A Multidimensional Investigation of Cognitive Control Deficits in Psychopathology

描述（由申请人提供）：精神病谱系障碍（PSD）很难鉴别诊断和治疗，通常会使受害者终身残疾。人们越来越认识到，传统上不同的精神障碍，如精神分裂症，情感障碍和双相情感障碍与精神病性特征共享重叠的症状。例如，除了阳性症状之外，PSD患者还经历认知控制/执行功能的缺陷，这可能是由于中皮层和中纹状体通路的失调。重要的是，认知缺陷导致人际和职业功能的缺陷，更传统的临床症状（例如，思维混乱），目前难以治疗。本申请将使用新的招募策略和新的多变量分析技术来建立经验的、基于神经元的聚类度量（即，与PSD中认知控制（主要结果）和日常功能（次要结果）障碍相关的回路水平病理学），无论传统诊断（DSM-V）如何。在当前模型中评估的其他潜在中介变量包括阴性症状和思维混乱。我们基于我们的初步数据，通过检查三种神经递质（多巴胺、谷氨酸和GABA）信号通路、轴突引导通路和突触长时程增强通路内特定基因突变（单核苷酸多态性; SNP）的聚集，研究了这些回路水平病理的潜在因果机制。最后，一个探索性的目的是评估在多种精神疾病中认知控制缺陷的表达是否由每个人的DNA中罕见缺失的总数（拷贝数变异; CNVs）介导。为了评估这些假设，175名连续招募的PSD患者将完成广泛的临床电池，并进行多模式神经成像。诱发和内在血流动力学活动将与白色物质测定（弥散张量成像）结合使用，以研究在具有真实世界有效性的多感觉认知控制任务期间认知控制回路（背内侧前额叶皮质、外侧前额叶皮质和尾状核）的完整性和连通性。PSD患者将使用K均值算法基于认知控制网络中灰质/白色物质病理学的单变量和多变量指数被分类为有意义的实体。然后，我们将确定这些集群描述认知控制和日常功能缺陷的预测有效性，使用留一法来验证模型。因此，本申请利用来自NIMH研究领域标准的多个分析单元（基因、电路、自我报告、行为和范例）来开发基于跨越传统诊断类别的认知控制受损的神经生理学和遗传生物标志物的新型分类系统。我们相信，超越传统的疾病分类学将导致更有意义的诊断，并最终更成功地治疗难治性症状，从而大大改善精神卫生保健。

DESCRIPTION (provided by applicant): Psychotic spectrum disorders (PSD) are difficult to differentially diagnose and treat, typically leaving their victims with lifetime disability. It is increasingly becoming recognized that traditionally distinct disorders such as schizophrenia, schizoaffective disorder and bipolar disorder with psychotic features share overlapping symptoms. For example, in addition to positive symptoms, PSD patients also experience deficits in cognitive control/executive functioning, which likely result from dysregulation of the mesocortical and mesostriatal pathways. Importantly, cognitive deficits contribute to deficits in interpersonal and occupational functioning, more traditional clinical symptoms (e.g., disorganized thinking) and are currently refractory to treatment. The current application will use novel recruiting strategies and novel multivariate analytic techniques to establish empirical, neuronally-based cluster metrics (i.e., circuit-level pathologies) that are associated with impairments in cognitive control (primary outcome) and everyday functioning (secondary outcome) in PSD regardless of traditional diagnoses (DSM-V). Other potential mediating variables evaluated in the current model include negative symptoms and disorganized thinking. We investigate potential causal mechanisms for these circuit- level pathologies by examining the aggregation of specific genetic mutations (single nucleotide polymorphisms; SNPs) within three neurotransmitter (dopamine, glutamate and GABA) signaling pathways, axonal guidance pathway, and synaptic long-term potentiation pathways based on our preliminary data. Finally, an exploratory aim evaluates whether the expression of cognitive control deficits across multiple psychiatric illnesses is mediated by each individual's total number of rare deletions in DNA (copy number variations; CNVs). To evaluate these hypotheses, 175 continuously recruited PSD patients will complete an extensive clinical battery and undergo multimodal neuroimaging. Evoked and intrinsic hemodynamic activity will be used in conjunction with white matter assays (diffusion tensor imaging) to investigate the integrity and connectivity of the cognitive control circuit (dorsal medial prefrontal cortex, lateral prefrontal cortex and caudate nucleus) during a multisensory cognitive control task with real-world validity. PSD patients will be classified into meaningful entities based on univariate and multivariate indices of grey/white matter pathology in the cognitive control network using a K-means algorithm. We will then determine the predictive validity of these clusters for describing deficits in cognitive control and everyday functioning, using the leave-one-out methodology to verify the model. Thus, the current application utilizes multiple units of analyses (genes, circuits, self-report, behavior, and paradigms) from the NIMH Research Domain Criteria to develop a novel classification system based on neurophysiological and genetic biomarkers of impaired cognitive control that spans traditional diagnostic categories. We are confident that moving beyond traditional nosologies will result in more meaningful diagnoses and ultimately more successful treatments for refractory symptoms, leading to substantial improvements in mental health care.