Analysis of mechanical and optical brain injury from optogenetic implants

Abstract

Deep brain stimulation (DBS) technology has become an effective clinical tool for treating symptoms of a range of conditions including Parkinson’s disease, epilepsy, treatment-resistant depression, and others. The electrical signal from a DBS electrode penetrates a limited distance through brain tissue and must be precisely placed to target the location of interest. Current DBS electrodes are prone to several complications including mistargeting (requiring revision), mechanical trauma, and glial scar formation leading to impaired implant function. Optogenetics is a relatively novel technology with the potential to reduce or overcome many of the issues with DBS electrode implants. Optogenetic implants use optical rather than electrical stimulation, targeting neurons modified to express light reactive channel rhodopsin proteins. The optical signals used in optogenetics have the potential to travel further through brain tissue than do electrical signals. Multiple wavelengths can be employed to stimulate or suppress separate neural populations from the same implant, and implant placement need not be as precise since only modified neurons will be affected. Channelrhodopsins have been engineered to produce a wide range of behaviours unavailable via electrical stimulation including stimulation, suppression and switchable activity. To successfully bring an optogenetic implant to clinical practice, it is necessary to determine its safety compared to existing techniques; optrodes could cause trauma to patient tissue via mechanical, thermal and optical mechanisms. To establish an effective regulatory framework for optogenetic implants, tools must be available to measure these effects in patient tissue. iii This study critically assesses the use of atomic force microscopy as a tool for measuring the mechanical properties of brain tissue, investigates cell-derived extracellular matrix models as tools for probing the mechanisms of brain tissue remodelling after injury and measures toxicity in brain tissue from exposure to optical wavelengths and intensities typical for optogenetic applications. Here, we (i) showed that measurement of acute brain slices with atomic force microscopy is significantly influenced by osmotic swelling and should be performed rapidly at low temperatures to mitigate these effects, (ii) found that cell-derived extracellular matrix possesses several properties that make it unconducive to mechanical measurement with atomic force microscopy or rheological tools and (iii) developed an experimental method for measuring optical toxicity in brain tissue that could be used to establish regulatory limits for clinical devices. Further investigation will yield additional improvements to these techniques, facilitating development of safer optogenetic implant technologies.