DEEP BRAIN STIMULATION FOR DEPRESSION USING DIRECTIONAL CURRENT STEERING AND INDIVIDUALIZED NETWORK TARGETING

摘要 治疗难治性抑郁症(TRD)的公共卫生负担推动了脑深部临床试验 不幸的是，刺激(DBS)产生了不一致的结果。潜在的差距和机遇 包括：(1)更好地了解疾病的神经回路；(2)需要精密的DBS设备， 可以以临床和生理验证的方式瞄准大脑网络；以及(3)更深入地了解 刺激剂量-反应关系。这些需求基于我们的总体假设，即网络- 引导神经调节对DBS治疗TRD的疗效至关重要。该项目旨在解决未得到满足的需求 通过识别对治疗抑郁症和使用下一代药物至关重要的大脑网络，对TRD患者进行评估 具有引导能力的精确DBS，可参与这些目标网络并开发新的治疗方法 为了TRD。我们使用波士顿科学公司(Boston Science)的Vercise DBS系统，该系统提供分段可控的领先优势 具有多个独立的电流源，可实现真正的定向转向。此外，这一系统 将刺激场建模(SFM)与磁共振波束成像相结合，以预测网络参与度。我们使用一种 以膝下扣带核(SGC)和腹囊/腹纹状体为靶点的创新方法 (VC/VS)，我们称之为皮质边缘DBS。这些目标是不同但部分重叠的枢纽 抑郁症网络和新兴的基础科学文献表明，它们在双向调节 抑郁回路。我们还应用了一种使用颅内立体脑电信号(SEEG)的范式转换方法 亚急性评估DBS植入后转向、SFMS和气管造影术的临床可靠性 定义并针对调节抑郁症症状的网络。目标1，癫痫监测 单位(EMU)，我们调查了Vercise选择性参与不同大脑网络的能力，并比较 诱发网络活动和调制的空间分布与SFM和纤维束成像预测的结果一致。 在目标2中，我们在欧洲货币联盟中进行了进一步的研究，以描绘与抑郁症相关的网络并展示 网络目标刺激下的行为变化。我们使用各种任务来探查不同的症状 领域和新的评估工具(计算机化自适应测试和自动面部影响 识别)以增强分类和模型算法，以优化刺激模式。在目标3中，我们 将AIMS 1和AIMS 2的结果合并在一起，以测试皮质边缘DBS在12例中的治疗潜力 TRD受试者，在为期8个月的开放标签试验中，重点关注安全性、可行性和初步疗效 随后随机、盲目撤除刺激以评估疗效。这项提议的影响 包括对当前以特定网络为目标的DBS技术的生理学验证，对 刺激参数对网络生理学的影响，加深了对精神分裂症病理生理学的理解 抑郁症，也许最重要的是，一种治疗TRD的新方法。这项研究也将是一个先驱 与大脑优先事项一致的DBS治疗开发的新的和高产量的试验台。

ABSTRACT The public health burden of Treatment Resistant Depression (TRD) has prompted clinical trials of deep brain stimulation (DBS) that have, unfortunately, produced inconsistent outcomes. Potential gaps and opportunities include a need: (1) to better understand the neurocircuitry of the disease; (2) for precision DBS devices that can target brain networks in a clinically and physiologically validated manner; and (3) for greater insight into stimulation dose-response relationships. These needs are based on our overarching hypothesis that network- guided neuromodulation is critical for the efficacy of DBS in TRD. This project aims to address the unmet need of TRD patients by identifying brain networks critical for treating depression and to use next generation precision DBS with steering capability to engage these targeted networks and develop a new therapy for TRD. We use the Boston Scientific (BS) Vercise DBS system, which offers a segmented steerable lead with multiple independent current sources that allows true directional steering. Moreover, this system integrates stimulation field modeling (SFM) with MR tractography to predict network engagement. We use an innovative approach of targeting both subgenual cingulate (SGC) and ventral capsule/ventral striatum (VC/VS), which we term corticomesolimbic DBS. These targets are hubs in distinct yet partially overlapping depression networks and emerging basic science literature implicates them in bidirectional modulation of depression circuits. We also apply a paradigm-shifting approach using intracranial stereo-EEG (sEEG) subacutely after DBS implant to evaluate the clinical reliability of steering, SFMs, and tractography and to define and then target the networks mediating symptoms of depression. In Aim 1, in the Epilepsy Monitoring Unit (EMU), we investigate the capability of Vercise to selectively engage distinct brain networks and compare the spatial distribution of evoked network activity and modulation with that predicted by SFM and tractography. In Aim 2, we conduct further studies in the EMU to delineate depression-relevant networks and show behavioral changes with network-targeted stimulation. We use a variety of tasks to probe different symptom domains and novel assessment tools (Computerized Adaptive Testing and Automated Facial Affect Recognition) to enhance classification and model algorithms to optimize stimulation patterns. In Aim 3, we bring the results from Aims 1 and 2 together, to test the therapeutic potential of corticomesolimbic DBS in 12 subjects with TRD, with a focus on safety, feasibility, and preliminary efficacy in a 8-month open label trial with a subsequent randomized, blinded withdrawal of stimulation to assess efficacy. The impact of this proposal includes physiological validation of current “steering” DBS technology to target specific networks, insights into effects of stimulation parameters on network physiology, an improved understanding of the pathophysiology of depression, and, perhaps most importantly, a novel approach for treating TRD. This research will also pioneer a novel and high-yield test bed for DBS therapy development consistent with BRAIN priorities.