Characterize differences in sleep spindles between Clinical High Risk and healthy controls longitudinally.

纵向描述临床高风险和健康对照之间的睡眠纺锤波差异 项目概述：精神分裂症及相关疾病是全球残疾的主要原因之一，因此， 使早期识别神经生物学脆弱性，这可能作为治疗目标， 研究优先。在最近的工作中，我们发现慢性精神分裂症患者在以下方面有明显的缺陷： 睡眠纺锤波第二阶段非快速眼动（N2）睡眠的标志，纺锤波很短（0.5-2秒）， 在12-16 Hz范围内的渐强/渐弱振荡。纺锤体异常也存在于早期病程中， 早发性精神分裂症和纺锤体相关指标，包括振幅、持续时间和密度， 与健康个体的认知能力、社会功能和神奇思维倾向有关， 包括青少年和年轻人。通过研究单个主轴参数，我们确定， 纺锤体密度和振幅降低与症状和认知障碍的严重程度相关 分别在慢性精神分裂症患者中。我们还发现，集成主轴活动（伊萨）， 将单个纺锤体参数结合在一个值中，是最具鉴别力的测量方法，约90% 精神分裂症和对照组之间的分离。临床高风险青少年是一个独特的群体 丰富的主要精神疾病的前兆，如精神分裂症，谁也经历紧急 认知障碍、社会功能障碍和亚综合征临床症状。我们不知道的是 纺锤体损伤的发生，以及它们如何影响这一人群的精神病理学发展。 因此，该项目的第一个广泛目标是描述睡眠纺锤波参数在调节睡眠中的作用。 认知，社会和临床功能轨迹，包括过渡到精神病，在青年CHR。 睡眠纺锤波是由丘脑网状核（TRN）与背侧丘脑的相互作用引发的。 丘脑的活动然后传递到皮层，在那里纺锤波振荡是同步的。的具体特征 纺锤波的密度、振幅和持续时间反映了丘脑、皮质和丘脑-皮质的神经功能 连接，分别。此外，GABA神经传递和丘脑-皮层连接在神经元的活动中起着关键作用。 产生和维持纺锤体振荡的作用。在最近的工作中，我们发现纺锤体缺陷是最常见的。 突出在额叶和前额头皮区域，并减少中背（MD）丘脑体积， 与精神分裂症患者源定位前额叶皮层（PFC）睡眠纺锤波减少有关。建筑 根据这些发现，我们将整合从电生理学到神经学， 分子，来表征这种与纺锤体相关的丘脑-皮质回路。具体来说，第二个广泛目标 这个项目是利用睡眠高强度来确定睡眠梭形缺陷的神经元和分子基础。 密度（hd）-EEG、7 T静息状态（rs）-fMRI和磁共振波谱成像（MRSI）。 为了解决这些总体目标，我们建议在45名患者和45名健康人中进行纵向研究。 对照组（HC），在两年内对临床和认知功能、HD-EEG、fMRI和MRSI进行三次评估。

Characterize differences in sleep spindles between Clinical High Risk and healthy controls longitudinally Project summary: Schizophrenia and related disorders are one of leading causes of disability worldwide, thus making the early identification of neurobiological vulnerabilities, which may serve as treatment targets, a critical research priority. In recent work, we found that individuals with chronic schizophrenia had a striking deficit in sleep spindles. A hallmark of Stage 2 Non-Rapid Eye Movement (N2) Sleep, spindles are short (0.5-2 s), waxing/waning oscillations within the 12-16 Hz range. Spindle abnormalities are also present in early course and early onset schizophrenia, and spindle-related measures, including amplitude, duration, and density, are associated with cognitive ability, social functioning, and tendency for magical thinking in healthy individuals, including adolescents and young adults. By investigating individual spindle parameters, we established that reduced spindle density and amplitude are associated with severity of symptoms and cognitive impairments respectively, in chronic schizophrenia patients. We also found that Integrated Spindle Activity (ISA), which combines individual spindle parameters in a single value, was the most discriminating measure, yielding ~90% separation between schizophrenia and control groups. Youth at Clinical High Risk (CHR) are a unique population enriched for precursors of major psychiatric disorders, such as schizophrenia, who also experience emergent cognitive impairments, social dysfunction, and sub-syndromal clinical symptoms. What we do not know is when spindle impairments occur, and how they may affect the development of psychopathology in this population. Thus, the first broad aim of this project is to characterize the role of sleep spindle parameters in moderating cognitive, social, and clinical functioning trajectories, including transition to psychosis, among youth at CHR. Sleep spindles are initiated by the interplay of the Thalamic Reticular Nucleus (TRN) with the dorsal thalamus. Thalamic activity is then relayed to the cortex, where spindle oscillations are synchronized. Specific features of spindles—density, amplitude and duration—reflect neural function in the thalamus, cortex, and thalamo-cortical connections, respectively. Moreover, GABA neurotransmission and thalamo-cortical connectivity play a critical role in generating and sustaining spindle oscillations. In recent work, we found that spindle deficits were most prominent in frontal and prefrontal scalp regions, and that reduced medio-dorsal (MD) thalamic volumes were associated with decreased sleep spindles in source localized prefrontal cortex (PFC) in schizophrenia. Building on these findings, we will integrate data across multiple levels of analysis, from electrophysiology to neural to molecules, to characterize this spindle-related thalamo-cortical circuitry. Specifically, the second broad aim of this project is to identify the neuronal and molecular underpinnings of sleep spindle defects using sleep high density (hd)-EEG, 7T resting state (rs)-fMRI, and Magnetic Resonance Spectroscopy Imaging (MRSI). In order to address these general aims, we propose to conduct longitudinal studies in 45 CHR and 45 healthy controls (HC), with three assessments of clinical and cognitive function, hd-EEG, fMRI, and MRSI over two years.