Biobehavioral Predictors of Illness Progression in Adolescent Depression

项目摘要/摘要 青少年抑郁症是一个主要的公共卫生问题，与严重的发病率和死亡率有关。我们 知道青少年抑郁症在严重程度和病程上有相当大的差异，但其潜在的机制 仍然不为人所知。这项建议解决了这一问题，旨在确定疾病的生物行为预测因素。 青少年的轨迹，以告知影响其进程的治疗。我们的总体假设是奖励 功能障碍及其潜在的神经免疫学机制与抑郁症的维持 青春年华。我们提出了以下模型：(1)外周炎症(如细胞因子、犬尿氨酸)与 (2)炎症蔓延至中枢神经系统，导致氧化应激[↓谷胱甘肽(谷胱甘肽，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赏回路， 导致快感缺乏，并导致抑郁症的进展。在支持方面，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--反映奖励过程的缺陷--而不是易怒 与更糟糕的结果相关，包括自杀和慢性病。我们还报告了两者之间的联系 循环细胞因子和犬尿氨酸既有快感缺乏又有奖赏神经回路。利用质子磁共振 波谱(~1H MRS)显示青少年扣带回前部(ACC)GABA减少 抑郁症是由快感缺失引起的。此外，使用功能磁共振成像，我们绘制了基于纹状体的连接之间的关系 与快感缺乏有关，并记录了奖励预期和实现的不同神经激活模式-两者 奖励导致快感缺乏症的过程。在试点研究中，我们发现ACC GABA和奖励- 预期脑激活可预测2年随访期快感缺乏的严重程度。建立在我们令人信服的 到目前为止，我们建议对奖励过程和神经免疫学机制进行前瞻性研究， 目的是确定预测青少年抑郁症病程的可修改路径。我们将研究120 有抑郁症状的青少年。三个实验室的临床综合评价及计算机化 奖励任务将在基线、12个月和24个月的跟踪调查中完成。在基线和12个月时，访问 将包括：a)免疫血液采集犬尿氨酸代谢物、免疫细胞图谱和细胞因子分泌 免疫后刺激(作为生物应激源)；b)功能磁共振静息状态和任务检查不同的奖励 过程(例如，预期、获得、学习)；以及c)1H MRS以探测ACC GABA和纹状体GSH AS 奖赏相关脑区炎性神经代谢后果的指标。结果衡量标准将 包括快感缺乏的严重程度(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。动态因果建模和 机器学习分类方法将探索所有被检查因素之间的关系。

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.