Seizure Frequency Is Associated with Effective Connectivity of the Hippocampal-Diencephalic-Cingulate in Epilepsy with Unilateral Mesial Temporal Sclerosis

Temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) is a common intractable epilepsy. To seek neural correlates of seizure recurrence, this study investigated aberrant intrinsic effective connectivity (iEC) in TLE with unilateral MTS and their associations with seizure frequency. Thirty patients with unilateral MTS (left/right MTS = 14/16) and 37 age-matched healthy controls underwent resting-state functional magnetic resonance imaging (rsfMRI) on a 3-Tesla magnetic resonance imaging (MRI) system. The structural equation modeling was employed to estimate the iEC of the three candidate epilepsy models, including the Papez circuit, hippocampal-diencephalic-cingulate (HDC) model, and simplified HDC model. After comparing the performance of model fitting, the best model was selected to compare iEC among the study groups. The linear regression analysis was performed to associate abnormal iEC with seizure frequency. The simplified HDC model was the best model to estimate iEC across the three study groups (p < 0.05), and it composed of the 26 interconnected pathway between the mesial temporal lobe, thalamus, and cingulate cortices. The linear regression analysis revealed a significant relationship between the shared iEC alterations in both patient groups and seizure frequency (adjusted-R² = 0.350; p = 0.037), including the three paths of mammillary body (MB) → bilateral anterior thalamic nuclei (left: standardized β-value = 0.580, p = 0.013; right: standardized β-value = -0.711, p = 0.006) and right hippocampus → MB (standardized β-value = 0.541, p = 0.045). Our findings provide new insights into neurophysiological significance relevant to seizure recurrence. Aberrant iEC on the neural paths connected to the MB can be a potential imaging marker, aiding the therapeutic management in TLE with unilateral MTS. Impact statement Within the simplified hippocampal-diencephalic-cingulate model, we identified that altered intrinsic effective connectivity (iEC) on the three paths connecting to the mammillary body was common in temporal lobe epilepsy (TLE) with left and right mesial temporal sclerosis (MTS) and was associated with seizure frequency. Therefore, these common iEC alterations could be a potential imaging marker, aiding the therapeutic management in patients with TLE with unilateral MTS.