Biobehavioral Predictors of Illness Progression in Adolescent Depression

青少年抑郁症疾病进展的生物行为预测因素

基本信息

批准号：
10580671
负责人：
Vilma Gabbay
金额：
$ 77.21万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580671
关键词：
Accounting Address Adolescent Adopted Adult Anhedonia Anterior Antioxidants Anxiety Behavioral Biological Biological Markers Blood Brain Brain region Cause of Death Cells Chronic Collection Corpus striatum structure Data Depressed mood Development Disease Exhibits Family Functional Magnetic Resonance Imaging Functional disorder Future Gambling Glutathione Goals Heterogeneity Hydrocortisone Immune Immunologic Stimulation Immunologics Individual Differences Inflammation Inflammatory Investigation Knowledge Kynurenine Laboratories Learning Magnetic Resonance Spectroscopy Maintenance Maps Marketing Measures Mediating Mental Depression Methods Modeling Morbidity - disease rate Neuroimmune Neuroimmunomodulation Neurotransmitters Outcome Outcome Measure Oxidative Stress Induction Pathway interactions Pattern Peripheral Pilot Projects Process Prospective Studies Protons Puberty Public Health Reporting Research Domain Criteria Rest Rewards Role Severities Stress Suicide Sum Symptoms Testing Trauma Visit Work Youth age group analytical method behavioral construct biobehavior causal model cell type child depression cingulate cortex computerized cytokine depressive symptoms experience follow-up gamma-Aminobutyric Acid indexing machine learning classification mortality multimodality neural neural circuit neurochemistry neuroimaging novel outcome prediction pleasure primary outcome prospective research clinical testing reward anticipation reward circuitry sex stressor subthreshold depression suicidal

项目摘要

PROJECT SUMMARY / ABSTRACT Adolescent depression is a major public health concern associated with significant morbidity and mortality. We know that adolescent depression varies considerably in severity and course, but its underlying mechanisms remain unknown. This proposal addresses this concern, aiming to identify biobehavioral predictors of illness trajectory in adolescents to inform treatment influencing its course. Our overall hypothesis is that reward dysfunction and its underlying neuro-immunological mechanisms contribute to maintenance of depression in youth. We propose the following model: (1) peripheral inflammation (e.g., cytokines, kynurenines) is associated with anhedonia; (2) inflammation extends to the CNS, inducing oxidative stress [↓glutathione (GSH, antioxidant)] and GABA (inhibitory neurotransmitter) deficits; (3) such neuro-chemical changes alter the reward circuitry, leading to anhedonia, and contribute to depression progression. In support, we documented that of adolescent depression’s core symptoms, only anhedonia—reflecting deficits in reward processes—and not irritability was associated with worse outcome, including suicidality and chronicity. We also reported associations between circulatory cytokines and kynurenines with both anhedonia and reward neurocircuitry. Utilizing proton MR spectroscopy (1H MRS), we showed that decreased anterior cingulate cortex (ACC) GABA in adolescent depression was driven by anhedonia. Additionally, using fMRI, we mapped striatal-based connectivity in relation to anhedonia and documented distinct neural activation patterns of reward anticipation and attainment—both reward processes that contribute to anhedonia. In pilot studies, we found that ACC GABA and reward- anticipation brain activation predicted anhedonia severity at 2-year follow-up. Building upon our compelling findings to date, we propose a prospective study of reward processes and neuroimmunological mechanisms, with the goal to identify modifiable pathways predictive of depression course in adolescents. We will study 120 adolescents with depressive symptoms. Three in-laboratory comprehensive clinical evaluation and computerized reward task sessions will be done at baseline, 12-, and 24-month follow-ups. At baseline and 12 months, visits will include: a) immune blood collection for kynurenine metabolites, immune cell profiling, and cytokine secretion post immune stimulation (as a biological stressor); b) fMRI resting state and tasks examining distinct reward processes (e.g., anticipation, attainment, learning); and c) 1H MRS to probe ACC GABA and striatal GSH as indices for inflammatory neurometabolic consequences in reward-related brain regions. Outcome measures will include anhedonia severity (primary), along with depression severity, functioning, anxiety, and suicidality. Principled variable selection approach will address multiple comparison concerns. Dynamic causal modeling and machine learning classification methods will explore the relationships among all examined factors.

项目概要/摘要青少年抑郁症是一个与显着发病率和死亡率相关的主要公共卫生问题。知道青少年抑郁症的严重程度和病程差异很大，但其潜在机制该提案解决了这一问题，旨在确定疾病的生物行为预测因素。我们的总体假设是奖励。功能障碍及其潜在的神经免疫机制有助于维持抑郁症我们提出以下模型：（1）外周炎症（例如细胞因子、犬尿氨酸）相关。伴有快感缺乏；（2）炎症延伸至中枢神经系统，诱发氧化应激[↓谷胱甘肽（GSH，抗氧化剂）] 和 GABA（抑制性神经递质）缺陷；（3）这种神经化学变化改变了奖励回路，导致快感缺乏，并导致抑郁症的进展，为了支持这一点，我们记录了青少年的情况。抑郁症的核心症状只有快感缺乏——反映了奖励过程的缺陷——而不是烦躁与更糟糕的结果相关，包括自杀和慢性病之间的关联。利用质子 MR 检测循环细胞因子和犬尿氨酸，同时具有快感缺乏和奖赏神经回路。光谱（1H MRS），我们发现青少年前扣带皮层（ACC）GABA 减少此外，使用功能磁共振成像，我们绘制了基于纹状体的连接关系。到快感缺失，并记录了奖励预期和获得的不同神经激活模式——两者在试点研究中，我们发现 ACC GABA 和奖励过程会导致快感缺乏。预期大脑激活可预测两年随访中快感缺失的严重程度。迄今为止的发现，我们提出了一项关于奖励过程和神经免疫机制的前瞻性研究，为了确定青少年抑郁症的可修改预测途径，我们将研究 120。具有抑郁症状的青少年的三个实验室综合临床评估和计算机化。奖励任务会议将在基线、12 个月和 24 个月的随访中进行在基线和 12 个月的随访中。将包括：a) 犬尿氨酸代谢物的免疫血液采集、免疫细胞分析和细胞因子分泌免疫刺激后（作为生物应激源）；b）功能磁共振成像静息状态和检查不同奖励的任务过程（例如预期、达到、学习）；和 c) 1H MRS 探测 ACC GABA 和纹状体 GSH 与奖励相关的大脑区域的炎症神经代谢后果的指数将。包括快感缺失的严重程度（主要），以及抑郁的严重程度、功能、焦虑和自杀倾向。有原则的变量选择方法将解决多重比较问题和动态因果建模。机器学习分类方法将探索所有检查因素之间的关系。