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

项目总结：使用人脑连接来识别因果神经解剖学 抑郁症状基质 抑郁症是全球残疾的主要原因。识别导致抑郁症的大脑区域 症状可以导致更好的治疗目标和疗法。大多数神经影像学研究确定大脑区域 活动与抑郁症状相关，但无法确定这些区域是否真的 引起症状。该项目的目标是将抑郁症状与人类神经解剖学联系起来。 损伤和脑刺激可以提供与人类神经解剖学的因果联系。因为症状可能来自 从连接到病变或刺激部位的区域，我们研究这些部位的连接性（不仅仅是它们的 位置）使用来自大群正常受试者的脑连接性数据（功能连接性MRI， n=1000）。这使我们能够将损伤或刺激引起的症状映射到大脑回路， 患者自身的连接数据。在NIMH的支持下，我们发现， 磁刺激（TMS）部位和深部脑刺激（DBS）部位， 症状都连接到14个独立数据集上的共同大脑回路（Siddiqi et. 2021年 自然人类行为）。与该回路的连接性是抗抑郁药反应的一个更好的预测因子， TMS或DBS比到其他候选区域的连接性（例如，亚膝扣带）。然而，这条线路 在将其转化为临床试验的目标之前需要验证。在这里，我们将验证我们的大脑 使用三个独立的因果信息源：病变（目标1）、DBS（目标2）和 TMS（目标3）。对于所有的目标，我们将使用我们发表的先验抑郁电路来预测整体抑郁症 成果。我们还将进行探索性的数据驱动分析，以测试不同的电路是否 导致不同的抑郁症状在目标1中，我们将前瞻性地测试我们的抑郁症是否 电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 预测不同诊断的大范围DBS患者DBS后抑郁评分的变化。在 目标3，我们将测试与我们回路的个体化连接是否前瞻性地预测抑郁症的变化 TMS的症状完成这些目标将验证我们的抑郁症电路在不同的诊断 并跨越三个独立的因果信息来源，提供比可能更强的验证。 仅通过一种方式实现。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回路。

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.