Sub-second neurochemistry of error signals and affective processing in depression

项目摘要 长期以来，血清素和多巴胺功能障碍一直与抑郁症的病理生理学有关。 然而，到目前为止，描绘这些神经调质在抑郁症中的作用在很大程度上是必要的， 依赖于推断，神经成像（包括PET，fMRI，EEG）研究揭示了大脑中的反应 与多巴胺和5-羟色胺释放相关的区域以及靶向多巴胺能和 肾上腺素能系统改善某些个体的症状。为了取得重大进展， 了解抑郁症的神经基础并开发新的治疗方法， 需要快速、准确地在体内跟踪神经调节剂反应。 最新的进展允许前所未有的能力，跟踪神经调质反应与高 时间分辨率和化学特异性。具体来说，我们能够直接同时测量 清醒人类的多巴胺和5-羟色胺反应，需要时间分辨率（~ 10 ms）， 研究神经调质释放与决策过程的关系。这些的产物 在亚秒分辨率下记录体内神经调节剂波动。本申请 将MPI Chiu的临床和情感神经科学专业知识与MPI Montague的这些进展相结合， 直接研究多巴胺和血清素对抑郁症的反应。 为了实现这一目标，我们将记录耐药的参与者的神经调质反应。 已经有颅内深部电极用于II期监测的癫痫患者。深度电极 由弗吉尼亚理工大学医疗附属机构Carilion Clinic（Project Co-I）的神经外科同事植入 Witcher; Carpet Clinic临床研究中心PI）。在记录期间，参与者将处于标准（即，非手术） 医院监测套件并执行i）情感处理任务（情绪Stroop）和ii）基于价值观 学习任务（双臂强盗）已经被我们的小组和其他人证明都参与过程 被认为与血清素和多巴胺功能有关，也与消极情绪有关， 快感缺失症状，分别是抑郁症。

PROJECT SUMMARY Serotonin and dopamine dysfunction have been long implicated in the pathophysiology of major depression. However, to date, delineating the role of these neuromodulators in depression has largely and necessarily relied on inference, with neuroimaging (including PET, fMRI, EEG) studies revealing responses in brain regions associated with dopamine and serotonin release and medications targeting the dopaminergic and serotoninergic systems improving symptoms for some individuals. In order to make significant advances in understanding the neural underpinnings of depression and developing novel therapeutics for the disorder, tracking neuromodulator responses quickly, accurately, and in vivo is required. Recent advances allow exactly the unprecedented ability to track neuromodulator responses with high temporal resolution and chemical specificity. Specifically, we are able to directly and simultaneously measure dopamine and serotonin responses in awake humans with the temporal resolution (~ 10 ms) required to examine the relationship of neuromodulator release with decision-making processes. The product of these advances is recordings of in vivo neuromodulator fluctuations at sub-second resolution. This application merges the clinical and affective neuroscience expertise of MPI Chiu with these advances of MPI Montague to directly examine the relationship of dopamine and serotonin responses to depression. To achieve this goal, we will record neuromodulator responses in participants with medication-resistant epilepsy who already have intracranial depth electrodes in place for phase-II monitoring. The depth electrodes are implanted by our neurosurgery colleagues at Virginia Tech’s medical affiliate Carilion Clinic (Project Co-I Witcher; Carilion Clinic clinical site PI). During recording, participants will be in a standard (i.e., non-surgical) hospital monitoring suite and perform i) an affective processing task (emotional Stroop) and ii) a value-based learning task (two-arm bandit) that have been shown by our group and others both to engage processes thought to be related to serotonin and dopamine function, and also to be related to negative mood and anhedonia symptoms, respectively, of depression.