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This research investigates the functional connectivity changes in patients with major depressive disorder, differentiating between those with and without anhedonia.

March 29, 2026Open Access

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

Key Points

This research investigates the functional connectivity changes in patients with major depressive disorder, differentiating between those with and without anhedonia.
Compared resting-state functional connectivity in 24 MDD patients with anhedonia, 17 without anhedonia, and 40 healthy controls using rs-fMRI.
Analyzed spatial associations with neurotransmitter receptor distribution using the JuSpace tool.
Extracted FC values from differential brain regions and correlated with clinical scoring scales.
MDD patients with anhedonia showed reduced FC between the habenula and left middle frontal gyrus compared to those without anhedonia.
Enhanced FC was noted between the habenula and bilateral putamen in anhedonia patients relative to healthy controls.
In MDD patients with anhedonia, FC changes correlated positively with specific neurotransmitter receptor distributions.

Abstract

Objective: 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

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