Neuroinflammation and PVS Deficits in Adolescents

描述（由申请人提供）：青春期是许多精神症状首次出现的关键发育时期。人们一直认为，奖赏回路的共同改变是青少年发病精神疾病发展的基础。为了解决在精神病理学早期识别生物标志物的关键需求，这个RDoC项目研究了青少年特定奖励过程的神经免疫学。具体来说，我们关注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，本项目考察了奖励预期（RE）与奖励获得的初始反应（IRRA），反映了奖励预期和接受。本研究探讨了一种新的理论，假设外周炎症和相关纹状体代谢变化诱导了奖励回路的特异性改变，这种改变在临床上表现为快感缺乏。我们研究了快感缺乏症的神经免疫学和神经回路，发现犬尿氨酸途径（KP）的外周活性（中枢神经免疫途径）与青少年快感缺乏症的严重程度呈正相关。利用磁共振波谱（1H MRS），我们记录了青少年缺乏症患者血液KP神经毒素与纹状体胆碱（脂质过氧化的生物标志物）之间的关联，以及成人大脑谷胱甘肽（抗氧化剂）与缺乏症严重程度之间的反比关系。使用功能磁共振成像，我们绘制并确定了与快感缺乏相关的独特的基于纹状体的内在功能连接（iFC）。此外，我们还开发了区分RE和IRRA的奖励侧卫任务（RFT）。基于这些令人信服的初步数据，我们提出了一项多模式研究来检查特异性PVS缺陷的神经免疫学。我们将研究100名具有不同精神症状（NOS，或完全综合征）的无精神药物青少年和30名健康对照组，年龄12-18岁，Tanner 4。该研究将包括全面、系统的诊断程序，包括快感缺乏、负面影响、疲劳和睡眠的维度评估。外周炎症测量将包括KP活性以及先天和适应性免疫区室的激活状态以及对心理和生物应激的反应。HPA轴将由唾液皮质醇水平索引。中枢神经系统炎症将通过1H MRS测量反映纹状体（奖赏回路中的关键区域）氧化应激、脂质过氧化和线粒体功能的化学物质来探测。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.