Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511.
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, California 90095.
J Neurosci. 2019 Feb 13;39(7):1301-1319. doi: 10.1523/JNEUROSCI.3470-17.2018. Epub 2018 Nov 26.
The 22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional connectivity MRI studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of human youth with 22q11DS ( = 42; 59.5% female) and demographically matched healthy controls ( = 39; 53.8% female). Neuroimaging data were acquired via single-band protocols and analyzed in line with methods provided by the Human Connectome Project. We computed functional relationships between individual-specific anatomically defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain Type I error protection was achieved through nonparametric permutation-based methods. The 22q11DS patients displayed dissociable disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamocortical coupling was increased in somatomotor regions and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to somatomotor and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggests that high genetic risk for psychiatric illness is linked with disruptions in large-scale corticosubcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect copy number variants for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders. Investigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. The 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a dissociable fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.
22q11.2 缺失综合征（22q11DS）是一种具有高外显率的复发性拷贝数变异，可导致发育性神经精神疾病。因此，对患有 22q11DS 的个体进行研究可能为理解此类复杂疾病的神经机制提供关键见解。在特发性精神分裂症中，静息态功能磁共振成像研究一致表明，丘脑和海马回路受到破坏。在这里，我们试图检验在这种遗传高风险情况下，这种回路是否也同样受到破坏。为此，我们在一组患有 22q11DS 的人类青少年（22q11DS 组：42 名，女性占 59.5%）和年龄匹配的健康对照组（对照组：39 名，女性占 53.8%）中评估了静息态功能连接模式。通过单波段方案采集神经影像学数据，并按照人类连接组计划提供的方法进行分析。我们计算了个体特异性解剖定义的丘脑和海马种子与大脑中所有灰质体素之间的功能关系。通过基于非参数置换的方法实现了全脑 I 型错误保护。22q11DS 患者与对照组相比，表现出丘脑和海马功能连接的分离性破坏。躯体运动区域的丘脑皮质耦合增加，而关联网络的耦合减少。对于海马体，在躯体运动和关联网络连接方面观察到相反的效果。22q11DS 中观察到的丘脑和海马功能连接障碍表明，精神疾病的高遗传风险与高级认知功能的皮质下皮质网络的破坏有关。这些效应突出了大效应拷贝数变异在告知特发性发育性神经精神疾病中观察到的神经破坏的机制方面的转化重要性。在高度外显的遗传综合征中研究神经影像学生物标志物是一种更具生物学可操作性的方法，可用于识别发育性神经精神疾病的神经回路破坏。22q11.2 缺失综合征特别容易导致精神障碍，因此是研究特发性疾病中涉及的系统级机制的重要转化模型。在这里，我们通过静息态 fMRI 显示了患有 22q11DS 的青少年中大感觉和执行网络的破坏。特别是，这项研究首次提供了证据，表明这些网络在与丘脑和海马的功能连接方面以可分离的方式受到破坏，这表明存在回路功能障碍。
