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，通常出现在年轻的成年人，干扰正常的社会发展。这种诊断存在于1-2%的人口中，跨越社会经济，人口和国家界限，影响退伍军人和平民，家庭，并因社会残疾造成社会数十亿美元的收入损失。与精神分裂症相关的社会缺陷会对患有精神分裂症的个体的生活造成严重破坏，这些缺陷独立地预测了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。尽管他们的临床重要性，社会缺陷是知之甚少，并抵制现有的治疗方案。此外，对社会刺激的异常神经和自主神经反应似乎是精神分裂症这些缺陷的基础。例如，当执行某些社交任务时，患者表现出副交感神经系统（PNS）的活动减少、杏仁核的活动增加以及腹侧前额叶皮质（vPFC）的活动减少。神经肽催产素在动物和人类的社会行为中起着重要作用，增加了健康和自闭症个体的亲社会行为并改善了社会认知。催产素也被证明对健康个体的神经和自主反应有积极影响。尽管催产素作为一种新的治疗社交缺陷和神经生理异常的补救措施的潜力，很少有研究探讨催产素对社会认知和行为或对精神分裂症患者的神经和自主神经对社会刺激的反应的影响。我们提出了一系列的实验，旨在调查催产素的亲社会的影响和量化的潜在临床有用的影响催产素与近期发作的精神分裂症患者的潜在神经生理机制。为了实现这些重要的目标，我们将首先检查单剂量的外源性催产素对行为和心理生理反应的影响，使用有效的社会认知措施，在45例新发精神分裂症患者和45名匹配的健康对照组。我们还将评估PNS活动，以呼吸性窦性心律不齐（RSA）为指标，以检验催产素通过增加PNS张力促进社会行为的假设。接下来，我们将研究催产素管理是否正常化的神经反应，以社会刺激，减少活动的杏仁核和增加活动的vPFC，使用一个良好的研究功能磁共振成像社会认知范式在36个这些患者和36个这些健康的对照组。如果成功，这些实验将：1）提供有关精神分裂症患者社会缺陷背后的神经生物学因素的新的重要数据; 2）导致更大规模的催产素临床试验，以改善新近发作的精神分裂症年轻个体的临床结果;和3）提供更深入的了解功能和机械关系，连接相互关联的神经生理系统，支持社会意义健康人和精神分裂症患者的行为。研究年轻的成年患者与近期发作的精神分裂症，最大限度地减少潜在的混淆慢性疾病，包括社会隔离，药物滥用和精神抑制剂的使用，并最大限度地提高这种干预的潜在长期影响。总的来说，这项工作有可能揭示精神分裂症中社会功能障碍的机制，并确定一种新的治疗方法来治疗这种难以治疗的疾病的社会缺陷。

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.