Spectral Topography of the Subthalamic Nucleus to Inform Next-Generation Deep Brain Stimulation

Background

The landscape of neurophysiological symptoms and behavioral biomarkers in basal ganglia signals for movement disorders is expanding. The clinical translation of sensing-based deep brain stimulation (DBS) also requires a thorough understanding of the anatomical organization of spectral biomarkers within the subthalamic nucleus (STN).

Objectives

The aims were to systematically investigate the spectral topography, including a wide range of sub-bands in STN local field potentials (LFP) of Parkinson's disease (PD) patients, and to evaluate its predictive performance for clinical response to DBS.

Methods

STN-LFPs were recorded from 70 PD patients (130 hemispheres) awake and at rest using multicontact DBS electrodes. A comprehensive spatial characterization, including hot spot localization and focality estimation, was performed for multiple sub-bands (delta, theta, alpha, low-beta, high-beta, low-gamma, high-gamma, and fast-gamma (FG) as well as low- and fast high-frequency oscillations [HFO]) and compared to the clinical hot spot for rigidity response to DBS. A spectral biomarker map was established and used to predict the clinical response to DBS.

Results

The STN shows a heterogeneous topographic distribution of different spectral biomarkers, with the strongest segregation in the inferior-superior axis. Relative to the superiorly localized beta hot spot, HFOs (FG, slow HFO) were localized up to 2 mm more inferiorly. Beta oscillations are spatially more spread compared to other sub-bands. Both the spatial proximity of contacts to the beta hot spot and the distance to higher-frequency hot spots were predictive for the best rigidity response to DBS.

Conclusions

The spatial segregation and properties of spectral biomarkers within the DBS target structure can additionally be informative for the implementation of next-generation sensing-based DBS. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS.Materials and Methods7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments.ResultsA total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson’s Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs.ConclusionThe implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.     

Apathy Induced by Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis

Apathy, the loss of motivation, is a common problem in Parkinson's disease (PD) and often observed following deep brain stimulation (DBS) of the subthalamic nucleus (STN). The aim of this meta-analysis was to determine the occurrence of apathy following STN DBS in literature. Relevant articles were searched in PubMed/Medline, SCOPUS, EMBASE, and Web of Sciences electronic databases. Studies were included if they reported apathy scores pre- and post-DBS or the cross-sectional difference between PD patients receiving STN DBS and patients receiving medication only. Thirty-three articles were included in the meta-analyses from 6,658 screened articles by two authors independently. A total of 1,286 patients were included with a mean age (±standard deviation [SD]) of 58.4 ± 8.5 years and a disease duration of 11.0 ± 5.8 years. The apathy score measured by means of the Apathy Evaluation Scale (AES), Starkstein Apathy Scale (SAS), and the Lille Apathy Rating Scale (LARS) was significantly higher after DBS than pre-operatively (g = 0.34, 95% confidence interval [CI] = 0.19–0.48, P < 0.001). An equal, significant difference in severity of apathy was found between STN DBS and medication only (g = 0.36, 95% CI = 0.03–0.65; P = 0.004). Statistical heterogeneity was moderately high, but the effects stood strong after multiple analyses and were independent of tapering off dopaminergic medication. The findings of this meta-analysis indicate that apathy is increased after STN DBS compared to the pre-operative state and to medication only (systematic review registration number: PROSPERO CRD42019133932). © 2020 Universiteit van Amsterdam. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

帕金森病病人脑深部电刺激器刺激参数调节策略

目的探讨帕金森（Parkinson disease，PD）病人脑深部电刺激器（brain deep stimulation,DBS）刺激参数调节的策略。方法回顾性分析82例（共141侧）PD病人的临床资料，均采用微电极记录下丘脑底核（subthalamic nucleus，STN）电刺激术治疗，双侧手术59例，单侧手术23例。采用微电极记录手术靶点区域细胞外放电信号并计算STN核团长度，术后复查MRI了解电极位置，估算出每个触点相对于STN的位置关系。每个触点采用相同刺激参数，单极刺激观察评估病人症状改善情况。刺激参数从低到高，直至病人出现副反应。选取病人最佳改善状态且副作用最小时电压值，进行4个触点比较，取最小值的触点为刺激靶点。调节并记录病人6个月、12个月和24个月所用电压、脉宽和频率大小。结果术后6个月刺激电压（2．9±0．8）V，术后12个月（3．0±0．4）V，术后24个月（3．0±0.7）V。刺激脉宽60-120μs，刺激频率130-185Hz。刺激触点共141个，其中121个（86％）个触点位于STN前背侧和周边纤维传导束，20个（14％）触点位于STN中央。结论丘脑底核前背侧部和周边纤维传导束，如未定带（zona incerta，ZI）和Forel区（fields of Forel，FF）是刺激的最佳靶点，用相对最低电量可以得到最佳疗效。刺激频率和脉宽对刺激效果影响较小，刺激电压基本不随时间推移增加。     

BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease

IntroductionThe efficacy of pharmacotherapy and deep brain stimulation of the subthalamic nucleus in treating Parkinson's disease motor symptoms is highly variable and may be influenced by patient genotype. The relatively common (prevalence about one in three) and protein-altering rs6265 single nucleotide polymorphism (C > T) in the gene BDNF has been associated with different clinical outcomes with levodopa.ObjectiveWe sought to replicate this reported association in early-stage Parkinson's disease subjects and to examine whether a difference in clinical outcomes was present with subthalamic nucleus deep brain stimulation.Materials and MethodsFifteen deep brain stimulation and 13 medical therapy subjects were followed for 24 months as part of the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152, FDA IDE #G050016). Primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire-39.ResultsOutcomes with drug therapy in subjects carrying the rs6265 T allele were significantly worse following 12 months of treatment compared to C/C subjects (UPDRS: +20 points, p = 0.019; PDQ-39: +16 points, p = 0.018). In contrast, rs6265 genotype had no effect on overall motor response to subthalamic nucleus deep brain stimulation at any time point; further, rs6265 C/C subjects treated with stimulation were associated with worse UPDRS part II scores at 24 months compared to medical therapy.ConclusionsGenotyping for the rs6265 polymorphism may be useful for predicting long-term response to drug therapy and counseling Parkinson's disease patients regarding whether to consider earlier subthalamic nucleus deep brain stimulation. Validation in a larger cohort of early-stage Parkinson's disease subjects is warranted.     

STN vs. Pallidal Stimulation in Parkinson Disease: Improvement With Experience and Better Patient Selection

Objectives. This is a prospective study to determine the outcomes of subthalamic nucleus (STN) vs. globus pallidus internus (GPi) deep brain stimulation (DBS) at our institution. Materials and Methods. We studied a total of 39 patients — 29 with STN and 10 with GPi DBS over a period of up to 6 years. Mean ages in the two groups were similar (59 and 60 years, respectively) and disease duration prior to implantation was similar (9.6 and 11.7 years, respectively). Unified Parkinson Disease Rating Scale (UPDRS) was recorded preoperatively and at follow‐up (at least at 6‐month intervals). Medications also were recorded, and each patient's levodopa equivalent units (LEU) were calculated. Results were analyzed using a paired Student's t‐test. Results. LEU reduced significantly (p < 0.05) in the STN group (5.7 to 3.7) but not the GPi group. Both targets significantly improved part 3 and part 4 scores of the UPDRS but GPi DBS did not improve part 2 scores (activities of daily living). STN DBS had much better outcome on the motor “off” scores of the UPDRS, whereas GPi only improved tremor. A comparison of the “earliest 10” and “most recent 10” STN patients showed a significant improvement in outcome in the most recent cases. Conclusions. In our group, STN was more effective for alleviating the symptoms of Parkinson disease, even in older patients with significant dyskinesias. Better patient selection and greater experience have led to more improvement in the more recent patients.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease

ObjectiveThe deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5–4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial.Materials and MethodsAttempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures.ResultsTwelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson’s Disease Rating Scale [UPDRS]–IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; p_interaction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire–39 (PDQ-39), and levodopa equivalent daily dose (LEDD).ConclusionsEleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT00282152.     

丘脑底核电刺激治疗帕金森病的临床应用

目的探讨丘脑底核(STN)脑深部电刺激术(DBS)治疗帕金森病(PD)的手术方法和脉冲发生器的程控调节。方法行STN DBS治疗PD61例,其中单侧30例,双侧31例。采用磁共振扫描结合微电极记录技术进行靶点定位。术后用UPDRS运动评分评价刺激效果。结果术后随访6～36个月,平均11.3个月。脉冲发生器开启时,在“关”状态下,UPDRS运动评分改善率5.2%;在“开”状态下,UPDRS运动评分改善率20.7%,未发现任何并发症。结论STN DBS能有效控制PD症状,手术并发症少,术后可调节参数,已成为治疗PD的重要手术方法。     

Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently

BackgroundBoth dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN).ObjectivesThe STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability.Materials and MethodsWe studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability.ResultsDBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia.ConclusionsOur results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.     

双侧丘脑底核脑深部电刺激术治疗帕金森病(附33例报道)

目的总结双侧脑深部电刺激术(DBS)治疗帕金森病(PD)的手术方法和效果。方法对具有严重双侧症状和轴性症状的33例PD病人进行同期双侧丘脑底核DBS治疗。采用磁共振扫描结合微电极记录技术进行靶点定位。术后采用统一帕金森病评定量表(UPDRS)运动评分评价刺激效果。结果术后随访3个月~4年,平均7.3个月。脉冲发生器开启时,UPDRS运动评分平均改善率在“关”状态下为62.3%,在“开”状态下为24.2%。记忆力下降2例,情绪改变7例,睁眼困难1例,肢体异动15例;无明显的致残性永久并发症和副作用。结论双侧丘脑底核DBS手术的安全性较高,可明显改善PD病人的运动功能。     

Asleep Deep Brain Stimulation in Patients With Isolated Dystonia: Stereotactic Accuracy,Efficacy, and Safety

ObjectivesLead placement for deep brain stimulation (DBS) is routinely performed using neuroimaging or microelectrode recording (MER). Recent studies have demonstrated that DBS under general anesthesia using an imaging-guided target technique (“asleep” DBS) can be performed accurately and effectively with lower surgery complication rates than the MER-guided target method under local anesthesia (“awake” DBS). This suggests that asleep DBS may be a more acceptable method. However, there is limited direct evidence focused on isolated dystonia using this method. Therefore, this study aimed to investigate the clinical outcomes and targeting accuracy in patients with dystonia who underwent asleep DBS.Materials and MethodsWe examined 56 patients (112 leads) with isolated dystonia who underwent asleep DBS targeting in the globus pallidus internus (GPi) and subthalamic nucleus (STN). The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores were assessed preoperatively and at 12-month follow-up (12 m-FU). The lead accuracy was evaluated by comparing the coordinates of the preoperative plan with those of the final electrode implantation location. Other measures analyzed included stimulation parameters and adverse events (AEs).ResultsFor both GPi and STN cohorts, mean BFMDRS motor scores were significantly lower at 12 m-FU (8.9 ± 10.9 and 4.6 ± 5.7 points) than at baseline (22.6 ± 16.4 and 16.1 ± 14.1 points, p < 0.001). The mean difference between the planned target and the distal contact of the leads was 1.33 ± 0.54 mm for the right brain electrodes and 1.50 ± 0.57 mm for the left, determined by Euclidian distance. No perioperative complications or AEs related to the device were observed during the complete follow-up. However, AEs associated with stimulation occurred in 12 and 6 patients in the GPi and STN groups, respectively.ConclusionsAsleep DBS may be an accurate, effective, and safe method for treating patients with isolated dystonia regardless of the stimulation target.     

丘脑底核脑深部电刺激对帕金森病焦虑状况的影响

目的探讨双侧丘脑底核脑深部电刺激(STN-DBS)对帕金森病人焦虑状况的影响。方法设置双侧STN-DBS组及左旋多巴类药物治疗组,配对入组,每组有效病例各31例。采用汉密尔顿焦虑量表(HAMA)、焦虑状态-特质问卷(STAI)、帕金森病生活质量39问卷(PDQ-39)及统一帕金森病评定量表第Ⅲ部分(UPDRS-Ⅲ)对病人进行评估分析。结果与术前及药物治疗组相比,STN-DBS组术后状态焦虑(S-AI)评分明显降低(均P<0.05)。STN-DBS组UPDRS-Ⅲ评分与S-AI评分在术后4个月内相关(均P<0.05),电压、脉宽与特质焦虑(T-AI)和HAMA评分均相关(均P<0.05);术后电压和脉宽对T-AI和HAMA评分的标准回归方程成立,回归系数均显著(均P<0.05)。结论 STN-DBS在改善帕金森病人运动障碍的同时,在短期内可改善即时焦虑情绪。在治疗范围内,STN-DBS电压和脉宽越高,帕金森病人的特质焦虑情绪和焦虑症状越严重。