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）：本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。尽管有相当多的证据表明丘脑在精神病中是异常的，但在丘脑病理学被确立为生物标志物之前，必须解决几个知识空白。首先，虽然注意力集中在mediodorsal（MD）核，从死后的研究和传统的成像方法的局限性相矛盾的结果，很难建立丘脑病理的解剖特异性。其次，尚不清楚丘脑皮质连接障碍是否会扩展到精神病性BD。由丘脑回路支持的认知功能（包括工作记忆（WM））的重叠缺陷表明情况可能就是这样。然而，导致认知障碍的途径的差异也预示着会有差异。在SZ中，认知障碍叠加在受损的病前功能的背景上，并且在疾病阶段保持稳定。在BD中，病前功能是完整的，并且在疾病的早期阶段认知损害相对温和;而慢性患者几乎与SZ无法区分。这导致了不同的精神病病因模型：SZ被概念化为神经发育障碍，BD是神经进展性疾病。这些模型预测重叠异常丘脑皮质回路慢性患者，但在精神病的早期阶段的差异性损害。最后，尽管有令人信服的证据，从动物模型连接丘脑-皮质障碍WM，丘脑-皮质网络功能障碍的功能后果知之甚少。在对慢性（目标1）和早期精神病（目标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病性障碍中认知障碍的不同轨迹而变化，并与WM损伤相关（目标3）。我们将检验以下特定假设：1）在慢性精神病中，SZ和精神病性BP患者都将表现出PFC和MD丘脑之间的连接性降低; 2）在早期精神病中，SZ（而不是精神病性BP）将表现出PFC-MD丘脑连接性降低。此外，我们将测试的假设，在以前的研究中观察到的慢性SZ，我们提出的是由于非典型的病前大脑成熟的躯体运动超连接，存在于早期SZ，但不是早期或慢性精神病性BP。如果得到证实，这些假设将提供一个强有力的方法来区分精神障碍的早期和慢性阶段的疾病，并进一步支持不同的病因模型的SZ和BD。或者，结果可能 表明SZ和BD之间的丘脑皮质病理学有更大的重叠，而不是理解和挑战这些疾病的不同病因模型。此外，在WM检查功能连接可以提供翻译证据支持WM损伤的机制丘脑皮质连接障碍模型，并确定潜在的治疗目标，以改善认知障碍。