Perceptual Organization Dysfunction as a Biomarker of Schizophrenia

描述(由申请人提供)：NIMH Matrics和CNTRICS倡议澄清了与治疗开发最相关的认知功能领域，目标是改善精神分裂症患者的认知和功能。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健全的，在患者群体中得到了很好的验证，并且在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的兴趣有所增加。识别这些任务对于我们在认知神经科学框架内对疾病进展和康复过程的理解是重要的。这些信息还将允许基于认知神经科学的治疗反应指标，从而实现更有针对性的药物开发努力和对药物反应的早期预测。对于这种类型的任务，有希望的候选人是感知组织的衡量标准。知觉组织的选定测试符合心理测量学的合理性标准(包括避免普遍的缺陷混淆)、患者研究中的验证和已知的神经生理学，尽管关于治疗效果的证据来自非常有限的数据。我们现在建议进行第一项研究，对精神分裂症患者从急性期到稳定期再到稳定期进行随访，以确定知觉组织功能障碍在康复过程中是否正常化。我们还将确定知觉组织指数是否与疾病亚型最相关，该疾病亚型的特征是病前功能差、预后差和紊乱的症状--过去的研究表明这些关系。此外，我们将研究第一集人群中知觉组织的过程，这是以前没有描述过的。一些证据表明，知觉组织在第一集是正常的或被夸大了。我们将澄清这种损害是在第一次发作时出现，还是在首次住院后15个月内出现。对于在随访期内开始表现出损害的患者，我们将确定新出现的异常与哪些临床和功能变化有关。我们将使用后续设计来探索这些问题，我们将招募首发和后发精神分裂症患者(以及健康对照组)，在入院和出院时对他们进行测试，然后在15个月内每3个月再次测试一次。我们还将研究知觉组织的变化与症状和功能水平的变化之间的协变性。拟议的项目符合NIMH战略计划的两个目标：1)战略1.3：确定和整合与精神障碍有关的生物标志物(生物标志物)和行为指标；以及2)战略2.1：确定精神障碍的发展轨迹。这项研究将确定基于预期知觉组织任务的绩效指数在多大程度上用作一般精神分裂症或严重残疾疾病亚型的疾病过程的生物标记物。 公共卫生相关性：该项目通过确定一种以无组织症状和预后不良为特征的精神分裂症患者亚型的治疗反应性的生物标记物，对公共卫生具有高度的相关性。对首发患者的知觉功能纵向检查也将有助于更好地了解哪些患者在首次住院后的第一个1.25年内功能下降，以及这种下降的相关认知机制和标志物。识别这些标志物可以识别需要更全面和更积极的治疗以促进康复的首发患者。对于首发和老年患者，识别治疗反应性(或缺乏治疗反应性)的生物标记物可以帮助定义和提高我们对特定类型的患者的理解，从而有助于新药开发工作，这些患者具有较高的预后风险。

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. PUBLIC HEALTH RELEVANCE: This project has high relevance for public health by identifying a biomarker of treatment responsiveness in a subtype of schizophrenia patient that is characterized by disorganized symptoms and poor prognosis. Examination of perceptual functioning longitudinally in first-episode patients will also allow for improved understanding of which patients decline in functioning over the first 1.25 years after initial hospitalization, and the associated cognitive mechanisms and markers of this decline. Identification of such markers may allow for identification of first episode patients who need more comprehensive and aggressive treatment to promote recovery. For first episode and older patients, identification of a biomarker of treatment responsiveness (or lack thereof) can aid new drug development efforts by helping to define, and improving our understanding of, a specific type of patient at high-risk for poor outcomes.