Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms

利用人脑连接来识别抑郁症状的因果神经解剖学基础

• 批准号: 10646488
• 负责人: MICHAEL D FOX
• 金额: $ 74.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646488
• 关键词: 3-Dimensional; Admission activity; Age; Antidepressive Agents; Behavior; Brain; Brain hemorrhage; Brain region; Clinical; Clinical Trials; Computer software; Data; Data Set; Deep Brain Stimulation; Diagnosis; Diagnostic; Enrollment; Epilepsy; Functional Magnetic Resonance Imaging; Future; Goals; Human; Human Characteristics; Ischemic Stroke; Lead; Lesion; Link; Location; Magnetic Resonance Imaging; Major Depressive Disorder; Maps; Mediating; Mental Depression; Modality; Motor; National Institute of Mental Health; Neuroanatomy; Neuronavigation; Obsession; Obsessive-Compulsive Disorder; Outcome; Parkinson Disease; Patients; Pattern; Pharmaceutical Preparations; Postoperative Period; Prospective Studies; Publishing; Recording of previous events; Rest; Seizures; Site; Source; Symptoms; Techniques; Testing; Therapeutic; Time; Transcranial magnetic stimulation; Translating; United States National Institutes of Health; Validation; Work; X-Ray Computed Tomography; clinical practice; cohort; compulsion; connectome; depressive symptoms; diagnostic value; disability; improved; individual patient; large datasets; neuroimaging; neuroregulation; noninvasive brain stimulation; physically handicapped; post stroke; post stroke depression; predictive marker; prospective; prospective test; response; sex; stroke outcome; stroke trials; therapeutic target

PROJECT SUMMARY: Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms Depression is the leading cause of disability worldwide. Identifying the brain regions causing depression symptoms can lead to better treatment targets and therapies. Most neuroimaging studies identify brain regions where activity correlates with depression symptoms but cannot determine whether these regions actually cause symptoms. The goal of this project is to causally link depression symptoms to human neuroanatomy. Lesions and brain stimulation can provide causal links to human neuroanatomy. Because symptoms can come from regions connected to the lesion or stimulation site, we study the connectivity of these sites (not just their location) using brain connectivity data from a large cohort of normal subjects (functional connectivity MRI, n=1000). This allows us to map symptoms caused by lesions or stimulation to brain circuits without connectivity data from the patients themselves. With NIMH support, we found that lesions, transcranial magnetic stimulation (TMS) sites, and deep brain stimulation (DBS) sites that cause a change in depression symptoms are all connected to a common brain circuit across 14 independent datasets (Siddiqi et. al 2021 Nature Human Behaviour). Connectivity to this circuit was a better predictor of antidepressant response to TMS or DBS than connectivity to other candidate regions (e.g., subgenual cingulate). However, this circuit requires validation before it can be translated into a target for clinical trials. Here, we will validate our brain circuit for depression using three independent causal sources of information: lesions (Aim 1), DBS (Aim 2), and TMS (Aim 3). For all aims, we will use our published a priori depression circuit to predict overall depression outcomes. We will also perform exploratory data-driven analyses to test whether different circuits are responsible for different symptoms of depression. In Aim 1, we will prospectively test whether our depression circuit can predict depression scores after stroke. In Aim 2, we will test whether our depression circuit can predict change in depression score after DBS across a wide range of DBS patients with different diagnoses. In Aim 3, we will test whether individualized connectivity to our circuit prospectively predicts change in depression symptoms with TMS. Completion of these Aims will validate our depression circuit across different diagnoses and across three independent causal sources of information, providing much stronger validation than could be achieved with one modality alone. If successful, this study will facilitate future trials directly targeting our brain circuit with therapeutic neuromodulation for depression.

项目摘要：使用人脑连通性来确定原因神经解剖学 抑郁症状的根源 抑郁症是世界范围内导致残疾的主要原因。确定导致抑郁的大脑区域 症状可以导致更好的治疗目标和治疗方法。大多数神经成像研究确定了大脑区域 活动与抑郁症状相关但不能确定这些区域是否真的 引起症状。这个项目的目标是将抑郁症状与人类神经解剖学之间的因果联系起来。 损伤和脑刺激可以提供与人类神经解剖学的因果联系。因为症状可能会出现 从连接到损伤或刺激部位的区域，我们研究这些部位的连通性(不仅仅是其 位置)使用来自一大群正常受试者的脑连通性数据(功能连通性MRI， N=1000)。这使得我们可以将损伤或刺激引起的症状映射到大脑回路，而不需要 来自患者自身的连接数据。在NIMH的支持下，我们发现病变，经颅 导致抑郁症改变的磁刺激(TMS)部位和脑深部刺激(DBS)部位 所有症状都与14个独立数据集(Siddiqi et.Al 2021 自然人类行为)。与此回路的连通性是抗抑郁药物疗效的更好预测指标 TMS或DBS比连接到其他候选区(例如，亚扣带区)更重要。然而，这条赛道 在将其转化为临床试验的靶点之前，需要进行验证。在这里，我们将验证我们的大脑 使用三个独立的因果信息来源治疗抑郁症的电路：病变(目标1)、DBS(目标2)和 TMS(目标3)。对于所有目标，我们将使用已公布的先验抑郁回路来预测总体抑郁 结果。我们还将执行探索性数据驱动分析，以测试不同的电路是否 对不同的抑郁症症状负责。在目标1中，我们将前瞻性地测试我们的抑郁症 回路可以预测中风后的抑郁评分。在目标2中，我们将测试我们的抑郁回路是否可以 在不同诊断的DBS患者中预测DBS后抑郁评分的变化。在……里面 目标3，我们将测试与我们的回路的个性化连接是否可以预测抑郁症的变化 TMS的症状。这些目标的完成将验证我们在不同诊断中的抑郁回路 以及三个独立的因果信息源，提供了比可能提供的更强的验证 仅用一种方式就能实现。如果成功，这项研究将促进未来直接针对我们大脑的试验 治疗抑郁症的神经调节电路。

项目成果

Reply: Heterogeneous neuroimaging findings, damage propagation and connectivity: an integrative view.

答复：异质神经影像学发现、损伤传播和连接：综合观点。

• DOI: 10.1093/brain/awz081
• 发表时间: 2019
• 期刊: Brain : a journal of neurology
• 作者: Darby,RRyan;Fox,MichaelD
• 通讯作者: Fox,MichaelD

Network Effects of Brain Lesions Causing Central Poststroke Pain.

• DOI: 10.1002/ana.26468
• 发表时间: 2022-11
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Kim, Na Young;Taylor, Joseph J.;Kim, Yong Wook;Borsook, David;Joutsa, Juho;Li, Jing;Quesada, Charles;Peyron, Roland;Fox, Michael D.
• 通讯作者: Fox, Michael D.

Mapping Lesion-Related Epilepsy to a Human Brain Network.

• DOI: 10.1001/jamaneurol.2023.1988
• 发表时间: 2023-09-01
• 期刊: JAMA neurology
• 影响因子: 29

Lead-OR: A multimodal platform for deep brain stimulation surgery.

• DOI: 10.7554/elife.72929
• 发表时间: 2022-05-20
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Oxenford, Simon;Roediger, Jan;Neudorfer, Clemens;Milosevic, Luka;Guttler, Christopher;Spindler, Philipp;Vajkoczy, Peter;Neumann, Wolf-Julian;Kuehn, Andrea;Horn, Andreas
• 通讯作者: Horn, Andreas

A Human Depression Circuit Derived From Focal Brain Lesions.

• DOI: 10.1016/j.biopsych.2019.07.023
• 发表时间: 2019-11-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Padmanabhan JL;Cooke D;Joutsa J;Siddiqi SH;Ferguson M;Darby RR;Soussand L;Horn A;Kim NY;Voss JL;Naidech AM;Brodtmann A;Egorova N;Gozzi S;Phan TG;Corbetta M;Grafman J;Fox MD
• 通讯作者: Fox MD