Reward processing and depressive subtypes: Identifying neural biotypes related to suicide risk, resilience, and treatment response

快感缺乏和动机丧失在抑郁症中很常见， 这是由大脑预期、评估和自适应地使用与奖励相关的信息的方式改变引起的。 信息.然而，奖励处理是一个复杂的，多回路的现象，精确的神经网络 导致缺乏或减少典型的享乐和动机输出的机制， 诊所的情况还在调查中抑郁症的临床表现中的异质性一直是一个重要的问题。 规则而不是例外，包括症状，严重程度和治疗反应的个体差异。 这种异质性使得对抑郁症病理生理学的理解变得复杂，并阻碍了抑郁症治疗的进展。 个性化疾病分类和治疗计划。如果精神科个性化医疗的目标 护理是要意识到，生物标志物，占抑郁症的全部表现需要 开发（并最终验证）。发现超越聚集性疾病水平的生物标志物 解释神经生物学变异的定义，这些变异可能是不同临床表现的基础 对这项更大的努力至关重要。 拟议的工作结合了临床动机的问题，深入研究神经生物学 机制，以评估奖励系统神经生物学如何有助于表达奖励相关的缺陷， 例如重度抑郁症（MDD）中快感缺乏和动力丧失，特别强调 理解抑郁异质性从概念上讲，我们将使用多测量方法，通过研究 退伍军人与i）一个被动的老虎机奖励任务，以隔离大脑的反应，奖励预期， 在没有混淆高阶认知需求的情况下接收，以及ii）延迟折扣任务， 评估奖励评估和决策所需的奖励处理的高阶方面。 在方法上，我们将使用多模态方法，结合功能磁共振成像，脑电图和行为 评估，以更全面地表征奖励相关的大脑功能及其临床相关性。此外 评估MDD退伍军人和健康对照（HC）之间的奖励效应，并检查 在一个大的（n=150）MDD组中的抑郁异质性，我们还将重点了解 奖励处理与抑郁症高度相关的临床特征之间的关系， 强调自杀倾向。具体目标1将在以下水平建立奖励处理中的MDD缺陷： 组平均值（即，MDD与HC的病例对照比较）。具体目标2将审查 根据我们的脑电图和功能磁共振成像结果， 处理度量，分离临床相关特征。具体目标3将比较 有不同程度的自杀倾向。

Anhedonia and amotivation are common in depressive presentations, and putatively thought to be caused by alterations in the ways in which the brain anticipates, evaluates, and adaptively uses reward-related information. However, reward processing is a complex, multi-circuit phenomenon, and the precise neural mechanisms that contribute to the absence or reduction of typical hedonic and motivational outputs seen in the clinic are still being elucidated. Heterogeneity in the clinical presentation of depression has long been a rule rather than an exception, including individual variation in symptoms, severity, and treatment response. This heterogeneity complicates understanding of depressive pathophysiology and thwarts progress toward personalized disease classification and treatment planning. If the goal of personalized medicine in psychiatric care is to be realized, biomarkers that account for the full range of depressive presentations need to be developed (and ultimately validated). Discovery of biomarkers that go beyond the level of aggregate disease definitions to account for neurobiological variation that presumably underlies distinct clinical manifestations is critical to this larger effort. The proposed work combines clinically motivated questions with in-depth study of neurobiological mechanisms to evaluate how reward system neurobiology contributes to expression of reward-related deficits, such as anhedonia and amotivation in major depressive disorder (MDD), with a particular emphasis on understanding depressive heterogeneity. Conceptually, we will use a multi-measure approach, by studying Veterans with i) a passive slot machine reward task to isolate brain responses to reward anticipation and receipt in the absence of confounding higher-order cognitive demands, and ii) a delay-discounting task to assess higher-order aspects of reward processing necessary for reward valuation and decision-making. Methodologically, we will use a multi-modality approach by combining fMRI, EEG, and behavioral assessment, to more fully characterize reward-related brain functions and their clinical correlates. In addition to evaluating reward effects between Veterans with MDD and healthy controls (HC), and examining depressive heterogeneity within a large (n=150) MDD group, we will also focus on understanding the relationship between reward processing and clinical features of high relevance to depression, with an emphasis on suicidality. Specific Aim 1 will establish MDD deficits in reward processing at the level of group averages (i.e., case-control comparisons of MDD vs. HC). Specific Aim 2 will examine the extent to which data-driven subtyping of MDD can derive “biotypes” in Veterans, based on our EEG and fMRI reward processing metrics, that segregate clinically relevant features. Specific Aim 3 will compare subgroups of MDD with varying levels of suicidality.