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: 10527321
• 负责人: Roscoe O. Brady
• 金额: $ 53.47万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527321
• 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; design; functional outcomes; improved; 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.

项目概要/摘要 精神障碍很容易通过所谓的幻觉“阳性症状”来识别， 妄想、思维混乱。然而，“消极症状”的严重程度（例如缺乏动力、快感缺乏、 和面部表情缺陷）是功能结果的最佳预测指标，例如就业和 独立住房。抗精神病药物对改善这些症状有一定效果。我们 对于这些症状如何在神经回路水平上介导缺乏共识。没有一个 生物“目标”，例如回路病理生理学，我们开发新干预措施的能力至关重要 受到阻碍。 我们实验室和其他实验室之前的工作使用了无任务或“静息状态”功能磁性 共振成像 (rsfMRI) 用于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，阴性症状的严重程度与小脑和大脑之间的连接失调相关。 背外侧前额皮质 (DLPFC)。我们使用以下方法凭经验测试了这种网络-症状关系： 重复经颅磁刺激（rTMS）来操纵网络连接。我们观察到 rTMS 功能连接性的诱导增加与阴性症状的改善密切相关 严重程度，与网络连接介导负面症状的假设一致。 我们建议检验以下假设：小脑-DLPFC 网络断开连接会导致负面影响 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 连接之前和之后的连接和症状严重程度。我们 将通过基于报告者以及独立于评估者的方法量化症状严重程度；客观措施 测试动机、快感缺失和面部表情。我们的假设是网络逆转 连接不良将导致负面症状严重程度和网络参与程度降低 将解释症状改善的个体差异。 如果成功，该项目将建立一个生物目标，供各种实验参与 改善精神障碍的这些致残性、耐药性症状的方法。