Mechanisms and Effects of Oxytocin on Social Cognition in Schizophrenia

催产素对精神分裂症社会认知的机制和影响

• 批准号: 8958790
• 负责人: Josh Woolley
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958790
• 关键词: Accounting; Address; Adolescence; Affect; Amygdaloid structure; Animals; Antipsychotic Agents; Area; Attention; Behavior; Behavioral; Chronic Disease; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Communication; Cues; Data; Diagnosis; Disease; Dose; Drug abuse; Early Intervention; Emotional; Emotions; Exhibits; Eye; Face; Family; Functional Magnetic Resonance Imaging; Functional disorder; Gly-Lys-Arg-oxytocin; Goals; Health Care Costs; Healthcare Systems; Human; Hyperactive behavior; Impairment; Income; Individual; Intervention; Label; Lead; Link; Measurement; Measures; Neurobiology; Neurodevelopmental Disorder; Neuropeptides; Occupational; Outcome; Oxytocin; Parasympathetic Nervous System; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiological; Physiology; Placebos; Play; Population; Prefrontal Cortex; Process; Psychophysiology; Recovery of Function; Research; Resistance; Role; Schizophrenia; Series; Sinus Arrhythmia; Social Behavior; Social Development; Social Functioning; Social Network; Social isolation; Societies; Stimulus; Substance abuse problem; Support System; Symptoms; System; Testing; Training; Veterans; Work; cost; disability; improved; indexing; neural patterning; neuromechanism; neurophysiology; novel; patient population; predict clinical outcome; relating to nervous system; remediation; research study; respiratory; response; severe mental illness; social; social cognition; socioeconomics; young adult

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.

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，通常出现在成年早期，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，破坏家庭，并因社会残疾而给社会造成数十亿美元的收入损失。与精神分裂症相关的社交缺陷对患有该疾病的个体的生活造成严重破坏，并且这些缺陷独立地预测除了阳性症状和其他认知缺陷之外更糟糕的临床、功能和职业结果。尽管社会缺陷具有临床重要性，但人们对它们知之甚少，并且对现有的治疗方案持抵制态度。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、杏仁核活动增加以及腹侧前额皮质（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着重要作用，可以增加健康和自闭症个体的亲社会行为并改善社会认知。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。尽管催产素具有作为治疗社交缺陷和修复神经生理异常的新疗法的潜力，但很少有研究探讨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作用的潜在神经生理学机制，并量化催产素对新发精神分裂症患者的潜在临床有用作用。为了实现这些重要目标，我们将首先使用经过验证的社会认知测量方法，对 45 名新发精神分裂症患者和 45 名匹配的健康对照受试者进行单剂量外源性催产素对行为和心理生理反应的影响。我们还将评估以呼吸性窦性心律失常 (RSA) 为指标的 PNS 活动，以检验催产素通过增加 PNS 张力来促进社交行为的假设。接下来，我们将在 36 名患者和 36 名健康对照受试者中使用经过充分研究的功能磁共振成像社会认知范式，检查催产素是否通过减少杏仁核活动和增加 vPFC 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颖且重要的数据； 2) 开展更大规模的催产素临床试验，以改善新发精神分裂症年轻人的临床结果； 3）更深入地了解连接相互关联的神经生理系统的功能和机械关系，这些系统支持健康和精神分裂症个体的社会有意义的行为。研究新发精神分裂症的年轻成年患者可以最大限度地减少慢性疾病的潜在影响，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措施的潜在长期影响。总体而言，这项工作有可能揭示精神分裂症的社会功能障碍机制，并为该疾病难以治疗的社会功能障碍找到一种新的治疗方法。