Age-dependent alterations in anterior cingulate excitation-inhibition balance in major depressive disorder revealed by 7-Tesla magnetic resonance spectroscopy

BACKGROUND: Altered excitation-inhibition (E/I) balance has been implicated in the pathophysiology of major depressive disorder (MDD), but previous magnetic resonance spectroscopy (MRS) findings have been inconsistent, partly due to methodological limitations. 7T MRS enables simultaneous quantification of glutamate (Glu) and γ-aminobutyric acid (GABA), and calculation of their ratio as an MRS-based proxy of E/I balance. METHODS: Using 7T MRS, we measured Glu and GABA levels in the dorsal anterior cingulate cortex (dACC) of 41 treated patients with MDD and 35 matched healthy controls (HC). The primary outcome was the Glu/GABA ratio. Analysis of covariance tested group effects controlling for age and sex. Associations with clinical symptoms (Hamilton Depression Rating Scale) and cognitive performance were also evaluated. RESULTS: A significant group × age interaction was observed (F(1, 57) = 8.49, p = 0.005), with Glu/GABA increasing with age in HC but not in MDD. No significant group differences were detected for Glu or GABA individually, although GABA levels showed a non-significant trend towards higher values in MDD. The Glu/GABA ratio was not associated with symptom severity or cognitive performance. Glu and GABA levels were positively correlated in both groups (MDD: r = 0.669, p < 0.001; HC: r = 0.513, p = 0.003), with no significant difference between the slopes. CONCLUSIONS: Treated patients with MDD exhibited an altered age-related trajectory of the Glu/GABA ratio in the dACC, characterized by a reduced Glu/GABA ratio and absence of the normative age-related increase, despite preserved Glu-GABA coupling.