Subgenual Anterior Cingulate Cortex Functional Connectivity Abnormalities in Depression: Insights from Brain Imaging Big Data and Precision-Guided Personalized Intervention via Transcranial Magnetic Stimulation
Authors: Chen Xiao , Lu Bin , Wang Yu-Wei , Li Xue-Ying , Wang Zi-Han , Li Hui-Xian , Liao Yi-Fan , Blumberger Daniel M. , Castellanos Francisco Xavier , Cao Li-Ping , Chen Guan-Mao , Chen Jian-Shan , Chen Tao , Chen Tao-Lin , Chen Yan-Rong , Cheng Yu-Qi , Chu Zhao-Song , Cui Shi-Xian , Cui Xi-Long , Deng Zhao-Yu , Gao Qing-Lin , Gong Qi-Yong , Guo Wen-Bin , He Can-Can , Hu Zheng-Jia-Yi , Huang Qian , Ji Xin-Lei , Jia Feng-Nan , Kuang Li , Li Bao-Juan , Li Feng , Li Tao , Li Xue , Lian Tao , Liu Xiao-Yun , Liu Yan-Song , Liu Zhe-Ning , Long Yi-Cheng , Lu Jian-Ping , Qiu Jiang , Shan Xiao-Xiao , Si Tian-Mei , Sun Peng-Feng , Wang Chuan-Yue , Wang Han-Lin , Wang Xiang , Wang Ying , Wu Chen-Nan , Wu Xiao-Ping , Wu Xin-Ran , Wu Yan-Kun , Xie Chun-Ming , Xie Guang-Rong , Xie Peng , Xu Xiu-Feng , Xue Zhen-Peng , Yang Hong , Yang Jian , Yu Hua , Yu Yong-Qiang , Yuan Min-Lan , Yuan Yong-Gui , Zang Yu-Feng , Zhang Ai-Xia , Zhang Ke-Rang , Zhang Wei , Zhu Jiajia , Zhang Zi-Jing , Zhao Jing-Ping , Zuo Xi-Nian ,   the DIRECT Consortium, Wang Hua-Ning , Yan Chao-Gan 
Published: March 2023

Background: The subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Nevertheless, previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. Methods: Leveraging a large multi-site cross-sectional sample (1660 MDD patients vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT), we systematically delineated case-control difference maps of sgACC-FC. Then, we explored the potential impact of such group-level abnormality profiles on the TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to localize TMS targets individually. Results: We found an enhanced sgACC-DLPFC FC in MDD patients compared to healthy controls (HC). Such group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. In two independent clinical samples, we showed that the magnitude of TMS targets' case-control differences in sgACC FC was related to clinical improvement. The MDD big data-guided individualized TMS targeting algorithm may generate individualized TMS targets that are clinically superior to group-level targets. Interpretation: We reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets. Keywords: major depressive disorder, transcranial magnetic stimulation, individualization, subgenual anterior cingulate cortex, functional connectivity, dual regression