Perceptual Organization Dysfunction as a Biomarker of Schizophrenia

描述（由申请人提供）：NIMH matrix和CNTRICS计划明确了认知功能领域，这些领域与针对精神分裂症患者改善认知和功能的治疗开发最相关。这些项目还确定了特定的任务，这些任务在心理测量学上是合理的，并且在患者群体中得到了很好的验证，而且，在CNTRICS的情况下，已经很好地理解了神经生理学。最近，人们对确定符合这些标准并对治疗效果敏感的任务越来越感兴趣。识别这些任务对于我们在认知神经科学框架内理解疾病进展和恢复过程是重要的。这些信息也将允许基于认知神经科学的治疗反应指标，因此更有针对性的药物开发工作和药物反应的早期预测。这类任务的有希望的候选者是知觉组织的测量。知觉组织的选定测试符合心理测量的可靠性标准（包括避免广义缺陷混淆），在患者研究中验证，以及已知的神经生理学，尽管在这一点上关于治疗效果的证据来自非常有限的数据。我们现在提议进行第一项研究，对精神分裂症患者进行随访，从急性到稳定再到疾病的稳定阶段，以确定知觉组织功能障碍是否在恢复过程中正常化。我们还将确定感知组织指数是否与以病前功能差、预后差和无组织症状为特征的疾病亚型最相关——这些关系是由过去的研究提出的。此外，我们将研究首次发病人群的知觉组织过程，这是以前没有描述过的。一些证据表明，知觉组织在第一次发作时是正常的或夸张的。我们将澄清这种损伤是在首次发作时出现，还是在初次住院后15个月内出现。对于在随访期间开始表现出损伤的患者，我们将确定新出现的异常与哪些临床和功能变化相关。我们将采用随访设计来探讨这些问题，我们将招募首发和晚期精神分裂症患者（以及健康对照组），在入院和出院时对他们进行测试，然后每3个月再次进行测试，为期15个月。我们还将研究知觉组织变化与症状和功能水平变化之间的共变。拟议的项目符合NIMH战略计划的两个目标：1)战略1.3：识别和整合与精神障碍相关的生物标记物（biomarkers）和行为指标；2)策略2.1：明确精神障碍的发展轨迹。这项研究将确定在多大程度上，基于表现的指数从有希望的知觉组织任务作为精神分裂症疾病过程的生物标志物，或严重残疾疾病亚型。

DESCRIPTION (provided by applicant): The NIMH MATRICS and CNTRICS initiatives have clarified the domains of cognitive functioning that are most relevant to treatment development targeting improved cognition and functioning in people with schizophrenia. These projects also identified specific tasks that are psychometrically sound and well validated in patient populations, and that, in the case of CNTRICS, have well understood neurophysiology. More recently, interest has increased in identifying tasks that meet these criteria and that are sensitive to treatment effects. Identification of such tasks is important for grounding our understanding of illness progression and recovery processes within a cognitive neuroscience framework. This information would also allow for cognitive neuroscience-based indicators of treatment responsiveness, and therefore for more targeted drug development efforts and early prediction of medication response. Promising candidates for this type of task are measures of perceptual organization. Selected tests of perceptual organization meet the criteria of psychometric soundness (including avoidance of generalized deficit confounds), validation in patient studies, and known neurophysiology, although evidence regarding treatment effects at this point comes from very limited data. We now propose to conduct the first study in which schizophrenia patients are followed-up from the acute to stabilization to stable phases of illness, to determine whether perceptual organization dysfunction normalizes over the course of recovery. We will also determine if perceptual organization indices are most relevant for an illness subtype characterized by poor premorbid functioning, poor prognosis, and disorganized symptoms - relationships suggested by past studies. In addition, we will examine the course of perceptual organization in a first-episode population, which has not been previously described. Some evidence suggests that perceptual organization is normal or exaggerated at first episode. We will clarify whether the impairment is present at first episode or whether it develops within 15 months after initial hospitalization. For patients who begin to demonstrate impairment during the follow-up period, we will determine with what clinical and functioning changes the emerging abnormality is associated. We will explore these issues using a follow-up design in which we will enroll first-episode and later-episode schizophrenia patients (and a healthy control group), test them at hospital admission and discharge, and then again every 3 months, over a 15-month period. We will also examine covariation between changes in perceptual organization and changes in symptoms and level of functioning. The proposed project is consistent with two objectives from the NIMH Strategic Plan: 1) Strategy 1.3: Identify and integrate biological markers (biomarkers) and behavioral indicators associated with mental disorders; and 2) Strategy 2.1: Define the developmental trajectories of mental disorders. This study will determine the extent to which performance-based indices from promising perceptual organization tasks serve as biomarkers of illness processes for schizophrenia in general, or for a severely disabled illness subtype.