TMS–EEG-derived excitation/inhibition ratio as a diagnostic biomarker for major depressive disorder

Abstract Major depressive disorder (MDD) is characterized by both physiological and psychological changes that impact daily function and quality of life. Despite advancements in treatment approaches, clinical outcomes remain variable, highlighting the need for reliable biomarkers to guide treatment selection and to monitor treatment responses. Transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) allows for the characterization of local cortical excitation and inhibition through TMS-evoked potentials (TEPs). However, interindividual variability and various artifacts have previously limited the utility of TEPs for biomarker development. We applied single-pulse TMS to the left dorsolateral prefrontal cortex (L-DLPFC), and recorded EEG responses in 28 individuals with MDD and 8 healthy controls. An individualized mapping procedure identified stimulation sites and intensities that minimized artifacts and ensured early TEP (<60 ms) deflections exceeded the predefined threshold of 6 μV. We quantified the ratio between the second and first peak-to-peak amplitudes of the TEP, as excitatory and inhibitory mechanisms have been identified to contribute to these peaks. The TEP peak ratio differed significantly between MDD participants and healthy controls ( p = 0.003), and correlated with depression symptom severity quantified with the Quick Inventory of Depressive Symptomatology Self-Report ( r = 0.459, p < 0.05), Ruminative Response Scale ( r = 0.656, p < 0.001), Patient Health Questionnaire ( r = 0.368, p < 0.05), and Positive Valence Systems Scale ( r = 0.332, p < 0.05). These correlations were not observed when an anatomy-based targeting method (Beam F3) was applied with the conventional stimulation intensity of 120% of the resting motor threshold. Our findings highlight the utility of a novel individualised mapping technique in capturing high-quality early TEPs through a real-time EEG readout for minimisation of artifacts and ensuring a minimum TMS-evoked response. The altered TEP peak ratio adds to the growing body of evidence that the excitation/inhibition imbalance plays a role in MDD neurophysiology and serves as a promising candidate biomarker that warrants further investigation.