Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

威廉姆斯综合征基因-大脑关系的多模态神经影像

• 批准号: 8556957
• 负责人: Karen FAITH Berman
• 金额: $ 134.83万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556957
• 关键词: Adult; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Behavior; Behavioral; Behavioral Genetics; Brain; Brain Diseases; Categories; Cerebrovascular Circulation; Characteristics; Child; Chromosomes, Human, Pair 7; Clinical; Cognition; Cognitive; Complement; Complex; Coupled; Data; Development; Diffusion Magnetic Resonance Imaging; Discrimination; Disease; Dorsal; Emotional; Employee Strikes; Equation; Face; Force of Gravity; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Genes; Genetic; Genetic Determinism; Handedness; Hippocampus (Brain); Housing; Human; Impairment; Incidence; Individual; Insula of Reil; Investigation; Judgment; Knowledge; Language Development; Light; Limbic System; Link; Live Birth; Magnetic Resonance Imaging; Maps; Measures; Mediating; Memory; Mental Retardation; Methodology; Methods; Mind; Modeling; Multimodal Imaging; Mutation; Nature; Neuroanatomy; Neurobiology; Neurodevelopmental Disorder; Participant; Pathology; Personality; Phenotype; Population; Positron-Emission Tomography; Prevalence; Process; Rare Diseases; Regulation; Relative (related person); Research; Single Nucleotide Polymorphism; Social Behavior; Social Environment; Staging; Stimulus; Stream; Structure; Sum; System; Taxes; Techniques; Veins; Visual; Visual Fields; Visuospatial; Williams Syndrome; Work; area striata; base; candidate identification; cognitive function; comparison group; developmental genetics; emotional stimulus; experience; follow-up; gray matter; improved; microdeletion; neurochemistry; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; neuropsychological; relating to nervous system; research study; response; sex; social; social cognition; spectroscopic imaging; success; visual process; visual processing; visual stimulus; volunteer; white matter

The Section on Integrative Neuroimaging has made substantial progress toward elucidating specific genetic contributions to brain structure and function through multimodal neuroimaging studies of Williams Syndrome (WS) individuals and carefully matched comparison volunteers. As discussed extensively in Eisenberg et al. (1), we have in recent years identified the neural substrates of the characteristic visuospatial construction deficits in this condition by demonstrating via multi-modal neuroimaging experiments disrupted dorsal stream specifically, intraparietal sulcal region activation during spatial judgments, neural integrity, and structure. These landmark findings invited the vital question of whether there were also upstream abnormalities in primary visual cortex that might also contribute during development to either the brain or behavioral WS phenotypes. In Olsen et al. (2) we used magnetic resonance imaging-based visual field mapping in order to establish the neurofunctional status of early visual processing in WS relative to that in controls matched for age and IQ. Although primary visual cortex (V1) boundaries varied in WS participants, this region did not differ in size between groups, and overlap maps showed that the average centers of gravity for the two groups were largely colocalized. This work provided the first use of retinotopy to define the functional neuroanatomy of V1 in WS and one of the first uses of this technique in a human pathological condition that affects visuospatial processing. These results are consistent with the notion that neural abnormalities underlying visuospatial construction arise at later stages in the dorsal visual processing stream, likely at or immediately proximal to our observations in the intraparietal sulcal region. In addition to visuospatial impairments, WS individuals harbor dyadic contrapuntal socio-emotional functioning, such that hypersociability is coupled with heightened non-social anxiety. This dramatic aspect of WS, with obvious implications for understanding neurogenetic bases for social cognition and anxiety generally, serves as a second focus of our research, and we have had considerable success in identifying plausible systems-level correlates of these phenotypes. In particular, we have found decreased fearful face stimuli evoked amygdala activation in WS for compared to IQ matched healthy controls and conversely, an increased in amygdala response in WS to non-social frightening stimuli as compared with matched healthy control participants. Importantly, using structural equation modeling, we found these differences to be linked to altered prefrontal regulation. To follow up on this important set of results, Munoz et al. (3) used social and non-social emotional stimuli during a verbal discrimination task that would reliably tax cognitive, prefrontal processes in addition to emotional, limbic systems. Evidence from this study confirmed our previous findings of exaggerated amygdala response to non-social frightening visual stimuli in WS and, further, indicated that task difficulty modulates prefrontal, but not amygdala, response in participants. These data support evidence of disruption in amygdala-prefrontal circuitry in WS but importantly indicate that core biases in social context-dependent emotional responsivity are unaffected by cognitive challenge. To the extent that the insular cortices have also been implicated in mediating social emotional response tendencies that define personality, our most recent multimodal investigations have sought to identify convergent alterations in anterior insula structure, function, and inter-regional connectivity, as well as determine the extent to which these measures predict the characteristic Williams syndrome (WS) personality. In Jabbi et al (4), we show that in WS there is an overall decrease in dorsal anterior insula (AI) gray-matter volume,but locally increased volume in the right ventral AI, as well as reduced white-matter integrity of the uncinate fasciculus connecting the insula with the amygdala and orbitofrontal cortex, widespread reductions in dorsal AI regional cerebral blood flow (rCBF) with locally increased rCBF in the right ventral AI, and abnormal relationships between rCBF in AI and other limbic regions. Importantly, these differences predicted the strength of the WS personality profile. We believe ongoing work in this vein will provide improved understanding of critical links between genetics and behavioral phenomenology relevant beyond WS itself. However, perhaps the greatest recent advancement made by the Section, however, has been the successful initiation of longitudinal multimodal neuroimaging studies of WS children. Though data accrual will require years of careful and concerted effort, the potential for these studies to shed unprecedented light on genetic contributions to brain development are enormous. In sum, our efforts have resulted in the identification of candidate neurofunctional substrates for hallmark neuropsychological abnormalities in WS, and continued progress toward better defining precise genetic, developmental and neurochemical contributions toward these disturbances is ongoing.

通过对威廉姆斯综合征（WS）个体和仔细匹配的对照志愿者进行多模态神经影像学研究，综合神经影像学部分在阐明特定遗传对大脑结构和功能的贡献方面取得了实质性进展。 正如Eisenberg等人（1）所广泛讨论的那样，近年来，我们通过多模态神经成像实验证明了背流特异性中断、空间判断期间顶内沟区激活、神经完整性和结构，从而确定了这种情况下特征性视觉空间构建缺陷的神经基质。 这些具有里程碑意义的发现提出了一个重要的问题，即初级视觉皮层是否也存在上游异常，这些异常也可能在发育过程中对大脑或行为WS表型产生影响。 在Olsen等人（2）的研究中，我们使用基于磁共振成像的视野标测，以确定WS相对于年龄和智商匹配的对照组的早期视觉处理的神经功能状态。 虽然WS参与者的初级视觉皮层（V1）边界不同，但该组之间的大小没有差异，重叠图显示两组的平均重心在很大程度上是共定位的。 这项工作提供了第一次使用retinotopy定义的功能神经解剖V1在WS和第一次使用这种技术在人类病理条件，影响视觉空间处理。这些结果是一致的概念，视觉空间结构的神经异常出现在后面的阶段，在背侧视觉处理流，可能在或立即接近我们的观察在顶内沟区。 除了视觉空间障碍外，WS个体还具有二元对立的社会情感功能，例如过度社交与高度的非社交焦虑相结合。 WS的这一戏剧性方面，对于理解社会认知和焦虑的神经遗传基础具有明显的意义，是我们研究的第二个重点，我们在确定这些表型的合理系统水平相关性方面取得了相当大的成功。 特别是，我们已经发现，减少恐惧的脸刺激诱发杏仁核激活WS相比，智商匹配的健康对照组，相反，增加杏仁核反应WS非社会性的可怕的刺激相比，匹配的健康对照组参与者。重要的是，使用结构方程模型，我们发现这些差异与前额叶调节的改变有关。为了进一步研究这组重要的结果，穆尼奥斯等人（3）在一项言语辨别任务中使用了社会和非社会情感刺激，这将可靠地对认知、前额叶过程以及情感、边缘系统产生影响。 这项研究的证据证实了我们以前的研究结果，夸大杏仁核的反应，非社会可怕的视觉刺激WS，并进一步表明，任务难度调制前额叶，但不是杏仁核，参与者的反应。这些数据支持的证据，在杏仁核-前额叶电路中断WS，但重要的是表明，在社会背景依赖的情绪反应的核心偏见是不受认知挑战。 在一定程度上，岛叶皮层也被牵连在介导的社会情绪反应的倾向，定义人格，我们最近的多模态调查，试图确定收敛性的改变，在前额叶结构，功能和区域间的连接，以及确定在何种程度上，这些措施预测特征威廉姆斯综合征（WS）的个性。在Jabbi等人（4）的研究中，我们发现WS患者背侧前额叶（AI）灰质体积总体减少，但右腹侧AI体积局部增加，连接小脑与杏仁核和眶额皮质的钩状束白质完整性降低，背侧AI局部脑血流量（rCBF）普遍减少，右腹侧AI局部rCBF增加，以及AI与边缘系统其他区域rCBF的异常关系。 重要的是，这些差异预测了WS人格特征的强度。 我们相信，在这方面正在进行的工作将提供更好的理解遗传学和行为现象学相关超越WS本身之间的关键联系。 然而，也许该科最近取得的最大进展是成功地启动了WS儿童的纵向多模式神经影像学研究。 虽然数据积累需要多年的仔细和协调一致的努力，但这些研究在揭示基因对大脑发育的贡献方面的潜力是巨大的。 总而言之，我们的努力已经确定了WS标志性神经心理异常的候选神经功能底物，并且在更好地定义对这些障碍的精确遗传、发育和神经化学贡献方面仍在继续取得进展。