Brain bioenergetics and slow wave activity in first episode psychosis

摘要 精神分裂症（SZ）是一种常见的严重精神疾病。有新的证据表明， 多种结构和功能性脑异常在疾病早期发展，结果可以改善 与发病率的逆转相反，早期干预的效果显著。目前，所有可用 抗精神病药物在类似的途径上是有效的;治疗失败是常见的，患者经常遭受 副作用.因此，迫切需要确定有助于促进细胞凋亡的新的生物学机制。 在疾病的早期病理学，并开发针对这些过程的新疗法。 高能磷酸盐（HEP）代谢的完整性对于提供所需能量至关重要， 无数的神经元功能，包括神经传递和可塑性-涉及SZ病理过程。 虽然ATP是主要的能量来源，但肌酸激酶（CK）酶反应在维持 通过产生HEP池作为PCr，并在能量增加期间从PCr产生ATP， 需求最近的研究表明，精神障碍中的几种生物能量机制异常， 包括静息时CK速率的降低。然而，CK在精神病患者的神经元激活过程中尚未被研究。 紊乱 确定大脑能量异常的介质将允许新的治疗方法。睡眠和 特别是慢波睡眠（SWS），在脑能量稳态和EEG功率密度方面具有恢复作用 在慢波频率（慢波活动，SWA）是与改善相关的措施， 能源措施。SZ的特征是广泛的睡眠障碍，包括第一次发作（FE），和 有证据表明，具体的SWS赤字。然而，睡眠特征和大脑能量的关联 这种疾病的代谢尚未研究。 鉴于这一背景，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过夜积累在 解释CK调制。为此，我们将收集过夜多导睡眠图数据并在体内使用 磷磁化转移 候选人是一名精神病学家，具有精神病患者神经影像学研究的背景。培训 该补助金的目标是让候选人获得1。睡眠研究; 2。方面的高级培训 脑功能的细胞生物学和生物化学方面; 3.高级统计培训; 4。培训 数据表达和赠款写作技巧。这些目标将通过指导、正式的 课程，以及一个非常合格的顾问和合作者团队的帮助。成功 完成这一职业发展计划将有助于候选人过渡到一个独立的 R 01级资金的调查员。

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.