γ-Aminobutyric acid and glutamate dysregulation in the dorsolateral prefrontal cortex of adolescents with first-episode major depressive disorder and the modulatory effects of repetitive transcranial magnetic stimulation

Laiyang Ma; Xiuyun Ma; Wenjing Huang; Jun Wang; Songhong Yue; Lili Xu; Xiaojin Ma; Yuhui Xiong; Jing Zhang; Wanjun Hu

doi:10.1093/psyrad/kkaf034

γ-Aminobutyric acid and glutamate dysregulation in the dorsolateral prefrontal cortex of adolescents with first-episode major depressive disorder and the modulatory effects of repetitive transcranial magnetic stimulation

Psychoradiology. 2025 Nov 20:6:kkaf034. doi: 10.1093/psyrad/kkaf034. eCollection 2026.

Authors

Laiyang Ma^{1

2

3}, Xiuyun Ma⁴, Wenjing Huang⁵, Jun Wang^{1

3}, Songhong Yue^{1

2

3}, Lili Xu^{1

2

3}, Xiaojin Ma^{1

2

3}, Yuhui Xiong⁶, Jing Zhang^{1

3}, Wanjun Hu^{1

2

3}

Affiliations

¹ Department of Magnetic Resonance, Lanzhou University Second Hospital, Lanzhou 730030, China.
² Second Clinical School, Lanzhou University, Lanzhou 730030, China.
³ Gansu Province Clinical Research Center for Functional and Molecular Imaging, Lanzhou 730030, China.
⁴ Department of Mental Health, Lanzhou University Second Hospital, Lanzhou 730030, China.
⁵ Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China.
⁶ GE Healthcare MR Research, Beijing 100000, China.

Abstract

Background: Major depressive disorder (MDD) is associated with dysregulation of γ-aminobutyric acid (GABA) and glutamate(Glu) neurotransmission in the prefrontal cortex. Proton magnetic resonance spectroscopy (1H-MRS) enables non-invasive in vivo quantification of GABA and Glx(glutamate + glutamine) levels. This study investigated neurochemical characteristics of the bilateral dorsolateral prefrontal cortex (DLPFC) in first-episode adolescent MDD (FEA-MDD) and repetitive transcranial magnetic stimulation (rTMS)'s impact on these changes.

Methods: 42 drug-naïve FEA-MDD patients underwent bilateral DLPFC MRS scans before and after rTMS, with 42 healthy controls (HCs) as baseline. All participants were right-handed. The Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) protocol detected GABA+ (GABA plus macromolecules and high carnosine) and Glx levels, processed via Gannet software.

Results: FEA-MDD patients exhibited significantly lower GABA+ and higher Glx levels in the left DLPFC than HCs; in the right DLPFC, no significant difference in GABA+ levels was observed, though Glx levels were elevated. After rTMS treatment, GABA+ levels in the left DLPFC increased significantly, whereas Glx levels showed a non-significant decreasing trend. Additionally, HCs had no hemispheric differences, while in FEA-MDD, the left DLPFC showed lower GABA+ and Glx levels compared to the right. We also found that in the left DLPFC, baseline GABA+ levels were negatively correlated with Hamilton Depression Scale (HAMD) scores; Glx levels showed positive correlations with scores on the Ruminative Response Scale (RRS), Self-Rating Depression Scale (SDS), and Self-Esteem Scale (SES).

Conclusions: FEA-MDD involves prefrontal GABA+/Glx dysregulation, and rTMS may aid in restoring neurotransmitter balance within the DLPFC. This study adds to the expanding body of evidence supporting the application of targeted neurochemical modulation in the treatment of FEA-MDD, while also providing insights into potential intervention mechanisms.

Keywords: aminobutyric acid and glutamine; major depressive disorder; proton magnetic resonance spectroscopy; repetitive transcranial magnetic stimulation.