Cognitive and psychiatric outcomes in the GALAXY trial: effect of anaesthesia in deep brain stimulation.

BACKGROUND: This study aims: (1) To compare cognitive and psychiatric outcomes after bilateral awake versus asleep subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson's disease (PD). (2) To explore the occurrence of psychiatric diagnoses, cognitive impairment and quality of life after surgery in our whole sample. (3) To validate whether we can predict postoperative cognitive decline. METHODS: 110 patients with PD were randomised to receive awake (n=56) or asleep (n=54) STN DBS surgery. At baseline and 6-month follow-up, all patients underwent standardised assessments testing several cognitive domains, psychiatric symptoms and quality of life. RESULTS: There were no differences on neuropsychological composite scores and psychiatric symptoms between the groups, but we found small differences on individual tests and cognitive domains. The asleep group performed better on the Rey Auditory Verbal Learning Test delayed memory test (f=4.2, p=0.04), while the awake group improved on the Rivermead Behavioural Memory Test delayed memory test. (f=4.4, p=0.04). The Stroop III score was worse for the awake group (f=5.5, p=0.02). Worse scores were present for Stroop I (Stroop word card) (f=6.3, p=0.01), Stroop II (Stroop color card) (f=46.4, p<0.001), Stroop III (Stroop color-word card) (f=10.8, p=0.001) and Trailmaking B/A (f=4.5, p=0.04). Improvements were seen on quality of life: Parkinson's Disease Questionnaire-39 (f=24.8, p<0.001), and psychiatric scales: Hamilton Depression Rating Scale (f=6.2, p=0.01), and Hamilton Anxiety Rating Scale (f=5.5, p=0.02). CONCLUSIONS: This study suggests that the choice between awake and asleep STN DBS does not affect cognitive, mood and behavioural adverse effects, despite a minor difference in memory. STN DBS has a beneficial effect on quality of life, mood and anxiety symptoms. TRIAL REGISTRATION NUMBER: NTR5809.

Directional versus ring-mode deep brain stimulation for Parkinson's disease: protocol of a multi-centre double-blind randomised crossover trial.

BACKGROUND: The effectiveness of Deep Brain Stimulation (DBS) therapy for Parkinson's disease can be limited by side-effects caused by electrical current spillover into structures adjacent to the target area. The objective of the STEEred versus RING-mode DBS for Parkinson's disease (STEERING) study is to investigate if directional DBS for Parkinson's disease results in a better clinical outcome when compared to ring-mode DBS. METHODS: The STEERING study is a prospective multi-centre double-blind randomised crossover trial. Inclusion criteria are Parkinson's disease, subthalamic nucleus DBS in a 'classic' ring-mode setting for a minimum of six months, and optimal ring-mode settings have been established. Participants are categorised into one of two subgroups according to their clinical response to the ring-mode settings as 'responders' (i.e., patient with a satisfactory effect of ring-mode DBS) or 'non-responder' (i.e., patient with a non-satisfactory effect of ring-mode DBS). A total of 64 responders and 38 non-responders will be included (total 102 patients). After an optimisation period in which an optimal directional setting is found, participants are randomised to first receive ring-mode DBS for 56 days (range 28-66) followed by directional DBS for 56 days (28-66) or vice-versa. The primary outcome is the difference between ring-mode DBS and directional DBS settings on the Movement Disorders Society Unified Parkinson's Disease Rating Scale - Motor Evaluation (MDS-UPDRS-ME) in the off-medication state. Secondary outcome measures consist of MDS-UPDRS-ME in the on-medication state, MDS-UPDRS Activities of Daily Living, MDS-UPDRS Motor Complications-Dyskinesia, disease related quality of life measured with the Parkinson's Disease Questionnaire 39, stimulation-induced side-effects, antiparkinsonian medication use, and DBS-parameters. Participants' therapy preference is measured at the end of the study. Outcomes will be analysed for both responder and non-responder groups, as well as for both groups pooled together. DISCUSSION: The STEERING trial will provide insights into whether or not directional DBS should be standardly used in all Parkinson's disease DBS patients or if directional DBS should only be used in a case-based approach. TRIAL REGISTRATION: This trial was registered on the Netherlands Trial Register, as trial NL6508 ( NTR6696 ) on June 23, 2017.

Tractography-based versus anatomical landmark-based targeting in vALIC deep brain stimulation for refractory obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD). Retrospective evaluation showed that stimulation closer to the supero-lateral branch of the medial forebrain bundle (slMFB), within the vALIC, was associated with better response to DBS. The present study is the first to compare outcomes of DBS targeted at the vALIC using anatomical landmarks and DBS with connectomic tractography-based targeting of the slMFB. We included 20 OCD-patients with anatomical landmark-based DBS of the vALIC that were propensity score matched to 20 patients with tractography-based targeting of electrodes in the slMFB. After one year, we compared severity of OCD, anxiety and depression symptoms, response rates, time to response, number of parameter adjustments, average current, medication usage and stimulation-related adverse effects. There was no difference in Y-BOCS decrease between patients with anatomical landmark-based and tractography-based DBS. Nine (45%) patients with anatomical landmark-based DBS and 13 (65%) patients with tractography-based DBS were responders (BF10 = 1.24). The course of depression and anxiety symptoms, time to response, number of stimulation adjustments or medication usage did not differ between groups. Patients with tractography-based DBS experienced fewer stimulation-related adverse effects than patients with anatomical landmark-based DBS (38 vs 58 transient and 1 vs. 17 lasting adverse effects; BF10 = 14.968). OCD symptoms in patients with anatomical landmark-based DBS of the vALIC and tractography-based DBS of the slMFB decrease equally, but patients with tractography-based DBS experience less adverse effects.

Predicting Response to vALIC Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder.

Background: Deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) is effective in half of patients, but also is invasive and labor-intensive.Objective: Selecting probable responders beforehand would more optimally allocate treatment resources and prevent patients' disappointment. Some centers use clinical and demographic predictors to exclude patients from DBS treatment, but the evidence base remains uncertain.Methods: This observational cohort study examined the association of baseline demographic and disease characteristics with a 1-year prospective course of OCD and depressive symptoms in a cohort of 70 consecutive patients who received DBS of the ventral anterior limb of the internal capsule (vALIC-DBS) for OCD according to DSM-IV or DSM-5 criteria between April 2005 and October 2017. Baseline characteristics and symptom decrease were analyzed using Fisher exact tests and binary logistic regression to examine whether they could predict individual response (> 35% reduction in Yale-Brown Obsessive Compulsive Scale score and 50% reduction in Hamilton Depression Rating Scale score, respectively).Results: Insight into illness was the only significant predictor of individual response, with a positive predictive value of 84.4%, while the negative predictive value was 44.0% (b = 0.247, χ21 = 5.259, P = .022). Late-onset OCD was associated with more symptom decrease (ß = -0.29; 95% CI, -0.53 to -0.04; P = .023) and comorbid personality disorder with less symptom decrease over time (ß = 0.88; 95% CI -0.29 to 1.47; P = .004), but they could not significantly predict vALIC-DBS response. A later age at onset, comorbid personality disorder, and insight into illness were associated with clinical outcomes after vALIC-DBS, but predictive values were not large enough to facilitate clinical patient selection.Conclusions: Clinical and demographic factors cannot yet predict outcome and should not be used to exclude patients from treatment with vALIC-DBS. These first individual prediction analyses for vALIC-DBS response in OCD are important, given that some centers up until now still exclude patients based on clinical characteristics such as comorbid personality disorders.

General Anesthesia vs Local Anesthesia in Microelectrode Recording-Guided Deep-Brain Stimulation for Parkinson Disease: The GALAXY Randomized Clinical Trial.

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.

Deep brain stimulation versus ablative surgery for treatment-refractory obsessive-compulsive disorder: A meta-analysis.

OBJECTIVE: Ablative surgery (ABL) and deep brain stimulation (DBS) are last-resort treatment options for patients suffering from treatment-refractory obsessive-compulsive disorder (OCD). The aim of this study was to conduct an updated meta-analysis comparing the clinical outcomes of the ablative procedures capsulotomy and cingulotomy and deep brain stimulation. METHODS: We conducted a PubMed search to identify all clinical trials on capsulotomy, cingulotomy, and DBS. Random effects meta-analyses were performed on 38 articles with a primary focus on efficacy in reducing OCD symptoms as measured by a reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score and the responder rate (≥35% reduction in Y-BOCS score). RESULTS: With responder rates of 48% and 53% after 12-16 months and 56% and 57% at last follow-up for ABL and DBS, respectively, and large effect sizes in the reduction in Y-BOCS scores, both surgical modalities show effectiveness in treating refractory OCD. Meta-regression did not show a statistically significant difference between ABL and DBS regarding these outcomes. Regarding adverse events, a statistically significant higher rate of impulsivity is reported in studies on DBS. CONCLUSION: This meta-analysis shows equal efficacy of ABL and DBS in the treatment of refractory OCD. For now, the choice of intervention should, therefore, rely on factors such as risk of developing impulsivity, patient preferences, and experiences of psychiatrist and neurosurgeon. Future research should provide more insight regarding differences between ABL and DBS and response prediction following direct comparisons between the surgical modalities, to enable personalized and legitimate choices between ABL and DBS.

Relative Contribution of Magnetic Resonance Imaging, Microelectrode Recordings, and Awake Test Stimulation in Final Lead Placement during Deep Brain Stimulation Surgery of the Subthalamic Nucleus in Parkinson's Disease.

INTRODUCTION: For deep brain stimulation (DBS) surgery of the subthalamic nucleus (STN) in Parkinson's disease (PD), many centers employ visualization of the nucleus on magnetic resonance imaging (MRI), intraoperative microelectrode recordings (MER), and test stimulation in awake patients. The value of these steps is a subject for ongoing debate. In the current study, we determined the relative contribution of MRI targeting, multitrack MER, and awake test stimulation in final lead placement during STN DBS surgery for PD. METHODS: Data on PD patients undergoing MRI-targeted STN DBS surgery with three-channel MER and awake test stimulation between February 2010 and January 2014 were analyzed to determine in which MER trajectory final leads were implanted and why this tract was chosen. RESULTS: Seventy-six patients underwent implantation of 146 DBS leads. In 92% of the STN, the final leads were implanted in one of the three planned channels. In 6%, additional channels were needed. In 2%, surgery was aborted before final lead implantation due to anxiety or fatigue. The final leads were implanted in the channels with the longest STN MER signal trajectory in 60% of the STN (38% of the bilaterally implanted patients). This was the central channel containing the MRI target in 39% of the STN (18% bilaterally). The most frequently noted reasons why another channel than the central channel was chosen for final lead placement were (1) a lower threshold for side effects (54%) and (2) no or a too short trajectory of the STN MER signal (40%) in the central channel. The latter reason correlated with larger 2D (x and y) errors in our stereotactic method. CONCLUSIONS: STN DBS leads were often not implanted in the MRI-planned trajectory or in the trajectory with the longest STN MER signal. Thresholds for side effects during awake test stimulation were decisive for final target selection in the majority of patients.

Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression.

OBJECTIVE: Deep brain stimulation (DBS) reduces depressive symptoms in approximately 40%-60% of patients with treatment-resistant depression (TRD), but data on long-term efficacy and safety are scarce. Our objective was to assess the efficacy and safety of DBS targeted at the ventral anterior limb of the internal capsule (vALIC) in 25 patients with TRD during a 1-year, open-label, maintenance period, which followed a 1-year optimisation period. METHODS: Depression severity was measured using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Montgomery-Asberg Depression Rating Scale (MADRS) and self-reported Inventory of Depressive Symptomatology (IDS-SR). Primary outcomes were response rate (≥50% HAM-D-17 score reduction) after the maintenance phase, approximately 2 years after DBS surgery, and changes in depression scores and occurrence of adverse events during the maintenance phase. RESULTS: Of 25 operated patients, 21 entered and 18 completed the maintenance phase. After the maintenance phase, eight patients were classified as responder (observed response rate: 44.4%; intention-to-treat: 32.0%). During the maintenance phase, HAM-D-17 and MADRS scores did not change, but the mean IDS-SR score decreased from 38.8 (95% CI 31.2 to 46.5) to 35.0 (95% CI 26.1 to 43.8) (p=0.008). Non-responders after optimisation did not improve during the maintenance phase. Four non-DBS-related serious adverse events occurred, including one suicide attempt. CONCLUSIONS: vALIC DBS for TRD showed continued efficacy 2 years after surgery, with symptoms remaining stable after optimisation as rated by clinicians and with patient ratings improving. This supports DBS as a viable treatment option for patients with TRD. TRIAL REGISTRATION NUMBER: NTR2118.

Substituting the Target After Unsatisfactory Outcome of Deep Brain Stimulation in Advanced Parkinson's Disease: Cases From the NSTAPS Trial and Systematic Review of the Literature.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are established treatment option in Parkinson's disease (PD). If DBS does not provide the desired effect, re-operation to the alternative target is a treatment option, but data on the effect of re-operation are scarce. OBJECTIVES: The objective of this study is to evaluate the clinical effect of re-operation the alternative target after failure of initial STN or GPi DBS for Parkinson's disease. MATERIALS AND METHODS: We descriptively analyzed the baseline characteristics, the effect of initial surgery and re-operation of eight NSTAPS (Netherlands SubThalamic and Pallidal Stimulation) patients and six previously published cases that underwent re-operation to a different target. RESULTS: In the NSTAPS cohort, two of the eight patients showed more than 30% improvement of off-drug motor symptoms after re-operation. The initial DBS leads of these patients were off target. In the cases from the literature, 30% off-drug motor improvement was seen in all three patients re-operated from GPi to STN and none of the three patients re-operated from STN to GPi. Only one of the three cases from the literature where any improvement was seen with the operation had a confirmed on target lead location after the first surgery, while the other two patients did not undergo post-operative imaging after the first surgery. CONCLUSIONS: Re-operation to a different target due to lack of effect appears to have a limited chance of leading to objective improvement if the leads were correctly placed during initial surgery.