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

快感缺乏和运动障碍在抑郁症状中很常见，推测是 由大脑预测、评估和适应性地使用与奖励相关的方式的改变引起的 信息。然而，奖赏加工是一个复杂的、多回路的现象，而且是精确的神经 导致典型的享乐主义和激励性产出缺失或减少的机制见 该诊所仍在澄清中。抑郁症临床表现的异质性长期以来一直是一种 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。 这种异质性使对抑郁症病理生理学的理解复杂化，并阻碍了 个性化疾病分类和治疗计划。如果精神科个体化医疗的目标是 需要注意的是，解释各种抑郁症表现的生物标记物需要 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问题和对神经生物学的深入研究。 评价奖赏系统神经生物学如何影响奖赏相关缺陷表达的机制， 如严重抑郁障碍(MDD)中的快感缺乏和运动障碍，特别强调 了解抑郁的异质性。从概念上讲，我们将使用多指标方法，通过研究 有i)被动老虎机奖励任务的退伍军人，分离大脑对奖励预期和奖励的反应 在没有混淆更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更高层次。 在方法上，我们将使用多通道方法，将fMRI、EEG和行为学结合起来 评估，以更全面地描述与奖励相关的大脑功能及其临床相关性。此外 目的：评价退伍军人MDD患者与健康对照(HC)的奖赏效应，并检查 在一个大的(n=150)MDD组中，抑郁的异质性，我们还将重点了解 奖赏加工与与抑郁症高度相关的临床特征的关系 强调自杀性。具体目标1将在奖励处理层面上建立MDD赤字 组平均数(即MDD与HC的病例对照比较)。具体目标2将审查以下方面的程度 根据我们的EEG和fMRI奖励，哪种数据驱动的MDD亚型可以在退伍军人中得出“生物型” 处理指标，分离临床相关特征。特定目标3将比较以下几个子组 有不同程度自杀倾向的MDD。

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.