Personalized circuit-based neuromodulation targets for depression

项目摘要/摘要 这项提案要求支持一项为期五年的培训和研究计划，以更好地了解 不同的大脑回路可以通过经颅磁刺激(TMS)进行标测和选择性刺激 治疗抑郁症的不同症状。 在拟议的培训计划中，我将以我以前的精神病学和计算经验为基础 在贝丝以色列女执事医疗中心执行一个多学科项目。我的职业发展计划 包括脑电路图、神经调节、生物统计/数据科学、精神病学表型、 临床试验和一般翻译研究。 TMS是一种有效的治疗重度抑郁症的方法，它能够调节特定的大脑回路。 然而，不同患者的疗效差异很大，其机制尚不清楚。近期工作 来自我们实验室的研究表明，TMS的疗效可以通过刺激特定的靶点来提高 连接配置文件。此外，不同的TMS靶点可以调节不同的大脑网络，这可能是 与不同的抑郁症症状有关。连接到每个刺激点的大脑回路可以 通过使用功能连接磁共振成像(FcMRI)进行映射，无论是在群体层面还是个人层面。一位将军 刺激部位连通性的估计地图可以从人类连接体中产生，这是一个标准化的 基于一千名健康对照的fcmri的人脑电路图。一张更精确的地图 可以基于特定于受试者的fcMRI数据来生成连接性。 这项建议旨在根据症状、情绪任务表现和 大脑连通性。在我的初步数据中，这种方法产生了明显的改进电路 在“焦虑症”和“焦虑症”症状群中。然而，这些结果受到了回溯的限制。 自然，对主观症状量表的依赖，以及对基于组的连接的依赖。在这份提案中，我将 通过在一项包含基于任务的前瞻性随机试验中确认我们的结果来解决这些限制 行为指标，并纳入特定于对象的连接性。 更广泛地说，这项研究旨在开发一种模型，用于映射与不同的 可通过治疗性脑刺激调节的症状群。这将为以下工作奠定基础 临床精神病学中跨诊断神经调节的个性化方法。

PROJECT SUMMARY/ABSTRACT This proposal requests support for a five-year program of training and research to better understand how distinct brain circuits can be mapped and selectively stimulated with transcranial magnetic stimulation (TMS) to treat different symptoms of major depression. In the proposed training plan, I will build upon my previous psychiatric and computational experience to perform a multidisciplinary project at Beth Israel Deaconess Medical Center. My career development plan includes training in brain circuit mapping, neuromodulation, biostatistics/data science, psychiatric phenotyping, clinical trials, and general translational research. TMS is an effective treatment for major depression which is capable of modulating specific brain circuits. However, efficacy varies greatly across patients and the mechanisms are not well-understood. Recent work from our lab shows that the efficacy of TMS can be improved by stimulating specific targets based on their connectivity profile. Additionally, different TMS targets can modulate different brain networks which may be involved in different symptoms of depression. The brain circuit connected to each stimulation site can be mapped by using functional connectivity MRI (fcMRI), either at the group level or the individual level. A general estimated map of stimulation site connectivity can be generated from the human connectome, a normative wiring diagram of the human brain based on fcMRI of a thousand healthy controls. A more precise map of connectivity can be generated based on subject-specific fcMRI data. This proposal aims to personalize TMS targets based on symptoms, emotional task performance, and brain connectivity. In my preliminary data, this approach yielded distinct circuits responsible for improvement in “dysphoric” versus “anxiosomatic” symptom clusters. However, these results are limited by retrospective nature, reliance on subjective symptom scales, and reliance on group-based connectivity. In this proposal, I will address these limitations by confirming our results in a prospective randomized trial, incorporating task-based behavioral metrics, and incorporating subject-specific connectivity. More broadly, this research aims to develop a model for mapping specific circuits associated with distinct symptom clusters that can be modulated with therapeutic brain stimulation. This will lay the foundation for personalized approaches to transdiagnostic neuromodulation in clinical psychiatry.