A pilot study of inter-regional phase amplitude coupling as comorbid depression biomarker in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with depression, but the neurobiological mechanisms underlying their bidirectional relationship remain unclear. Phase-amplitude coupling (PAC) refers to the interaction between the phase of low-frequency oscillations and the amplitude of high-frequency oscillations within the same brain signal, reflecting coordination between different brain rhythms for communication and cognitive processes. While prior studies, including our own, have explored PAC within individual brain regions, inter-regional PAC (irPAC) has not been studied in TLE and comorbid depression. We investigated irPAC in 17 TLE patients with electrodes implanted in the hippocampus, amygdala, and four cortical and subcortical regions (superior temporal, superior frontal, mesial orbitofrontal, and rostral anterior cingulate) in Papez circuit and default mode network. Modulation indices for directional brain region pairings were computed using a data-driven approach. Our analysis revealed a distinct delta–beta coupling signature that differentiated depressed from non-depressed TLE patients and correlated significantly with Beck Depression Inventory scores (Spearman’s ratio ∼ 0.5), with similar correlation strengths observed for seizure frequency in the Epilepsy Monitoring Unit. These findings suggest that aberrant inter-regional oscillatory interactions within limbic–cortical circuits may contribute to depression in epilepsy. The delta-beta irPAC signal may represent depression-related neural signatures that are distinct from general epilepsy network dysfunction. This work provides new insights into the interplay between epilepsy and depression in Papez circuit and default mode network.