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

在顽固性强迫症（OCD）患者中，腹侧纹状体（VS）脑深部电刺激 (DBS)在大约60%的病例中有效地减轻了症状的严重程度。然而，在以下方面仍有改进的余地： 临床益处和减少DBS诱导的行为副作用，尤其是轻躁狂。一个关键 因素可能是未能适应性地调整DBS以响应负和正的相位变化 价态（即，OCD相关的痛苦和轻躁狂，分别）。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，以做出相应的调整， 患者的行为状态。具体目标1是训练该设备以准确地对强迫症的急性波动进行分类- 相关的痛苦和轻躁狂的出现，并区分这些国家从其他情感状态， 不需要调整刺激。具体目标2是开发自适应控制策略， 自动调整刺激参数以调节这些不期望的状态。它是假设 OCD相关痛苦的加重需要增加刺激（更高的振幅或更宽的脉冲宽度） 而轻躁狂将对减少的刺激作出反应。这些目标将通过两个阶段来实现 aDBS在10例难治性OCD成人中的早期可行性研究。受试者将进入为期6个月的开放试验- 标记双侧aDBS，随后进行2个月的连续认知行为治疗（CBT）。随后，他们 将进入为期4周的盲态停药期，以评估持续DBS的需求。在I期，5名受试者将 根据FDA人体器械豁免（HDE）批准的程序对OCD患者进行VS DBS手术。 电极植入将使用每个患者的“精确标测”进行优化和个性化 解剖连接从高场纤维束成像在本地空间。DBS编程会议还将 用于训练算法以分类不同的价态。例如，症状激发范式 会引发不同程度的可控制的强迫症相关的痛苦。在这个范例中多重时间流- 将捕获锁定的生理和行为数据以构建分类器：局部场电位（LFP） 从VS，头皮EEG和自动面部情感识别（AFAR），客观地衡量 情感效价我们假设使用LFP/EEG数据组合的分类器将比VS更好地执行 LFPs单独，但直接的皮层记录将需要准确的分类和创建一个完整的 嵌入式，独立的，aDBS系统在II期，5例受试者将接受VS DBS手术，沿着双侧 硬膜下放置皮质电图（ECoG）记录导线在前额叶目标，通过休息通知 I期和术前扫描的功能性MRI。新的分类器将基于VS构建， 在转移到门诊之前，在诊所测试ECoG LFP和自适应刺激算法。 满足所有研究里程碑将产生一个原型门诊aDBS系统， 强迫症症状和设备相关副作用的波动。

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.