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: 10418621
• 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/10418621
• 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; non-affective psychoses; 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.

抽象的 精神分裂症（SZ）是一种常见且严重的精神疾病。有新的证据表明 多种大脑结构和功能异常在疾病早期出现，结果可以改善 与逆转发病率相比，早期干预效果显着。不过目前所有可用的 抗精神病药物对类似途径有效；治疗失败很常见，患者经常遭受以下痛苦 副作用。因此，迫切需要确定新的生物学机制，以促进 疾病早期的病理学并针对这些过程开发新的治疗方法。 高能磷酸盐 (HEP) 代谢的完整性对于提供生物体所需的能量至关重要 无数的神经元功能，包括与 SZ 病理学有关的神经传递和可塑性过程。 虽然 ATP 是主要能量来源，但肌酸激酶 (CK) 酶反应在维持 通过创建 PCr 形式的 HEP 池并在能量增加期间从 PCr 生成 ATP 来稳定 ATP 浓度 要求。最近的研究表明精神障碍的几种生物能量机制存在异常， 包括静息时 CK 率的降低。然而，CK 尚未在精神病患者的神经元激活过程中进行研究。 失调。 识别大脑能量异常的调节因素将允许新的治疗方法。睡觉，以及 特别是慢波睡眠（SWS），对大脑能量稳态和脑电图功率密度具有恢复作用 慢波频率（慢波活动，SWA）是与改善相关的措施 能源措施。 SZ 的特点是普遍的睡眠障碍，包括第一发作 (FE)，以及 有证据表明特定的 SWS 缺陷。然而，睡眠特征和大脑能量的关联 尚未研究这种疾病的代谢。 鉴于此背景，我们建议研究 CK 酶在神经元激活过程中的活性 FE 非情感性精神病患者，并确定减少 SWA 过夜积累的作用 解释 CK 调制。为此，我们将收集隔夜多导睡眠图数据并在体内使用 磷磁化转移。 候选人是一位精神病学家，具有精神病神经影像学研究背景。训练 该补助金的目标是让候选人获得 1. 睡眠研究方面的培训； 2. 高级培训 脑功能的细胞生物学和生化方面； 3、统计学高级培训； 4. 培训 数据呈现和资助写作技巧。这些目标将通过指导、正式的 课程作业，以及由顾问和合作者组成的高素质团队的帮助。成功者 完成此职业发展计划将有助于候选人过渡到独立 具有R01级别资助的研究者。