Network Mediation of Experiential and Expressive Deficits in Psychotic Disorders

精神障碍体验和表达缺陷的网络中介

• 批准号: 10058274
• 负责人: Roscoe O. Brady
• 金额: $ 60万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058274
• 关键词: Anhedonia; Antipsychotic Agents; Biological; Brain; Cerebellum; Cerebrum; Consensus; Correlation Studies; Data; Delusions; Diagnosis; Disease; Employment; Experimental Designs; Expressed Emotion; Facial Expression; Functional Magnetic Resonance Imaging; Functional disorder; Future; Hallucinations; Housing; Image; Individual; Intervention; Laboratories; Link; Measures; Mediating; Mediation; Methods; Motivation; Names; Participant; Pharmaceutical Preparations; Physiology; Prefrontal Cortex; Psychopathology; Psychotic Disorders; Quality of life; Randomized; Refractory; Reporter; Resistance; Rest; Schizophrenia; Severities; Site; Symptoms; Testing; Unemployment; Work; base; design; functional outcomes; innovation; network dysfunction; network models; neural circuit; neural correlate; neuroimaging; neuroregulation; novel therapeutic intervention; psychotic symptoms; recruit; reduce symptoms; repetitive transcranial magnetic stimulation; response; symptomatic improvement; theories; trait

Project Summary / Abstract Psychotic disorders are readily identified by the so-called `positive symptoms' of hallucinations, delusions, and thought disorder. However, the severity of `negative symptoms' (e.g. amotivation, anhedonia, and facial expression deficits) are the best predictors of functional outcomes such as employment and independent housing. Antipsychotic medications are modestly effective in ameliorating these symptoms. We lack a consensus understanding of how these symptoms are mediated at the level of neural circuits. Without a biological `target' such as circuit pathophysiology, our ability to develop new interventions is critically hampered. Previous work from our laboratory and others have used task-free or `resting state' functional Magnetic Resonance Imaging (rsfMRI) to examine the neural correlates of negative symptom severity. Our preliminary data determined that negative symptom severity is correlated with dysconnectivity between the cerebellum and Dorso-Lateral Pre-Frontal Cortex (DLPFC). We empirically tested this network-symptom relationship using repetitive transcranial magnetic stimulation (rTMS) to manipulate network connectivity. We observed that rTMS induced increases in functional connectivity were strongly associated with improvement in negative symptom severity, consistent with the hypothesis that network connectivity mediates negative symptomology. We propose to test the hypothesis that cerebellar-DLPFC network dysconnectivity causes negative symptoms in schizophrenia. Using a within-subject, longitudinal experimental design, we will measure network connectivity and symptom severity before and after rTMS manipulation of cerebellar-DLPFC connectivity. We will quantify symptom severity via reporter based methods as well as rater-independent; objective measures that test amotivation, anhedonia, and facial expression. Our hypothesis is that reversal of network dysconnectivity will give rise to reduced negative symptom severity and the magnitude of network engagement will explain individual variance in symptomatic improvement. If successful, this project will establish a biological target for engagement by a variety of experimental methods towards the amelioration of these disabling, medication-resistant symptoms of psychotic disorders.

项目摘要 /摘要 精神病疾病很容易被所谓的幻觉的“积极症状”确定， 妄想和思想障碍。然而，“负面症状”的严重程度（例如，动机，anhedonia， 面部表情不足）是功能结果的最佳预测指标，例如就业和 独立住房。抗精神病药在改善这些症状方面非常有效。我们 缺乏对这些症状如何在神经回路水平介导的理解。没有一个 生物学“靶”，例如电路病理生理学，我们开发新干预措施的能力至关重要 受阻。 我们实验室和其他人的先前工作使用了无任务或“休息状态”功能磁性 共振成像（RSFMRI）检查阴性症状严重程度的神经相关性。我们的初步 数据确定负面症状的严重程度与小脑和小脑和 Dorso-lightal前额叶皮层（DLPFC）。我们使用 重复的经颅磁刺激（RTMS）来操纵网络连通性。我们观察到RTMS 诱导的功能连通性增加与负面症状的改善密切相关 严重程度，与网络连通性介导负面症状的假设一致。 我们建议测试小脑DLPFC网络dysconnectynectivity的假设 精神分裂症的症状。使用受试者内的纵向实验设计，我们将测量网络 RTMS操纵小脑DLPFC连通性之前和之后的连通性和症状严重程度。我们 将通过基于记者的方法以及与评估者无关的方法来量化症状严重程度；客观措施 该测试的动机，狂欢和面部表达。我们的假设是网络的逆转 功能障碍性将导致负面症状严重程度降低和网络参与度的幅度 将解释有症状改善的个体差异。 如果成功，该项目将建立通过各种实验的生物学目标 改善这些残疾，耐药性疾病症状的方法。