Neurometabolic mechanisms of aberrant resting brain activity in schizophrenia

精神分裂症异常静息脑活动的神经代谢机制

• 批准号: 10116956
• 负责人: Michael Jacob
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116956
• 关键词: Address; Affect; Anatomy; Animals; Antipsychotic Agents; Arousal; Autonomic nervous system; Biological Assay; Biological Markers; Blood; Blood Vessels; Body mass index; Brain; Brain region; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical; Clinical Research; Cognitive; Collaborations; Coupling; Data; Diabetes Mellitus; Educational workshop; Electroencephalography; Frequencies; Functional Magnetic Resonance Imaging; Funding; Genetic study; Glucose; Goals; Grant; Heart; Human; Impairment; Lead; Link; Measures; Medical; Mental Health; Mental disorders; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methodology; Methods; Mitochondria; Modality; Modeling; Modification; Neuroanatomy; Neuronal Dysfunction; Neurosciences; Output; Oxygen; Participant; Pathology; Patients; Periodicity; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Principal Investigator; Psychopathology; Research; Research Personnel; Rest; Risk; Role; Schizophrenia; Severities; Signal Transduction; Smoking; Stress; Testing; Tissues; Training; Variant; Vascular Diseases; Veterans; blood oxygen level dependent; cardiovascular disorder risk; career; clinical biomarkers; comorbidity; dosage; functional magnetic resonance imaging/electroencephalography; hemodynamics; indexing; mindfulness; multimodality; neuroimaging; neuropsychiatric disorder; neurotransmission; novel; premature; psychiatric symptom; psychotic symptoms; recruit; relating to nervous system; respiratory; response; sedentary lifestyle; tool

Schizophrenia is a debilitating psychiatric illness that increases the risk for medical comorbidities, such as metabolic syndrome, diabetes, and cardiovascular disease. Metabolic comorbidities are the leading causes of premature death for veterans with schizophrenia. Although cellular and genetic studies have suggested that metabolic impairments may underlie neural dysfunction, studies in clinical neuroscience are limited. Resting state, functional magnetic resonance imaging (fMRI), is widely used as a clinical research tool and has identified a “default mode network” that is hypermetabolic in schizophrenia and may underlie psychiatric symptoms. fMRI does not assay neural activity directly, and instead, reflects slow changes in the regional level of blood oxygen commonly interpreted as a surrogate for neural activity. Moreover, these metabolic signals are influenced by systemic physiology, including cardiorespiratory activity under the control of the autonomic nervous system. Metabolic signals from fMRI are typically modeled to reflect neurometabolic coupling, the recruitment of blood and oxygen to support active neural tissue. However, autonomic dysregulation and metabolic dysfunction can impair neurometabolic coupling. In schizophrenia, autonomic signals are dysregulated and are associated with aberrant default mode network activity, but links to neural activity and neurometabolic coupling remain unknown. Electroencephalography (EEG), can measure neural activity directly, but with limited temporal precision. The use of concurrent, simultaneous EEG-fMRI is a promising research tool utilized in animal and human studies to examine neurometabolic coupling. This CDA-1 proposal hypothesizes that neurometabolic coupling is dysregulated in schizophrenia and can be measured using simultaneous EEG-fMRI The experimental context for this CDA-1 is Dr. Judith Ford’s Merit grant, which examines simultaneously acquired EEG-fMRI data of cognitive processing during rumination and mindfulness. This CDA- 1 proposes a path to scientific independence by examining the role of neurometabolic coupling and autonomic activity in aberrant, resting brain activity in schizophrenia. Treatments targeting underlying pathology in schizophrenia are lacking and current pharmacotherapies exacerbate metabolic disease. Measures of neurometabolic coupling may serve as a biomarker to guide novel treatments, leading to new perspectives on the intersection between metabolic disease and mental health. This two-year CDA-1 provides training in the acquisition and analysis of simultaneous EEG-fMRI to examine neurometabolic coupling. In addition, this CDA -1 generates pilot data examining the role of autonomic activity in neurometabolic coupling to support a CDA-2 application. The career and training plan will develop the Principal Investigator’s expertise in multimodal, psychiatric neuroimaging through coursework, methodological workshops, and collaboration with established investigators. This study combines modalities (Autonomic signals, EEG and fMRI) to achieve two specific aims: 1) Examine the neuroanatomy and temporal dynamics of neurometabolic coupling in schizophrenia and, 2) Assess the role of autonomic activity on neurometabolic coupling in SZ, by measuring cardiorespiratory activity concurrently with simultaneous EEG-fMRI. All aims support the primary goal of mentored training in simultaneous EEG-fMRI to develop scientific independence and expertise in the role of neurometabolism and autonomic activity in schizophrenia. This goal will be accomplished through this proposed CDA-1, the primary findings generated by Aim #1 and the pilot data generated by Aim #2 to support a CDA-2 application.

精神分裂症是一种使人衰弱的精神疾病，它增加了医疗合并症的风险，如 如代谢综合征、糖尿病和心血管疾病。代谢合并症是主要原因。 患有精神分裂症的退伍军人过早死亡。尽管细胞和遗传学研究表明 代谢障碍可能是神经功能障碍的基础，临床神经科学的研究有限。休息 状态，即功能磁共振成像(FMRI)，被广泛用作临床研究工具，并已 发现了精神分裂症患者高代谢的“默认模式网络”，这可能是精神疾病的基础 症状。功能磁共振成像并不直接分析神经活动，而是反映区域水平的缓慢变化。 通常被解释为神经活动的替代物的血氧。此外，这些代谢信号是 受全身生理学的影响，包括自主神经控制下的心肺活动 神经系统。来自功能磁共振成像的代谢信号通常被建模以反映神经代谢耦合，即 补充血液和氧气以支持活跃的神经组织。然而，自主神经失调和 代谢功能障碍会损害神经代谢偶联。在精神分裂症患者中，自主神经信号 并与异常的默认模式网络活动有关，但与神经活动和 神经代谢偶联仍不清楚。脑电(EEG)，可以测量神经活动 直接，但时间精度有限。同时使用脑电-功能磁共振成像是一种很有前途的方法。 在动物和人类研究中用来检查神经代谢耦合的研究工具。这份CDA-1提案 假设精神分裂症患者的神经代谢偶联失调，可以用 同步脑电-功能磁共振成像 CDA-1的实验背景是朱迪思·福特博士的功勋拨款，它检查了 同时获取沉思和正念过程中认知加工的EEG-fMRI数据。这份CDA- 1通过研究神经代谢偶联和自主神经的作用，提出了一条科学独立的途径。 精神分裂症患者异常活动、静息状态下的脑活动。针对潜在病理的治疗 精神分裂症是缺乏的，目前的药物治疗加剧了代谢性疾病。衡量标准 神经代谢偶联可作为一种生物标志物来指导新的治疗方法，从而为 代谢性疾病和心理健康之间的交集。这项为期两年的CDA-1课程提供以下培训 同时采集和分析EEG-fMRI以检查神经代谢偶联。此外，这一CDA 生成试验数据，检查自主活动在神经代谢耦合中的作用，以支持CDA-2 申请。职业生涯和培训计划将发展首席调查员在多式联运方面的专长， 通过课程作业、方法研讨会和与已建立的 调查人员。这项研究结合了模式(自主神经信号、脑电和功能磁共振)来实现两个特定的目标： 1)检查精神分裂症患者神经代谢偶联的神经解剖学和时间动力学，2) 通过测量心肺活动来评估自主神经活动在深圳神经代谢偶联中的作用 同时进行脑电-功能磁共振检查。所有目标都支持指导培训的主要目标 同时进行脑电-功能磁共振成像，以发展神经代谢和功能的作用的科学独立性和专门知识 精神分裂症患者的自主神经活动。这一目标将通过拟议的CDA-1、主要的 AIM#1生成的调查结果和AIM#2生成的试点数据支持CDA-2申请。