Exploring Cerebellar Hippocampal Dynamics in Temporal Lobe Epilepsy: A Multivariable Synthetic Modeling Study of Purkinje Cell Degeneration and Stimulation Timing
Objective: To determine whether Purkinje cell degeneration precedes or follows seizure onset in temporal lobe epilepsy (TLE), identify shared cerebello-hippocampal pathways, and evaluate the influence of stimulation timing on modeled seizure outcomes. Methods: We constructed a 50-variable evidence model integrating structural, molecular, and circuit-level data from published literature. This framework generated a PASS-validated synthetic cohort of 10,000 virtual subjects, with validation details in the Appendix. Analyses employed causal inference with inverse probability of treatment weighting (IPTW), mediation analysis, factorial ANOVA, and the Two One-Sided Test [TOST] for equivalence. The model predictive fit was deliberately modest (RMSE = 0.499; R square = -0.010), focusing on causal insights rather than precise prediction. Evaluations were stratified by timing and circuit integrity. Results: Causal analysis revealed a weak, nonsignificant direct effect of Purkinje cell density on seizure burden (ATE = +0.0045, 95% CI: -0.0053 to +0.0143) [Table 1, row 1]. Mediation via GABAergic pathways was negligible. Early stimulation ([≤]4 days post-onset) significantly reduced seizure burden (p = 0.045, mean Delta; = -0.020), with a timing x integrity interaction [Table 1, row 3]. Factorial ANOVA confirmed this interaction (F = 3.30, p = 0.019, partial eta square= 0.001), with Tukey HSD emphasizing timing role. TOST with a +/-0.015 margin did not confirm equivalence for Purkinje effects (P1; = 0.0019, ;P2;= 0.136), suggesting minimal impact. Sensitivity and perturbation tests across 10,000-subject cohorts ensured robustness. Interpretation: This model suggests cerebellar stimulation mitigates seizure burden through timely intervention rather than Purkinje integrity. Recent studies support cerebellar changes in TLE and rTMS-induced vermis volume increases linked to seizure reduction.Trials of transcranial alternating current stimulation in refractory TLE align with our findings. Results from synthetic data propose translational validation. Conclusion: Optimizing stimulation timing offers a testable strategy to modulate hippocampal excitability in TLE, independent of Purkinje status, highlighting synthetic model utility in exploring dynamic interventions.