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Whether treatment response in patients with Parkinson disease depends on brain atrophy is insufficiently understood. The goal of this study is to identify specific atrophy patterns associated with response to dopaminergic therapy and deep brain stimulation.In this study, we analyzed the association of gray matter brain atrophy patterns, as identified by voxel-based morphometry, with acute response to levodopa (N = 118) and subthalamic nucleus deep brain stimulation (N = 39). Motor status was measured as a change in points on the Unified Parkinson's Disease Rating Scale III score. Baseline values were obtained before surgery, after cessation of dopaminergic medication for at least 12 hours; response to medication was assessed after administration of a standardized dose of levodopa. Response to deep brain stimulation was measured three months after surgery in the clinical condition after withdrawal of dopaminergic medication.Although frontoparietal brain gray matter loss was associated with subpar response to deep brain stimulation, there was no significant link between brain atrophy and response to levodopa.We conclude that response to deep brain stimulation relies on gray matter integrity; hence, gray matter loss may present a risk factor for poor response to deep brain stimulation and may be considered when making decision regarding clinical practice.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson's disease. However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We aimed to assess treatment effects of stimulation parameters suggested by a recently published algorithm (StimFit) based on neuroimaging data.This double-blind, randomised, crossover, non-inferiority trial was carried out at Charité - Universitätsmedizin, Berlin, Germany, and enrolled patients with Parkinson's disease treated with directional octopolar electrodes targeted at the STN. All patients had undergone DBS programming according to our centre's standard of care (SoC) treatment before study recruitment. Based on perioperative imaging data, DBS electrodes were reconstructed and StimFit was applied to suggest optimal stimulation settings. Patients underwent motor assessments using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) during OFF-medication and in OFF-stimulation and ON-stimulation states under both conditions, StimFit and SoC parameter settings. Patients were randomly assigned (1:1) to receive either StimFit-programmed DBS first and SoC-programmed DBS second, or SoC-programmed DBS first and StimFit-programmed DBS second. The allocation schedule was generated using a computerised random number generator. Both the rater and patients were masked to the sequence of SoC and StimFit stimulation conditions. All patients who participated in the study were included in the analysis. The primary endpoint of this study was the absolute mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation, with a non-inferiority margin of 5 points. The study was registered at the German Register for Clinical Trials (DRKS00023115), and is complete.Between July 10, 2020, and Oct 28, 2021, 35 patients were enrolled in the study; 18 received StimFit followed by SoC stimulation, and 17 received SoC followed by StimFit stimulation. Mean MDS-UPDRS-III scores improved from 47·3 (SD 17·1) at OFF-stimulation baseline to 24·7 (SD 12·4) and 26·3 (SD 12·4) under SoC and StimFit stimulation, respectively. Mean difference between motor scores was -1·6 (SD 7·1; 95% CI -4·0 to 0·9; superiority test psuperiority=0·20; n=35), establishing non-inferiority of StimFit stimulation at a margin of -5 points (non-inferiority test pnon-inferiority=0·0038). In six patients (17%), initial programming of StimFit settings resulted in acute side-effects and amplitudes were reduced until side-effects disappeared.Automated data-driven algorithms can predict stimulation parameters that lead to motor symptom control comparable to SoC treatment. This approach could significantly decrease the time necessary to obtain optimal treatment parameters.Deutsche Forschungsgemeinschaft through NeuroCure Clinical Research Center and TRR 295.

ObjectiveThis study aims to shed light on structural networks associated with stimulation-induced dysarthria (SID) and to derive a data-driven model to predict SID in patients with Parkinson’s Disease (PD) and deep brain stimulation (DBS) of the subthalamic nucleus (STN).MethodsRandomized, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fiber-based mapping approach, based on the calculation of fiber-wise Odds Ratios for SID, was employed to identify the distributional pattern of SID in the STN’s vicinity. The ability of the data-driven model to classify stimulation volumes as “causing SID” or “not causing SID” was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS.ResultsLocal fiber-based stimulation maps showed an involvement of fibers running lateral and postero-medial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC-analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (AUCleft= 0.88, AUCright= 0.88).InterpretationThis study reveals an involvement of both, cerebello-thalamic fibers, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS.

BackgroundSubthalamic deep brain stimulation (DBS) is an established therapy to treat Parkinson’s disease (PD). To maximize therapeutic outcome, optimal DBS settings must be carefully selected for each patient. Unfortunately, this is not always achieved because of: (1) increased technological complexity of DBS devices, (2) time restraints, or lack of expertise, and (3) delayed therapeutic response of some symptoms. Biomarkers to accurately predict the most effective stimulation settings for each patient could streamline this process and improve DBS outcomes.ObjectiveTo investigate the use of evoked potentials (EPs) to predict clinical outcomes in PD patients with DBS.MethodsIn ten patients (12 hemispheres), a monopolar review was performed by systematically stimulating on each DBS contact and measuring the therapeutic window. Standard imaging data were collected. EEG-based EPs were then recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. Linear mixed models were used to assess how well both EPs and image-derived information predicted the clinical data.ResultsEvoked potential peaks at 3 ms (P3) and at 10 ms (P10) were observed in nine and eleven hemispheres, respectively. Clinical data were well predicted using either P3 or P10. A separate model showed that the image-derived information also predicted clinical data with similar accuracy. Combining both EPs and image-derived information in one model yielded the highest predictive value.ConclusionEvoked potentials can accurately predict clinical DBS responses. Combining EPs with imaging data further improves this prediction. Future refinement of this approach may streamline DBS programming, thereby improving therapeutic outcomes.Clinical trial registrationClinicalTrials.gov, identifier NCT04658641.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for patients with Parkinson’s disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control with a decrease in energy consumption. However, only little is known about the effect of short pulse width stimulation beyond the setting of an acute challenge. Objective: To compare 4 weeks of STN-DBS with conventional pulse width stimulation (60 μs) to 4 weeks of STN-DBS with short pulse width stimulation (30 μs) regarding motor symptom control. Methods: This study was a monocentric, double-blinded, randomized crossover non-inferiority trial investigating whether short pulse width stimulation with 30 μs maintains equal motor control as conventional 60 μs stimulation over a period of 4 weeks (German Clinical Trials Register No. DRKS00017528). Primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life. Results: Due to a high dropout rate, the calculated sample size of 27 patients was not met and 24 patients with Parkinson’s disease and STN-DBS were included in the final analysis. However, there were no differences in any investigated outcome parameter between the two treatment conditions. Conclusion: This study demonstrates that short pulse width settings (30 μs) provide non-inferior motor symptom control as conventional (60 μs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia.

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson’s Disease (PD). However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We conducted a double-blind, ran-domized, cross-over, non-inferiority trial to assess treatment effects of stimulation parameters suggested by a recently published algorithm (StimFit) based on neuroimaging data.MethodsThe trial was carried out at Charité – Universitätsmedizin, Berlin, Germany and enrolled 35 PD patients treated with directional octopolar electrodes targeted at the STN. All patients had undergone DBS programming according to our centers standard of care (SoC) treatment before study recruitment. Based on perioperative imaging data DBS electrodes were reconstructed and StimFit was applied to suggest optimal stimulation settings. Patients underwent motor assessments using MDS-UPDRS-III during OFF-medication and in OFF-and ON-stimulation states under both conditions, StimFit and SoC parameter settings that were double blinded and randomized in a 1:1 ratio. The primary endpoint of this study was the absolute mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation, with a non-inferiority margin of five points.FindingsSTN DBS resulted in mean MDS-UPDRS-III improvements of 48 % for SoC and 43 % with StimFit as compared to OFF-stimulation condition. The mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation was not significant (1.6 points), and non-inferiority was established. In six patients (17 %) initial programming of StimFit settings resulted in acute side-effects and amplitudes were reduced until side-effects disappeared.InterpretationAutomated data-driven algorithms can predict stimulation parameters which lead to motor symptom control comparable to standard of care treatment. This approach could significantly decrease the time necessary to obtain optimal treatment parameters thereby fostering the design of more complex DBS electrodes. Long-term data including effects on quality of life require further investigation.

OBJECTIVE This study was undertaken to gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS). METHODS Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was then validated in a leave-one-out design. RESULTS Fibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al-Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p

Background: Directional leads are increasingly used in deep brain stimulation. They allow shaping the electrical field in the axial plane. These new possibilities increase the complexity of programming. Thus, optimized programming approaches are needed to assist clinical testing and to obtain full clinical benefit. Objectives: This simulation study investigates to what extent the electrical field can be shaped by directional steering to compensate for lead malposition. Method: Binary volumes of tissue activated (VTA) were simulated, by using a finite element method approach, for different amplitude distributions on the three directional electrodes. VTAs were shifted from 0 to 2 mm at different shift angles with respect to the lead orientation, to determine the best compensation of a target volume. Results: Malpositions of 1 mm can be compensated with the highest gain of overlap with directional leads. For larger shifts, an improvement of overlap of 10–30% is possible, depending on the stimulation amplitude and shift angle of the lead. Lead orientation and shift determine the amplitude distribution of the electrodes. Conclusion: To get full benefit from directional leads, both the shift angle as well as the shift to target volume are required to choose the correct amplitude distribution on the electrodes. Current directional leads have limitations when compensating malpositions >1 mm; however, they still outperform conventional leads in reducing overstimulation. Further, their main advantage probably lies in the reduction of side effects. Databases like the one from this simulation could serve for optimized lead programming algorithms in the future.

Background: Directional deep brain stimulation (DBS) enlarges the therapeutic window by increasing side-effect thresholds and improving clinical benefits. To determine the optimal stimulation settings and interpret clinical observations, knowledge of the lead orientation in relation to the patient’s anatomy is required. Objective: To determine if directional leads remain in a fixed orientation after implantation or whether orientation changes over time. Method: Clinical records of 187 patients with directional DBS electrodes were screened for CT scans in addition to the routine postoperative CT. The orientation angle of each electrode at a specific point in time was reconstructed from CT artifacts using the DiODe algorithm implemented in Lead-DBS. The orientation angles over time were compared with the originally measured orientations from the routine postoperative CT. Results: Multiple CT scans were identified in 18 patients and the constancy of the orientation angle was determined for 29 leads at 48 points in time. The median time difference between the observations and the routine postoperative CT scan was 82 (range 1–811) days. The mean difference of the orientation angles compared to the initial measurement was –1.1 ± 3.9° (range –7.6 to 8.7°). Linear regression showed no relevant drift of the absolute value of the orientation angle over time (0.8°/year, adjusted R2: 0.040, p = 0.093). Conclusion: The orientation of directional leads was stable and showed no clinically relevant changes either in the first weeks after implantation or over longer periods of time.

Objective To compare directional monopolar, bipolar, and directional bipolar thalamic deep brain stimulation (DBS) in tremor patients. Methods Fourteen tremor patients (7 Essential Tremor and 7 Parkinson's Disease) implanted with directional DBS electrodes in the ventral intermediate nucleus (VIM) were enrolled. Side-effect thresholds of monopolar directional stimulation (DIRECT) were compared to circular DBS as well as, in a randomized design, to those of two different bipolar stimulation settings (BIPOLAR = circular anode; BI-DIRECT = directional anode). Tremor suppression (Tremor Rating Scale, TRS) right below the side-effect threshold was also assessed. Results Directional DBS in the individually best direction showed higher side-effect thresholds than circular DBS (p = 0.0063). The thresholds were raised further using either one of the bipolar stimulation paradigms (BIPOLAR p = 0.0029, BI-DIRECT p = 0.0022). The side-effect thresholds did not differ between both bipolar settings, but side-effects were less frequent with BI-DIRECT. No difference in TRS scores with stimulation just below the side-effect threshold was found between all stimulation conditions. Conclusions Side-effect thresholds of monopolar directional and bipolar stimulation with both circular and directional anodes were higher compared to traditional monopolar circular stimulation in the VIM. Bipolar DBS with directional anodes evoked side-effect less frequently than bipolar and monopolar directional stimulation. All stimulation settings had comparable effects on tremor suppression just below their side-effect thresholds. Thus, directional and different bipolar settings should be explored in patients with bothersome side-effects of thalamic stimulation when monopolar stimulation settings are not satisfying. Further studies are needed to explore the efficiency of the different bipolar stimulation paradigms.

Background: Wearables (= wearable computer) enable continuous and noninvasive monitoring of a range of vital signs. Mobile and cost-effective devices, combined with powerful data analysis tools, open new dimensions in assessing body functions (“digital biomarkers”). Methods: To answer the question whether wearables are ready for use in the medical context, a PubMed literature search and analysis for their clinical-scientific use using publications from the years 2008 to 2018 was performed. Results: A total of 79 out of 314 search hits were publications on clinical trials with wearables, of which 16 were randomized controlled trials. Motion sensors were most frequently used to measure defined movements, movement disorders, or general physical activity. Approximately 20% of the studies used sensors to detect cardiovascular parameters. As for the sensor location, the wrist was chosen in most studies (22.8%). Conclusion: Wearables can be used in a precisely defined medical context, when taking into account complex influencing factors.

BACKGROUND Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson’s disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Contains fulltext : 241592.pdf (Publisher’s version ) (Open Access) Objectives: Obsessive-compulsive disorder (OCD) is a psychiatric disorder with alterations of cortico-striato-thalamo-cortical loops and impaired performance monitoring. Electrophysiological markers such as conflict-related medial frontal theta (MFT) and error-related negativity (ERN) may be altered by clinically effective deep brain stimulation (DBS) of the anterior limb of the internal capsule and nucleus accumbens (ALIC/NAc). We hypothesized that ALIC/NAc DBS modulates electrophysiological performance monitoring markers. Materials and Methods: Fifteen patients (six male) with otherwise treatment-refractory OCD receiving ALIC/NAc DBS performed a flanker task with EEG recordings at three sessions: presurgery, and at follow-up with DBS on and off. We examined MFT, ERN, and task performance. Furthermore, we investigated interrelations with clinical efficacy and the explored the influence of the location of individual stimulation volumes on EEG modulations. Results: MFT and ERN were significantly attenuated by DBS with differences most pronounced between presurgery and DBS-on states. Also, we observed reaction time slowing for erroneous responses during DBS-off. Larger presurgery ERN amplitudes were associated with decreased clinical efficacy. Exploratory anatomical analyses suggested that stimulation volumes encompassing the NAc were associated with MFT modulation, whereas ALIC stimulation was associated with modulation of the ERN and clinical efficacy. Conclusion: ALIC/NAc DBS diminished MFT and ERN, demonstrating modulation of the medial frontal performance monitoring system in OCD. Furthermore, our findings encourage further studies to explore the ERN as a potential predictor for clinical efficacy. 8 p.

JCO clinical cancer informatics 6, e2100126 (2022). doi:10.1200/CCI.21.00126, Published by American Society of Clinical Oncology, Alexandria, VA

Directional deep brain stimulation (DBS) leads are now widely used, but the orientation of directional leads needs to be taken into account when relating DBS to neuroanatomy. Methods that can reliably and unambiguously determine the orientation of directional DBS leads are needed. In this study, we provide an enhanced algorithm that determines the orientation of directional DBS leads from postoperative CT scans. To resolve the ambiguity of symmetric CT artifacts, which in the past, limited the orientation detection to two possible solutions, we retrospectively evaluated four different methods in 150 Cartesia™ directional leads, for which the true solution was known from additional X-ray images. The method based on shifts of the center of mass (COM) of the directional marker compared to its expected geometric center correctly resolved the ambiguity in 100% of cases. In conclusion, the DiODe v2 algorithm provides an open-source, fully automated solution for determining the orientation of directional DBS leads.

BACKGROUND Finding the optimal deep brain stimulation (DBS) parameters from a multitude of possible combinations by trial and error is time consuming and requires highly trained medical personnel. OBJECTIVE We developed an automated algorithm to identify optimal stimulation settings in Parkinson's disease (PD) patients treated with subthalamic nucleus (STN) DBS based on imaging-derived metrics. METHODS Electrode locations and monopolar review data of 612 stimulation settings acquired from 31 PD patients were used to train a predictive model for therapeutic and adverse stimulation effects. Model performance was then evaluated within the training cohort using cross-validation and on an independent cohort of 19 patients. We inverted the model by applying a brute-force approach to determine the optimal stimulation sites in the target region. Finally, an optimization algorithm was established to identify optimal stimulation parameters. Suggested stimulation parameters were compared to the ones applied in clinical practice. RESULTS Predicted motor outcome correlated with observed outcome (R = 0.57, P

BackgroundDeep brain stimulation (DBS) of the medial thalamus is an evolving therapy for severe, treatment-refractory Tourette syndrome (TS). It remains unanswered which functionally connected networks need to be modulated to obtain optimal treatment results.MethodsWe assessed treatment response of 15 patients with TS untergoing thalamic DBS six and twelve months postoperatively using the Yale Global Tic Severity Scale (YGTSS) tic score. For each time point, functional connectivity maps seeding from stimulation sites were calculated based on a normative functional connectome derived from 1000 healthy subjects. Resulting maps were analyzed in a voxel-wise mixed model for repeated measurements to identify patterns of connectivity associated with tic reduction.ResultsConnectivity of stimulation to the medial frontal cortex, bilateral insulae and sensorimotor cortex was associated with tic reduction. Connectivity with the temporal lobe, cerebellum, ventral striatum and orbitofrontal cortex was negatively associated. The overall connectivity pattern was robust to leave-one-out cross-validation, explaining 25 % of outcome variance (R = 0.500; p = 0.005).ConclusionsWe delineated a functional connectivity profile seeding from stimulation sites associated with TS-DBS outcome. This pattern comprised areas linked to the processing of premonitory urges and tic execution, thereby extending our current understanding of effective neuromodulation for TS.

Background Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). Methods One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. Results Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. Conclusions Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. (c) 2019 International Parkinson and Movement Disorder Society

OBJECTIVE To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.

BackgroundSubthalamic nucleus deep brain stimulation is a well-established treatment for patients with Parkinson’s disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control.ObjectivesTo investigate in patients with Parkinson’s disease and nucleus subthalamicus deep brain stimulation (STN-DBS) whether short pulse width stimulation with 30µs maintains equal motor control as conventional 60µs stimulation over a period of 4 weeks.MethodsIn this monocentric, double-blinded, randomized crossover trial, 30 patients with Parkinson’s disease and STN-DBS were enrolled and assigned to 4 weeks of stimulation with 30µs and 4 weeks of stimulation with 60µs in randomized order (German Clinical Trials Register No. DRKS00017528). The primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life.ResultsA total of 24 patients were included in the final analysis. There was no difference in motor symptom control between the two treatment conditions. Concerning secondary outcomes there was no difference in energy consumption, non-motor symptoms, side-effects, or quality of life. On the individual level, patients preferring 30µs tended to be more dyskinetic in the 60µs setting, whereas patients preferring 60µs experienced more off-time in the 30µs setting.ConclusionsShort pulse width settings (30µs) provide equal motor symptom control as conventional (60µs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia.

We investigated whether Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) influences social validation as measured by a Judge-Advisor task. In contrast to healthy controls and patients with their DBS OFF, patients with their stimulation switched on do not experience a gain of confidence after receiving competent advice.

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn&ndash, Tolosa&ndash, Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.

Background Atrial fibrillation (A-fib) is the most common arrhythmia; however, detection of A-fib is a challenge due to irregular occurrence. Purpose Evaluating feasibility and performance of a non-invasive medical wearable for detection of A-fib. Methods In the CoMMoD-A-fib trial admitted patients with a high risk for A-fib carried the wearable and an ECG Holter (control) in parallel over a period of 24 hours under not physically restricted conditions. The wearable with a tight-fit upper arm band employs a photoplethysmography (PPG) technology enabling a high sampling rate. Different algorithms (including a deep neural network) were applied to 5 min PPG datasets for detection of A-fib. Proportion of monitoring time automatically interpretable by algorithms (= interpretable time) was analyzed for influencing factors. Results In 102 inpatients (age 71.0±11.9 years; 52% male) 2306 hours of parallel recording time could be obtained; 1781 hours (77.2%) of these were automatically interpretable by an algorithm analyzing PPG derived intervals. Detection of A-Fib was possible with a sensitivity of 92.7% and specificity of 92.4% (AUC 0.96). Also during physical activity, detection of A-fib was sufficiently possible (sensitivity 90.1% and specificity 91.2%). Usage of the deep neural network improved detection of A-fib further (sensitivity 95.4% and specificity 96.2%). A higher prevalence of heart failure with reduced ejection fraction was observed in patients with a low interpretable time (p=0.080). Conclusion Detection of A-fib by means of an upper arm non-invasive medical wearable with a high resolution is reliably possible under inpatient conditions. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Internal grant program (PhD and Dr. rer. nat. Program Biomedicine) of the Faculty of Health at Witten/Herdecke University, Germany. HELIOS Kliniken GmbH (Grant-ID 047476), Germany

Atrial fibrillation (AF) is the most common arrhythmia and has a major impact on morbidity and mortality, however, detection of asymptomatic AF is challenging. This study sims to evaluate the sensitivity and specificity of non-invasive AF detection by a medical wearable. In this observational trial, patients with AF admitted to a hospital carried the wearable and an ECG Holter (control) in parallel over a period of 24 h, while not in a physically restricted condition. The wearable with a tight-fit upper armband employs a photoplethysmography technology to determine pulse rates and inter-beat intervals. Different algorithms (including a deep neural network) were applied to five-minute periods photoplethysmography datasets for the detection of AF. A total of 2306 h of parallel recording time could be obtained in 102 patients, 1781 h (77.2%) were automatically interpretable by an algorithm. Sensitivity to detect AF was 95.2% and specificity 92.5% (area under the receiver operating characteristics curve (AUC) 0.97). Usage of deep neural network improved the sensitivity of AF detection by 0.8% (96.0%) and specificity by 6.5% (99.0%) (AUC 0.98). Detection of AF by means of a wearable is feasible in hospitalized but physically active patients. Employing a deep neural network enables reliable and continuous monitoring of AF.

ObjectiveOpen questions remain regarding the optimal target, or sweetspot, for deep brain stimulation (DBS) in e.g. Parkinson’s Disease. Previous studies introduced different methods of mapping DBS effects to determine sweetspots. While having a direct impact on surgical targeting and postoperative programming in DBS, these methods so far have not been investigated in ground-truth data.Materials & MethodsThis study investigated five previously published DBS mapping methods regarding their potential to correctly identify a ground-truth sweetspot. Methods were investigated in silico in eight different use-case scenarios, which incorporated different types of clinical data, noise, and differences in underlying neuroanatomy. Dice-coefficients were calculated to determine the overlap between identified sweetspots and the ground-truth. Additionally, out-of-sample predictive capabilities were assessed using the amount of explained variance R2.ResultsThe five investigated methods resulted in highly variable sweetspots. Methods based on voxel-wise statistics against average outcomes showed the best performance overall. While predictive capabilities were high, even in the best of cases Dice-coefficients remained limited to values around 0.5, highlighting the overall limitations of sweetspot identification.ConclusionsThis study highlights the strengths and limitations of current approaches to DBS sweetspot mapping. Those limitations need to be taken into account when considering the clinical implications. All future approaches should be investigated in silico before being applied to clinical data.

Thalamic deep brain stimulation (DBS) is an effective treatment for patients with medically refractory essential tremor. However, stimulation-induced side-effects, especially stimulation-induced dysarthria (SID), interfere severely with quality of life and postoperative tremor control. Here, we present a functional and structural network approach to SID to gain insights into the associated brain areas and to predict stimulation-induced worsening of intelligibility. Monopolar reviews were conducted in 14 essential tremor patients with bilateral thalamic DBS by increasing the stimulation amplitude contact-wise until (i) a maximum of 10mA, (ii) the occurrence of intolerable side effects, or (iii) the onset of SID. Speech assessments included intelligibility ratings when reading a German standard text and a fast syllable repetition task. To detect brain areas associated with SID, a functional connectivity difference image of volumes of tissue activated (VTAs) causing SID, and VTAs not causing SID was created employing a state-of-the-art functional connectome, Lead-DBS, as well as the SPM toolbox. Additionally, discriminative fibers for stimulation-induced worsening of intelligibility were identified in a structural connectome using linear mixed effect models and validated in a leave-one-out design. A total of 111 contact assessments were included for further analysis. The functional connectivity difference image indicated stronger connectivity of VTAs causing SID (N = 51) to the precentral gyrus with a positive medio-lateral gradient, parts of the inferior and medial frontal gyrus, the supramarginal gyrus, the superior temporal gyrus, as well as the superior and the inferior cerebellar lobules, and the vermis. In the thalamic region, discriminative fibers for stimulation-induced worsening of intelligibility were located antero-laterally to fibers associated with tremor control as published by Al-Fatly et al. (2019). The overlap of the respective clinical stimulation setting’s VTAs with these fibers explained 33.2% of the variance of individual change in intelligibility compared to “OFF stimulation” in a leave-one-out design. This study demonstrates that SID in essential tremor patients is related to a modulation of the functional connectome of speech production by thalamic DBS. In spite of the proximity of functional and structural connectivity patterns for tremor control, as identified by Al-Fatly et al. (2019), and deterioration of speech, as identified in the present study, we were able to derive a fiber-based atlas structure, that could help to avoid SID in essential tremor patients. These findings might contribute to future lead placement and postoperative programming strategies.

BackgroundSubthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in Parkinson's disease (PD). Few studies have investigated the influence of the location of neurostimulation on NMS.ObjectiveTo investigate the impact of active contact location on NMS in STN-DBS in PD.MethodsIn this prospective, open-label, multicenter study including 50 PD patients undergoing bilateral STN-DBS, we collected NMSScale (NMSS), NMSQuestionnaire (NMSQ), Hospital Anxiety and Depression Scale (anxiety/depression, HADS-A/-D), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, motor complications, activities of daily living (ADL), and levodopa equivalent daily dose (LEDD) preoperatively and at 6 months follow-up. Changes were analyzed with Wilcoxon signed-rank/t-test and Bonferroni-correction for multiple comparisons. Although the STN was targeted visually, we employed an atlas-based approach to explore the relationship between active contact locations and DBS outcomes. Based on fused MRI/CT-images, we identified Cartesian coordinates of active contacts with patient-specific Mai-atlas standardization. We computed linear mixed-effects models with x-/y-/z-coordinates as independent, hemispheres as within-subject, and test change scores as dependent variables.ResultsNMSS, NMSQ, PDQ-8, motor examination, complications, and LEDD significantly improved at follow-up. Linear mixed-effect models showed that NMS and QoL improvement significantly depended on more medial (HADS-D, NMSS), anterior (HADS-D, NMSQ, PDQ-8), and ventral (HADS-A/-D, NMSS, PDQ-8) neurostimulation. ADL improved more in posterior, LEDD in lateral neurostimulation locations. No relationship was observed for motor examination and complications scores.ConclusionsOur study provides evidence that more anterior, medial, and ventral STN-DBS is significantly related to more beneficial non-motor outcomes.