In vivoblue light illumination for optogenetic inhibition: effect on local temperature and excitability of the rat hippocampus.

Objective.The blue light-activated inhibitory opsin, stGtACR2, is gaining prominence as a neuromodulatory tool due its ability to shunt-inhibit neurons and is being frequently used inin vivoexperimentation. However, experiments involving stGtACR2 use longer durations of blue light pulses, which inadvertently heat up the local brain tissue and confound experimental results. Therefore, the heating effects of illumination parameters used forin vivooptogenetic inhibition must be evaluated.Approach.To assess blue light (473 nm)-induced heating of the brain, we used a computational model as well as direct temperature measurements using a fiber Bragg grating (FBG). The effects of different light power densities (LPDs) and pulse durations on evoked potentials (EP) recorded from dentate gyrus were assessed. For opsin-negative rats, LPDs between 127 and 636 mW mm-2and pulse durations between 20 and 5120 ms were tested while for stGtACR2 expressing rats, LPD of 127 mW mm-2and pulse durations between 20 and 640 ms were tested.Main results.Increasing LPDs and pulse durations logarithmically increased the peak temperature and significantly decreased the population spike (PS) amplitude and latencies of EPs. For a pulse duration of 5120 ms, the tissue temperature increased by 0.6 °C-3.4 °C. All tested LPDs decreased the PS amplitude in opsin-negative rats, but 127 mW mm-2had comparatively minimal effects and a significant effect of increasing light pulse duration was seen from 320 ms and beyond. This corresponded with an average temperature increase of 0.2 °C-1.1 °C at the recorded site. Compared to opsin-negative rats, illumination in stGtACR2-expressing rats resulted in much greater inhibition of EPs.Significance.Our study demonstrates that light-induced heating of the brain can be accurately measuredin vivousing FBG sensors. Such light-induced heating alone can affect neuronal excitability. Useful neuromodulation by the activation of stGtACR2 is still possible while minimizing thermal effects.

Technological Challenges in the Development of Optogenetic Closed-Loop Therapy Approaches in Epilepsy and Related Network Disorders of the Brain.

Epilepsy is a chronic, neurological disorder affecting millions of people every year. The current available pharmacological and surgical treatments are lacking in overall efficacy and cause side-effects like cognitive impairment, depression, tremor, abnormal liver and kidney function. In recent years, the application of optogenetic implants have shown promise to target aberrant neuronal circuits in epilepsy with the advantage of both high spatial and temporal resolution and high cell-specificity, a feature that could tackle both the efficacy and side-effect problems in epilepsy treatment. Optrodes consist of electrodes to record local field potentials and an optical component to modulate neurons via activation of opsin expressed by these neurons. The goal of optogenetics in epilepsy is to interrupt seizure activity in its earliest state, providing a so-called closed-loop therapeutic intervention. The chronic implantation in vivo poses specific demands for the engineering of therapeutic optrodes. Enzymatic degradation and glial encapsulation of implants may compromise long-term recording and sufficient illumination of the opsin-expressing neural tissue. Engineering efforts for optimal optrode design have to be directed towards limitation of the foreign body reaction by reducing the implant's elastic modulus and overall size, while still providing stable long-term recording and large-area illumination, and guaranteeing successful intracerebral implantation. This paper presents an overview of the challenges and recent advances in the field of electrode design, neural-tissue illumination, and neural-probe implantation, with the goal of identifying a suitable candidate to be incorporated in a therapeutic approach for long-term treatment of epilepsy patients.