Cognitive Neuroscience of the Psychosis Prodrome

描述（由申请人提供）：此K23申请提出了一个培训和指导研究计划，将为申请人提供与认知神经科学和功能神经成像相关的新技能，这将支持独立研究事业的发展，调查超高风险（UHR）精神病患者临床和功能结果的认知和神经机制。拟议的培训计划包括fMRI方法的严格培训，以及统计分析，编程和负责任的人体研究行为的相关课程。加州大学戴维斯分校的学术和专业环境为该提案的实施提供了丰富的资源，包括始终如一的经验丰富的指导团队，杰出的研究和临床教师，两台现场磁共振成像（MRI）扫描仪和致力于研究目的的支持人员。除了这个优秀的研究培训环境，申请人将有机会持续获得已建立的临床人群进行受试者招募，以及一个强有力的部门承诺，以发展申请人的研究事业。本研究旨在利用功能磁共振成像技术阐明精神病超高风险个体的临床和功能恶化风险的认知标志物。这项研究将通过探索UHR个体和健康匹配对照中前额叶介导的认知控制和潜在神经生物学回路的完整性，扩展先前在精神分裂症个体中建立的发现。认知控制由大脑区域的分布式网络提供服务，它协调思想和行动，以产生目标导向的行为。认知控制障碍一直在精神分裂症患者中得到证实，最近，认知控制障碍与临床和功能障碍有关。虽然在UHR人群中观察到认知行为测量的损伤，但这种损伤背后的神经机制尚未确定。此外，这种认知障碍与临床和社会心理领域恶化之间的联系尚未得到系统的探索。本研究利用事件相关功能磁共振成像（fMRI）范式来研究背外侧前额叶皮层（DLPFC）在需要高水平认知控制的任务中的作用，DLPFC是分布式认知控制网络的一个组成部分。据推测，与正常对照相比，UHR个体将表现出认知控制能力下降，同时DLPFC激活减少。此外，据预测，在UHR组中，DLPFC与支持认知控制的分布式神经网络之间的连通性也会减少。最后，为了确定认知控制下的DLPFC回路的功能障碍是否与这些高危个体的临床和功能结果有关，将检查皮质激活与临床症状和社会心理功能之间的关系。根据目前NIMH战略计划的目标，这项调查的结果将为精神病发病前前额叶连接的作用提供新的信息，为那些精神病风险最高的个体提供潜在的神经生物学标记以及疾病进展的可能发展轨迹。此外，这项研究将拓宽我们对前额叶功能对高危青少年临床和社会心理功能影响的理解，增强早期识别算法，并有助于开发更有效的早期干预措施。

DESCRIPTION (provided by applicant): This K23 application proposes a training and mentored research plan that will provide the applicant with new skills related to cognitive neuroscience and functional neuroimaging that will support the development of an independent research career investigating the cognitive and neural mechanisms underlying clinical and functional outcome in individuals at ultra-high-risk (UHR) for psychosis. The proposed training plan incorporates rigorous training in fMRI methodology, and relevant coursework in statistical analysis, programming, and the responsible conduct of human research. The academic and professional environment at UC Davis provides rich resources for the implementation of this proposal, including consistent access to an experienced mentorship team, a distinguished research and clinical faculty, two on-site magnetic resonance imaging (MRI) scanners and support staff dedicated to research purposes. In addition to this outstanding research training environment, the applicant will have ongoing access to established clinical populations for subject recruitment, and a strong departmental commitment to the development of the applicant's research career. The proposed mentored research study seeks to elucidate cognitive markers of risk for clinical and functional deterioration in individuals at ultra-high-risk for psychosis using fMRI. This investigation will extend previous findings established in individuals with schizophrenia by exploring prefrontally-mediated cognitive control and the integrity of underlying neurobiological circuitry in UHR individuals and healthy matched controls. Cognitive control, which is subserved by a distributed network of brain regions, coordinates thoughts and actions in order to generate goal-directed behavior. Cognitive control impairments have been consistently demonstrated in individuals with schizophrenia and, more recently, linked to clinical and functional impairment. While impairments on behavioral measures of cognition have been observed in UHR populations, the neural mechanisms underlying such impairments have not been established. Further, the link between such cognitive impairments and deterioration in clinical and psychosocial domains has not been systematically explored. This investigation utilizes an event-related functional magnetic resonance imaging (fMRI) paradigm to examine the role of the dorsolateral prefrontal cortex (DLPFC), which serves as an integral part of the distributed cognitive control network, during a task requiring high levels of cognitive control. It is hypothesized that UHR individuals will demonstrate reduced cognitive control with concurrent reductions in DLPFC activation when compared to normal controls. Furthermore, it is predicted that connectivity between the DLPFC and the distributed neural network that supports cognitive control will also be reduced in the UHR group. Finally, relationships between cortical activation and measures of clinical symptomatology and psychosocial functioning will be examined in order to determine if dysfunction in the DLPFC circuit underlying cognitive control contributes to clinical and functional outcome in these at-risk individuals. In concordance with the goals of the current NIMH Strategic Plan, results of this investigation will provide novel information on the role of prefrontal connectivity during the period preceding psychosis onset, offering insight into potential neurobiological markers as well as the possible developmental trajectory of illness progression for those individuals who are at highest risk for developing psychosis. Further, this study will broaden our understanding of the impact of prefrontal functioning on clinical and psychosocial functioning for at-risk adolescents, enhancing early identification algorithms and contributing to the development of more effective early intervention efforts. PUBLIC HEALTH RELEVANCE: The identification of putative markers of risk for psychosis is an essential step toward enhancing early detection and intervention efforts. This research proposes to use an fMRI paradigm to investigate cognitive control processes in the prefrontal cortex to identify markers of risk for clinical and functional deterioration in youth at ultra-high risk for psychosis.