Stress Regulation, Working Memory, and Cognitive Disorganization In Adolescence

 描述(申请人提供)：青春期是精神病理学核心症状出现的高峰期。认知障碍(CD)是精神病的一个关键症状维度，最常出现在青春期，反映出思维的混乱，由奇怪的行为、冷漠和注意力受损来定义。CD超越了DSM的诊断类别，预测了精神障碍的发病和严重程度，并与神经心理损害有关。遗传学研究已报道CD具有高度的遗传性，因此被认为是分子遗传学研究的一种有前途的表型。尽管它在预示精神病风险方面发挥了关键作用，但人们对CD在青少年中的神经生物学基础知之甚少。然而，据报道，经历组织紊乱的青少年在工作记忆容量(WMC)和唤醒/压力调节(ASR)方面存在严重缺陷。这两种行为结构在青春期表现出戏剧性的成熟变化，这是向更高水平的认知、情感调节和心理社会适应过渡所必需的。尽管有强有力的流行病学证据表明应激在精神病的病因中所起的作用，以及工作记忆障碍在精神病中的中心地位，但人们对它们在青春期CD中的贡献知之甚少。检查与青春期工作记忆和压力调节相关的神经和生理系统，以及它们对CD严重性的贡献，提供了关键的一步 以阐明导致精神病发病的病理生理学机制。这种方法与RDoC框架一致，RDoC框架鼓励使用聚合测量来研究领域(本提案中的认知系统和唤醒调节)和代表具有精神病临床风险症状的个人表达的基本行为的结构(工作记忆容量和压力调节)的潜在神经生物学。我们将使用一种整合了功能神经成像、电生理和行为测量的多模式方法来确定跨神经、生理和行为单位的工作记忆和唤醒/应激调节结构的汇聚测量，并通过临床量表来表征非典型ASR和受损的WMC在CD症状严重程度中的作用。在目标1中，我们将评估180名青少年(9-16岁)的工作记忆障碍和非典型唤醒/应激调节对CD症状严重程度的影响。在目标2中，我们将模拟WM和ASR结构之间的关系以及它们对CD严重性的影响。在目标3中，我们将考察CD症状严重程度、WM和ASR的行为和电生理指标的纵向轨迹，以及它们与在目标1和目标2中获得的基线神经、行为和生理指标的关系。对于每个目标，我们将探索性别差异和青春期成熟对青春期应激调节和工作记忆的调节作用，以及它们在决定功能结果方面的影响。影响：了解与青春期工作记忆能力和压力调节相关的神经和生理系统，以及它们对CD严重性的贡献，是阐明促进精神病出现和恶化的核心病理生理机制的关键一步。

 DESCRIPTION (provided by applicant): Adolescence is a peak time for the emergence of the core symptoms of psychopathology. Cognitive disorganization (CD) is a key symptom dimension of psychosis that emerges most commonly in adolescence, reflects a disorganization of thought and is defined by the presence of bizarre behavior, alogia, and impaired attention. CD transcends DSM diagnostic categories, predicts the onset and severity of psychotic disorders, and is associated with neuropsychological impairment. Genetic studies have reported that CD is highly heritable, and therefore has been proposed as a promising phenotype for molecular genetic studies. Despite its critical role in heralding risk for psychosis, little is knon about the neurobiological underpinnings of CD in adolescents. It has been reported however that adolescents experiencing disorganization have significant deficits in working memory capacity (WMC) and arousal/stress regulation (ASR). These two behavioral constructs show dramatic maturational changes during adolescence, which are necessary for the transition to higher-level cognition, affect regulation and psychosocial adaptation. Despite the strong epidemiologic evidence for the role of stress in the etiology of psychosis, and the centrality of working memory impairments in psychosis, little is known about their contribution to CD in adolescence. Examining the neural and physiological systems associated with working memory and stress regulation in adolescence, and their contribution to CD severity, offers a critical step in elucidating the pathophysiological mechanisms that contribute to the onset of psychosis. This approach is consistent with the RDoC framework, which encourages using converging measurements to study the underlying neurobiology of domains (Cognitive System and Arousal Regulation in this proposal), and constructs (working memory capacity and stress regulation) that represent fundamental behaviors expressed by individuals with clinical risk symptoms for psychosis. We will use a multimodal approach integrating functional neuroimaging, electrophysiological, and behavioral measures to ascertain converging measures of working memory and arousal/stress regulation constructs across neural, physiological, and behavioral units, and to characterize the contributions of atypical ASR and impaired WMC in the severity of CD symptoms measured through clinical scales. In Aim 1, we will evaluate the contributions of working memory impairments and atypical arousal/stress regulation in 180 adolescents (ages 9-16) to the severity of CD symptom. In AIM 2 we will model the relationship between WM and ASR constructs and their impact on CD severity. In AIM 3, we will examine the longitudinal trajectory of CD symptom severity, behavioral and electrophysiological measures of WM and ASR, and their associations with baseline neural, behavioral, and physiological measures acquired in AIMs 1 and 2. For each aim, we will explore the modulatory role of sex differences and pubertal maturation on stress-regulation and working memory during adolescence, and their influence in determining functional outcomes. IMPACT: Understanding the neural and physiological systems associated with working memory capacity and stress regulation in adolescence, and their contribution to CD severity, is a crucial step for elucidating the core pathophysiological mechanisms that promote the emergence and exacerbation of psychosis.