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Negative Valence Systems in Schizophrenia

精神分裂症中的负价系统

基本信息

批准号：
10441604
负责人：
JENNIFER URBANO BLACKFORD
金额：
$ 66.14万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441604
关键词：
Acute Address Amygdaloid structure Animal Model Anxiety Anxiety Disorders Aversive Stimulus Behavior Brain Brain region Clinical Cognition Data Delusions Detection Development Dimensions Disease Distress Emotions Foundations Fright Functional Magnetic Resonance Imaging Future Galvanic Skin Response Human Hydrocortisone Impairment Individual Intervention Knowledge Light Measures Mediating Mental disorders Methods Modeling Motor Negative Valence Neurobiology Outcome Paranoia Pattern Persons Physiological Physiology Pilot Projects Play Prefrontal Cortex Prevalence Quality of life Research Research Domain Criteria Resolution Rest Rodent Role Schizophrenia Sensory Social Functioning Stimulus Structure of terminal stria nuclei of preoptic region Subgroup Symptoms System Testing Uncertainty anxiety symptoms base biological adaptation to stress common symptom comorbidity conditioned fear experience in vivo neurobiological mechanism neuroimaging novel response severe mental illness suicidal risk

项目摘要

Schizophrenia is a severe and heterogeneous mental disorder that impacts most domains of function including behavior, cognition, and emotion. Recent models have highlighted important alterations of the emotion brain networks in schizophrenia that contribute to schizophrenia symptoms, like paranoia and delusions. To date, the studies of emotion in schizophrenia have primarily focused on fear processing and have shown heightened amygdala responses to neutral stimuli and altered amygdala-prefrontal cortex connectivity. However, recent research suggests that another brain region—the bed nucleus of the stria terminalis (BNST)—may play a critical role in anxiety and that BNST-mediated anxiety is distinct from amygdala-mediated fear. The RDoC’s Negative Valence System recognizes this fear-anxiety distinction and has separate constructs for Response to Acute Threat (amygdala) and Response to Potential Harm (BNST). To our knowledge, the BNST has yet to be examined in individuals with schizophrenia. Using methods pioneered by our lab to study the human BNST, we have collected preliminary data in schizophrenia. Our pilot data provides initial evidence for BNST connectivity differences in both response to unpredictable threat, a measure of the response to potential harm construct, and during a resting state in individuals with schizophrenia compared to healthy controls. Further, we found evidence that BNST alterations in schizophrenia differ for those who do or do not have comorbid anxiety. Individuals with schizophrenia and anxiety disorders demonstrated stronger connectivity between BNST and multiple brain regions involved in threat detection, uncertainty, and anxiety relative to those with schizophrenia and no anxiety disorder. The current study will investigate BNST connectivity in three groups: individuals with schizophrenia with a comorbid anxiety disorder (SZ+ANX), individuals with schizophrenia without a comorbid anxiety disorder (SZ-ANX), and healthy controls (HC). We hypothesize that individuals with schizophrenia will have altered BNST connectivity in response to unpredictable threat and altered BNST intrinsic connectivity relative to HC. In addition we predict that SZ+ANX group will show BNST hyperconnectivity relative to SZ- ANX. We will test these hypotheses with three specific aims. (1) Investigate BNST connectivity in response to unpredictable threat in individuals with schizophrenia; (2) Determine whether there are differences in BNST intrinsic connectivity in individuals with schizophrenia; (3) Test for relationships among BNST connectivity, stress responses (skin conductance and cortisol), and clinical symptoms in schizophrenia. Given the prevalence of anxiety in schizophrenia, BNST alterations within schizophrenia are likely and may shed new light on the neurobiological mechanisms underlying emotion alterations in schizophrenia. The results from the proposed study can provide a foundation for future studies of emotion in schizophrenia, determine whether there are neurobiological differences in anxiety subgroups, and guide the development of novel neuroscientifically-informed treatments.

精神分裂症是一种严重的异质性精神障碍，影响大多数功能领域，包括行为、认知和情感。最近的模型强调了情绪脑的重要变化精神分裂症中的网络会导致精神分裂症症状，如偏执和妄想。迄今为止，对精神分裂症情绪的研究主要集中在恐惧处理上，并显示出杏仁核对中性刺激的反应和改变的杏仁核-前额皮质连接。然而，最近研究表明，另一个大脑区域——终纹床核（BNST）——可能发挥着重要作用。 BNST 介导的焦虑与杏仁核介导的恐惧不同。 RDoC 的负价系统认识到这种恐惧与焦虑的区别，并具有单独的反应结构急性威胁（杏仁核）和对潜在伤害的反应（BNST）。据我们所知，BNST 尚未在精神分裂症患者中进行检查。使用我们实验室首创的方法来研究人类 BNST，我们收集了精神分裂症的初步数据。我们的试点数据为 BNST 连接性提供了初步证据对不可预测的威胁的反应的差异，对潜在危害构造的反应的衡量标准，以及精神分裂症患者在静息状态下与健康对照者的比较。进一步，我们发现有证据表明，对于患有或不患有焦虑症的人来说，精神分裂症的 BNST 改变有所不同。患有精神分裂症和焦虑症的个体表现出 BNST 和与精神分裂症患者相关的多个大脑区域涉及威胁检测、不确定性和焦虑并且没有焦虑症。当前的研究将调查三组 BNST 连接性：合并焦虑症（SZ+ANX）的精神分裂症，没有合并症的精神分裂症患者焦虑症（SZ-ANX）和健康对照（HC）。我们假设精神分裂症患者会改变了 BNST 连接性以应对不可预测的威胁，并改变了 BNST 内在连接性相对于HC。此外，我们预测 SZ+ANX 组将表现出相对于 SZ- 的 BNST 超连接性 ANX。我们将通过三个具体目标来检验这些假设。 (1) 调查 BNST 连接性以响应精神分裂症患者面临不可预测的威胁； (2)判断BNST是否存在差异精神分裂症患者的内在联系； (3) 测试BNST连通性之间的关系，应激反应（皮肤电导和皮质醇）以及精神分裂症的临床症状。鉴于精神分裂症中焦虑症的患病率，精神分裂症中的 BNST 改变很可能并且可能会产生新的阐明精神分裂症情绪改变背后的神经生物学机制。结果来自拟议的研究可以为未来精神分裂症情绪研究提供基础，确定是否焦虑亚组之间存在神经生物学差异，并指导新的开发神经科学的治疗方法。