Mapping the Longitudinal Neurobiology of Early-course Schizophrenia

项目总结 精神分裂症(SCZ)是一种严重致残的神经发育障碍，导致显着的功能障碍。SCZ 假设是由于突触障碍影响了大脑皮质-丘脑的大规模神经连接- 纹状体-皮质(CTSC)通路。神经成像证据支持这一观点，因为它显示了联想能力的改变 慢性SCZ中CTSC回路的皮质和连接中断。然而，复杂的进化神经生物学 早期的SCZ仍然没有特征性。这限制了早期疾病阶段的治疗，因为干预是至关重要的 利用狭小的“机会之窗”阻止疾病的发展。因此，了解脑出血的神经生物学 早期SCZ是早期发现、预测预后和针对性个体化治疗的主要目标。一个 许多SCZ研究中的主要复杂因素是抗精神病药物治疗的混杂存在。因此，我们的目标是 未用药的早期SCZ患者共发生的功能和结构连接障碍的特征和量化 神经改变与SCZ主要症状、认知缺陷和治疗反应的关系。为了实现这一目标，我们将 150例未用药的早期SCZ患者的神经连接障碍的纵向进展 初步进入西中国医院附属诊所就诊。我们将在6、12和24点对患者进行纵向跟踪 几个月后，与150名匹配的健康对照组进行比较。我们将使用最先进的功能和结构 方法通过人类连接组计划的优化，实现前沿的多模式神经影像集成。AS 值得注意的是，越来越多的证据表明，CTSC环涉及SCZ，特别是更高阶的前额叶和丘脑区域(例如 内侧-背侧结构)，提示CTSC功能障碍与SCZ症状之间存在机械联系。因此，首先我们的目标是 为了测试已识别的CTSC标记是否显示同时(或可分离的)结构和功能改变 未用药的SCZ患者，如果这些回路纵向改变。第二，我们将测试结构和功能 神经影像改变与SCZ主要症状和认知缺陷的严重程度有关。这提供了一种亟需的 SCZ患者纵向CTSC连接障碍与症状和认知的关系。关键的是，这是平衡的 纵向设计可以区分早期病程中的“状态”和“特质”神经影像标记物 临床相关变量。最后，众所周知，许多SCZ患者对抗精神病药物反应不佳。 然而，治疗反应差的神经标记物仍然没有被映射(反过来，治疗反应)。一把钥匙 美国和中国提出的合作伙伴关系的优势恰恰是能够对大样本进行纵向研究 从无药物观察开始，由西中国广泛而强大的招聘基础设施提供支持 医院。因此，我们的第三个目标是量化与以下因素相关的纵向结构和功能CTSC连接障碍 治疗反应。总而言之，这项研究将从以下几个方面开始映射纵向的“状态”与“特征”的神经标记 无药物治疗的早期疾病阶段(目标1)，将这些变化与症状动态(目标2)和治疗反应联系起来 (目标3)。这种映射对于为旨在最大化个体化早期干预策略的未来工作提供信息至关重要。

PROJECT SUMMARY Schizophrenia (SCZ) is a profoundly disabling neurodevelopmental disorder causing marked functional impairment. SCZ is hypothesized to arise from synaptic disturbances affecting large-scale neural connectivity along cortico–thalamic- striatal–cortical (CTSC) pathways. Neuroimaging evidence supports this view by showing alterations in associative cortices and connectivity disruptions across CTSC circuits in chronic SCZ. Yet, the complex evolving neurobiology of early-course SCZ remains uncharacterized. This limits treatments for early illness phases when intervention is crucial by capitalizing on the narrow `window' of opportunity to halt disease progression. Thus, understanding the neurobiology of early-course SCZ is a major objective for early detection, prognosis prediction and targeted individualized therapy. A major complicating factor in many SCZ studies is the confounding presence of antipsychotic treatment. Thus, our goal is to characterize co-occurring functional and structural dysconnectivity in unmedicated early-course SCZ and quantify neural changes in relation to cardinal SCZ symptoms, cognitive deficits and treatment response. To achieve this, we will examine longitudinal progression of neural dysconnectivity in 150 unmedicated early-course SCZ patients after their initial admission into clinics affiliated with West China Hospital. We will follow patients longitudinally at 6, 12, and 24 months later in comparison with 150 matched healthy controls. We will use state-of-the-art functional and structural methods optimized by the Human Connectome Project to achieve cutting-edge multi-modal neuroimaging integration. As noted, mounting evidence implicates CTSC loops in SCZ, particularly higher-order prefrontal and thalamic regions (e.g. medio-dorsal structures), suggesting mechanistic links between CTSC dysfunction and SCZ symptoms. Thus, first we aim to test if the identified CTSC markers exhibit concurrent (or dissociable) structural and functional alterations in unmedicated SCZ patients and if these circuits alter longitudinally. Second, we will test if structural and functional neuroimaging alterations relate to severity of cardinal SCZ symptoms and cognitive deficits. This provides a much-needed mapping between longitudinal CTSC dysconnectivity, symptoms and cognition in SCZ. Critically, this balanced longitudinal design can distinguish `state' versus `trait' neuroimaging markers during early illness course in relation to clinically relevant variables. Finally, it is well established that many SCZ patients do not respond well to antipsychotics. Yet, the neural markers of poor treatment response remain unmapped (and conversely treatment response). A key advantage of the proposed U.S.-China partnership is precisely the capacity to longitudinally study large sample sizes starting from medication-free observations, afforded by extensive and robust recruitment infrastructure at West China Hospital. Thus, our third aim is to quantify longitudinal structural and functional CTSC dysconnectivity in relation to treatment response. Collectively, this study will map longitudinal `state' versus `trait' neural markers starting from medication-free early illness stages (Aim 1), relate these changes to symptom dynamics (Aim 2) and treatment response (Aim 3). This mapping is vital to inform future work aimed at maximizing individualized early intervention strategies.