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Objectives: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) has an ambiguous relation to speech. Speech impairment can be a stimulation-induced side effect, and parkinsonian dysarthria can improve with STN-DBS. Owing to the lack of an up-to-date and evidence-based approach, DBS reprogramming for speech impairment is largely blind and greatly relies on the physician's experience. In this study, we aimed to establish an evidence- and experience-based algorithm for managing speech impairment in patients with PD treated with STN-DBS., Materials and Methods: We performed a single-center retrospective study to identify patients with STN-DBS and speech impairment. Onset of speech impairment, lead localization, and assessment of DBS-induced nature of speech impairment were collected. When DBS settings were adjusted for improving speech, the magnitude and duration of effect were collected. We also performed a systematic literature review to identify studies describing the effects of parameter adjustments aimed at improving speech impairment in patients with PD receiving STN-DBS., Results: In the retrospective study, 245 of 631 patients (38.8%) with STN-DBS had significant speech impairment. The probability of sustained marked improvement upon reprogramming was generally low (27.9%). In the systematic review, 23 of 662 identified studies were included. Only two randomized controlled trials have been performed, providing evidence for interleaving-interlink stimulation only. Considerable methodologic heterogeneity precluded the conduction of a meta-analysis., Conclusions: Speech impairment in STN-DBS for PD is frequent, but high-quality evidence regarding DBS parameter adjustments is scarce, and the probability of sustained improvement is low. To improve this outcome, we propose an evidence- and experience-based approach to address speech impairment in STN-DBS that can be used in clinical practice., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

There is a growing interest in deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) as a potential therapeutic modality for Parkinson's disease dementia (PDD). Low-frequency stimulation has yielded encouraging results in individual patients; however, these are not yet sustained in larger studies. With the aim to expand the understanding of NBM-DBS, we share our experience with serendipitous NBM-DBS in patients treated with DBS of the internal Globus pallidus (GPi) for Parkinson's disease. Since NBM is anatomically located ventral to GPi, several GPi-treated patients appeared to have the distal contact of DBS-electrode(s) positioned in the NBM. We hypothesized that unintentional high-frequency NBM-DBS over a period of one year would result in the opposite effect of low-frequency NBM-stimulation and cause cognitive decline. We studied a cohort of 33 patients with bilateral high-frequency DBS in the GPi for Parkinson's disease, of which twelve were unintentionally co-stimulated in NBM. The subgroups of unintentional unilateral ( N = 7) and bilateral NBM-DBS ( N = 5) were compared to the control group of bilateral GPi-DBS ( N = 11). Here, we show that unintentional high-frequency NBM-DBS did not cause a significantly faster decline in cognitive function. Further research is warranted for characterizing the therapeutic role of NBM-DBS.

Importance: It is unknown if there is a difference in outcome in asleep vs awake deep brain stimulation (DBS) of the subthalamic nucleus for advanced Parkinson disease., Objective: To determine the difference in adverse effects concerning cognition, mood, and behavior between awake and asleep DBS favoring the asleep arm of the study., Design, Setting, and Participants: This study was a single-center prospective randomized open-label blinded end point clinical trial. A total of 187 persons with Parkinson disease were referred for DBS between May 2015 to March 2019. Analysis took place from January 2016 to January 2020. The primary outcome follow-up visit was conducted 6 months after DBS., Interventions: Bilateral subthalamic nucleus DBS was performed while the patient was asleep (under general anesthesia) in 1 study arm and awake in the other study arm. Both arms of the study used a frame-based intraoperative microelectrode recording technique to refine final target placement of the DBS lead., Main Outcomes and Measures: The primary outcome variable was the between-group difference in cognitive, mood, and behavioral adverse effects as measured by a composite score. The secondary outcomes included the Movement Disorders Society Unified Parkinson's Disease Rating Scale, the patient assessment of surgical burden and operative time., Results: A total of 110 patients were randomized to awake (local anesthesia; n = 56; mean [SD] age, 60.0 (7.4) years; 40 [71%] male) or to asleep (general anesthesia; n = 54; mean [SD] age, 61.3 [7.9] years; 38 [70%] male) DBS surgery. The 6-month follow-up visit was completed by 103 participants. The proportion of patients with adverse cognitive, mood, and behavioral effects on the composite score was 15 of 52 (29%) after awake and 11 of 51 (22%) after asleep DBS (odds ratio, 0.7 [95% CI, 0.3-1.7]). There was no difference in improvement in the off-medication Movement Disorders Society Unified Parkinson's Disease Rating Scale Motor Examination scores between groups (awake group: mean [SD], -27.3 [17.5] points; asleep group: mean [SD], -25.3 [14.3] points; mean difference, -2.0 [95% CI, -8.1 to 4.2]). Asleep surgery was experienced as less burdensome by patients and was 26 minutes shorter than awake surgery., Conclusions and Relevance: There was no difference in the primary outcome of asleep vs awake DBS. Future large randomized clinical trials should examine some of the newer asleep based DBS technologies because this study was limited to frame-based microelectrode-guided procedures., Trial Registration: trialregister.nl Identifier: NTR5809.

In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents., (© The Author(s) 2016.)

Background: Effects on non-motor symptoms, mainly cognitive and psychiatric side effects, could influence the decision for either globus pallidus pars interna (GPi) or subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD)., Objective: 1) To compare cognitive and psychiatric outcomes 3 years after GPi DBS versus STN DBS, and 2) to report on occurrence of suicidal ideation, psychiatric diagnoses, social functioning, and marital satisfaction 3 years after DBS., Methods: Patients were randomized to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized assessments were performed at baseline, 1 year, and 3 years. We used linear mixed model analyses to investigate between-group differences on the Mattis Dementia Rating Scale (MDRS), neuropsychological tests, and psychiatric questionnaires 3 years after DBS., Results: Eighty-seven patients (68%) completed at least one neuropsychological test after 3 years. No significant between-group differences were found on the MDRS (p = 0.61), neuropsychological tests (p-values between 0.17 and 0.87), and psychiatric questionnaires (p-values between 0.23 and 0.88) 3 years after DBS. The Mini International Neuropsychiatric Interview did not indicate a substantial number of psychiatric diagnoses after 3 years. Social functioning and marital satisfaction were comparable in both groups., Conclusions: Three years after GPi DBS and STN DBS no pronounced between-group differences on measures of cognitive and psychiatric functioning could be demonstrated. Overall, cognitive and psychiatric outcome 3 years after DBS do not provide a clear direction for clinicians when considering which of these two surgical targets to choose., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease (PD)., Methods: We randomly assigned patients to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized psychiatric and social questionnaires were assessed at baseline and after 12 months., Results: No differences were found between GPi DBS and STN DBS on psychiatric evaluation. Within-group comparisons showed small but statistically significant changes on several measures in both groups. Descriptive statistics indicated slight changes in social functioning. Marital satisfaction of patients and partners remained relatively stable after GPi and STN DBS., Conclusions: We found neither differences in psychiatric and social outcome between GPi DBS and STN DBS nor any relevant within-group differences. The decision for GPi DBS or STN DBS cannot be based on expected psychiatric or social effects., (© 2015 International Parkinson and Movement Disorder Society.)

Objective: To compare motor symptoms, cognition, mood, and behavior 3 years after deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) in advanced Parkinson disease (PD)., Methods: Patients with PD eligible for DBS were randomized to bilateral GPi DBS and bilateral STN DBS (1:1). The primary outcome measures were (1) improvement in motor symptoms in off-drug phase measured with the Unified Parkinson Disease Rating Scale (UPDRS) and (2) a composite score for cognitive, mood, and behavioral effects, and inability to complete follow-up at 36 months after surgery., Results: Of the 128 patients enrolled, 90 were able to complete the 3-year follow-up. We found significantly more improvement of motor symptoms after STN DBS (median [interquartile range (IQR)] at 3 years, GPi 33 [23-41], STN 28 [20-36], p = 0.04). No between-group differences were observed on the composite score (GPi 83%, STN 86%). Secondary outcomes showed larger improvement in off-drug functioning in the AMC Linear Disability Scale score after STN DBS (mean ± SD, GPi 65.2 ± 20.1, STN 72.6 ± 18.0, p = 0.05). Medication was reduced more after STN DBS (median levodopa equivalent dose [IQR] at 3 years, GPi 1,060 [657-1,860], STN 605 [411-875], p < 0.001). No differences in adverse effects were recorded, apart from more reoperations to a different target after GPi DBS (GPi n = 8, STN n = 1)., Conclusions: Off-drug phase motor symptoms and functioning improve more after STN DBS than after GPi DBS. No between-group differences were observed on a composite score for cognition, mood, and behavior, and the inability to participate in follow-up., Classification of Evidence: This study provides Class II evidence that STN DBS provides more off-phase motor improvement than GPi DBS, but with a similar risk for cognitive, mood, and behavioral complications., (© 2016 American Academy of Neurology.)

Objective: To assess the neuropsychological outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN) for advanced Parkinson disease., Methods: We randomly assigned patients to receive either GPi DBS or STN DBS. Standardized neuropsychological tests were performed at baseline and after 12 months. Patients and study assessors were masked to treatment allocation., Results: Univariate analysis of change scores indicated group differences on Stroop word reading and Stroop color naming (confidence interval [CI] 1.9-10.0 and 2.1-8.8), on Trail Making Test B (CI 0.5-10.3), and on Wechsler Adult Intelligence Scale similarities (CI -0.01 to 1.5), with STN DBS showing greater negative change than GPi DBS. No differences were found between GPi DBS and STN DBS on the other neuropsychological tests. Older age and better semantic fluency at baseline predicted cognitive decline after DBS., Conclusions: We found no clinically significant differences in neuropsychological outcome between GPi DBS and STN DBS. No satisfactory explanation is available for the predictive value of baseline semantic fluency for cognitive decline., Classification of Evidence: This study provides Class I evidence that there is no large difference in neuropsychological outcome between GPi DBS and STN DBS after 12 months. The study lacks the precision to exclude a moderate difference in outcomes., (© 2015 American Academy of Neurology.)

Background: Patients with advanced Parkinson's disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS., Methods: We recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinson's disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074., Findings: Between Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinson's disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups., Interpretation: Although there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinson's disease., Funding: Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterised by tremor, rigidity and bradykinesia. The current treatment, for example with levodopa or dopamine-agonists, is complicated by response fluctuations, dyskinesias and gastro-intestinal side-effects. These, and various other reasons including fear of levodopa toxicity, have led to reluctance in starting medical treatment in PD. Especially during the last decade it has become clear that there is no scientific substrate for this reluctance. The aim should be to minimize the restraints in daily activity caused by PD, where medications including levodopa and dopamine-agonists have proven to be effective.