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.

项目摘要/摘要