Cognitive Neuroscience of the Psychosis Prodrome

描述(由申请人提供)：这份K23申请提出了一项培训和指导研究计划，将为申请者提供与认知神经科学和功能神经成像相关的新技能，以支持独立研究生涯的发展，调查精神错乱的超高风险(UHR)个体临床和功能结果背后的认知和神经机制。拟议的培训计划包括功能磁共振成像方法方面的严格培训，以及统计分析、编程和负责任的人体研究方面的相关课程。加州大学戴维斯分校的学术和专业环境为这项建议的实施提供了丰富的资源，包括持续获得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。除了这种出色的研究培训环境外，申请者还将不断接触到现有的临床人群进行学科招聘，并对申请者的研究生涯的发展做出强有力的部门承诺。这项拟议的指导性研究旨在利用功能磁共振成像阐明精神病超高风险个体临床和功能恶化的认知标志。这项研究将通过探索前额叶介导的认知控制和UHR个体和健康匹配对照组潜在神经生物回路的完整性来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辅助，协调思想和行动，以产生目标导向的行为。认知控制障碍在精神分裂症患者中一直被证明，最近，与临床和功能障碍有关。虽然在UHR人群中观察到了认知行为指标的损害，但这种损害的神经机制尚未建立。此外，这种认知障碍与临床和心理社会领域的恶化之间的联系还没有得到系统的探索。这项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质(DLPFC)在需要高水平认知控制的任务中的作用，背外侧前额叶皮质是分布式认知控制网络的组成部分。据推测，与正常对照组相比，UHR个体将表现出认知控制能力降低，同时DLPFC激活也减少。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接性也将降低。最后，将检查皮质激活与临床症状和心理社会功能指标之间的关系，以确定认知控制基础上的DLPFC回路功能障碍是否有助于这些高危个体的临床和功能结果。与当前NIMH战略计划的目标一致，这项研究的结果将提供关于在精神病发病前一段时间前额叶连接的作用的新信息，为那些具有最高精神病发病风险的个人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的洞察。此外，这项研究将扩大我们对前额叶功能对高危青少年临床和心理社会功能的影响的理解，增强早期识别算法，并有助于制定更有效的早期干预努力。 公共卫生相关性：确定精神病的假定风险标志是加强早期发现和干预努力的关键一步。这项研究建议使用功能磁共振成像范式来研究前额叶皮质的认知控制过程，以确定患有超高精神病风险的年轻人临床和功能恶化的风险标志物。

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.