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.

项目概要 该 UH3 申请旨在解决难治性重度抑郁症的主要公共卫生负担 （trMDD）通过开发一种新型的深部脑刺激（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，其中个性化的电路活动生物标志物 仅在需要时才识别病理状态并用于触发治疗刺激。 根据我们的概念模型，MDD 是一个动态过程，当功能失调时就会出现症状 一个或多个与情绪相关的大脑网络中出现的活动因人而异。 我们的方法有可能通过个性化来最大限度地提高疗效。 刺激位置定位，同时最大限度地减少维持治疗效果所需的刺激，从而 我们提出了一个三阶段的方案，以减少副作用、神经适应和保护装置的寿命。 可行性、安全性和初步疗效研究基于我们在 12 名患有此病的患者中测试该方法的试点工作 第一阶段将涉及手术植入 10 个颅内脑电图 (iEEG) 电极，为期 10 天。 第二阶段为个性化地点选择和生物标志物发现进行强化住院监测。 涉及植入慢性 DBS 装置（NeuroPace RNS® 系统），并将电极放置在传感中 和第一阶段确定的刺激目标。然后是基于生物标记的 MDD 状态检测算法 开发并纳入闭环治疗的第三阶段包括随机、双盲、假手术。 受控和主动控制（由假生物标志物触发的间歇性刺激）交叉研究 由此产生的个体化闭环 DBS 疗法将有助于为批准铺平道路。 NeuroPace RNS 系统用于 trMDD，如果成功，将首次展示个性化 闭环 DBS 是治疗 trMDD 的一种有前途的疗法，也证明了更大规模的后续试验的合理性。 展示生物标志物开发和治疗靶点选择的概念验证，这可以至关重要 我们对回路功能障碍的理解促进了 MDD 的发展和个性化治疗的发展 针对MDD和其他神经精神疾病的闭环DBS。