Responsive Neurostimulation for Treatment Resistant Depression

项目总结 这项UH3申请旨在解决难治性重度抑郁症带来的主要公共卫生负担 (TrMDD)通过开发一种新形式的脑深部刺激(DBS)。这种方法是独一无二的 最近的DBS优化方法，因为它结合了个性化的刺激目标位置 选择和闭环刺激策略，其中个性化的电路活动生物标记物 病理状态被识别，并仅在需要时用于触发治疗性刺激。这种方法是 根据我们的概念模型，MDD是一个动态过程，在这个过程中，症状会在功能障碍时出现 活动出现在一个或多个与情绪有关的大脑网络中。受影响的网络因人而异 导致症状异质性。我们的方法有可能通过个性化使效果最大化 刺激定位，同时最小化维持治疗效果所需的刺激，从而 最大限度地减少副作用和神经适应，并保护设备寿命。我们建议分三个阶段 在我们的试点工作的基础上进行的可行性、安全性和初步疗效研究，在12名 严重的trMDD。第一阶段将包括手术植入10个颅内脑电(IEEG)电极，为期10天 为个人化的地点选择和生物标记物的发现进行密集的住院监护期。第二阶段 包括植入慢性DBS设备(NeuroPace RNS®系统)，在传感器中放置电极 以及阶段1中识别的刺激目标。然后，基于生物标志物的MDD状态检测算法 开发并整合成闭环系统疗法。第三阶段包括随机、双盲、假冒- 受控和主动控制(由假生物标记物触发的间歇性刺激)交叉研究 由此产生的个体化闭环式DBS治疗。这项研究将有助于为批准 针对trMDD的NeuroPace RNS系统，如果成功，将首次展示个性化 闭合循环DBS是治疗trMDD的一种有前途的疗法，值得进行更大规模的后续试验。它还会 演示生物标记物开发和治疗目标选择的概念验证，这可能对 促进我们对MDD潜在的回路功能障碍的理解和个性化的发展 针对MDD和其他神经精神疾病的闭环式DBS。

PROJECT SUMMARY This UH3 application seeks to address the major public health burden of treatment-resistant major depression (trMDD) by developing a novel form of Deep Brain Stimulation (DBS). This approach is unique among recent approaches toward DBS optimization in that it incorporates individualized stimulation target location selection and a closed-loop stimulation strategy where a personalized circuit activity biomarker of the pathologic state is identified and used to trigger therapeutic stimulation only when needed. This approach is based on our conceptual model that MDD is a dynamic process in which symptoms arise when dysfunctional activity emerges in one or more brain mood-related networks. The networks affected differ among individuals leading to symptom heterogeneity. Our approach has the potential to maximize efficacy by personalizing stimulus location targeting while minimizing the stimulation needed to maintain a therapeutic effect, thereby minimizing side-effects and neural adaptation and preserving device longevity. We propose a 3-stage feasibility, safety, and initial efficacy study based on our pilot work to test this approach in 12 patients with severe trMDD. Stage 1 will involve surgical implantation of 10 intracranial EEG (iEEG) electrodes for a 10- day period of intensive inpatient monitoring for personalized site selection and biomarker discovery. Stage 2 involves implantation of a chronic DBS device (NeuroPace RNS® System) with electrodes placed in sensing and stimulation targets identified in stage 1. A biomarker-based MDD state detection algorithm is then developed and integrated into closed-loop therapy. Stage 3 consists of a randomized, double-blind, sham- controlled and active-controlled (intermittent stimulation triggered by a sham biomarker) cross-over study of the resulting individualized closed-loop DBS therapy. This research will help pave the way for approval of the NeuroPace RNS System for trMDD and, if successful, will demonstrate for the first time that personalized closed-loop DBS is a promising therapy for trMDD, justifying a larger subsequent trial. It would also demonstrate proof-of-concept for biomarker development and therapeutic target selection that could critically advance our understanding of the circuit dysfunction underlying MDD and the development of personalized closed-loop DBS for MDD and other neuropsychiatric conditions.