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

项目摘要 抑郁症是全球残疾的主要原因，需要新的治疗方法。识别大脑 导致抑郁症状的区域可以导致治疗目标和更好的治疗。然而，识别 这些地区是困难的。患者的神经成像确定了与活动相关的大脑区域， 抑郁症的症状，但不能确定这些区域是否真正导致症状。动物模型 允许因果操纵，但只能近似人类症状。该基金的目标是将 抑郁症症状与人类神经解剖学的因果关系。在这里，我重点介绍两个信息来源 可以提供这些神经解剖学上的因果联系。第一种是脑局灶性病变的患者， 抑郁症症状第二种是接受了局灶性脑刺激的抑郁症患者， 症状缓解。在这两种情况下，症状和病变部位之间存在因果关系， 刺激.然而，这种因果关系可能是间接的。病变引起的症状可能来自大脑区域 连接到病变位置而不是病变位置本身。同样，大脑刺激的好处可以 来自与刺激部位相连的远端区域的调制。因此，利用这些因果关系 信息来源需要一张人类大脑连接图。由于美国国立卫生研究院的倡议，如人类 连接组计划和高功率MRI扫描仪，这样的地图现在是可用的。我最近开发了一种 一种使用这些大脑连接图来更好地定位病变引起的症状并识别 介导对局部脑刺激的反应的区域。在这里，我利用这项技术来识别大脑区域， 引起抑郁症状（Aim 1）和介导抗抑郁药对局灶性脑反应的脑区 刺激（目标2）。成功完成这些目标将有助于深入了解因果神经解剖学 抑郁症状的底物。这些知识将有助于鉴定生物标志物，以评估 未来的治疗方法，侵入性和非侵入性脑刺激的最佳治疗靶点， 基于患者特定症状特征的目标。然后，这些治疗目标可以在以下方面进行经验性测试： 未来的治疗试验

PROJECT SUMMARY Depression is the leading cause of disability worldwide and new treatments are needed. Identifying the brain regions causing depression symptoms can lead to treatment targets and better therapies. However, identifying these regions has been difficult. Neuroimaging of patients identifies brain areas where activity correlates with depression symptoms, but can't determine whether these regions actual cause symptoms. Animal models allow for causal manipulations, but only approximate human symptoms. The goal of this grant is to link depression symptoms to human neuroanatomy in a causal way. Here I focus on two sources of information that can provide theses causal neuroanatomical links. The first is patients with focal brain lesions causing depression symptoms. The second is patients with depression who have received focal brain stimulation for symptomatic relief. In both cases, there is a causal link between symptoms and the site of the lesion or stimulation. However, this causal link can be indirect. Lesion-induced symptoms can come from brain regions connected to the lesion location rather than the lesion location itself. Similarly, benefits of brain stimulation can come from modulation of distant regions connected to the site of stimulation. As such, utilizing these causal sources of information requires a map of human brain connectivity. Due to NIH initiatives like the human connectome project and high powered MRI scanners, such maps are now available. I've recently developed a technique that uses these brain connectivity maps to better localize lesion induced symptoms and identify regions mediating response to focal brain stimulation. Here, I leverage this technique to identify brain regions causing depression symptoms (Aim 1) and brain regions mediating antidepressant response to focal brain stimulation (Aim 2). Successful completion of these aims will lend insight into the causal neuroanatomical substrate of depression symptoms. Such knowledge will facilitate identification of biomarkers for evaluating future therapies, optimal therapeutic targets for invasive and noninvasive brain stimulation, and individualized targets based on patient-specific symptom profiles. These treatment targets can then be empirically tested in future therapeutic trials.