Prosthetic systems for therapeutic optical activation and silencing of genetically targeted neurons

Abstract

Many neural disorders are associated with aberrant activity in specific cell types or neural projection pathways embedded within the densely-wired, heterogeneous matter of the brain. An ideal therapy would permit correction of activity just in specific target neurons, while leaving other neurons unaltered. Recently our lab revealed that the naturally-occurring light-activated proteins channelrhodopsin-2 (ChR2) and halorhodopsin (Halo/NpHR) can, when genetically expressed in neurons, enable them to be safely, precisely, and reversibly activated and silenced by pulses of blue and yellow light, respectively. We here describe the ability to make specific neurons in the brain light-sensitive, using a viral approach. We also reveal the design and construction of a scalable, fully-implantable optical prosthetic capable of delivering light of appropriate intensity and wavelength to targeted neurons at arbitrary 3-D locations within the brain, enabling activation and silencing of specific neuron types at multiple locations. Finally, we demonstrate control of neural activity in the cortex of the non-human primate, a key step in the translation of such technology for human clinical use. Systems for optical targeting of specific neural circuit elements may enable a new generation of high-precision therapies for brain disorders.

FEF inactivation with improved optogenetic methods

“…Further, the tools presented here optimize the wavelength of light, based on actual measurements from the living brain, and control for heating. Previous studies, which used perfused brain preparations or synthetic brain tissue phantoms (53), underestimated tissue absorption for 200-600 nm (blue and green) light propagation. Specifically, we report absorption coefficients two-to threefold larger than the largest reported in a recent study of fresh and frozen brain slices (30) and about 10-fold larger than the values that Yaroslavsky et al (29) reported based on measurements taken in postmortem human tissue.…”

“…We are aware of two studies that sought to parameterize optical heating in vivo (41,53), but no previous study has attempted to control the brain tissue heating due to illumination. Temperature increases >4°C may induce damage, and firing rate increases with a temperature increase of >2°C in some heat-sensitive brain areas (54)(55)(56)(57).…”

Light induced stimulation and delay of cardiac activity

“…On the one hand it could be used as a pacemaker by generating APs, and on the other hand it could be used for reducing the amount of APs and thereby suppressing 45 fibrillation. The required light intensities could also be provided by state of the art LEDs [49] allowing the generation of an implantable medical device [43].…”

“…Though genetic engineering can be tricky and requires sophisticated techniques for high efficiency or influence free transfection, two main approaches exist in vivo; viral transfection [36], 30 with high efficiencies but increased biological safety risk, or electrofection, with high efficiencies but limited application regions [37,38,39]. Several tissues have been successfully transfected with Ch2 allowing optical stimulation including retina [40], somatosensory neurons [41], and cortex [42] and 35 devices for light delivery have been designed [43]. Although this new tool in electrophysiology provides plenty of innovative ways of interfacing electrogenic cells, several drawbacks still have to be faced before implementation of such concepts can be progressed.…”

Holographic optogenetic stimulation of patterned neuronal activity for vision restoration

“…A pattern photo-stimulation system for artificially controlling neural activity in a vision prosthesis or for general neurostimulation applications is not expected to have this limitation (due to minimal light scattering in the inner retinal layers) and will ideally allow cellular-resolution, rapid, massively parallel, light-efficient stimulation across macroscopic (millimeter-scale) coverage areas. To date, however, optical excitation of optogenetically targeted populations is often delivered nonspecifically to the whole population using wide-field flashes with intense lamps 1,3,10 , LEDs (light-emitting diodes) and optical fibre coupled illumination 11,12 or in simple patterns using rapid random-access laser deflection 13,14 , digital micromirror arrays 8,9,[15][16][17][18] and micro-LED arrays 6,19 .…”