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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.

Purpose There is a high demand on spinal surgery in patients with Parkinson’s disease (PD) but the results are sobering. Although detailed clinical and radiological diagnostics were carried out with great effort and expense, the biodynamic properties of the spine of PD patients have never been considered. We propose a noninvasive method to quantify the impairment of motion abilities in patients with PD. Methods We present an analytical cross-sectional study of 21 patients with severe PD. All patients underwent a biodynamic assessment during a standardized movement-choreography. Thus, individual spinal motion profiles of each patient were objectively assessed and compared with a large comparative cohort of individuals without PD. Moreover, clinical scores to quantify motor function and lumbar back pain were collected and X-ray scans of the spine in standing position were taken and analysed. Results Biodynamic measurement showed that 36.9% of the assessed motions of all PD patients were severely impaired. Men were generally more functionally impaired than women, in 52% of all motion parameters. The neurological and radiological diagnostics recorded pathological values, of which UPDRS-III ON correlated with findings of the biodynamics assessment (R = 0.52, p = 0.02). Conclusions The decision to operate on a PD patient’s spine is far-reaching and requires careful consideration. Neurological and radiological scores did not correlate with the biodynamics of the spine. The resulting motion profile could be used as individual predictive factor to estimate whether patients are eligible for spinal surgery or alternative therapies.

Deep brain stimulation (DBS) has become a well-established treatment modality for Parkinson’s disease (PD), especially regarding motor fluctuations, dyskinesias, and tremor. Although postural abnormalities (i.e., Camptocormia [CC] and Pisa syndrome [Pisa]) are known to be a major symptom of PD as well, the influence of DBS on postural abnormalities is unclear. The objective of this study is to analyze the existing literature regarding DBS for PD-associated postural abnormalities in a systematic review and meta-analysis. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review and meta-analysis of 18 studies that reported the effect of DBS regarding postural abnormalities. After screening of 53 studies, a total of 98 patients (44 female, 53 males, 1 not reported; mean age: 62.3, range 30–83 years) with postural abnormalities (CC n = 98; Pisa n = 11) were analyzed from 18 included studies. Of those patients, 94.9% underwent STN-DBS and 5.1% had GPi as DBS target area. A positive outcome was reported for 67.8% with CC and 72.2% with Pisa. In the meta-analysis, younger age and lower pre-operative UPDRS-III (ON/OFF) were found as positive predictive factors for a positive effect of DBS. DBS might be a potentially effective treatment option for PD-associated postural abnormalities. However, the level of evidence is rather low, and definition of postoperative outcome is heterogenous between studies. Therefore larger, prospective trials are necessary to give a clear recommendation.

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.

Subthalamic nucleus (STN) beta (13 - 35 Hz) activity is a biomarker reflecting motor state in Parkinson's disease (PD). Adaptive deep brain stimulation (DBS) aims to use beta activity for therapeutic adjustments, but many aspects of beta activity in real-life situations are unknown.The aim was to investigate Christmas-related influences on beta activity in PD.Differences in Christmas Day to nonfestive daily averages in chronic biomarker recordings in 4 PD patients with a sensing-enabled STN DBS implant were retrospectively analyzed. Sweet-spot and whole-brain network connectomic analyses were performed.Beta activity was significantly reduced on Christmas Eve in all patients (4.00-9.00 p.m.: -12.30 ± 10.78%, P = 0.015). A sweet spot in the dorsolateral STN connected recording sites to motor, premotor, and supplementary motor cortices.We demonstrate that festive events can reduce beta biomarker activity. We conclude that circadian and holiday-related changes should be considered when tailoring adaptive DBS algorithms to patient demands. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction and goal The investigation of gender differences in treatment response is crucial for effective personalized therapies. With only 30%, women are underrepresented in trials for deep brain stimulation (DBS) in Parkinson’s disease (PD). It is therefore important to evaluate gender-specific outcomes of DBS in PD in order to improve therapeutic counseling. Methods We analyzed clinical outcome parameters of 203 patients with PD that underwent DBS surgery targeting the subthalamic nucleus (STN) at our movement disorder center. A total of 27.6% of patients were female and 72.4% male. Motor and non-motor scores were compared before and 1 year after DBS surgery (1y FU) using Wilcoxon signed-rank tests and gender specific outcomes were analyzed with chi-square tests. Results At 1y FU, we found significant improvement in UPDRS II, UPDRS III (35.78 ± 36.14% MedOFF vs. StimON-MedOFF), UPDRS IV, depression (BDI-II), and health-related disability as (ADL) that showed no gender-specific differences. No significant change was revealed for UPDRS I, QUIP, and DemTect for the entire cohort. However, when analyzing both groups separately, only women improved in general cognition (plus 1.26 ± 3.03 DemTect points, p = 0.014*), whereas only men ameliorated in depression (minus 1.97 ± 6.92 BDI-II points, p = 0.002**) and impulsivity (minus 2.80 ± 7.27 QUIP points, p = 0.004**). Chi-square tests, however, revealed no significant differences between genders. Conclusion and outlook STN-DBS is a highly effective treatment for motor and non-motor symptoms of PD for both women and men but our study hints towards gender-specific outcomes in non-motor-domains like cognition, depressive symptoms, and impulsivity. To explore this in more detail, larger cohorts need to be investigated in multicenter trials.

The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone.This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments.STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months.Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III.At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background and purpose: Biomarkers for future adaptive deep brain stimulation still need evaluation in clinical routine. Here, we aimed to assess stimulation-induced modulation of beta-band activity and clinical symptoms in a Parkinson's disease patient during chronic neuronal sensing using a novel implantable pulse generator. Methods: Subthalamic activity was recorded OFF and ON medication during a stepwise increase of stimulation amplitude. Off-line fast fourier transfom -based analysis of beta-band activity was correlated with motor performance rated from blinded videos. Results: The stepwise increase of stimulation amplitude resulted in decreased beta oscillatory activity and improvement of bradykinesia. Mean low beta-band (13-20 Hz) activity correlated significantly with bradykinesia (ρ = 0.662, p < 0.01). Conclusions: Motor improvement is reflected in reduced subthalamic beta-band activity in Parkinson's disease, supporting beta activity as a reliable biomarker. The novel PERCEPT neurostimulator enables chronic neuronal sensing in clinical routine. Our findings pave the way for a personalized precision-medicine approach to neurostimulation.

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.

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.

Current efforts to optimise subthalamic deep brain stimulation in Parkinson's disease patients aim to harness local oscillatory activity in the beta frequency range (13-35 Hz) as a feedback-signal for demand-based adaptive stimulation paradigms. A high prevalence of beta peak activity is prerequisite for this approach to become routine clinical practice. In a large dataset of postoperative rest recordings from 106 patients we quantified occurrence and identified determinants of spectral peaks in the alpha, low and high beta bands. At least one peak in beta band occurred in 92% of patients and 84% of hemispheres off medication, irrespective of demographic parameters, clinical subtype or motor symptom severity. Distance to previously described clinical sweet spot was significantly related both to beta peak occurrence and to spectral power (rho -0.21, p 0.006), particularly in the high beta band. Electrophysiological landscapes of our cohort's dataset in normalised space showed divergent heatmaps for alpha and beta but found similar regions for low and high beta frequency bands. We discuss potential ramifications for clinicians' programming decisions. In summary, this report provides robust evidence that spectral peaks in beta frequency range can be detected in the vast majority of Parkinsonian subthalamic nuclei, increasing confidence in the broad applicability of beta-guided deep brain stimulation.

Background With increasing prevalence of Parkinson's disease (PD), instrumentation surgery of the thoracolumbar spine of PD patients grows in importance. Poor operative results with high rates of revision surgery have been reported. The goal of this study was to compare the biomechanical complications of thoracolumbar instrumentation surgery of patients with and without PD. Methods In a retrospective case-control study, we compared 16 PD patients with a matched cohort of 104 control patients regarding the following postinstrumentation complications: (1) adjacent joint disease, (2) material failure, and (3) material loosening. Also, we compared the spinal bone density, which is the main prognostic criteria for failed instrumentation surgery, between the groups. Results We found the rate of material revision to be significantly higher in PD patients (43.8 vs. 13.5%, p = 0.008, odds ratio (OR) = 5.0). Furthermore, the indications for revision surgery differed between the groups, with more hardware failures in the PD group and more adjacent segment degeneration in the control group. PD patients profited from modern operation techniques (percutaneous instrumentation and CT-navigated screw implantation). Hospitalization was significantly longer for PD patients (20.2 ± 15.1 vs. 14.1 ± 8.9 days, p = 0.03). Conclusion PD patients exhibit challenging biomechanical demands on instrumenting the spine. Besides osteoporosis, especially sagittal imbalance, gait disturbance, and altered muscle tone may be contributive. PD patients may particularly profit from navigated and less invasive surgical techniques.

INTRODUCTION Subthalamic DBS in Parkinson's disease has been associated with cognitive decline in few cases. Volume reduction of the nucleus basalis of Meynert (NBM) seems to precede cognitive impairment in Parkinson's disease. In this retrospective study, we evaluated NBM volume as a predictor of cognitive outcome 1 year after subthalamic DBS. METHODS NBM volumes were calculated from preoperative MRIs using voxel-based morphometry. Cognitive outcome was defined as the relative change of MMSE or DemTect scores from pre-to 1 year postoperatively. A multiple linear regression analysis adjusted for the number of cognitive domains affected in the preoperative neuropsychological testing and UPDRS III was conducted. To account for other variables and potential non-linear effects, an additional machine learning analysis using random forests was applied. RESULTS 55 patients with Parkinson's disease (39 male, age 61.4 ± 7.5 years, disease duration 10.8 ± 4.7 years) who received bilateral subthalamic DBS electrodes at our center were included. Although overall cognition did not change significantly, individual change in cognitive abilities was variable. Cognitive outcome could be predicted based on NBM size (B = 208.98, p = 0.022*) in the regression model (F(3,49) = 2.869; R2 of 0.149; p = 0.046*). Using random forests with more variables, cognitive outcome could also be predicted (average root mean squared error between predicted and true cognitive change 11.28 ± 9.51, p = 0.039*). Also in this model, NBM volume was the most predictive variable. CONCLUSION NBM volume can be used as a simple non-invasive predictor for cognitive outcome after DBS in Parkinson's disease, especially when combined with other clinical parameters that are prognostically relevant.

Correction to: Neurological Sciences (2023)https://doi.org/10.1007/s10072-023-06598-yThe above article was published with error in author names. The correct capturing of the author name “Ana Luísa de Almeida Marcelino” has been updated.The Original article has been corrected.

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.

Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.

Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using 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 between optimal stimulation sites and potential network effects in the two types of dystonia have not been carried out.Here, we retrospectively investigate clinical results following DBS for cervical and generalized dystonia in a multi-center cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce a novel approach to map optimal stimulation sites to anatomical space. Second, we analyse stimulation in context of a detailed pathway model of the subcortex to investigate the modulation of which tracts accounts for optimal clinical improvements. Third, we investigate stimulation in context of a broad-lense whole-brain functional connectome to illustrate potential multisynaptic network effects. Finally, we construct a joint model using local, tract- and network-based effects to explain variance in clinical outcomes in cervical and generalized dystonia.Our results show marked differences in optimal stimulation sites that map to the somatotopic structure of the internal pallidum. We further highlight that modulation of the pallidofugal main axis of the basal ganglia may be optimal for treatment of cervical dystonia, while pallidothalamic bundles account for effects in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in form of connectivity to cerebellum and somatomotor cortex.Our results suggest a multi-level model that could account for effectivity of treatment in cervical and generalized dystonia and could potentially help guide DBS programming and surgery, in the future.

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

Deep brain stimulation of the internal globus pallidus is a highly effective and established therapy for primary generalized and cervical dystonia, but therapeutic success is compromised by a non-responder rate of up to 25%, even in carefully-selected groups. Variability in electrode placement and inappropriate stimulation settings may account for a large proportion of this outcome variability. Here, we present probabilistic mapping data on a large cohort of patients collected from several European centres to resolve the optimal stimulation volume within the pallidal region. A total of 105 dystonia patients with pallidal deep brain stimulation were enrolled and 87 datasets (43 with cervical dystonia and 44 with generalized dystonia) were included into the subsequent 'normative brain' analysis. The average improvement of dystonia motor score was 50.5 ± 30.9% in cervical and 58.2 ± 48.8% in generalized dystonia, while 19.5% of patients did not respond to treatment (

Introduction: Deep brain stimulation (DBS) has been an established surgical procedure in the field of functional neurosurgery for many years. The experimental electrophysiological method of local field potential (LFP) recordings in postsurgically externalized patients has made substantial contributions to the better understanding of pathophysiologies underlying movement disorders. As interest in LFP recordings for the development of improved stimulation strategies increases, this study’s aim was to provide evidence concerning safety of this research method, in a major DBS center. Methods: We retrospectively analyzed incidence and infection characteristics in adult patients who underwent two-staged DBS surgery with temporary externalization of leads in our center between January 2008 and November 2019. We focused on whether patients had participated in LFP recordings, and evaluated incidence of infections at 3 months and 1 year after the surgery based on medical records. Infection rates were compared to major DBS studies and reports focusing on the risk of infection due to externalization of DBS leads. Results were visualized using descriptive statistics. Results: Between January 2008 and November 2019, DBS surgery was performed in 528 patients (389/139 patients in the LFP/non-LFP group), mainly for movement disorders such as Parkinson’s disease (308), dystonia (93), and essential tremor (86). Of the patients, 72.9% participated in LFP recordings. The incidence of infections in the acute postsurgical phase (3 months) was 2.46% and did not differ significantly between the LFP group (1.8%) and the non-LFP group (4.32%). The overall incidence after 1 year amounted to 3.6% (19 patients) with no difference between LFP/non-LFP groups. Incidence rates reported in the literature show a large variety (2.6–10%), and the incidence reported here is within the lower range of reported incidences. Discussion/Conclusion: This study demonstrates that DBS is a surgical procedure with a low risk of infection in a large patient cohort. Importantly, it shows that LFP recordings do not have a significant effect on the incidence of infections in patients with externalization. With a representative cohort of more than 380 patients participating in LFP-recordings, this underlines LFP as a safe method in research and supports further use of this method, for example, for the development of adaptive stimulation protocols.

Objective Observational study to evaluate long-term effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the ventral intermediate thalamic nucleus (VIM) on patients with medically refractory myoclonus dystonia (MD). Background More recently, pallidal as well as thalamic DBS have been applied successfully in MD but long-term data are sparse. Methods We retrospectively analyzed a cohort of seven MD patients with either separate (n = 1, VIM) or combined GPi- DBS and VIM-DBS (n = 6). Myoclonus, dystonia and disability were rated at baseline (BL), short-term (ST-FU) and long-term follow-up (LT-FU) using the United Myoclonus Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Tsui rating scale, respectively. Quality of life (QoL) and mood were evaluated using the SF-36 and Beck Depression Inventory questionnaires, respectively. Results Patients reached a significant reduction of myoclonus at ST-FU (62% ± 7.3%; mean ± SE) and LT-FU (68% ± 3.4%). While overall motor BFMDRS changes were not significant at LT-FU, patients with GPi-DBS alone responded better and predominant cervical dystonia ameliorated significantly up to 54% ± 9.7% at long-term. Mean disability scores significantly improved by 44% ± 11.4% at ST-FU and 58% ± 14.8% at LT-FU. Mood and QoL remained unchanged between 5 and up to 20 years postoperatively. No serious long-lasting stimulation-related adverse events were observed. Conclusions We present a cohort of MD patients with very long follow-up of pallidal and/or thalamic DBS that supports the GPi as the favourable stimulation target in MD with safe and sustaining effects on motor symptoms (myoclonus>dystonia) and disability.

The subthalamic nucleus is part of a global stopping network that also includes the presupplementary motor area and inferior frontal gyrus of the right hemisphere. In Parkinson’s disease, subthalamic deep brain stimulation improves movement initiation and velocity, but its effect on stopping of ongoing movement is unknown. Here, we examine the relation between movement stopping and connectivity of stimulation volumes to the stopping network. Stop and go times were collected in 17 patients with Parkinson’s disease on and off subthalamic stimulation during visually cued initiation and termination of continuous, rotational movements. Deep brain stimulation contacts were localized; the stimulation volume computed and connectivity profiles estimated using an openly available, normative structural connectome. Subthalamic stimulation significantly increased stop times, which correlated with the connectivity of the stimulation volume to presupplementary motor area and inferior frontal gyrus of the right hemisphere. The robustness of this finding was validated using three separate analysis streams: voxel-wise whole-brain connectivity, region of interest connectivity and a tract-centred method. Our study sheds light on the role of the fronto-subthalamic inhibitory triangle in stopping of ongoing movements and may inspire circuit based adaptive stimulation strategies for control of stopping impairment, possibly reflected in stimulation-induced dyskinesia.

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.

Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) not only stimulates focal target structures but also affects distributed brain networks. The impact this network modulation has on non-motor DBS effects is not well-characterized. By focusing on the affective domain, we systematically investigate the impact of electrode placement and associated structural connectivity on changes in depressive symptoms following STN-DBS, which have been reported to improve, worsen, or remain unchanged. Methods: Depressive symptoms before and after STN-DBS surgery were documented in 116 patients with PD from 3 DBS centers (Berlin, Queensland, and Cologne). Based on individual electrode reconstructions, the volumes of tissue activated (VTAs) were estimated and combined with normative connectome data to identify structural connections passing through VTAs. Berlin and Queensland cohorts formed a training and cross-validation dataset used to identify structural connectivity explaining change in depressive symptoms. The Cologne data served as the test-set for which depressive symptom change was predicted. Results: Structural connectivity was linked to depressive symptom change under STN-DBS. An optimal connectivity map trained on the Berlin cohort could predict changes in depressive symptoms in Queensland patients and vice versa. Furthermore, the joint training-set map predicted changes in depressive symptoms in the independent test-set. Worsening of depressive symptoms was associated with left prefrontal connectivity. Interpretation: Fibers connecting the electrode with left prefrontal areas were associated with worsening of depressive symptoms. Our results suggest that for the left STN-DBS lead, placement impacting fibers to left prefrontal areas should be avoided to maximize improvement of depressive symptoms. ANN NEUROL 2020;87:962-975

Introduction Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm. Methods Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn-Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669. Results Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae. Conclusion The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia.

BACKGROUND Deep brain stimulation (DBS) is a well-established therapy for otherwise intractable movement disorders. Thus far, most patients receive nonrechargeable implantable pulse generators (IPG). Eventually, another intervention to replace the IPG is inevitable. OBJECTIVE We assessed IPG model-specific differences in longevity in patients planned for IPG replacement. Also, we evaluated the influence of the total electric energy delivered (TEED), the amount of previous IPG replacements, and previous IPG model changes on the longevity. METHODS We collected the demographic data and DBS settings of 47 patients (19 with Parkinson's disease, 7 with essential tremor, and 21 with dystonia) that were treated either with Medtronic's Kinetra® (N = 16) or Activa® PC (N = 31). Statistical analysis was performed using Mann-Whitney U test and Spearman's rank correlation. RESULTS Battery longevity was shorter in the Activa PC than in the Kinetra (40.16 ± 15.22 vs. 70.35 ± 24.45 months; p

Background Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Short-term results of efficacy in DBS are incongruent and studies investigating long-term effects are warranted. Methods We assessed efficacy of SCG-DBS in eight patients randomized into a delayed-onset group (sham-DBS four weeks) and a non-delayed-onset group. The primary outcome measure was improvement on the Hamilton Depression Rating-Scale (HAMD-24-item-version). Response was defined as HAMD-24 reduction of at least 50% compared to baseline. Assessment was double-blind for a period of eight weeks and after 6,- 12,- 24,- and 28,- months open-label. Results The average improvement in HAMD-24 scores after 6,- 12,- and 24-months were 34%, 25%, and 37%. After 6 months, HAMD-24 revealed a significant difference (P = .022) and 37.5% of the patients were responders. After 12 months, HAMD-24 scores dropped, but no significant difference was observed. After 24 months, a significant improvement was found (P = .041). After the four weeks lasting sham vs. DBS-ON period, there was no group difference (P = .376) in HAMD-24 and patients did not improve during sham stimulation. Patients were followed until 28 months and two up to 4 years under SCG-DBS and average response rate was 51%, whereas two patients were remitters (33,3%). Limitations The small sample size limited the statistical power and external validity. Conclusions Long-term improvement after SCG-DBS revealed a stable effect. There was no significant difference in response rates between the delayed and non-delayed-onset group. DBS for TRD remains experimental and longitudinal investigations of large samples are needed.

Objective: Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease-specific physiomarker was identified that is now used to investigate adaptive closed-loop stimulation in first studies. In dystonia such a physiomarker is missing. Methods: Pallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. This way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlates with clinical improvement. Results: Dystonic symptom severity significantly correlated with theta, but not beta oscillatory amplitudes (ρ=0.4; P=0.009) and interhemispheric coherence (ρ=0.5; P=0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (ρ=0.23; P=0.002), which coincided with three previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long term DBS correlated with theta peak amplitude (ρ=0.38; P=0.018). Interpretation: Our findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed-loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. This article is protected by copyright. All rights reserved.

Angela Merkl,1,2 Eva Röck,1 Tanja Schmitz-Hübsch,1,3 Gerd-Helge Schneider,4 Andrea A Kühn1,3,5 1Department of Neurology, Charité – University Medicine Berlin, Campus Virchow Klinikum, 2Department of Psychiatry and Psychotherapy, Charité – University Medicine Berlin, Campus Benjamin Franklin, 3NeuroCure, Charité – University Medicine Berlin, 4Department of Neurosurgery, Charité – University Medicine Berlin, Campus Virchow Klinikum, 5Berlin School of Mind and Brain, Charité – University Medicine Berlin, Berlin, Germany Background: In Parkinson’s disease (PD), cognitive symptoms and mood changes may be even more distressing for the patient than motor symptoms.Objective: Our aim was to determine the effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on working memory (WM) and mood.Methods: Sixteen patients with PD were assessed with STN-DBS switched on (DBS-ON) and with dopaminergic treatment (Med-ON) compared to switched off (DBS-OFF) and without dopaminergic treatment (Med-OFF). The primary outcome measures were a Visual Analog Mood Scale (VAMS) and an emotional 2-back WM task at 12 months after DBS in the optimal DBS-ON/Med-ON setting compared to DBS-OFF/Med-OFF.Results: Comparison of DBS-OFF/Med-OFF to DBS-ON/Med-ON revealed a significant increase in alertness (meanoff/off =51.59±24.54; meanon/on =72.75; P=0.016) and contentedness (meanoff/off=38.73±24.41; meanon/on=79.01±17.66; P=0.001, n=16), and a trend for reduction in sedation (P=0.060), which was related to stimulation as shown in a subgroup of seven patients. The N-back task revealed a significant increase in accuracy with DBS-ON/Med-ON compared to DBS-OFF/Med-OFF (82.0% vs 76.0%, respectively) (P=0.044), regardless of stimulus valence.Conclusion: In line with previous studies, we found that patients rated themselves subjectively as more alert, content, and less sedated during short-term DBS-ON. Accuracy in the WM task increased with the combination of DBS and medication, possibly related to higher alertness of the patients. Our results add to the currently mixed results described for DBS on WM and suggest that there are no deleterious DBS effects on this specific cognitive domain. Keywords: deep brain stimulation, Parkinson’s disease, working memory, neuropsychiatric&nbsp

In Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) for treatment of Parkinson's Disease (PD), there is a paradigm shift away from focal stimulation of target structures toward effects of stimulation on distributed brain networks. While the relationship between modulated networks and motor outcomes has received much attention, network impact of non-motor DBS effects has been less well characterized. In the affective domain, STN DBS improves depressive symptoms in some patients, while it leads to no change or even symptom-worsening in others. Here, we systematically investigate the impact of electrode placement and associated structural connectivity on changes in depressive symptoms following STN-DBS. Depressive symptoms before and 6 to 12 months after STN-DBS surgery were documented in 116 PD patients from three DBS centers (Berlin, Queensland, Cologne). Individual electrode placements were reconstructed based on preoperative and postoperative imaging using LeadDBS software. Applying a finite element approach the volumes of tissue activated (VTA) were estimated and combined with normative connectome data to identify structural connections passing through VTAs. Berlin and Queensland data (N=80) were used for training and crossvalidation to identify a structural connectivity profile that could explain improvement or worsening of depressive symptoms. The Cologne dataset (n=36) served as test-set for which depressive symptom change was predicted. We identified a robust pattern linking structural connectivity to depressive symptoms under STN-DBS. An optimal connectivity map trained on the Berlin cohort could predict changes in depressive symptoms in Queensland patients (R =0.52, p

Background STN-DBS effectively treats motor symptoms of advanced PD. Nonmotor cognitive symptoms, such as impaired impulse control or decision making, may either improve or worsen with DBS. A potential mediating factor of DBS-induced modulation of cognition is the electrode position within the STN with regard to functional subareas of parallel motor, cognitive, and affective basal ganglia loops. However, to date, the volume of tissue activated and weighted stimulation of STN motor versus nonmotor territories are yet to be linked to differential DBS effects on cognition. Objectives We aim to investigate whether STN-DBS influences risk-reward trade-off decisions and analyze its dependency on electrode placement. Methods Seventeen PD patients ON and OFF STN-DBS and 17 age-matched healthy controls conducted a sequential decision-making task with escalating risk and reward. We computed the effect of STN-DBS on risk-reward trade-off decisions, localized patients' bilateral electrodes, and analyzed the predictive value of volume of tissue activated in STN motor and nonmotor territories on behavioral change. Results We found that STN-DBS not only improves PD motor symptoms, but also normalizes overly risk-averse decision behavior in PD. Intersubject variance in electrode location could explain this behavioral change. Specifically, if STN-DBS activated preferentially STN motor territory, patients' risk-reward trade-off decisions more resembled those of healthy controls. Conclusions Our findings support the notion of convergence of different functional circuits within the STN and imply a positive effect of well-placed STN-DBS on nonmotor cognitive functioning in PD. © 2018 International Parkinson and Movement Disorder Society.

Objective Beta band oscillations in the subthalamic nucleus (STN) have been proposed as a pathophysiological signature in patients with Parkinson's disease (PD). The aim of this study was to investigate the potential association between oscillatory activity in the STN and symptom severity in PD. Methods Subthalamic local field potentials were recorded from 63 PD patients in a dopaminergic OFF state. Power-spectra were analyzed for the frequency range from 5 to 95 Hz and correlated with individual UPDRS-III motor scores in the OFF state. Results A correlation between total UPDRS-III scores and 8 to 35 Hz activity was revealed across all patients (ρ = 0.44, P

Deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (sgACC) has emerged as a new therapeutic option in patients with treatment resistant depression (TRD). At the same time, DBS offers a unique opportunity as an innovative research tool to study brain function in vivo Indirect measures of brain function such as positron-emission-tomography imaging findings have revealed a hypermetabolism in the sgACC area in patients with TRD that normalizes in parallel with treatment response to DBS. We used direct intracranial recordings via implanted DBS electrodes to study the neuronal oscillatory activity in the sgACC area during a picture viewing task including emotional and neutral stimuli in eight patients with TRD who underwent DBS.We found a stimulus-induced decrease in beta-band and increase in gamma-band activity, with a main effect of valence for event-related desynchronisation in the beta-frequency range (14-30 Hz). Unpleasant stimuli induced the strongest and most sustained beta-power decrease. The degree of beta-band modulation upon emotional stimuli correlated with the patients' rating of stimulus valence. Our findings confirm the involvement of the sgACC area in emotional processing that was more enhanced for unpleasant stimuli. Moreover, stimulus evaluation may be encoded by modulations of beta-band activity.

Objectives Recent studies suggest that oscillatory beta activity could be used as a state biomarker in patients with Parkinson's disease for subthalamic closed-loop stimulation with the intention of improving clinical benefit. Here we investigate the feasibility of subthalamic recordings via a novel chronically implanted pulse generator. Methods Subthalamic local field potential recordings were obtained from eight patients before and during deep brain stimulation (DBS). All data were analyzed in the frequency domain using Fourier transform-based methods and compared between ON and OFF stimulation conditions. Results Distinct peaks of oscillatory beta band activity were found in 12 of 15 electrodes. DBS induced a significant frequency specific suppression of oscillatory beta activity (p = 0.002). Conclusion The results of the study suggest that oscillatory beta band synchronization and its modulation by DBS is recordable with a system suitable for chronic implantation and may serve as a biomarker for subthalamic closed-loop stimulation in patients with Parkinson's disease.

Background Deep brain stimulation (DBS) is an approved therapy option for movement disorders such as Parkinson's disease (PD), essential Tremor (ET), and dystonia. While current research focuses on rechargeable implantable pulse generators (IPGs), little is known about changes of the motor functions after IPG replacement and the consequences of additionally implanted hardware. Objective To assess changes of the motor functions, the therapy impedances, and the total electric energy delivered (TEED) after elective IPG replacement. Methods We prospectively acquired the data of 47 patients with PD, ET, and dystonia treated with bilateral DBS. Motor functions were rated prior to and after surgery using the revised Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III), the Fahn-Tolosa-Marin Tremor-Rating-Scale (FTM-TRS), and the Unified Dystonia Rating Scale (UDRS). Furthermore, the therapy impedances and TEED were assessed at the aforementioned times. Results While preoperative motor scores were 48.32 ± 17.16 in PD, 39.71 ± 12.28 in ET, and 18.48 ± 16.30 in dystonia patients, postoperative scores were 47.84 ± 24.33, 32.86 ± 15.82, and 15.02 ± 15.17, respectively. Only in dystonia patients, motor scores significantly differed. Perioperative therapy impedance changes were 142.66 ± 105.35 Ω (Kinetra® to Activa® PC), -68.75 ± 43.05 Ω (Activa® PC to Activa® PC), and - 51.38 ± 38.75 Ω (Activa® PC to Activa® RC). Perioperative TEED changes were - 37.15 ± 38.87 μJ, 2.03 ± 35.91 μJ, and 12.39 ± 6.31 μJ in that first, second, and third group, respectively. Both the therapy impedances and TEED significantly differed between groups. Conclusion Although there were no statistically significant changes in the motor functions of all patients after elective IPG replacement, the therapy impedances were significantly higher and TEED was significantly lower after IPG replacement with concurrent Pocket Adapter implantation.