Altered Bilateral Motor Cortex Excitability and Peripheral Glutamate/GABA Imbalance in Generalized Anxiety Disorder: A TMS Investigation.

OBJECTIVE

Generalized anxiety disorder (GAD) imposes a substantial burden on individuals and society, yet its underlying neurophysiological mechanisms remain unclear. This study aimed to investigate whether GAD is associated with abnormalities in bilateral motor cortex excitability and peripheral neurochemical balance.

METHODS

This case-control study compared 30 unmedicated GAD patients with 30 age- and gender-matched healthy controls. Cortical excitability indices-including resting motor threshold (rMT), motor evoked potential amplitude (MEP-A) and latency (MEP-L), and cortical silent period (CSP)-were assessed using single-pulse transcranial magnetic stimulation (spTMS). Peripheral serum levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) were also measured. P-values for primary outcomes were corrected using the Bonferroni correction.

RESULTS

Key findings revealed a pathological imbalance in bilateral motor cortex excitability in GAD patients. This was characterized by a significant increase in left rMT (the corrected p<0.05) and a decrease in left MEP-A (the corrected p<0.05), alongside an increase in right MEP-A (the corrected p<0.05), resulting in a significantly reduced left-to-right MEP-A ratio (the corrected p<0.001). No significant inter-group differences were found for MEP-L or CSP after Bonferroni correction.

CONCLUSION

These results demonstrate that GAD involves systemic dysregulation across neurophysiological and neurochemical domains, featuring left-lateralized cortical hypoexcitability and right-lateralized hyperexcitability, coupled with altered peripheral glutamate-GABA balance. The combined use of TMS-derived excitability metrics and peripheral neurochemical markers may offer novel objective indicators to supplement clinical assessment in GAD. Further research is needed to establish the diagnostic specificity of these biomarkers. This study was registered with the Chinese Clinical Trial Registry (ChiCTR2200066311).