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Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity

Introduction Brain stimulation is a fundamental and effective therapy for neurological diseases including Parkinson’s disease, essential tremor, and epilepsy. One key challenge in delivering effective brain stimulation is identifying the stimulation parameters, such as the amplitude, frequency, contact configuration, and pulse width, that induce an optimal change in symptoms, behavior, or neural activity. Most clinical and translational studies use constant-frequency pulses of stimulation, but stimulation with irregular pulse patterns or non-pulsatile waveforms might induce unique changes in neural activity that could enable better therapeutic responses. Here, we comprehensively evaluate several optogenetic stimulation waveforms, report their differing effects on hippocampal spectral activity, and compare these induced effects to activity recorded during natural behavior. Methods Sprague-Dawley rats were prepared for pan-neuronal excitatory optogenetic stimulation of the medial septum (hSyn-ChR2) and 16-channel microelectrode recording in CA1 and CA3 layers of the hippocampus. We performed grid and random sampling of the parameters comprising several stimulation waveforms, including standard pulse, nested pulse, sinusoid, double sinusoid, and Poisson pulse waveforms. Results We comprehensively report the effects of changing stimulation parameters in these parameter spaces on two key biomarkers of hippocampal function, theta (4-10 Hz) and gamma (32-50 Hz) power. Similarly, robust excitation of hippocampal gamma power was observed across all waveforms, whereas no set of stimulation parameters was sufficient to consistently increase power in the theta band beyond baseline levels of activity (despite the prominent role of the medial septum in pacing hippocampal theta oscillations). Using a manifold learning algorithm to compare high-dimensional neural activity, we show that irregular stimulation patterns produce differing effects with respect to multi-band patterns of activity and can induce activity patterns that more closely resemble activity recorded during natural behavior than conventional parameters. Conclusion Our counter-intuitive findings – that stimulation of the medial septum ubiquitously does not increase hippocampal theta power, and that different waveforms have similar effects on single power bands – contradict recent trends in brain stimulation research, necessitating greater caution and fewer mechanistic assumptions as to how a given stimulation target or waveform will modulate a neurophysiological biomarker of disease. We also reveal that irregular stimulation patterns can have biomimetic utility, promoting their exploration in medical applications where inducing a particular activity pattern can have therapeutic benefit. Last, we demonstrate a scalable data-driven analysis strategy that can make the discovery of such physiologically informed temporal stimulation patterns more empirically tractable in translational settings.