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Polarization sensitive optical coherence tomography (PSOCT) has been shown to image and delineate white matter fibers in a label-free manner by revealing optical birefringence within the myelin sheath using a microscope setup. In this proof-of-concept study, we adapt recent advancements in endoscopic PSOCT to perform depth-resolved imaging of white matter structures deep inside intact porcine brain tissue ex-vivo, through a small, rotational fiber probe. The probe geometry is comparable to microelectrodes currently used in neurosurgical interventions. The presented imaging system is mobile, robust, and uses biologically safe levels of optical radiation making it well suited for clinical translation. In neurosurgery, where accuracy is imperative, endoscopic PSOCT through a narrow-gauge fiber probe could provide intra-operative feedback on the location of critical white matter structures.

As the technological hurdles are overcome and optogenetic techniques advance to have more control over neurons, therapies based on these approaches will begin to emerge in the clinic. Here, we consider the technical challenges surrounding the transition of this breakthrough technology from an investigative tool to a true therapeutic avenue. The emerging strategies and remaining tasks surrounding genetically encoded molecules which respond to light as well as the vehicles required to deliver them are discussed.The use of optogenetics in humans would represent a completely new paradigm in medicine and would be associated with unprecedented technical considerations. To be applied for stimulation of neurons in humans, an ideal optogenetic tool would need to be non-immunogenic, highly sensitive, and activatable with red light or near-infrared light (to maximize light penetration while minimizing photodamage). To enable sophisticated levels of neuronal control, the combined use of optogenetic actuators and indicators could enable closed-loop all-optical neuromodulation. Such systems would introduce additional challenges related to spectral orthogonality between actuator and indicator, the need for decision making computational algorithms and requirements for large gene cassettes. As in any gene therapy, the therapeutic efficiency of optogenetics will rely on vector delivery and expression in the appropriate cell type. Although viral vectors such as those based on AAVs are showing great potential in human trials, barriers to their general use remain, including immune responses, delivery/transport, and liver clearance. Limitations associated with the gene cassette size which can be packaged in currently approved vectors also need to be addressed.