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

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 抑郁症是全球残疾的主要原因，需要新的治疗方法。辨认大脑 导致抑郁症状的区域可以导致治疗目标和更好的治疗方法。然而，识别 这些地区一直很困难。患者的神经成像确定了与活动相关的大脑区域 抑郁症状，但不能确定这些区域是否真正引起症状。动物模型 允许进行因果操作，但仅允许近似人类症状。这笔赠款的目标是将 抑郁症状与人类神经解剖学有因果关系。在这里，我将重点介绍两个信息来源 可以提供这些因果神经解剖学联系。第一种是脑局灶性病变的患者 抑郁症状。第二个是抑郁症患者，他们接受了局部脑刺激 症状缓解。在这两种情况下，症状与病变部位或 刺激。然而，这种因果联系可能是间接的。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距离区域的调制。因此，利用这些因果关系 信息源需要一张人脑连接图。由于国家卫生研究院的倡议，如人类 Connectome项目和高功率核磁共振扫描仪，这样的地图现在可以使用。我最近开发了一种 一种使用这些大脑连接图更好地定位病变引起的症状和识别 对局灶性脑刺激的反应进行调节的区域。因为该技术利用了现有的连接性 数据，它不需要患者本身的连接成像。因此，这项技术可以是 应用于任何损伤或刺激数据集，并已提供了对各种神经精神病学的见解 症状。在这里，我利用这项技术来识别导致抑郁症状的大脑区域(目标1)和 调节局部脑刺激的抗抑郁反应的脑区(目标2)。成功完成 这些目的将有助于深入了解抑郁症症状的因果神经解剖学基础。是这样的 知识将有助于识别用于评估未来治疗、最佳治疗靶点的生物标记物 用于侵入性和非侵入性脑刺激，以及基于患者特定症状的个性化靶点 配置文件。这些治疗目标随后可以在未来的治疗试验中进行经验性测试。

PROJECT SUMMARY: Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms 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. Because this technique utilizes existing connectivity data, it does not require connectivity imaging of the patients themselves. As such, the technique can be applied to any lesion or stimulation dataset and has already lent insight into a variety of neuropsychiatric symptoms. Here, I leverage this technique to identify brain regions causing depression symptoms (Aim 1) and brain regions mediating anti-depressant 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.