Responsive Neurostimulation for Treatment Resistant Depression

反应性神经刺激治疗难治性抑郁症

• 批准号: 10513243
• 负责人: ANDREW D KRYSTAL
• 金额: $ 175.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513243
• 关键词: Address; Affect; Algorithms; Ambulatory Care; Biological Markers; Brain; Chronic; Clinical; Cross-Over Studies; Deep Brain Stimulation; Detection; Development; Devices; Discrimination; Disease; Dose; Double-Blind Method; Electrodes; Electroencephalography; Functional disorder; Heterogeneity; Implant; Individual; Inpatients; Lead; Location; Longevity; Major Depressive Disorder; Maps; Modeling; Monitor; Moods; Operative Surgical Procedures; Outcome Assessment; Pathologic; Patients; Phase; Process; Protocols documentation; Public Health; Randomized; Recurrence; Refractory; Research; Resistance; Safety; Serious Adverse Event; Severities; Site; Stimulus; Symptoms; System; Testing; Therapeutic; Therapeutic Effect; Time; Uncertainty; Work; algorithm development; battery life; biomarker development; biomarker discovery; biomarker identification; depressive symptoms; detection platform; detector; disability; efficacy study; implantation; improved; neural circuit; neural network; neuroadaptation; neuropsychiatry; novel; patient subsets; preservation; primary outcome; randomized trial; secondary outcome; side effect; simulation; symptomatic improvement; therapeutic target; treatment optimization; treatment-resistant depression

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.

项目摘要 UH 3申请旨在解决难治性重度抑郁症的主要公共卫生负担 （trMDD）通过开发一种新形式的脑深部电刺激（DBS）。这种方法是独一无二的， DBS优化的最新方法，包括个性化刺激目标位置 选择和闭环刺激策略，在闭环刺激策略中， 病理状态被识别并仅在需要时用于触发治疗刺激。这种方法 基于我们的概念模型，MDD是一个动态过程，当功能失调时会出现症状 活动出现在一个或多个大脑情绪相关网络中。受影响的网络因个体而异 导致症状的异质性。我们的方法有可能通过个性化来最大限度地提高疗效 刺激定位靶向，同时最小化维持治疗效果所需的刺激，从而 最小化副作用和神经适应并保持装置寿命。我们提出了一个三阶段 可行性，安全性和初步疗效研究，基于我们的试点工作，以测试这种方法在12例患者， 重度trMDD。第1阶段将涉及手术植入10个颅内EEG（iEEG）电极，为期10天。 针对个性化研究中心选择和生物标志物发现的强化住院监测期。阶段2 涉及植入慢性DBS器械（NeuroPace RNS®系统），电极置于感知位置 以及在阶段1中确定的刺激目标。然后提出了一种基于标记的MDD状态检测算法， 开发并整合到闭环治疗中。第3阶段包括随机、双盲、假手术， 对照和活性对照（假生物标志物触发的间歇刺激）交叉研究 从而产生个体化闭环DBS治疗。这项研究将有助于为批准 用于trMDD的NeuroPace RNS系统，如果成功，将首次证明个性化 闭环DBS是治疗trMDD的一种有前景的疗法，证明了后续更大规模试验的合理性。它还将 证明了生物标志物开发和治疗靶点选择的概念验证， 推进我们对MDD潜在回路功能障碍的理解， 闭环DBS治疗MDD和其他神经精神疾病。