Increased Aperiodic Exponents Track Depressive Symptom Severity in Refractory Epilepsy

Major depressive disorder (MDD) remains a leading cause of disability, and approximately one-third of patients do not respond to standard treatments and develop treatment-resistant disease. Progress toward personalized neuromodulation has been limited by a lack of objective brain-based biomarkers that can guide circuit target selection and track symptom burden in real time. Here, we tested whether the aperiodic exponent of intracranial electroencephalography (iEEG) local field potentials provides a neurophysiological marker of current depressive symptom severity.

We analyzed resting-state iEEG data from a cohort of patients undergoing invasive monitoring for refractory epilepsy (N = 20), comprising >1800 intracranial contacts sampling distributed cortical and subcortical regions, with depressive symptoms quantified immediately prior to recording using the Beck Depression Inventory-II.

Region- and network-level analyses localized aperiodic exponent effects to frontolimbic and insular circuits-including the orbitofrontal cortex, anterior cingulate cortex, insula, and amygdala-and to the large-scale salience network (SAL) and default mode network, where exponents scaled continuously with symptom burden. In addition, exponents within the SAL tracked anhedonia. The whole-brain mean aperiodic exponent discriminated minimal versus elevated depressive symptom status (area under the curve = 0.82).

Together, these results identified intracranial aperiodic exponents as a scalable, circuit-relevant marker of current depressive symptom burden with potential utility for biomarker-informed, individualized neuromodulation in MDD.