObjectiveThis study investigates the association between pallidal low‐frequency activity and motor sign severity in dystonia after chronic deep brain stimulation for several months.MethodsLocal field potentials were recorded in 9 dystonia patients at 5 timepoints (T1–T5) during an OFF‐stimulation period of 5 to 7 hours in parallel with clinical assessment using Burke‐Fahn‐Marsden Dystonia Rating Scale. A linear mixed effects model was used to investigate the potential association of motor signs with local field potential activity in the low frequency (3–12 Hz) and beta range (13–30 Hz).ResultsA significant association of Burke‐Fahn‐Marsden Dystonia Rating Scale scores with low‐frequency activity (3–12 Hz; b = 4.4; standard error = 1.5, degrees of freedom = 43, P = 0.006, 95% confidence interval, 1.3–7.5), but not beta activity (13–30 Hz) was revealed within participants across timepoints.ConclusionLow‐frequency activity is associated with dystonic motor sign severity, even months after chronic deep brain stimulation. Our findings corroborate the pathophysiological role of low‐frequency activity in dystonia and highlight the potential utility as a biomarker for adaptive neuromodulation. © 2019 International Parkinson and Movement Disorder Society

BACKGROUND: Gait disturbances are frequent side effects related to chronic thalamic deep brain stimulation (DBS) that may persist beyond cessation of stimulation. OBJECTIVE: We investigate the temporal dynamics and clinical effects of an overnight unilateral withdrawal of DBS on gait disturbances. METHODS: 10 essential tremor (ET) patients with gait disturbances following thalamic DBS underwent clinical and kinematic gait assessment ON DBS, after instant and after an overnight unilateral withdrawal of DBS of the hemisphere corresponding to the non-dominant hand. The effect of stimulation withdrawal on gait performance was quantitatively assessed using clinical rating and inertial sensors and compared to gait kinematics from 10 additional patients with ET but without subjective gait impairment. DBS leads were reconstructed and active contacts were visualized in relation to surrounding axonal pathways and nuclei. RESULTS: Patients with gait deterioration following DBS exhibited greater excursion of sagittal trunk movements and greater variability of stride length and shank range of motion compared to ET patients without DBS and without subjective gait impairment. Overnight but not instant withdrawal of unilateral DBS resulted in significant reduction of SARA axial subscore and stride length variability, while tremor control of the dominant hand was preserved. Cerebellothalamic, striatopallidofugal and corticospinal fibers were in direct vicinity of transiently deactivated contacts. CONCLUSION: Non-dominant unilateral cessation of VIM DBS may serve as a therapeutic option as well as a diagnostic tool to detect stimulation-induced gait disturbances that is applicable in ambulatory settings due to preserved functionality of the dominant hand.

Gait impairments in Parkinson's disease remain a scientific and therapeutic challenge. The advent of new deep brain stimulation (DBS) devices capable of recording brain activity from chronically implanted electrodes has fostered new studies of gait in freely moving patients. The hope is to identify gait-related neural biomarkers and improve therapy using closed-loop DBS. In this context, animal models offer a wealth of opportunities to investigate gait network impairments at multiple biological scales and address unresolved questions from clinical research. Yet, the contribution of rodent models to the development of future neuromodulation therapies will rely on translational validity. In this review, we summarize the most effective strategies to model parkinsonian gait in rodents. We discuss how clinical observations have inspired targeted brain lesions in animal models, and whether resulting motor deficits and network oscillations match recent findings in humans. We conclude that future research should incorporate behavioral tests with increased cognitive demands to potentially uncover episodic gait impairments in rodents. Additionally, we expect that basic research will benefit from the implementation of evolving signal processing strategies from clinical research. This coevolution of translational research may contribute to the future optimization of gait therapy in Parkinson's disease.

BACKGROUND Instrumented assessment of motor symptoms has emerged as a promising extension to the clinical assessment of several movement disorders. The use of mobile and inexpensive technologies such as some markerless motion capture technologies is especially promising for large-scale application but has not transitioned into clinical routine to date. A crucial step on this path is to implement standardized, clinically applicable tools that identify and control for quality concerns. OBJECTIVE The main goal of this study comprises the development of a systematic quality control (QC) procedure for data collected with markerless motion capture technology and its experimental implementation to identify specific quality concerns and thereby rate the usability of recordings. METHODS We developed a post hoc QC pipeline that was evaluated using a large set of short motor task recordings of healthy controls (2010 recordings from 162 subjects) and people with multiple sclerosis (2682 recordings from 187 subjects). For each of these recordings, 2 raters independently applied the pipeline. They provided overall usability decisions and identified technical and performance-related quality concerns, which yielded respective proportions of their occurrence as a main result. RESULTS The approach developed here has proven user-friendly and applicable on a large scale. Raters’ decisions on recording usability were concordant in 71.5%-92.3% of cases, depending on the motor task. Furthermore, 39.6%-85.1% of recordings were concordantly rated as being of satisfactory quality whereas in 5.0%-26.3%, both raters agreed to discard the recording. CONCLUSIONS We present a QC pipeline that seems feasible and useful for instant quality screening in the clinical setting. Results confirm the need of QC despite using standard test setups, testing protocols, and operator training for the employed system and by extension, for other task-based motor assessment technologies. Results of the QC process can be used to clean existing data sets, optimize quality assurance measures, as well as foster the development of automated QC approaches and therefore improve the overall reliability of kinematic data sets.

Introduction Deep brain stimulation (DBS) is a highly efficacious treatment for essential tremor (ET). Still, the optimal anatomical target in the (sub)thalamic area is a matter of debate. The aim of this study was to determine the optimal target of DBS for ET regarding beneficial clinical outcome and impact on activities of daily living as well as stimulation-induced side effects and compare it with previously published coordinates. Methods In 30 ET patients undergoing bilateral DBS, severity of tremor was assessed by blinded video ratings before and at 1-year follow-up with DBS ON and OFF. Tremor scores and reported side effects and volumes of tissue activated were used to create a probabilistic map of DBS efficiency and side effects. Results DBS was effective both in tremor suppression as well as in improving patient reported outcomes, which were positively correlated. The “sweet spot” for tremor suppression was located inferior of the VIM in the subthalamic area, close to the superior margin of the zona incerta. The Euclidean distance of active contacts to this spot as well as to 10 of 13 spots from the literature review was predictive of individual outcome. A cluster associated with the occurrence of ataxia was located in direct vicinity of the “sweet spot”. Conclusion Our findings suggest the highest clinical efficacy of DBS in the posterior subthalamic area, lining up with previously published targets likely representing the dentato-rubro-thalamic tract. Side effects may not necessarily indicate lead misplacement, but should encourage clinicians to employ novel DBS programing options.

ObjectiveGait disturbances are frequent side effects occurring during chronic thalamic deep brain stimulation (DBS) in patients with essential tremor (ET). Adapting stimulation settings to shorter pulse widths has been shown to reduce side effects of subthalamic DBS. Here, we assess how a reduction of pulse width changes gait performance of affected patients.MethodsSensor-based gait assessment was performed to record spatiotemporal gait parameters in 10 healthy subjects (HS) and 7 patients with ET with gait disturbances following thalamic DBS. Patients were tested during standard DBS, after 72 hours of stimulation withdrawal and at least 30 days after adjusting DBS settings to a shorter pulse width of 40 µs (DBS40PW).ResultsPatients with ET on standard DBS showed significantly higher variability of several spatiotemporal gait parameters compared with HS. Variability of stride length and range of motion of the shanks significantly decreased OFF DBS as compared with standard DBS. This improvement was maintained over 30 days with DBS40PW while providing effective tremor suppression in six out of seven patients.ConclusionShorter pulse widths may reduce gait disturbances in patients with ET that are induced by DBS while preserving a level of tremor suppression equal to standard stimulation settings.

Essential tremor is the most prevalent movement disorder and is often refractory to medical treatment. Deep brain stimulation offers a therapeutic approach that can efficiently control tremor symptoms. Several deep brain stimulation targets (ventral intermediate nucleus, zona incerta, posterior subthalamic area) have been discussed for tremor treatment. Effective deep brain stimulation therapy for tremor critically involves optimal targeting to modulate the tremor network. This could potentially become more robust and precise by using state-of-the-art brain connectivity measurements. In the current study, we utilized two normative brain connectomes (structural and functional) to show the pattern of effective deep brain stimulation electrode connectivity in 36 essential tremor patients. Our structural and functional connectivity models were significantly predictive of post-operative tremor improvement in out-of-sample data (p< 0.001 for both structural and functional leave-one-out cross-validation). Additionally, we segregated the somatotopic brain network based on head and hand tremor scores. These resulted in segregations that mapped onto the well-known somatotopic maps of both motor cortex and cerebellum. Crucially, this shows that slightly distinct networks need to be modulated to ameliorate head vs. hand tremor and that those networks could be identified based on somatotopic zones in motor cortex and cerebellum.Finally, we propose a multi-modal connectomic deep brain stimulation sweet spot that may serve as a reference to enhance clinical care, in the future. This spot resided in the posterior subthalamic area, encroaching on the inferior borders of ventral intermediate nucleus and sensory thalamus. Our results underscore the importance of integrating brain connectivity in optimizing deep brain stimulation targeting for essential tremor.

Background Limb and gait ataxia following chronic VIM-DBS is a frequent and clinically relevant phenomenon ( Hwynn et al., 2011 ), which is likely caused by disruption of physiological cerebello-thalamic signaling and inadvertent cerebellar activation ( Reich et al., 2016 ). Ataxia dramatically improves after a pause of stimulation for more than 72 h. At the same time, tremor will reoccur, leaving the patient disabled. To date, no effective therapeutic option for stimulation-induced gait ataxia has been identified. Shorter pulse width than 60 μs have been suggested to broaden the therapeutic windows as fiber tracts involved in tremor suppression and induction of ataxia have differential electrophysiological properties ( Reich et al., 2015 , Groppa et al., 2014 ). Here, we explore the therapeutic value of 40 μs pulse width in treatment of stimulation-induced gait ataxia. Methods 5 patients received special access codes that allowed their neurostimulators to be programmed beyond regular limits. Spatiotemporal gait parameters were measured using an accelerometer-based kinematic motion analysis system (Mobility Lab, APDM). Measurements were repeated (1) ON best stimulation for tremor suppression (2) after 4 days of withdrawal of stimulation (3) after more than 6 weeks of adjusted stimulation with 40 μs pulse width. Clinical assessment of gait ataxia and tremor was done using Score for Assessment and Rating of Ataxia (SARA) items 1–3 and the Tremor-Rating-Score (TRS). Patients were asked to self-report their global impression of change (GIC-S). Results 4 of 5 patients self-reported an improvement of gait performance off stimulation and at DBS at short pulse width. Tremor scores were reduced with VIM-DBS similar for 40 μs (9.2 ± 3.8) and 60 μs (9.6 ± 4.0) pulse width compared to OFF DBS (21.4 ± 5.5; p = 0.065) and SARA axial items (1–3) decreased with stimulation OFF (2.8 ± 0.86) and 40 μs VIM-DBS (2.4 ± 0.74;) compared to 60 μs VIM-DBS (6.0 ± 0.89; p = 0.065). Coefficient of variability (CoV) of stride length and of shank range of motion were significantly reduced both OFF DBS and with 40 μs VIM-DBS (p Conclusions Our results add further evidence to the growing number of studies pointing to gait ataxia as a severe yet reversible side effect of thalamic stimulation rather than disease progression. Shorter pulsewidths may therefore be a promising approach to target stimulation-induced side effects while maintaining desired clinical efficacy of tremor suppression.

Summary Background Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. Methods We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov ( NCT02008721 ) and EudraCT (2012-000928-18), and is completed. Findings Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference −0·94 [SE 1·41; 95% CI −3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. Interpretation 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. Funding ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Luneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi-DBS) is an established treatment for patients with medication-refractory cervical dystonia ( Volkmann et al., 2014 ), but individual response to DBS is highly variable and predictive factors for the clinical outcome have not been identified yet. Cortical plasticity induced by paired associative stimulation is modulated by DBS in patients with generalized dystonia and has been related to the stability of the DBS effect after switching off stimulation ( Ruge et al., 2011 ). Here, we investigated DBS-induced changes in cortical plasticity over time in patients with cervical dystonia and explored whether differences in response to DBS might be explained by individual variability of neurophysiological markers of plasticity. Methods PAS25 was applied using transcranial magnetic stimulation (TMS) to investigate cortical plasticity in 9 patients with cervical dystonia preoperatively and 3 months after activation of pallidal DBS. PAS response was calculated as mean MEP response at timepoints 0, 15 and 30 min after PAS and expressed as percentage of pre-PAS MEP. Clinical changes were assessed using the TWSTRS severity subscore. Spearman’s correlation coefficient was calculated to evaluate the relationship between neurophysiological measures and clinical scores. Three out of 9 patients were lost to neurophysiological follow up due to intra- and postoperative complications or incompatibility of the neurostimulator for TMS. Results Mean TWSTRS pre OP (17.4 ± 2.1) was reduced with pallidal DBS by 49.5% (post OP TWSTRS: 8.8 ± 2.8; Wilcoxon signed rank test: p = 0.0078; n = 9). Mean PAS response post OP (125.0% ±24.7; n = 6) was smaller compared to pre OP (165.1 ± 26.3) but did not reach significance. Individual courses of both clinical and neurophysiological changes were highly variable across subjects. Preoperative TWSTRS correlated significantly with pre-operative PAS-response ( n = 9; R = 0.78; p = 0.018). In the 6 patients that could be followed up by TMS, the decrease in PAS-response correlated with the decrease in TWSTRS score absolute values at timepoint 6 months after DBS ( n = 6; p = 0.028; R = 0.89). Conclusions Maladaptive plasticity has been discussed to play a major role in the pathophysiology of dystonia ( Quartarone et al., 2003 ). On the other hand, increased cortical plasticity might also imply a greater capability for neuromodulation ( Ruge et al., 2011 ). We found a significant correlation between symptom severity and PAS-induced cortical plasticity as well as a relation of both clinical benefit and neurophysiological change during DBS in patients with cervical dystonia. The individual susceptibility for plastic changes may partially explain the broad range of clinical benefit from DBS in dystonia. Furthermore, the correlation of plasticity with clinical benefit might indicate PAS-induced plasticity as a potential predictive factor for DBS outcome that should be explored in larger studies.