Abnormal left prefrontal N100 and its relationship with fronto-limbic metabolism in major depressive disorder

Dysfunction within inhibitory GABAergic systems is implicated in the pathophysiology of major depressive disorder (MDD). The N100, a transcranial magnetic stimulation-evoked potential (TEP), reflects inhibitory neural processes mediated by GABA-B receptors. Yet, the relationship between the N100, stress levels, and cerebral glucose metabolism in MDD remains under-investigated. We sought to elucidate the fundamental processes of frontal inhibitory function by examining the left prefrontal N100 in patients with MDD and healthy controls (HCs). Sixty-six patients with MDD and 20 HCs were recruited; the N100 component was derived from single-pulse TEPs targeting the left dorsolateral prefrontal cortex. Patients were stratified into low-severity (score ≤ 16) and high-severity (score ≥17) groups based on the 17-item Hamilton Depression Rating Scale (HDRS-17). Cerebral metabolic activity was estimated using 18F-FDG PET standardized uptake values (SUVs). N100 amplitudes were significantly greater in the low-severity depression group compared to HCs (p = 0.002) and exhibited a positive correlation with daily life stress exclusively in HCs (r = 0.653, p = 0.002). In the MDD group, higher N100 amplitudes were associated with increased SUVs in the prefrontal cortex (p = 0.037) and inversely correlated with SUVs in the right middle temporal cortex, right inferior parietal cortex, and middle cingulum (SVC-corrected p < 0.05). Furthermore, N100 amplitudes correlated positively with the number of treatment failures specifically in the non-treatment-resistant depression (nTRD) subgroup. These data indicate that the N100 is significantly associated with depression severity and may represent a dynamic, compensatory neurophysiological mechanism aiming to restore the excitatory/inhibitory balance in response to aberrant fronto-limbic metabolism.