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：
8691200
负责人：
Andrew Robert Mayer
金额：
$ 60.13万
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/8691200
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）：精神病谱系障碍（PSD）很难差异诊断和治疗，通常会使受害者终身残疾。越来越多地认识到，传统上不同的疾病，例如精神分裂症，精神分裂症和具有精神病特征的躁郁症，具有重叠的症状。例如，除阳性症状外，PSD患者还经历了认知控制/执行功能的缺陷，这可能是由于中皮层和介质途径的失调引起的。重要的是，认知缺陷会导致人际交往和职业功能，更传统的临床症状（例如，混乱的思维）缺陷，目前是对治疗的难治性。当前的应用将使用新颖的招聘策略和新型的多元分析技术来建立与认知控制（主要结果）和日常功能（主要结果）和日常功能（次要结果）相关的基于经验的基于神经元的集群指标（即电路级病理学） PSD不管传统诊断如何（DSM-V）。当前模型中评估的其他潜在介导变量包括负面症状和混乱的思维。我们通过研究特定遗传突变（单核苷酸多态性； SNP）在三个神经递质（多巴胺，多巴胺，谷氨酸和GABA）信号通路，轴突指导途径以及突触长期实力实力的实力预力途径中，研究了这些电路水平病理学的潜在因果机制。基于我们的初步数据。最后，探索性目的评估了多种精神病疾病的认知控制缺陷的表达是否是由每个人在DNA中的稀有缺失总数（拷贝数变化； CNV）介导的。为了评估这些假设，175名不断招募的PSD患者将完成广泛的临床电池并进行多模式神经影像学。诱发和内在的血液动力学活性将与白质测定（扩散张量成像）结合使用，以研究认知控制回路（背侧前额叶皮层，前额叶前额叶皮层，侧面前额叶皮层和尾状核）的完整性和连通性，并在多功能认知控制的过程中现实世界的有效性。 PSD患者将根据使用K-Means算法在认知控制网络中灰色/白质病理学的单变量和多变量指数将PSD患者分为有意义的实体。然后，我们将使用剩余的方法来验证模型的方法来确定这些集群对描述认知控制和日常功能缺陷的预测有效性。因此，当前的应用程序利用NIMH研究领域标准的多个分析（基因，电路，自我报告，行为和范式）来开发基于神经生理学和遗传生物标记物的新型分类系统，这些系统跨越了跨越传统诊断诊断的认知控制的受损类别。我们有信心，超越传统的疾病将导致更有意义的诊断，并最终对难治性症状进行更成功的治疗方法，从而大大改善精神卫生保健。