Xia Mingrui, Liu Jin, Mechelli Andrea, Sun Xiaoyi, Ma Qing, Wang Xiaoqin, Wei Dongtao, Chen Yuan, Liu Bangshan, Huang Chu-Chung, Zheng Yanting, Wu Yankun, Chen Taolin, Cheng Yuqi, Xu Xiufeng, Gong Qiyong, Si Tianmei, Qiu Shijun, Lin Ching-Po, Cheng Jingliang, Tang Yanqing, Wang Fei, Qiu Jiang, Xie Peng, Li Lingjiang, He Yong
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.
Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China.
Mol Psychiatry. 2022 Mar;27(3):1384-1393. doi: 10.1038/s41380-022-01519-5. Epub 2022 Mar 25.
Patients with major depressive disorder (MDD) exhibit concurrent deficits in both sensory and higher-order cognitive processing. Connectome studies have suggested a principal primary-to-transmodal gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether this gradient structure is disrupted in patients with MDD and how this disruption associates with gene expression profiles and treatment outcome remain unknown. Using a large cohort of resting-state fMRI data from 2227 participants (1148 MDD patients and 1079 healthy controls) recruited at nine sites, we investigated MDD-related alterations in the principal connectome gradient. We further used Neurosynth, postmortem gene expression, and an 8-week antidepressant treatment (20 MDD patients) data to assess the meta-analytic cognitive functions, transcriptional profiles, and treatment outcomes related to MDD gradient alterations, respectively. Relative to the controls, MDD patients exhibited global topographic alterations in the principal primary-to-transmodal gradient, including reduced explanation ratio, gradient range, and gradient variation (Cohen's d = 0.16-0.21), and focal alterations mainly in the primary and transmodal systems (d = 0.18-0.25). These gradient alterations were significantly correlated with meta-analytic terms involving sensory processing and higher-order cognition. The transcriptional profiles explained 53.9% variance of the altered gradient pattern, with the most correlated genes enriched in transsynaptic signaling and calcium ion binding. The baseline gradient maps of patients significantly predicted symptomatic improvement after treatment. These results highlight the connectome gradient dysfunction in MDD and its linkage with gene expression profiles and clinical management, providing insight into the neurobiological underpinnings and potential biomarkers for treatment evaluation in this disorder.
重度抑郁症（MDD）患者在感觉和高阶认知加工方面均存在并发缺陷。连接组研究表明，功能性脑网络中存在一个主要的从初级到跨模态的梯度，支持从感觉到认知的连续谱。然而，MDD患者的这种梯度结构是否受到破坏，以及这种破坏如何与基因表达谱和治疗结果相关联，仍然未知。我们使用来自九个研究地点招募的2227名参与者（1148名MDD患者和1079名健康对照）的大量静息态功能磁共振成像（fMRI）数据，研究了主要连接组梯度中与MDD相关的改变。我们还分别使用Neurosynth、死后基因表达和一项为期8周的抗抑郁治疗（20名MDD患者）数据，来评估与MDD梯度改变相关的元分析认知功能、转录谱和治疗结果。相对于对照组，MDD患者在主要的从初级到跨模态梯度上表现出整体地形改变，包括解释率降低、梯度范围减小和梯度变化（Cohen's d = 0.16 - 0.21），且局部改变主要发生在初级和跨模态系统（d = 0.18 - 0.25）。这些梯度改变与涉及感觉加工和高阶认知的元分析术语显著相关。转录谱解释了改变后的梯度模式53.9%的方差，最相关的基因富集于突触间信号传导和钙离子结合。患者的基线梯度图显著预测了治疗后的症状改善。这些结果突出了MDD中连接组梯度功能障碍及其与基因表达谱和临床管理的联系，为该疾病的神经生物学基础和治疗评估的潜在生物标志物提供了见解。
