Currently, electrical stimulation (ES) is used during intraoperative nerve monitoring (IONM) to detect the onset of nerve damage but suffers from current spread making results more uncertain. Infrared neural stimulation (INS) is more spatially precise than ES and has the potential to improve nerve damage detection. Here, we compare ES and INS for IONM in an in vivo animal model. INS and ES had comparable specificities, but INS exhibited a higher sensitivity than ES for less severe forms of damage. These results provide a foundation for using INS in IONM procedures and insight into future clinical translation.

The development of optogenetic approaches for brain research to a new level of knowledge. In this field, the use of plant photoreceptors phytochromes (Phys) optic transition between states absorbing red light (Pr) and far-red light (Pfr), can expand the spectral range of optogenetics to the near-infrared (NIR) range. NIR wavelengths exhibit higher penetration of soft tissues, whereas for the skull it is very low. Here we review our recent results in using bacterial Phy (BPhy) for brain research where we suggested activating BPhy with a femtosecond laser emitting in the 1 – 1.5 micrometer range. Results revealed that the USP laser was capable of nonlinear Pr transformation to Pfr with the highest efficiency at wavelengths between 1170 and 1280 nm.

We found that a single and brief IR light pulse induced a TTX-independent membrane depolarization, whose amplitude depends on the pulse duration and total energy deposition. The depolarization facilitated action potential (AP) generation when the axon was near firing threshold. This depolarization was followed by a membrane hyperpolarization at higher energy levels, which reversed near potassium equilibrium potential and could inhibit AP firing. Pharmacological results indicated that barium-sensitive potassium channels contributed to the hyperpolarization, while further administration of TEA did not change the hyperpolarization. We show that individual and brief IR light pulses can evoke both excitatory and inhibitory effects.

Infrared (IR) inhibition can induce selective heat block on small-diameter axons. We hypothesize that the selective IR inhibition effect can be reproduced by resistance heating via a heating cuff. We tested the hypothesis in vitro on the pleural-abdominal connective of Aplysia californica. The IR optical fiber, heating cuff, and a thermocouple were co-located to ensure both heating modalities induced a similar temperature increase on the nerve. Electrically stimulated compound action potentials were recorded and segmented to characterize the inhibition effect on different axonal subgroups. The dose-response curve showed that resistance heating can reproduce the selective IR inhibition effect.

Infrared neural stimulation (INS) is a label-free method that uses infrared light to excite neural tissue. Because the biophysical mechanism of INS is not fully understood, we present a computational modeling study demonstrating photomechanical effects in a rat sciatic nerve from infrared pulses across a range of pulse widths. By comparing the resulting pressure and displacement across different pulse widths, this allows for insight of the sensitivity of the photomechanical effects from laser irradiation. Additionally, a further look into the initial spike of the Ho:YAG laser shows that a photomechanical component could possibly explain the lower stimulation threshold.

Neuromodulation at high precision poses great significance in advancing fundamental knowledge in neuroscience and offering novel clinical treatments. Here we reported our development of the photoacoustic neural stimulation in four different platform technologies. These technologies include implantable fiber based photoacoustic emitters, nanocomposite based photoacoustic films, photoacoustic nanotransducers, and optic-driven focus ultrasound (OFUS) with transcranial capability for non-invasive applications. Specifically, in OFUS, a curved photoacoustic film forms a concave ultrasound lens to achieve the ultrasound focus with about 100 micron, opening up new opportunities for high precision non-invasive neural stimulation.

Degeneration of photoreceptors, retinal cells including retinal pigment epithelium, and retinal ganglion cells characterizes visual disorders involving retinal dysfunction. The efficient and targeted gene delivery into retinal cells is critical for treatment of a variety of visual disorders. Here, we report use of an OCT guided, spatially targeted, near-infrared laser microirradiation platform to successfully deliver genes encoding ambient-light activatable multi-characteristic opsin (MCO) to retinal cells in non-human primates. The efficacy of gene delivery was evaluated by fundus imaging of the reporter (mCherry) fluorescence, and immunohistochemistry. Functional improvement was measured by red-ERG which was attributed to MCO’s broadband activation spectrum.

Recent developments in optogenetics allow for quick and minimally invasive methods of mapping functional brain circuits in animal models. DeepLabCut (DLC), a toolbox for markerless pose estimation, offers the ability to track features in 3-dimensions. We demonstrate a hybrid method utilizing DLC and light-based, optogenetic motor mapping to concurrently localize motor representations of multiple limbs in mice. Our results suggest that behaviorally-relevant, motor movements involving multiple limbs reside in overlapping cortical representations of each limb. Applications of this technique include characterizing recovery of finer, articulated movements of affected limbs after stroke, or mapping brain network activity during naturalistic behavior.

Stargardt Disease is an inherited macular degeneration caused by mutation of genes, primarily ABCA4 in the photoreceptor cells leading to their dysfunction and degeneration in the macula. Here, we report results of ambient-light vision restoration in Stargardt mice (Abca4tm1Ght/J) upon intravitreal delivery of AAV-carried MCO (vMCO) as evaluated by electrophysiology, Optical Coherence Tomography (OCT) and visually guided behavior. Further, safety of MCO-enabled vision restoration therapy was evaluated by measurement of Intraocular Pressure, OCT and Immunohistochemistry. The vMCO based ambient light activatable optogenetic therapy has potential to be a disease-agnostic therapy to address the unmet need of inherited retinal degenerative diseases.

Sensory perceptions entail the activation of thousands of interrelated neurons, each of these neurons can fire at distinct rates at different times. Despite this vast ‘activity space’ not all possible combinations of activity happen – instead lower dimensional subspaces define what are valid or invalid patterns. However, even the most advanced manipulation approaches so far are incapable of recreating a specific multi-neuron pattern. Here we describe a new approach based on holographic multiphoton optogenetics that allows us to write the numerically correct number of action potentials into a group of neurons, allowing us to write directly and flexibly to activity space.

This Conference Presentation, Restoration of high-sensitivity object and pattern vision in motion, was recorded at SPIE Photonics West held in San Francisco, California, United States.

This Conference Presentation, Optogenetic vision restoration with multi-characteristic opsins in bipolar cells, was recorded at SPIE Photonics West held in San Francisco, California, United States.