Neuroimage. 2025 Nov 6:121567. doi: 10.1016/j.neuroimage.2025.121567. Online ahead of print.
ABSTRACT
BACKGROUND: GABAergic dysfunction contributes to Major Depressive Disorder (MDD). This study examines excitatory/inhibitory (E/I) imbalance, specifically GABA deficits in the left dorsolateral prefrontal cortex (DLPFC), and their link to anhedonia and cognitive impairment in MDD. It also investigates alterations in the coupling between local E/I activity and functional connectivity (FC) within the triple network.
METHODS: We included 41 medication-naïve MDD patients and 33 healthy controls (HCs). Participants underwent Snaith-Hamilton Pleasure Scale (SHAPS) and cognitive assessments. GABA+/Cr, Glx, and GABA+/Glx ratios were measured in the left DLPFC using proton magnetic resonance spectroscopy (¹H-MRS). Resting-state functional magnetic resonance imaging (fMRI) data were analyzed via independent component analysis (ICA), identifying five major brain networks.
RESULTS: Female MDD patients exhibited reduced GABA+/Cr in the left DLPFC (p = 0.021). GABA+/Cr negatively correlated with SHAPS scores (r = -0.33, p = 0.04) and Trail Making Test Part B (TMT-B) completion times (r = -0.36, p = 0.03) in MDD patients. HCs showed positive correlations between GABA+/Cr and FC within the LECN (r = 0.41, p = 0.02) and between the LECN-dDMN (r = 0.39, p = 0.03) and LECN-pSN (r = 0.46, p = 0.01); these correlations were absent in the MDD group.
CONCLUSIONS: Female patients with MDD exhibit a specific reduction in GABA levels in the left DLPFC. Furthermore, these lower GABA levels are associated with increased anhedonia and poorer executive function. Critically, the neurochemical coupling between GABA and large-scale brain networks is also disrupted in MDD.
PMID:41205935 | DOI:10.1016/j.neuroimage.2025.121567
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