Altered Habenula Resting-State Functional Connectivity and Spatial Associations with Neurotransmitter Receptor Distribution of Major Depressive Disorder with and without Anhedonia

Xiaoyun Luo,1,* Yanru Wu,1,* Lijin Yuan,1 Yiyun Wang,1 Jing Li,1 Pu Xu,1 Jigang Lian,1 Xiaoyan Liu,2 Zonglin Shen1,3 1Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 2Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Yunnan Clinical Medical Center for Mental Disorders, Kunming, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyan Liu, Email liuxiaoyan1990@126.com Zonglin Shen, Email shenzl1987@163.comObjective: This study aimed to examine functional connectivity (FC) alterations in patients with major depressive disorder (MDD), specifically comparing those with and without anhedonia.Methods: 24 MDD patients with anhedonia (MDD-WA), 17 MDD patients without anhedonia (MDD-WoA), and 40 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Intrinsic brain function was assessed using resting-state FC and spatial associations with neurotransmitter receptor distribution analyses. The habenula (Hb) was selected as the region of interest (ROI), and the whole-brain FC of the Hb was compared across groups. Spatial correlations between inter-group FC differences and whole-brain neurotransmitter receptor/transporter expression templates, derived using the JuSpace tool, were analyzed. Additionally, FC values from differential brain regions were extracted and correlated with the scores on the clinical scale.Results: Compared to MDD-WoA patients, MDD-WA patients exhibited reduced FC between the Hb and the left middle frontal gyrus (MFG). Enhanced FC was observed between the Hb and bilateral putamen in MDD-WA patients compared to HCs. Additionally, in the MDD-WA group, changes in the Hb whole-brain FC demonstrated positive correlations with the spatial density distribution of specific neurotransmitter receptors and transporters. In contrast, MDD-WoA showed no significant Hb FC differences or neurotransmitter correlations compared to HCs. No significant correlations were found between the FC values of the intergroup-different brain regions and the total SHAPS-C, total HAMD-17, and all HAMD-17 factor scores (anxiety/somatization, weight loss, cognitive disturbance, retardation, and sleep disturbance).Conclusion: In patients with MDD-WA, FC between the habenula and bilateral putamen, as well as between the habenula and left MFG, was altered. Given that the putamen is a core component of the striatum, all these findings suggest that habenula-prefrontal-striatal dysconnectivity may represent an anhedonia-specific biomarker in MDD. The FC patterns between the habenula and bilateral putamen/left middle frontal gyrus, along with the related neurotransmitter profiles identified in this study, may serve as objective indicators for monitoring therapeutic efficacy in the future.Keywords: major depressive disorder, anhedonia, habenula, functional connectivity, neurotransmitter receptors