Default mode connectivity in typical development & the schizophrenia prodrome

描述（由申请人提供）：大多数精神分裂症患者在明显疾病发作之前会出现前驱症状。在这一前驱期的大脑完整性的措施可能反映精神分裂症的脆弱性。然而，精神分裂症神经发育改变的时间仍然未知。虽然围产期脑损伤已被牵连在精神分裂症的发病机制，青春期也一直感兴趣，因为它是在这个发育窗口期，临床症状通常出现。有几种理论认为，青春期神经发育异常是发展为全面精神分裂症的基础。然而，很少有研究关注大规模神经网络的连通性，或者直接比较健康青少年和临床上患精神分裂症（精神分裂症）的高危人群之间的大脑发育轨迹。更少的研究已经检查了环境因素的作用，如物质使用对大脑发育的影响。特别是，大麻的使用已被确定为精神分裂症病因学中的一个潜在环境风险因素，激发了关于大麻暴露如何与大脑改变相互作用的问题。对大脑网络连接的分析可能特别适合于解决与大麻相关的神经发育轨迹问题，以及大麻暴露对精神病风险的潜在相互作用。“默认模式网络”（DMN）是一种神经网络，与认知任务条件相比，它在休息时显示出增加的fMRI活动。精神分裂症的先前研究报告精神病性症状与DMN的超连通性的关联，并且扩散张量成像（DTI）分析已经检测到连接DMN区域的纤维通路的微结构一致性较差。总之，这些研究结果表明，DMN连接的结构和功能方面的改变，精神分裂症，支持专注于DMN的发展轨迹在精神分裂症患者。此外，由于DMN是可检测的任务性能的情况下，它是很好的准备，以评估大脑行为的关系，在发展的临床研究，其中相当大的组间认知任务性能的差异，可以复杂的解释传统的任务为基础的功能磁共振成像研究。拟议的研究将结合联合收割机分析静息状态的功能磁共振成像与DTI，以测量DMN连接的功能和结构方面，重点是检查DMN的发展轨迹，从青春期到成年期的健康对照组。此外，我们将研究DMN功能和结构的完整性如何与青少年大麻使用有关。最后，我们将研究DMN连接是否与症状严重程度有关，并预测转化为精神病。考虑到与精神分裂症谱相关的广泛的认知效应，神经系统的观点可能特别有益于揭示脆弱个体发展为精神病的大脑改变。

DESCRIPTION (provided by applicant): Most patients with schizophrenia experience a prodrome, prior to the onset of frank illness. Measures of brain integrity during this prodromal period may reflect schizophrenia vulnerability. However, the timing of neuro- developmental alterations in schizophrenia remains unknown. Although perinatal brain insults have been implicated in the pathogenesis of schizophrenia, adolescence has also been of interest because it is during this developmental window that clinical symptoms typically arise. Several theories pose that abnormal adolescent neuromaturation underlies progression to full-blown schizophrenia. However, few studies have looked at connectivity of large-scale neural networks, or directly compared the trajectories of brain development between healthy adolescents and those at clinical high risk for developing schizophrenia (CHR). Even less research has examined the role of environmental factors such as substance use on brain development in CHR individuals. In particular, cannabis use has been identified as a potential environmental risk factor in the etiology of schizophrenia, motivating questions about how cannabis exposure might interact with brain alterations associated with the CHR phenotype. Analysis of brain network connectivity may be particularly well-suited to addressing questions concerning the neurodevelopmental trajectory associated with CHR, as well as the potential interaction of cannabis exposure on psychosis risk. The "default-mode network" (DMN) is a neural network that shows increased fMRI activity at rest, compared to cognitive task conditions. Prior studies of schizophrenia report associations of psychotic symptoms with hyperconnectivity of the DMN, and diffusion tensor imaging (DTI) analyses have detected poorer microstructural coherence of the fiber pathways connecting DMN regions. Together, these findings suggest that both structural and functional aspects of DMN connectivity are altered in schizophrenia, supporting a focus on the DMN's developmental trajectory in CHR individuals. Moreover, because the DMN is detectable in the absence of task performance, it is well-poised to evaluate brain-behavior relationships in developmental clinical studies, in which sizeable between-group cognitive task performance differences can complicate interpretation of traditional task-based fMRI studies. The proposed study will combine analyses of resting state fMRI with DTI in order to measure both functional and structural aspects of DMN connectivity, with a focus on examining the DMN's developmental trajectory from adolescence to adulthood in CHR and healthy comparison subjects. Further, we will examine how DMN functional and structural integrity relates to cannabis use in CHR youth. Lastly, we will examine whether DMN connectivity relates to symptom severity and predicts conversion to psychosis. Given the wide range of cognitive effects associated with the schizophrenia spectrum, a neural systems perspective may be particularly profitable in shedding light on the brain alterations underlying progression to psychosis in vulnerable individuals.