Adaptive DBS in Non-Motor Neuropsychiatric Disorders: Regulating Limbic Circuit Imbalance

在难治性强迫症患者中，腹侧纹状体(VS)深部脑刺激 (DBS)在约60%的病例中有效地降低了症状严重程度。然而，在以下方面仍有改进的空间 临床益处和减少DBS引起的行为副作用，特别是轻躁狂症。一位批评者 因素可能是未能根据消极和积极的阶段性变化对DBS进行适应性调整 无效化状态(即分别为与强迫症相关的苦恼和轻躁狂)。新一代自适应DBS (ADBS)系统可以记录、刺激和使用来自大脑的信号来对 病人的行为状态。具体目标1是训练该设备准确地对强迫症的剧烈波动进行分类 相关的苦恼和轻躁狂的出现，并将这些状态与其他情感状态区分开来 不需要在刺激方面进行调整。具体目标2是开发自适应控制策略，以 自动调整刺激参数以调节这些不需要的状态。据推测， 强迫症相关痛苦的加重需要更多的刺激(更高的幅度或更宽的脉宽) 而轻躁狂症会对刺激减少做出反应。这些目标将分两个阶段执行 10例成人难治性强迫症早期应用aDBS的可行性研究受试者将进入为期6个月的开放试验- 标记双侧aDBS，然后进行2个月的辅助认知行为治疗(CBT)。随后，他们 将进入为期4周的盲断期，以评估对持续DBS的需求。在第一阶段，5个科目将 根据FDA人类设备豁免(HDE)批准程序对强迫症的VS DBS进行手术。 电极植入将被优化和个性化，使用每个患者的 来自自然空间高场声束造影术的解剖连接。DBS节目安排会议也将 用来训练算法对不同的价态进行分类。例如，症状激发范式 会引发不同程度的与强迫症相关的可控痛苦。在这个范例中，有多个时间流- 锁定的生理和行为数据将被捕获以构建分类器：局部场电位(LFP) 从VS、头皮EEG和自动面部情感识别(AFAR)，它客观地测量 情感价位。我们假设，使用组合的LFP/EEG数据的分类器的性能将比VS更好 仅限于LFP，但需要直接的皮质记录才能准确分类和创建完整的 嵌入式、自给自足的DBS系统。在第二阶段，5名受试者将同时接受双侧VS DBS手术 通过休息将皮层脑电(ECoG)记录导联放置在额叶前部目标的硬膜下 从I期和术前扫描开始进行功能磁共振检查。新的分类器将基于VS和 在转到门诊环境之前，在临床上测试ECOG LFP和自适应刺激算法。 达到所有研究里程碑将产生一个原型动态ADBS系统，它将管理 强迫症症状的波动和与设备相关的副作用自动发生。

In patients with intractable Obsessive-Compulsive Disorder (OCD), ventral striatum (VS) deep brain stimulation (DBS) effectively reduces symptom severity in about 60% of cases. However, there is room for improvement in both clinical benefits and reduction of DBS-induced behavioral side effects, especially hypomania. A critical factor may be failure to adaptively adjust DBS in response to phasic changes in negatively and positively valenced states (i.e., OCD-related distress and hypomania, respectively). New generation adaptive DBS (aDBS) systems can record, stimulate and use signals from the brain to make responsive adjustments to the patient's behavioral state. Specific Aim 1 is to train the device to accurately classify acute fluctuations in OCD- related distress and emergence of hypomania and distinguish these states from other affective states that do not require adjustments in stimulation. Specific Aim 2 is to develop adaptive control policies that can automatically adjust stimulation parameters to regulate these undesired states. It is hypothesized that exacerbations in OCD-related distress will require increased stimulation (higher amplitude or wider pulse width) whereas hypomania will respond to decreased stimulation. These aims will be executed using a two-phase Early Feasibility Study of aDBS in 10 adults with intractable OCD. Subjects will enter a 6-month trial of open- label bilateral aDBS followed by 2 months of adjunctive cognitive behavioral therapy (CBT). Subsequently, they will enter a 4-week blinded discontinuation period to assess need for ongoing DBS. In Phase I, 5 subjects will have surgery as per procedures of the FDA Human Device Exemption (HDE) approval for VS DBS in OCD. Electrode implantation will be optimized and personalized using “precision mapping” of each patient's anatomical connectivity from high-field tractography in native space. DBS programming sessions will also serve to train the algorithms to classify different valence states. For example, a symptom provocation paradigm will elicit different levels of manageable OCD-related distress. During this paradigm multiple streams of time- locked physiological and behavioral data will be captured to build a classifier: Local Field Potentials (LFPs) from the VS, Scalp EEG, and Automated Facial Affect Recognition (AFAR), which objectively measures emotional valence. We hypothesize that classifiers using combined LFP/EEG data will perform better than VS LFPs alone, but that direct cortical recordings will be needed for accurate classification and creation of a fully embedded, self-contained, aDBS system. In Phase II, 5 subjects will have VS DBS surgery along with bilateral subdural placement of electrocorticographic (ECoG) recording leads at a prefrontal target, informed by resting state functional MRI from Phase I and pre-operative scans. New classifiers will be built based on VS and ECoG LFPs and adaptive stimulation algorithms tested in the clinic before transfer to the ambulatory setting. Meeting all study milestones would result in a prototype ambulatory aDBS system that would manage fluctuations in OCD symptoms and device-related side effects automatically.