Neurocognitive endophenotypes of obsessive compulsive disorder and their brain correlates

强迫症(OCD)的原因还不够清楚。这可能是由于对这种疾病的临床现象学描述的病因学有效性有限。尽管有强有力的证据表明，双胞胎和家庭研究中的强迫症特征和精神障碍具有遗传性，但到目前为止，与基因变异之间的关联还很弱。精神障碍的内表型(EPT)是比临床综合征本身更接近生物学基础的数量生物学或认知特征。因此，它们有望使寻找相关基因更有效率，促进相互作用的心理因素的检测，并总体上促进更好的致病模型和更好的治疗方法的发展。目前，有非常有希望的证据表明有三名EPT候选人患有强迫症。它们是：1.与动作监控相关的事件相关脑电位；2.内源性动作启动的眼跳指标；3.运动反应抑制的行为指标。然而，这些EPT候选者只在小样本研究中得到证实，他们与强迫症症状尺寸和亚型以及他们的神经基础的关系尚不清楚。我们计划使用足够大的样本进一步分析这三个候选者，以便a)确认它们是可靠的强迫症EPT，b)将它们与强迫症症状尺寸和发病年龄具体联系起来，以及c)测试EPT候选者与结构和功能大脑测量的关系。作为未来的展望，将测试已确认的EPT变量与候选基因变异的关联，并将进行专注于EPTS影响的纵向研究。在本项目中，我们的目标是比较200名强迫症患者、200名强迫症患者的一级亲属和200名健康对照受试者。本办法的一个主要优点是以足够的力量重新审查和扩展相关调查结果，并将其纳入一个连贯的模式。本项目将在两个研究中心(柏林、波恩)进行，以有希望的大量试验性研究为基础，结合两个贡献研究小组的研究和方法专长。

The causes for obsessive-compulsive disorder (OCD) are insufficiently known. This is probably due to the limited etiological validity of the clinical-phenomenological description of the disorder. Despite strong evidencefor heritability of obsessive-compulsive traits and disorder in twin and family studies only weak associations with gene variants have been established so far. Endophenotypes (EPT) for mental disorders are quantitativebiological or cognitive traits that are closer to the biological underpinnings than the clinical syndrome itself. Therefore, they are expected to make the search for relevant genes more efficient, to facilitate the detection of interacting psychological factors, and, generally, to foster the development of better pathogenetic models and better therapies. At present, there is highly promising evidence for three EPT candidates for OCD. Those are 1. Event-related brain potential correlates of action monitoring, 2. Saccadic indicators of endogenuous action initiation, and 3. behavioral indicators of motor response inhibition. However, these EPT candidates have been confirmed in small sample studies only, and their relation to symptom dimensions and subtypes of OCD as well as to their neural underpinnings remains unclear as yet. We plan to further analyse the three candidates using an adequately large sample, in order to a) confirm them as reliable EPTs of OCD, b) relate them specifically to OCD symptom dimensions and age at disease onset, and c) test the relationship of the EPT candidates to structural and functional brain measures. As a future perspective, associations of confirmed EPT variables with candidate gene variants will be tested, and longitudinal studies focusing on the effects of EPTs will be conducted. In the present project, we aim to compare 200 patients with OCD, 200 first-degree relatives of OCD patients, and 200 healthy comparison subjects. A main strength of the present approach is its reexamination and extension of relevant findings with sufficient power and the integration into a coherent model. The present project will be conducted in two research centers (Berlin, Bonn), is based on promising and substantial pilot studies and combines the research and methodological expertise of the two contributing research groups.