Deriving TMS Targets for Mood Valence and Mood Stabilization in Bipolar Disorder

项目摘要 双相情感障碍(BD)需要新的治疗方法。经颅磁刺激(TMS)显示 对BD有希望，但治疗躁狂、抑郁和情绪稳定的最佳治疗目标尚不清楚。 研究导致BD症状的脑损伤提供了对神经解剖学的因果洞察。这些因果关系 洞察力对于目标识别至关重要。病变网络标测(LNM)利用人类 Connectome将大脑病变映射到大脑网络而不是单个脑区域，从而增强病变 定位和目标识别。由福克斯实验室(Mentor)首创的LNM显示出优化TMS的前景 单相抑郁的目标。福克斯实验室最近的两项研究使用LNM来因果地检查大脑电路 涉及躁狂症(n=56，两个数据集)和抑郁症(n=461，五个数据集)。然而，有两个关键因素 这项先前工作的局限性。首先，躁狂和抑郁被分析为独立的状态，而不是 在BD中价谱的相反的两极。这一限制将通过以下单一模型分析来解决 躁狂症、抑郁症和控制性损害。其次，这些研究没有验证BD患者的靶点。这 限制将通过使用功能神经成像验证BD患者的病变衍生靶点来解决 和行为测试。目标1是推导和验证情绪效价的TMS目标。这些价态特定 靶点将在先验的前额叶皮质中通过躁狂症和抑郁症的LNM对比(反之亦然)来获得。 结果将通过将他们的全脑连接性与基于任务的 BD患者的价态偏向。目标2是推导和验证TMS的情绪稳定目标。这 价态-非特定目标将根据先验的躁狂症和抑郁症与对照组的LNM对比得出 腹外侧额叶皮质面罩，所产生的目标将通过关联其全脑来验证 与BD患者基于任务的情绪调节措施的连通性。 这项研究与NIMH 2020战略计划目标一致，即开发新的工具，用于 描述与情感过程有因果关系的大脑网络。R01或R61/33的后续拨款 检查TMS是否改变了TMS患者的行为指标、功能连接性和临床结果 BD与NIMH的实验治疗学方法一致。这项资助是为了提供逐步的 完成这一计划所需的科学培训，从LNM和生物统计学到涉及以下内容的转化研究 BD患者的表型和影像。它也非常符合成为一名 独立资助的内科科学家，主要领导介入精神病学研究项目 专注于基于电路的TMS目标的推导、验证和测试。有了这一目标，就没有比这更好的了 比布里格姆和妇女医院更值得培训的地方，后者是哈佛医学院的附属医院，提供世界级的 Mentors，大脑回路治疗中心的一项强大的TMS服务，哈佛大学催化剂 临床/翻译科学中心和阿蒂努拉·A·马蒂诺斯生物医学成像中心。

Project Summary New treatments are needed for bipolar disorder (BD). Transcranial magnetic stimulation (TMS) shows promise for BD, but the optimal treatment targets for mania, depression, and mood stabilization are unknown. Studying brain lesions that cause BD symptoms provides causal insights into neuroanatomy. These causal insights are critically important for target identification. Lesion network mapping (LNM) leverages the human connectome to map brain lesions onto brain networks rather than single brain regions, enhancing lesion localization and target identification. Pioneered by the Fox lab (Mentor), LNM shows promise for optimizing TMS targets for unipolar depression. Two recent Fox lab studies used LNM to examine the brain circuitry causally implicated in mania (n=56, two datasets) and depression (n=461, five datasets). However, there are two critical limitations of this prior work. First, mania and depression were analyzed as independent states rather than opposing poles of a valence spectrum in BD. This limitation will be addressed with a single model analysis of mania, depression, and control lesions. Second, these studies did not validate targets in patients with BD. This limitation will be addressed by validating lesion-derived targets in patients with BD using functional neuroimaging and behavioral testing. Aim 1 is to derive and validate TMS targets for mood valence. These valence-specific targets will be derived with LNM contrasts of mania vs. depression (and vice versa) in an a priori prefrontal cortex mask, and the results will be validated by correlating their whole-brain connectivity to task-based measures of valence bias in patients with BD. Aim 2 is to derive and validate a TMS target for mood stabilization. This valence-nonspecific target will be derived with LNM contrasts of mania plus depression vs. controls in an a priori ventrolateral prefrontal cortex mask, and the resulting target will be validated by correlating its whole-brain connectivity to a task-based measure of emotion regulation in patients with BD. This study aligns with the NIMH 2020 Strategic Plan objective of developing novel tools with which to characterize brain networks causally implicated in affective processes. A follow-up R01 or R61/33 grant examining whether TMS alters behavioral metrics, functional connectivity, and clinical outcomes in patients with BD aligns with NIMH’s experimental therapeutics approach. This grant was designed to provide the stepwise scientific training necessary to fulfill this plan, from LNM and biostatistics to translational research involving phenotyping and imaging of patients with BD. It also fits well with the long-term goal of becoming an independently funded physician-scientist who leads an Interventional Psychiatry research program primarily focused on deriving, validating, and testing circuit-based TMS targets. With this goal in focus, there is no better place to train than Brigham and Women’s Hospital, a Harvard Medical School affiliate offering world-class mentors, a robust TMS service in the Center for Brain Circuit Therapeutics, Harvard Catalyst Clinical/Translational Science Center, and Athinoula A. Martinos Center for Biomedical Imaging.