Mechanisms and Effects of Oxytocin on Social Cognition in Schizophrenia

描述(由申请人提供)： 精神分裂症是一种破坏性的神经发育障碍，通常出现在青年时期，干扰正常的社会发展。这种诊断出现在1%-2%的人口中，跨越了社会经济、人口和国家界限，影响了退伍军人和平民，粉碎了家庭，并因社会残疾而导致社会损失数十亿美元的收入。与精神分裂症相关的社会缺陷对患精神分裂症的人的生活造成严重破坏，这些缺陷独立地预测出比阳性症状和其他认知缺陷更糟糕的临床、功能和职业结果。尽管社会缺陷在临床上很重要，但人们对其知之甚少，并且对可用的治疗方案产生了抵触。此外，对社会刺激的异常神经和自主反应似乎是精神分裂症这些缺陷的基础。例如，患者在执行某些社交任务时，表现出副交感神经系统(PNS)活动减少，杏仁核活动增加，腹侧前额叶皮质(VPFC)活动减少。神经肽催产素在动物和人类的社会行为中发挥重要作用，增加健康和自闭症患者的亲社会行为和改善社会认知。催产素也被证明对健康个体的神经和自主反应有积极的影响。尽管催产素有可能成为治疗社会缺陷和修复神经生理异常的一种新方法，但很少有研究研究催产素对精神分裂症患者的社会认知和行为或对社会刺激的神经和自主反应的影响。我们提出了一系列实验，旨在研究催产素亲社会效应的潜在神经生理学机制，并量化催产素在新近发病的精神分裂症患者中的潜在临床有用效应。为了实现这些重要的目标，我们将首先在45名新近发病的精神分裂症患者和45名匹配的健康对照受试者中，使用有效的社会认知测量来检验单剂量外源性催产素对行为和心理生理反应的影响。我们还将评估PNS的活性，以呼吸性窦性心律失常(RSA)为指标，以验证催产素通过增加PNS音调促进社交行为的假设。接下来，我们将在其中36名患者和36名健康对照受试者中，使用经过充分研究的fMRI社会认知范式，研究催产素的应用是否通过减少杏仁核的活动和增加vPFC的活动来使神经对社会刺激的反应正常化。如果成功，这些实验将：1)提供有关精神分裂症患者社交缺陷背后的神经生物学因素的新的重要数据；2)导致对催产素进行更大规模的临床试验，以改善新近发病的年轻精神分裂症患者的临床结果；以及3)使人们更深入地了解相互关联的神经生理系统之间的功能和机制关系，这些系统支持健康和精神分裂症患者具有社会意义的行为。研究新近发病的年轻精神分裂症患者，可以最大限度地减少慢性病的潜在混杂，包括社会隔离、药物滥用和抗精神病药物的使用，并最大限度地提高这种干预的潜在长期影响。总体而言，这项工作有可能揭示精神分裂症患者社会功能障碍的机制，并为这种疾病难以治疗的社会缺陷找到一种新的治疗方法。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating neurodevelopmental disorder that often emerges in young adulthood, interfering with normal social development. The diagnosis is present in 1-2% of the population and cuts across socioeconomic, demographic and national lines, affects veterans as well as civilians, shaters families, and costs society billions in lost income due to social disability. The social deficits associated with schizophrenia wreak havoc on the lives of individuals who develop the disorder, and these deficits independently predict worse clinical, functional, and occupational outcomes above and beyond positive symptoms and other cognitive deficits. Despite their clinical importance, social deficits are poorly understood and resistant to available treatment options. Furthermore, abnormal neural and autonomic responses to social stimuli appear to underlie these deficits in schizophrenia. For example, patients demonstrate decreased activity of the parasympathetic nervous system (PNS), increased activity of the amygdala, and decreased activity of the ventral prefrontal cortex (vPFC) when performing certain social tasks. The neuropeptide oxytocin plays an important role in social behavior in animals and humans, increasing pro-social behavior and improving social cognition in healthy and autistic individuals. Oxytocin has also been shown to have positive effects on neural and autonomic responses in healthy individuals. Despite its potential as a new treatment for social deficits and for remediation of neurophysiological abnormalities, few studies have examined the effects of oxytocin on social cognition and behavior or on neural and autonomic responses to social stimuli in patients with schizophrenia. We propose a series of experiments aimed at both investigating the underlying neurophysiological mechanisms of oxytocin's pro-social effects and quantifying the potentially clinically useful effects of oxytocinin patients with recent-onset schizophrenia. In order to accomplish these important goals, we will first examine the effects of a single dose of exogenous oxytocin on behavioral and psychophysiological responses using validated social cognition measures in 45 patients with recent-onset schizophrenia and 45 matched healthy comparison subjects. We will also assess PNS activity as indexed by respiratory sinus arrhythmia (RSA) in order to test the hypothesis that oxytocin promotes social behavior by increasing PNS tone. Next, we will examine if oxytocin administration normalizes neural responses to social stimuli by decreasing activity of the amygdala and increasing activity of the vPFC, using a well-studied fMRI social cognition paradigm in 36 of these patients and 36 of these healthy comparison subjects. If successful, these experiments will: 1) Provide novel and important data on the neurobiological factors that underlie social deficits in patients with schizophrenia; 2) Lead to larger clinical trials of oxytoin to improve clinical outcomes in young individuals with recent-onset schizophrenia; and 3) Provide a deeper understanding of the functional and mechanistic relationships linking interrelated neurophysiologic systems that support socially meaningful behavior in healthy and schizophrenic individuals. Studying young adult patients with recent-onset schizophrenia minimizes potential confounds of chronic illness including social isolation, drug abuse and neuroleptic use and maximizes the potential long-term impact of this intervention. Overall, this work has the potential to uncover mechanisms of social dysfunction in schizophrenia, and to identify a novel treatment for the difficult-to-treat social deficits of the illness.