Epilepsy affects tens of millions globally, with approximately one-third of patients experiencing drug-resistant seizures. Surgical intervention, typically involving anterior hippocampal and amygdala ablation, is the standard care for mesial temporal lobe epilepsy (TLE). Despite this, a significant portion of patients (around one-third) continue to experience seizures after surgery. This suggests the existence of additional seizure foci, potentially within the posterior hippocampus. This research investigated the fasciola cinereum (FC), a subregion of the posterior hippocampal tail, as a possible additional seizure node.

Existing literature supports the efficacy of anterior hippocampal and amygdala ablation for TLE. However, studies consistently report a substantial number of patients who remain seizure-prone post-surgery. Research on the posterior hippocampus as a potential seizure focus has been limited. While the FC is anatomically defined, its functional role in seizure propagation remains unclear. This study aimed to address this gap by investigating the FC's involvement in TLE using both animal models and human patient data.

The study utilized a multi-faceted approach combining in vivo experiments in mice and analysis of human patient data. In mice, a light- and calcium-gated molecular integrator (scFLARE) was used to label neurons active during seizures induced by kainic acid injection. Closed-loop optogenetic inhibition of genetically defined FC neurons was then employed to assess the impact on seizure duration. In human patients (n=6) undergoing stereoelectroencephalography (sEEG), electrodes targeted the FC to record epileptic activity during seizures. One patient underwent laser interstitial thermal therapy (LITT) specifically targeting the FC after an initial anterior hippocampal and amygdala ablation. Detailed analysis of neuronal activity patterns, high-frequency oscillations (HFOs), and seizure onset zones was performed across both mouse models and human patients.

In epileptic mice, scFLARE labeling revealed prominent activation of FC neurons during spontaneous seizures. Closed-loop optogenetic inhibition of these neurons significantly reduced seizure duration. In the human cohort, sEEG data consistently showed FC involvement in seizure activity, with various patterns of FC engagement observed. One patient demonstrated a significant reduction in seizures after targeted FC lesioning following prior anterior hippocampal ablation. Analysis of human EEG data identified high-frequency oscillations (HFOs) in the FC, which were consistent with a participation in seizure propagation.

This study provides compelling evidence for the FC's role as a critical seizure node in both mouse models and human patients with TLE. The findings highlight the FC as a potential therapeutic target for patients who fail to achieve seizure control after conventional anterior hippocampal resection or ablation. The consistent observation of HFOs in the FC during seizures strengthens the evidence for its functional role in seizure initiation or propagation. The results also suggest that a more comprehensive approach to surgical intervention, encompassing the posterior hippocampal tail, may improve outcomes for patients with drug-resistant TLE.

The research strongly suggests that the fasciola cinereum (FC) is a crucial node in the seizure network of TLE. Targeted interventions focused on the FC, particularly in patients who have not achieved seizure freedom after conventional surgery, may significantly improve treatment outcomes. Future studies should explore the effectiveness of various interventional strategies targeting the FC, including more extensive surgical resection or refined LITT procedures.

The relatively small sample size of the human patient cohort limits the generalizability of the findings. The study focused primarily on patients with mesial TLE and results should be interpreted with caution in those with other epilepsy types. Further research is needed to fully elucidate the FC's role in different epilepsy subtypes and to optimize targeted interventions.