A dynamical computational model of theta generation in hippocampal circuits to study theta-gamma oscillations during neurostimulation.

Neurostimulation of the hippocampal formation has shown promising results for modulating memory but the underlying mechanisms remain unclear. In particular, the effects on hippocampal theta-nested gamma oscillations and theta phase reset, which are both crucial for memory processes, are unknown. Moreover, these effects cannot be investigated using current computational models, which consider theta oscillations with a fixed amplitude and phase velocity. Here, we developed a novel computational model that includes the medial septum, represented as a set of abstract Kuramoto oscillators producing a dynamical theta rhythm with phase reset, and the hippocampal formation, composed of biophysically realistic neurons and able to generate theta-nested gamma oscillations under theta drive. We showed that, for theta inputs just below the threshold to induce self-sustained theta-nested gamma oscillations, a single stimulation pulse could switch the network behavior from non-oscillatory to a state producing sustained oscillations. Next, we demonstrated that, for a weaker theta input, pulse train stimulation at the theta frequency could transiently restore seemingly physiological oscillations. Importantly, the presence of phase reset influenced whether these two effects depended on the phase at which stimulation onset was delivered, which has practical implications for designing neurostimulation protocols that are triggered by the phase of ongoing theta oscillations. This novel model opens new avenues for studying the effects of neurostimulation on the hippocampal formation. Furthermore, our hybrid approach that combines different levels of abstraction could be extended in future work to other neural circuits that produce dynamical brain rhythms.