Preventing seizures by microperturbations

Abstrakt

The seizure emergence mechanisms remain among the most critical unresolved challenges in epilepsy research. We investigated how and why perturbations, exogenous or endogenous, can influence the promotion or delay of seizure onset [1], building on prior observations from in vivo, in vitro, and in silico studies [2]. In line with the increasingly adopted view of epileptic dynamics in terms of slow-fast systems, we performed a theoretical analysis of the phase response of a generic relaxation oscillator. As relaxation oscillators are effectively bistable systems at the fast time scale, it is intuitive that perturbations of the non-seizing state with a suitable direction and amplitude cause an immediate transition to seizure. By contrast, smaller amplitude perturbations may delay the spontaneous seizure initiation by tapping into the same slow feedback mechanism that drives seizure termination. By studying the system flow structure, in particular the isochrons of relaxation oscillators, we showed this is a generic phenomenon. Therefore, depending on perturbation amplitudes, frequency and timing (and any potential parameters of the slow flow component), a train of perturbations causes an occurrence increase, decrease, or complete suppression of seizures. This dependence lends itself to analysis and mechanistic understanding. We illustrate this by analysis and numerical simulations of the response to perturbations in several epileptic models with slow-fast dynamics, including the phenomenor [2] and reduced Epileptor [3]. We shall conclude by discussion of the limits of generalizability of the theoretical findings to higher-dimensional models such as the original Epileptor (qualitative replication in simulations, see [1]), or Epileptor-2 (apparently qualitatively different dynamics with potential consequences for therapeutic stimulation procedures).