X染色体是人类基因组中一条特殊的染色体，在人脑发育和智力水平的发展过程中扮演了重要的角色。Turner综合征是由于女性体细胞中单条X染色体全部或部分缺失导致的先天性基因缺陷疾病，是研究人类X染色体对脑和行为影响的天然“敲除”模型。本论文利用该“敲除”模型样本，结合一系列的多模态磁共振成像技术和分析方法，从多个角度开展了针对X染色体对人脑结构与功能作用规律及机制的研究，具体可以分为以下三个方面: X染色体对人脑白质结构网络半球模块的作用规律及其认知后果。大脑是生物界中最为精密且高效的系统之一。海量的神经元之间通过树突和轴突相互连接构成了极为复杂的脑网络，并具有如模块化结构等卓越的拓扑特性。已有的研究发现Turner患者会表现出单侧半脑白质的损伤。为了探究X染色体对人脑白质结构组成的影响，本研究采用了脑网络的分析方法对Turner女性以及年龄匹配的健康女性进行了分析。通过使用优化的纤维追踪技术构建了被试的半脑白质结构网络，并应用数据驱动的方法划分出了半脑白质结构网络的模块。组间比较的结果发现，Turner女性的双侧半脑顶叶模块表现出了拓扑效率的显著降低。进一步地中介分析确定了一条位于右脑的“X染色体-右脑顶叶模块-工作记忆”中介通路。此外，结合静息态功能磁共振数据的分析还发现了Turner女性脑结构和功能连接之间耦合程度的降低，且主要发生在右脑网络的连接中。该研究首次开展了在Turner综合征患者中的脑白质网络模块研究，并发现了X染色体、脑、行为之间的重要中介通路。这些结果为理解X染色体对大脑白质结构组成的作用规律提供了新的线索，并提示了半脑白质结构网络模块在X染色体和大脑功能/行为能力关系中的重要作用。 X染色体对人脑功能连接半球特异化的影响规律。人脑功能活动的半球特异化是许多高级认知功能的神经基础。已有研究提示X染色体会差异性地影响人脑的左、右半球，并且会影响具有半球优势效应的认知功能的表现。为了探究X染色体对半脑功能活动特异化的影响模式，本研究从脑功能在半球间的分离和整合角度入手，对Turner患者女性及正常对照女性的静息态功能磁共振影像进行了分析。研究计算并使用了同源功能连接强度和功能连接不对称性指标分别对半脑功能的整合与分离过程进行量化。结果发现，Turner患者在顶叶和额下回表现出同源功能连接强度的显著降低，但半脑功能连接不对称性并没有出现显著的异常。此外，Turner患者颞下回的同源功能连接与功能连接不对称性之间的关系也发生了显著地改变。这些结果说明，X染色体可以影响特定同源区域的半脑间功能整合过程，并且可以调控半脑功能分离与功能整合之间的相互作用从而影响大脑半球功能的特异化。这些发现为大脑半球功能特异化的X染色体相关遗传基础提供了直接证据。 X染色体缺失引发的卵巢功能异常和雌激素缺乏对人脑发育的影响模式。雌激素对大脑神经系统的形成和发育具有重要的作用。由于X染色体的缺失，Turner患者会出现卵巢功能的异常并继而引发体内雌激素的严重缺乏。迄今为止，Turner患者的卵巢功能异常及雌激素缺乏是否会影响、以及在多大程度上影响其人脑结构和功能的发育仍处于未知。为此，本研究将青春期年龄段的Turner女性按照卵巢功能异常的程度划分为卵巢功能减退组和卵巢功能衰竭组。利用多模态磁共振影像数据，计算了体素水平的灰质和白质体积指标、白质的部分各向异性分数、轴向和径向弥散率以及静息态功能连接强度，对每名Turner个体的脑结构和功能进行了多维度的量化。统计结果发现，左侧眶额皮层的灰质体积以及双侧的皮质脊髓束、前丘脑辐射、左侧的上纵束和扣带束的白质弥散特性均表现出了显著的年龄×组别交互效应，即这些区域的脑灰质和白质结构的发育轨迹在两组间呈现显著不同的趋势;功能连接强度指标没有发现交互作用显著的区域。本研究首次在Turner患者群体中揭示了X染色体剂量缺失引发的卵巢功能异常和雌激素缺乏对人脑结构发育过程的影响，并且提示了临床中针对Turner患者的雌激素替代治疗的重要意义。 综上，本论文通过采用多模态的磁共振成像技术和分析方法，从体素、区域间功能连接以及脑白质结构网络等多个角度探究了X染色体缺失及其引发的下游雌激素缺乏对人脑结构和功能的影响。相关的研究结果对于理解X染色体对人脑的影响规律具有重要的科学价值，也为Turner综合征的临床治疗和行为干预提供了实验依据。

The X chromosome plays a crucial role in the development of the human brain and intelligence. Turner's syndrome (TS) is a genetic condition caused by the absence of all or part of an X chromosome in females and offers a valuable human “knockout” model to study the effects of the X chromosome on the human brain and behaviors. In this thesis, we conducted three studies in TS patients using multimodal magnetic resonance imaging (MRI) data, aiming to reveal the functioning patterns of the X chromosome in the human brain. The three studies were briefly summarized as below. Hemispheric Module-Specific Influence of the X Chromosome on White Matter Connectivity. The human brain is one of the most complex networks, exhibiting a number of non- trivial topological features such as the modular organization. Previous studies on TS showed lateralized impairments in white matter connectivity measures. However, little is known about whether and how the loss of the X chromosome influences the brain structural wiring patterns in human. We acquired a multimodal MRI dataset and cognitive assessments from girls with TS and age-matched healthy controls to address these questions. Hemispheric white matter networks and modules were derived using refined diffusion MRI tractography. Statistical comparisons revealed a reduced topological efficiency of bilateral parietal modules in TS girls. Particularly, the efficiency of right parietal module significantly mediated the effect of the X chromosome on working memory performance. In addition, TS girls showed structural and functional connectivity decoupling across specific modular connections, predominantly in the right hemisphere. These findings provide novel insights into the functional pathways in the brain which are regulated by the X chromosome and highlight a module-specific genetic contribution to white matter connectivity in the human brain. The Effects of the X Chromosome on Hemispheric Functional Specialization of the Human Brain. Hemispheric specialization of the human brain is closely associated with multiple brain cognitive functions. Previous studies indicated that the X chromosome acts on the brain and cognitive functions in a hemispheric-specific manner. To evaluate the effect of the X chromosome on hemispheric functional specialization, we analyzed the resting state MRI data and cognitive assessments from girls with TS and age-matched control girls. Asymmetry of intra-hemispheric weighted degree (AIWD) and homotopic functional connectivity (HoFC) were calculated, representing the two main aspects of the hemispheric functional organization: segregation and integration. Statistical results revealed significant decreases in frontal and parietal HoFC, but no significant change in AIWD. Further, TS patients also showed significantly altered AIWD-HoFC relationship surrounding the inferior temporal region. These results suggest that the X chromosome influences brain hemispheric functional specialization by adjusting the hemispheric functional integration and by modulating the interaction between hemispheric segregation and integration. The findings provide direct evidence for the X-linked genetics underlying the human brain hemispheric functional specialization. The Effects of the X Chromosome Deficiency-induced Hypogonadism and Estrogen Deficiency on Human Brain Development. Due to the X chromosome deficiency, girls with TS mostly present a loss of ovarian function, resulting in severe deficiency of estrogen which is an important hormone for brain development. However, it still remains unknown whether and to what extent the hypogonadism and estrogen deficiency influence brain development in TS. To this point, we used multimodal MRI data of girls with TS to calculate the voxel-wise brain structural (i.e., gray matter morphology and white matter connectivity) and functional phenotypes (i.e., resting- state FC). To evaluate this effect, girls with TS were first divided into ovarian hypofunction group and ovarian failure group. Statistical analyses revealed significant age-by-group interactions in the gray matter volume around the left medial orbitofrontal cortex and in white matter diffusion parameters around the bilateral corticospinal tract, anterior thalamic radiation and left superior longitudinal fasciculus and cingulum bundle, but no such effects were observed in resting-state FC. This is the first study demonstrating how ovarian dysfunction affects brain structural development within TS patients. These findings highlighted an important clinical role of estrogen replacement therapy in boosting brain development in TS population. In summary, we accomplished a serial of studies in TS patients using multimodal MRI data and multi-level analytical methods. The relevant findings offered valuable insight into the effects of the X chromosome on human brain structure and function, and also provided important clues for the clinical treatment and behavioral intervention in X-linked brain diseases.