Thalamocortical Networks in Psychosis

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。尽管有大量证据表明丘脑在精神病中是异常的，但在将丘脑病理学作为生物标志物建立之前，必须解决几个知识空白。首先，尽管人们的注意力集中在中背核（MD）上，但来自死后研究的相互矛盾的发现和传统成像方法的局限性使得很难确定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延伸到精神病性双相障碍。丘脑回路支持的认知功能重叠缺陷，包括工作记忆（WM），表明可能是这种情况。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，认知障碍叠加在发病前功能受损的背景上，并在整个疾病阶段保持稳定。在双相障碍中，发病前的功能是完整的，认知障碍在疾病的早期阶段相对温和；而慢性患者和SZ几乎没有区别。这导致了精神病的不同病因模型：SZ被定义为一种神经发育障碍，而BD是一种神经进行性疾病。这些模型预测了慢性患者丘脑皮质回路的重叠异常，但在精神病的早期阶段存在差异损伤。最后，尽管来自动物模型的令人信服的证据表明丘脑皮质连接障碍与WM有关，但丘脑皮质网络功能障碍的功能后果尚不清楚。在慢性精神病（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障碍中认知障碍的不同轨迹而变化，并与WM障碍有关（Aim 3）。我们将测试以下具体假设：1)在慢性精神病中，SZ和精神病性BP患者都表现出PFC和MD丘脑之间的连通性降低；2)在早期精神病中，SZ，而不是精神病性BP，会表现出PFC-MD丘脑连通性降低。此外，我们将验证在先前的慢性SZ研究中观察到的躯体运动超连接的假设，我们提出这是由于非典型的病态前脑成熟，存在于早期SZ，但不存在早期或慢性精神病性BP。如果得到证实，这些假设将为区分疾病早期和慢性阶段的精神障碍提供有力的方法，并进一步支持SZ和BD的不同病因模型

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.