Thalamocortical Networks in Psychosis

精神病中的丘脑皮质网络

• 批准号: 8918748
• 负责人: Neil D. Woodward
• 金额: $ 46.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918748
• 关键词: Address; Affect; Animal Model; Attention; Biological Markers; Bipolar Disorder; Brain; Caregiver Burden; Chronic; Chronic Schizophrenia; Cognition; Cognitive; Cognitive deficits; Conflict (Psychology); Development; Differential Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease model; Exhibits; Functional Magnetic Resonance Imaging; Health; Image; Impaired cognition; Impairment; Investigation; Knowledge; Life; Link; Maintenance; Maps; Medial Dorsal Nucleus; Memory impairment; Modeling; Outcome; Pathology; Pathway interactions; Patients; Prefrontal Cortex; Psychotic Disorders; Rest; Schizophrenia; Short-Term Memory; Specificity; Staging; Structure; Testing; Thalamic structure; Work; base; cognitive function; differential expression; economic cost; network dysfunction; neurodevelopment; neuroimaging; neuropsychiatry; psychosocial; relating to nervous system

DESCRIPTION (provided by applicant): This project will investigate thalamocortical networks in schizophrenia (SZ) and psychotic bipolar disorder (BD). Despite considerable evidence that the thalamus is abnormal in psychosis, several knowledge gaps must be addressed before thalamic pathology can be established as a biomarker. First, although attention has focused on the mediodorsal (MD) nucleus, conflicting findings from post-mortem studies and limitations of conventional imaging approaches has made it difficult to establish the anatomical specificity of thalamic pathology. Second, it is not known if thalamocortical dysconnectivity extends to psychotic BD. Overlapping deficits in cognitive functions supported by the thalamic circuitry, including working memory (WM), suggests this may be the case. However, differences in the pathways leading to cognitive impairment also predict there will be differences. In SZ, cognitive impairment is superimposed on a background of compromised pre-morbid functioning and remains stable across illness stages. In BD, pre-morbid functioning is intact and cognitive impairment is relatively modest in the early stage of the illness; whereas chronic patients are virtually indistinguishable from SZ. This has led to different etiological models of psychosis: SZ is conceptualized as a neurodevelopment disorder and BD a neuroprogressive illness. These models predict overlapping abnormalities in thalamocortical circuitry in chronic patients, but differential impairment in the early stage of psychosis. Finally, despite compelling evidence from animal models linking thalamocortical dysconnectivity to WM, the functional consequences of thalamocortical network dysfunction are poorly understood. In separate studies of chronic (Aim 1) and early stage psychosis (Aim 2), we will determine if thalamocortical network pathology varies in accordance with the different trajectories of cognitive impairment in psychotic disorders, and is related to WM impairment (Aim 3). We will test the following specific hypotheses: 1) in chronic psychosis, both SZ and psychotic BP patients will exhibit reduced connectivity between the PFC and MD thalamus; and 2) in early stage psychosis, SZ, but not psychotic BP, will exhibit reduced PFC-MD thalamus connectivity. Additionally, we will test the hypothesis that somatomotor hyper-connectivity observed in prior studies of chronic SZ, which we proposed is due to atypical pre-morbid brain maturation, is present in early stage SZ, but not early stage or chronic psychotic BP. If confirmed, these hypotheses will provide a powerful approach to differentiating psychotic disorders at both early and chronic stages of the illness, and further support the different etiological models of SZ and BD. Alternatively, the results might indicate there is greater overlap in thalamocortical pathology between SZ and BD than appreciated and challenge the different etiological models of these disorders. Moreover, examining functional connectivity during WM may provide translational evidence supporting a mechanistic thalamocortical dysconnectivity model of WM impairment and identify potential treatment targets for ameliorating cognitive impairment.

描述（由申请人提供）：该项目将研究精神分裂症（SZ）和精神病性双相情感障碍（BD）的丘脑皮质网络。尽管有大量证据表明丘脑在精神病中是异常的，但必须在丘脑病理学确定生物标志物之前要解决一些知识差距。首先，尽管注意力集中在肾上腺核（MD）核上，但验尸研究和常规成像方法的局限性矛盾，使得难以建立丘脑病理学的解剖学特异性。其次，尚不清楚丘脑皮质障碍性是否扩展到精神病性BD。丘脑电路支持的认知功能的重叠缺陷，包括工作记忆（WM），这可能是这种情况。但是，导致认知障碍的途径的差异也预测会有差异。在SZ中，认知障碍叠加在受损前的功能的背景下，并且在疾病阶段保持稳定。在BD中，疗程前的功能完好无损，在疾病的早期阶段，认知障碍相对谦虚。而慢性患者实际上与SZ没有区别。这导致了精神病的不同病因学模型：SZ被概念化为神经发育障碍和BD神经保护疾病。这些模型预测了慢性患者丘脑皮质回路的重叠异常，但是在精神病的早期阶段差异障碍。最后，尽管将丘脑皮质​​功能障碍与WM联系起来的动物模型的令人信服的证据，但丘脑皮质网络功能障碍的功能后果知之甚少。在对慢性（AIM 1）和早期精神病（AIM 2）的单独研究中，我们将确定丘脑皮质网络病理学是否根据精神疾病中认知障碍的不同轨迹而变化，并且与WM损害有关（AIM 3）。我们将检验以下特定假设：1）在慢性精神病中，SZ和精神病患者均表现出PFC和MD Thalamus之间的连通性降低； 2）在早期的精神病中，SZ而不是精神病性BP，PFC-MD Thalamus连通性将降低。此外，我们将检验以下假设：在先前的慢性SZ研究中观察到的体成体超连接性，我们提出的是由于早期SZ的非典型前脑脑成熟，但不存在于早期阶段或慢性精神病性BP。如果得到证实，这些假设将为疾病的早期和慢性阶段区分精神疾病提供强大的方法，并进一步支持SZ和BD的不同病因模型。或者，结果可能 表明SZ和BD之间丘脑皮质病理学的重叠量要大于欣赏和挑战这些疾病的不同病因模型。此外，检查WM期间的功能连通性可能会提供转化证据，以支持WM损伤的机械性丘脑皮质障碍性模型，并确定潜在的治疗靶标，以改善认知障碍。