Targeted optogenetic stimulation of the thalamic reticular nucleus: A novel strategy for modulating epileptiform discharges

The distinct advantage of optogenetic stimulation in precise neuromodulation enables us to dissect the intrinsic mechanisms by which such stimulation of the thalamic reticular nucleus (RE) suppresses epileptic seizures. Since irradiance (I_rr) is a key factor affecting optogenetic stimulation, we first explore the effect of I_rr on epileptic seizures. The results indicate that increasing I_rr can suppress the seizures and alter the system’s bifurcation structure. The numbers of Hopf bifurcations and saddle–node bifurcations of limit cycles decrease as I_rr increases, and the saddle–node bifurcation of the fixed point is a key factor driving the abrupt transition of the system from a high-saturation discharge state to a low-saturation discharge state. Subsequently, we apply optogenetic stimulation in square-wave and Gaussian pulse forms to assess the impacts of three core parameters (pulse width w_s, pulse frequency f, and I_rr) on epileptic discharge states. Our numerical simulation results reveal that square-wave pulsed optogenetic stimulation effectively suppresses seizure activity when the pulse width is increased to 15 ms (f = 40 Hz, I_rr = 0.3 mW/mm²), the pulse frequency to 100 Hz (w_s = 5 ms, I_rr = 0.3 mW/mm²), and the irradiance to 0.8 mW/mm² (w_s = 5 ms, f = 40 Hz), respectively. In contrast, using the same analytical method, we find that Gaussian pulsed stimulation requires elevating the respective parameters (pulse width, frequency, irradiance) to 30 ms, 250 Hz, and 1.9 mW/mm² for the effective suppression of seizure activity. Therefore, square-wave pulses require a smaller parameter threshold to achieve the effect of inhibiting epileptic seizures. From a physiological perspective, square-wave pulsed optogenetic stimulation is thus more suitable as a potential candidate for clinical trials.