Neuroinflammation and PVS Deficits in Adolescents

描述(申请人提供)：青春期是一个关键的发展时期，在此期间许多精神症状首次出现。有人争辩说，奖赏回路中的常见变化是青少年精神疾病发展的基础。这个RDoC项目解决了在精神病理学课程早期识别生物标记物的关键需求，检查了青少年特定奖励过程的神经免疫学。具体地说，我们专注于快感缺乏的临床现象学，这是精神疾病的一个显著特征，通常表现为前驱精神症状。然而，快感缺乏代表了几种不同的PVS缺陷的最终临床结果。因此，这个项目检查了奖励期望(RE)与对奖励获得的初始反应(IRRA)，反映了奖励预期和收到。这项研究调查了一种新的理论假设，即外周炎症和相关的纹状体代谢变化导致奖赏回路的特定变化，临床表现为快感缺乏。我们研究了快感缺乏的神经免疫学和神经元回路，发现犬尿氨酸途径(KP)的外周活性与青少年快感缺乏的严重程度呈正相关。使用磁共振波谱(1HMRS)，我们记录了快感厌食症青少年血液KP神经毒素和纹状体胆碱(脂质过氧化的生物标记物)之间的关联，以及成人中脑谷胱甘肽(抗氧化剂)和快感缺失严重程度之间的负相关关系。使用功能磁共振成像，我们定位并确定了与快感缺失相关的不同的纹状体固有功能连接(IFC)。此外，我们开发了区分RE和IRRA的奖励侧翼任务(RFT)。在这些令人信服的初步数据的基础上，我们建议进行一项多模式研究，以检查特定PVS缺陷的神经免疫学。我们将研究100名患有不同精神症状(NOS或全部症状)的不服用精神药物的青少年和30名健康对照组，年龄12-18岁，年龄4岁。这项研究将包括全面、系统的诊断程序，包括快感缺乏、消极情绪、疲劳和睡眠的维度评估。外周炎症指标将包括KP活性以及先天和获得性免疫隔间的激活状态以及对心理和生物应激的反应。HPA轴将以唾液皮质醇水平为指标。1HMRS将通过测量反映纹状体中氧化应激、脂质过氧化和线粒体功能的化学物质来探测中枢神经系统的炎症，纹状体是奖赏回路中的一个关键区域。具体的奖励过程将使用RFT和基于纹状体的IFC进行研究。

DESCRIPTION (provided by applicant): Adolescence is a critical developmental period during which many psychiatric symptoms first emerge. It has been argued that common alterations within the reward circuitry underlie the development of adolescent-onset psychiatric conditions. Addressing a critical need for the identification of biomarkers early in the course of psychopathologies, this RDoC project examines the neuroimmunology of specific reward processes in adolescents. Specifically, we focus on the clinical phenomenology of anhedonia, a salient feature across psychiatric conditions that often presents as a prodromal psychiatric symptom. However, anhedonia represents a final clinical outcome of several distinct PVS deficits. Therefore, this project examines Reward Expectancy (RE) versus Initial Responsiveness to Reward Attainment (IRRA), reflecting reward anticipation and receipt. This research investigates a novel theory hypothesizing that peripheral inflammation and associated striatal metabolic changes induce specific alterations in the reward circuitry that clinically manifest as anhedonia. We have studied the neuroimmunology and neuronal circuitry of anhedonia and found positive associations between peripheral activity of the kynurenine pathway (KP)-a central neuroimmunological pathway-and anhedonia severity in adolescents. Using MR spectroscopy (1H MRS), we documented associations between blood KP neurotoxins and striatal choline (biomarker for lipid peroxidation) in anhedonic adolescents along with inverse relationships between brain glutathione (antioxidant) and anhedonia severity in adults. Using fMRI, we mapped and identified distinct striatal-based intrinsic functional connectivity (iFC) associated with anhedonia. Additionally, we developed the reward flanker task (RFT) that distinguishes between RE and IRRA. Building upon these compelling preliminary data, we propose a multimodal study to examine the neuroimmunology of specific PVS deficits. We will study 100 psychotropic-free adolescents with diverse psychiatric symptomology (NOS, or full syndromes) and 30 healthy controls group-matched, ages 12-18, Tanner e 4. The study will consist of comprehensive, systematic diagnostic procedures that include dimensional assessments of anhedonia, negative affect, fatigue, and sleep. Peripheral inflammatory measures will include KP activity along with activation status of innate and adaptive immune compartments and responses to both psychological and biological stresses. HPA axis will be indexed by saliva cortisol levels. CNS inflammation will be probed by 1H MRS by measuring chemicals reflecting oxidative stress, lipid peroxidation and mitochondrial function in the striatum, a key region within the reward circuitry. Specific reward processes will be studied using the RFT and striatal based iFC.