Pearlson Godfrey D, Calhoun Vince D
Olin Neuropsychiatry Research Center, Institute of Living Hartford, CT 06106, USA.
Front Hum Neurosci. 2009 Nov 24;3:37. doi: 10.3389/neuro.09.037.2009. eCollection 2009.
In complex genetic disorders such as schizophrenia, endophenotypes have potential utility both in identifying risk genes and in illuminating pathophysiology. This is due to their presumed status as closer in the etiopathological pathway to the causative genes than is the currently defining clinical phenomenology of the illness and thus their simpler genetic architecture than that of the full syndrome. There, many genes conferring slight individual risk are additive or epistatic (interactive) with regard to cumulative schizophrenia risk. In addition the use of endophenotypes has encouraged a conceptual shift away from the exclusive study of categorical diagnoses in manifestly ill patients, towards the study of quantitative traits in patients, unaffected relatives and healthy controls. A more recently employed strategy is thus to study unaffected first-degree relatives of schizophrenia patients, who share some of the genetic diathesis without illness-related confounds that may themselves impact fMRI task performance. Consistent with the multiple biological abnormalities associated with the disorder, many candidate endophenotypes have been advanced for schizophrenia, including measures derived from structural brain imaging, EEG, sensorimotor integration, eye movements and cognitive performance (Allen et al., 2009), but recent data derived from quantitative functional brain imaging measures present additional attractive putative endophenotypes. We will review two major, conceptually different approaches that use fMRI in this context. One, the dominant paradigm, employs defined cognitive tasks on which schizophrenia patients perform poorly as "cognitive stress tests". The second uses very simple probes or "task-free" approaches where performance in patients and controls is equal. We explore the potential advantages and disadvantages of each method, the associated data analytic approaches and recent studies exploring their interface with the genetic risk architecture of schizophrenia.
在诸如精神分裂症这样的复杂遗传疾病中，内表型在识别风险基因和阐明病理生理学方面都具有潜在效用。这是因为与目前用于定义该疾病的临床现象学相比，它们在病因病理途径中被认为更接近致病基因，因此其遗传结构比整个综合征的遗传结构更简单。在那里，许多赋予个体轻微风险的基因在累积精神分裂症风险方面是相加的或上位性的（相互作用的）。此外，内表型的使用促使了一种概念上的转变，即从仅对明显患病患者的分类诊断研究，转向对患者、未患病亲属和健康对照的数量性状研究。因此，一种最近采用的策略是研究精神分裂症患者的未患病一级亲属，他们共享一些遗传素质，而没有可能自身影响功能磁共振成像任务表现的与疾病相关的混杂因素。与该疾病相关的多种生物学异常一致，许多候选内表型已被提出用于精神分裂症研究，包括源自结构性脑成像、脑电图、感觉运动整合、眼球运动和认知表现的测量指标（艾伦等人，2009年），但最近从定量功能性脑成像测量指标得出的数据呈现出另外一些有吸引力的假定内表型。我们将回顾在这种情况下使用功能磁共振成像的两种主要的、概念上不同的方法。一种是占主导地位的范式，采用精神分裂症患者表现不佳的特定认知任务作为“认知压力测试”。第二种使用非常简单的探测方法或“无任务”方法，患者和对照在这些方法中的表现是相同的。我们探讨每种方法的潜在优缺点、相关的数据分析方法以及最近探索它们与精神分裂症遗传风险结构之间联系界面的研究。
