Brain bioenergetics and slow wave activity in first episode psychosis

首发精神病中的脑生物能学和慢波活动

• 批准号: 9892310
• 负责人: Abdullah Cagri Yuksel
• 金额: $ 17.05万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9892310
• 关键词: Antipsychotic Agents; Biochemical; Bioenergetics; Biological; Biological Process; Bipolar Disorder; Brain; Cells; Cellular biology; Characteristics; Chronic Schizophrenia; Consumption; Coupled; Creatine Kinase; Data; Development Plans; Disease; Early Intervention; Electroencephalography; Energy Metabolism; Energy-Generating Resources; Enzymes; Frequencies; Funding; Glucose; Glutamates; Goals; Grant; Homeostasis; Impaired cognition; Impairment; Intermediate Variables; Intervention; Laboratories; Link; Measures; Mediating; Mediator of activation protein; Mentorship; Metabolic; Metabolism; Mitochondria; Modality; Molecular; Morbidity - disease rate; Natural regeneration; Neurons; Occipital lobe; Organ; Outcome; Oxidative Phosphorylation; Oxygen; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorus; Photic Stimulation; Play; Polysomnography; Process; Psychiatrist; Psychotic Disorders; Reaction; Research; Research Personnel; Rest; Role; Schizophrenia; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Structure; Synapses; Techniques; Testing; Time; Training; Treatment Failure; Writing; brain abnormalities; career development; density; experimental study; first episode psychosis; frontal lobe; functional decline; improved; in vivo; information processing; inorganic phosphate; neuroimaging; neurotransmission; non rapid eye movement; novel; novel strategies; partial response; preservation; response; severe psychiatric disorder; side effect; skills; sleep abnormalities; statistics; targeted treatment

ABSTRACT Schizophrenia (SZ) is a common and severe psychiatric disorder. There is emerging evidence that multiple structural and functional brain abnormalities develop early in the illness and outcomes can improve significantly with early intervention as opposed to reversal of morbidity. However, all currently available antipsychotics are effective on similar pathways; treatment failure is common and patients frequently suffer from side effects. Therefore, there is a critical need to identify new biological mechanisms that contribute to the pathology early in the illness and to develop novel treatments targeting these processes. Integrity of the high energy phosphate (HEP) metabolism is essential for providing energy required by myriad neuronal functions, including neurotransmission and plasticity -processes implicated in SZ pathology. While ATP is the primary energy source, creatine kinase (CK) enzyme reaction plays a central role in maintaining stable ATP concentrations by creating a HEP pool as PCr, and generating ATP from PCr during increased energy demand. Recent studies show abnormalities in several bioenergetic mechanisms in psychotic disorders, including reductions in CK rate at rest. However, CK has not been studied during neuronal activation in psychotic disorders. Identifying mediators of brain energy abnormalities will allow novel treatment approaches. Sleep, and specifically slow wave sleep (SWS), has a restorative role in brain energy homeostasis, and EEG power density at the slow wave frequency (slow wave activity, SWA) is the measure associated with the improvements in energy measures. SZ is characterized by pervasive sleep disturbances, including in the first episode (FE), and there is evidence for specific SWS deficits. However, the association of sleep characteristics and brain energy metabolism in this disorder has not been studied. Given this background, we propose to study the activity of CK enzyme during neuronal activation in patients with FE non-affective psychosis, and identify the role of reduced overnight accumulation of SWA in explaining CK modulation. For this purpose, we will collect overnight polysomnography data and use in vivo phosphorus magnetization transfer. Candidate is a psychiatrist with a background in neuroimaging research in psychotic disorders. Training objectives for this grant are for the candidate to gain 1. Training in sleep research; 2. Advanced training in cell biology and biochemical aspects of brain function; 3. Advanced training in statistics; 4. Training in data presentation and grant writing skills. These goals will be accomplished by mentorship, formal coursework, and the help of an exceptionally-qualified team of advisors and collaborators. The successful completion of this career development plan will assist the candidate in making the transition to an independent investigator with R01 level funding.

摘要 精神分裂症(SZ)是一种常见而严重的精神障碍。有新的证据表明 多种结构和功能的脑异常在疾病早期发展，预后可以改善 早期干预，而不是逆转发病率，这一点意义重大。然而，目前所有可用的 抗精神病药物在相似的途径上有效；治疗失败是常见的，患者经常遭受 副作用。因此，迫切需要确定新的生物学机制，这些机制有助于 在疾病的早期进行病理检查，并针对这些过程开发新的治疗方法。 高能磷酸盐(HEP)代谢的完整性是提供所需能量所必需的 无数的神经元功能，包括神经传递和可塑性--与SZ病理有关。 虽然ATP是主要的能量来源，但肌酸激酶(CK)的酶反应在维持 通过创建作为聚合酶链式反应的HEP池并在能量增加期间从聚合酶链式反应生成三磷酸腺苷来稳定三磷酸腺苷浓度 需求。最近的研究表明，精神障碍中的几种生物能量机制存在异常， 包括降低静息CK率。然而，在精神病患者神经元激活过程中，CK还没有被研究过 精神错乱。 确定大脑能量异常的介体将使新的治疗方法成为可能。睡觉，还有 特别是慢波睡眠(SWS)，对大脑能量稳态和脑电功率密度具有恢复作用 在慢波频率(慢波活动，SWA)是与以下各项改善相关的指标 能源措施。SZ的特点是普遍存在睡眠障碍，包括第一集(FE)，以及 有证据表明存在特定的社保赤字。然而，睡眠特征和大脑能量之间的联系 这种疾病的代谢还没有被研究过。 在这一背景下，我们建议研究神经元激活过程中CK酶的活性。 FE非情感性精神病患者，并确定减少SWA在夜间堆积的作用 解释CK的调制。为此，我们将收集夜间多导睡眠图数据，并在体内使用 磷磁化转移。 应聘者是一名精神病学家，具有精神障碍神经成像研究的背景。培训 这项资助的目标是：1.睡眠研究方面的培训；2.睡眠研究方面的高级培训 大脑功能的细胞生物学和生化方面；3.统计学方面的高级培训；4.培训 数据陈述和助学金撰写技巧。这些目标将通过正式的导师指导来实现 课程作业，以及由非常合格的顾问和合作者组成的团队的帮助。成功者 完成这一职业发展计划将有助于候选人过渡到独立的 拥有R01级资金的调查员。