Limb loss and spinal cord injury are two debilitating conditions that continue to grow in prevalence. Prosthetic limbs and limb reanimation present two ways of providing affected individuals with means to interact in the world. These techniques are both dependent on a robust interface with the peripheral nerve. Current methods for interfacing with the peripheral nerve tend to suffer from low specificity, high latency and insufficient robustness for a chronic implant. An optical peripheral nerve interface may solve some of these problems by decreasing invasiveness and providing single axon specificity. In order to implement such an interface three elements are required: (1) a transducer capable of translating light into a neural stimulus or translating neural activity into changes in fluorescence, (2) a means for delivering said transducer and (3) a microscope for providing the stimulus light and detecting the fluorescence change. There are continued improvements in both genetically encoded calcium and voltage indicators as well as new optogenetic actuators for stimulation. Similarly, improvements in specificity of viral vectors continue to improve expression in the axons of the peripheral nerve. Our work has recently shown that it is possible to virally transduce axons of the peripheral nerve for recording from small fibers. The improvements of these components make an optical peripheral nerve interface a rapidly approaching alternative to current methods.
Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine’, has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific (individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell (axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.
Current neural interfaces are hampered by lack of specificity and selectivity for neural interrogation. A method that might improve these interfaces is an optical peripheral nerve interface which communicates with individual axons via optogenetic reporters. To determine the feasibility of such an interface, we delivered the genetically encoded calcium indicator GCaMP6f to the mouse peripheral nerve by intramuscular injection of adenoassociated viral vector (AAV1) under the control of the CAG (chicken beta actin- cytomegalovirus hybrid promoter). Small diameter axons in the common peroneal nerve were transduced and demonstrated electrically inducible calcium transients ex vivo. Responses to single electrical stimuli were resolvable, and increasing the number of stimuli resulted in a monotonic increase in maximum fluorescence and a prolongation of calcium transient kinetics. This work demonstrates the viability of using a virally-delivered, genetically-encoded calcium indicator to read-out from peripheral nerve axons.
Gaucher disease, a lysosomal storage disorder and hemophagocytic lymphohistiocytosis (HLH), a disorder of the immune system, have several overlapping clinical features including cytopenias, elevated serum ferritin, and splenomegaly. Prior reports of acute infantile neuronopathic, Type 2 Gaucher disease manifesting with signs of HLH have
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