Glymphatic dysfunction couples with cortical excitation-inhibition imbalance in epilepsy: Evidence from Rasmussen...

The glymphatic system (GS) facilitates perivascular clearance of interstitial solutes and is modulated in part by neuronal activity. However, its relationship to cortical excitability in epilepsy remains unclear. We aim to clarify the mechanistic link between GS function and cortical excitation-inhibition (E-I) balance in patients with epilepsy.

We investigated this coupling in patients with Rasmussen encephalitis (RE), a rare epileptic disorder with unilateral cortical pathology. Using a hemispheric within-subject design (N = 20), we compared the affected hemisphere (AH) and unaffected hemisphere (UH) within each patient, assessing glymphatic function via diffusion MRI (diffusion tensor imaging-analysis along the perivascular space [DTI-ALPS] index) and E-I dynamics via resting-state EEG spectral decomposition.

The AH exhibited reduced DTI-ALPS indices, elevated aperiodic exponents, and increased delta-theta oscillatory power. Across individuals, lower ALPS values in the AH correlated with higher aperiodic exponents (r = -.496, p = .026), but not with periodic EEG features. Principal component analysis (PCA) of channel-level aperiodic asymmetry (exponent-informed PCA) revealed a spatial pattern localized to atrophic cortical regions, which also showed strong correspondence with interhemispheric ALPS asymmetry (r = -.570, p = .009).

These findings demonstrate a spatially convergent link between glymphatic dysfunction, cortical activity with predominant inhibitory tone, and focal atrophy in the AH. Our results indicate that impaired perivascular clearance is correlated with altered cortical excitability, highlighting the potential role of the GS in maintaining neural stability in the epilepsy.