Effects of subthalamic nucleus deep brain stimulation on emotional working memory capacity and mood in patients with Parkinson's disease

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

Long-term effects of pallidal deep brain stimulation in tardive dystonia: a follow-up of 5–14 years

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

Deep brain stimulation for Parkinson’s disease–related postural abnormalities: a systematic review and meta-analysis

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

Long-term effects of bilateral pallidal deep brain stimulation in dystonia: a follow-up between 8 and 16 years

Objective: Observational study to evaluate the long-term motor and non-motor effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) on medically refractory dystonia. Background: Dystonia is a chronic disease affecting mainly young patients with a regular life expectancy and lifelong need for therapy. Pallidal DBS is an established treatment for severe isolated dystonia but long-term data are sparse. Methods: We considered 36 consecutive patients with isolated generalized (n = 14) and cervical/segmental (n = 22) dystonia operated at Charité-University Hospital between 2000 and 2007 in a retrospective analysis for long-term outcome of pallidal DBS. In 19 of these patients, we could analyze dystonic symptoms and disability rated by the Burke–Fahn–Marsden Dystonia Rating scale (BFMDRS) at baseline, short-term (ST-FU, range 3–36 months) and long-term follow-up (LT-FU, range 93–197 months). Quality of life and mood were evaluated using the SF36 and Beck Depression Index (BDI) questionnaires. Results: Patients reached an improvement in motor symptoms of 63.8 ± 5.7% (mean ± SE) at ST-FU and 67.9 ± 6.1% at LT-FU. Moreover, a significant and stable reduction in disability was shown following DBS (54.2 ± 9.4% at ST-FU and 53.8 ± 9.2% at LT-FU). BDI and SF36 had improved by 40% and 23%, respectively, at LT-FU (n = 14). Stimulation-induced adverse events included swallowing difficulties, dysarthria, and bradykinesia. Pulse generator (n = 3) and electrodes (n = 5) were revised in seven patients due to infection. Conclusions: Pallidal DBS is a safe and efficacious long-term treatment for dystonia with sustained effects on motor impairment and disability, accompanied by a robust improvement in mood and quality of life

Long‐term effects of pallidal and thalamic deep brain stimulation in myoclonus dystonia

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

Subthalamic beta band suppression reflects effective neuromodulation in chronic recordings

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

Nucleus basalis of Meynert predicts cognition after deep brain stimulation in Parkinson's disease

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

Reinforcement magnitudes modulate subthalamic beta band activity in patients with Parkinson's disease

We set out to investigate whether beta oscillations in the human basal ganglia are modulated during reinforcement learning. Based on previous research, we assumed that beta activity might either reflect the magnitudes of individuals' received reinforcements (reinforcement hypothesis), their reinforcement prediction errors (dopamine hypothesis) or their tendencies to repeat versus adapt responses based upon reinforcements (status-quo hypothesis). We tested these hypotheses by recording local field potentials (LFPs) from the subthalamic nuclei of 19 Parkinson's disease patients engaged in a reinforcement-learning paradigm. We then correlated patients' reinforcement magnitudes, reinforcement prediction errors and response repetition tendencies with task-related power changes in their LFP oscillations. During feedback presentation, activity in the frequency range of 14 to 27 Hz (beta spectrum) correlated positively with reinforcement magnitudes. During responding, alpha and low beta activity (6 to 18 Hz) was negatively correlated with previous reinforcement magnitudes. Reinforcement prediction errors and response repetition tendencies did not correlate significantly with LFP oscillations. These results suggest that alpha and beta oscillations during reinforcement learning reflect patients' observed reinforcement magnitudes, rather than their reinforcement prediction errors or their tendencies to repeat versus adapt their responses, arguing both against an involvement of phasic dopamine and against applicability of the status-quo theory

Dopamine-dependent scaling of subthalamic gamma bursts with movement velocity in patients with Parkinson’s disease

Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson’s disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson’s disease

3D-surface reconstruction of cellular cryo-soft X-ray microscopy tomograms using semi-supervised deep learning

Cryo-soft X-ray tomography (cryo-SXT) is a powerful method to investigate the ultrastructure of cells, offering resolution in the tens of nm range and strong contrast for membranous structures without requirement for labeling or chemical fixation. The short acquisition time and the relatively large volumes acquired allow for fast acquisition of large amounts of tomographic image data. Segmentation of these data into accessible features is a necessary step in gaining biologically relevant information from cryo-soft X-ray tomograms. However, manual image segmentation still requires several orders of magnitude more time than data acquisition. To address this challenge, we have here developed an end-to-end automated 3D-segmentation pipeline based on semi-supervised deep learning. Our approach is suitable for high-throughput analysis of large amounts of tomographic data, while being robust when faced with limited manual annotations and variations in the tomographic conditions. We validate our approach by extracting three-dimensional information on cellular ultrastructure and by quantifying nanoscopic morphological parameters of filopodia in mammalian cells