A Multidimensional Investigation of Cognitive Control Deficits in Psychopathology

精神病理学中认知控制缺陷的多维调查

基本信息

批准号：
8899274
负责人：
Andrew Robert Mayer
金额：
$ 3.61万
依托单位：
THE MIND RESEARCH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-02 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899274
关键词：
Algorithms Behavior Behavioral Biological Assay Biological Markers Bipolar Disorder Brain Categories Classification Clinical Clinical Trials Cognition Cognitive deficits Copy Number Polymorphism Corpus striatum structure DNA copy number DSM-V Data Data Set Delusional disorder Development Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Disease Dopamine Dorsal Exhibits Future Gene Mutation Genes Genetic Genetic Determinism Genetic Markers Genetic Risk Glutamates Goals Gray unit of radiation dose Hallucinations Healthcare Impaired cognition Impairment Individual Investigation Lateral Left Link Long-Term Potentiation Measures Medial Mediating Mental Health Methodology Methods Metric Modality Modeling Mutation National Institute of Mental Health Neurobiology Neurotransmitters Occupational Pathology Pathway interactions Patients Pattern Phenotype Population Prefrontal Cortex Psychopathology Psychotic Disorders Public Health Recording of previous events Recruitment Activity Refractory Relative (related person)Research Domain Criteria Role Schizoaffective Disorders Schizophrenia Schizophreniform Disorder Sensory Signal Pathway Single Nucleotide Polymorphism Specific qualifier value Symptoms Synapses System Techniques Thinking Treatment Protocols axonal guidance base caudate nucleus cognitive control cost diagnostic accuracy disability executive function experience gamma-Aminobutyric Acid genetic analysis genetic risk factor hemodynamics improved indexing multisensory neuroimaging neurophysiology novel novel strategies primary outcome psychotic symptoms public health relevance secondary outcome self reported behavior success white matter

项目摘要

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.

描述（由申请人提供）：精神谱系障碍（PSD）很难进行鉴别诊断和治疗，通常会给受害者带来终生残疾。人们越来越认识到，精神分裂症、分裂情感性障碍和具有精神病特征的双相情感障碍等传统上不同的疾病具有重叠的症状。例如，除了阳性症状外，PSD 患者还会出现认知控制/执行功能缺陷，这可能是由于中皮质和中纹状体通路失调所致。重要的是，认知缺陷会导致人际和职业功能缺陷、更传统的临床症状（例如思维混乱），并且目前难以治疗。当前的应用程序将使用新颖的招募策略和新颖的多变量分析技术来建立与认知控制（主要结果）和日常功能（次要结果）损伤相关的基于经验的、基于神经元的聚类指标（即回路水平病理）。 PSD 与传统诊断无关 (DSM-V)。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）的聚集来研究这些回路水平病理的潜在因果机制根据我们的初步数据。最后，一个探索性目标是评估多种精神疾病中认知控制缺陷的表达是否是由每个人的 DNA 罕见缺失总数（拷贝数变异；CNV）介导的。为了评估这些假设，175 名持续招募的 PSD 患者将完成广泛的临床试验并接受多模式神经影像学检查。诱发和内在血流动力学活动将与白质测定（弥散张量成像）结合使用，以研究多感觉认知控制任务期间认知控制回路（背内侧前额叶皮层、外侧前额叶皮层和尾状核）的完整性和连接性现实世界的有效性。使用 K 均值算法，根据认知控制网络中灰质/白质病理学的单变量和多变量指数，将 PSD 患者分类为有意义的实体。然后，我们将使用留一法验证模型，确定这些集群在描述认知控制和日常功能缺陷方面的预测有效性。因此，当前的应用程序利用 NIMH 研究领域标准的多个分析单元（基因、回路、自我报告、行为和范例）来开发一种基于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，该系统跨越了传统的诊断类别。我们相信，超越传统的疾病分类学将带来更有意义的诊断，并最终对难治性症状进行更成功的治疗，从而显着改善精神卫生保健。