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

奖励处理和抑郁亚型：识别与自杀风险、复原力和治疗反应相关的神经生物型

• 批准号: 10595485
• 负责人: SUSANNA FRYER
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595485
• 关键词: Age; Anhedonia; Behavior; Behavior assessment; Behavioral; Biological Markers; Brain; Choice Behavior; Classification; Clinic; Clinical; Cognitive; Cognitive Therapy; Complex; Data; Decision Making; Depressed mood; Diagnosis; Disease; Electroencephalography; Evaluation; Event; Feedback; Feeling suicidal; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Healthcare Systems; Heterogeneity; Individual; Major Depressive Disorder; Measures; Mental Depression; Mental Health Services; Methodology; Methods; Modality; Motivation; Neurobiology; Neurosciences; Output; Pattern; Precision therapeutics; Prediction of Response to Therapy; Prevalence; Process; Psychiatric therapeutic procedure; Recurrence; Rewards; Risk Assessment; Severities; Subgroup; Suicide attempt; Symptoms; System; Taxonomy; Testing; Time; United States; Variant; Veterans; Work; biomarker discovery; biotypes; case control; clinically relevant; comparison group; cost; depressive symptoms; disability; discounting; disease classification; functional magnetic resonance imaging/electroencephalography; hedonic; ideation; improved; individual variation; insight; military veteran; multimodality; neural; neurobiological mechanism; neuromechanism; personalized health care; personalized medicine; pleasure; psychiatric comorbidity; resilience; response; reward anticipation; reward processing; segregation; suicidal; suicidal risk; therapy resistant; trait; treatment planning; treatment response; unsupervised learning

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.

在抑郁表现中很常见，痛苦和动机很常见，被认为是 由大脑预期，评估和自适应使用与奖励相关的方式的改变引起的 信息。但是，奖励处理是一种复杂的多电路现象，并且是确切的中性 导致缺乏或减少典型享乐和动机产出的机制 该诊所仍在阐明。抑郁症临床表现的异质性长期以来一直是 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。 这种异质性使人们对抑郁病理生理学的理解变得复杂，而阻碍了 个性化疾病分类和治疗计划。如果精神科中个性化医学的目标 要认识的是，要考虑到全部抑郁表现的生物标志物需要 开发（并最终得到验证）。发现超出整体疾病水平的生物标志物 说明神经生物学变异的定义大概是不同的临床表现的基础 对于这项更大的努力至关重要。 提议的工作组合通过对神经生物学的深入研究以临床动机的问题 评估奖励系统神经生物学如何有助于表达与奖励相关的缺陷的机制， 例如，抗抑郁症（MDD）的抗痛和动机，特别强调 了解抑郁异质性。从概念上讲，我们将通过研究使用多种测量方法 i）一个被动插槽机奖励任务，以隔离大脑反应以奖励预期和 在没有混淆的高阶认知需求的情况下，收据，ii）延迟缩短任务 评估奖励价值和决策所需的奖励处理的高阶方面。 从方法上讲，我们将通过结合fMRI，脑电图和行为方式使用多模式的方法 评估，以更充分地表征与奖励相关的大脑功能及其临床相关性。此外 评估具有MDD和健康对照（HC）的退伍军人之间的奖励效应，并检查 大型（n = 150）MDD组内的抑郁异质性，我们还将专注于理解 奖励处理与与抑郁的高相关性的临床特征之间的关系， 强调自杀。具体目标1将在奖励处理中定义在 组平均值（即MDD与HC的病例对照比较）。具体目标2将检查范围 哪些数据驱动的MDD亚型可以根据我们的脑电图和fMRI奖励来得出退伍军人的“生物型” 处理指标，隔离临床相关的特征。特定目标3将比较 自杀水平不同的MDD。