Closed-loop functional optogenetic stimulation

Abstract

Optogenetics has been used to orchestrate temporal- and tissue-specific control of neural tissues and offers a wealth of unique advantages for neuromuscular control. Here, we establish a closed-loop functional optogenetic stimulation (CL-FOS) system to control ankle joint position in murine models. Using the measurement of either joint angle or fascicle length as a feedback signal, we compare the controllability of CL-FOS to closed-loop functional electrical stimulation (CL-FES) and demonstrate significantly greater accuracy, lower rise times and lower overshoot percentages. We demonstrate orderly recruitment of motor units and reduced fatigue when performing cyclical movements with CL-FOS compared with CL-FES. We develop and investigate a 3-phase, photo-kinetic model to elucidate the underlying mechanisms for temporal variations in optogenetically activated neuromusculature during closed-loop control experiments. Methods and insights from this study lay the groundwork for the development of closed-loop optogenetic neuromuscular stimulation therapies and devices for peripheral limb control.

Optogenetic recruitment of spinal reflex pathways from large‐diameter primary afferents in non‐transgenic rats transduced with AAV9/Channelrhodopsin 2

“…recruitment occurs from fast-conducting fibres; Lertmanorat & Durand, 2004;Llewellyn et al 2010), DRG neurons with the best ChR2 transduction efficiency that should elicit the earliest and largest volley may not always be the fastest conducting neurons. A previous study reported that the recruitment order of afferent fibres by optical stimulation followed the expression levels of ChR2 (Srinivasan et al 2018). Therefore, we reasonably expected a slower conduction time in the optically elicited volley.…”

“…A previous study reported that the recruitment order of afferent fibres by optical stimulation followed the expression levels of ChR2 (Srinivasan et al . ). Therefore, we reasonably expected a slower conduction time in the optically elicited volley.…”

“…Second, optical stimulation to recruit afferent fibres is restricted to those expressing ChR2, and the recruitment order was shown to follow the expression levels of ChR2 (Srinivasan et al . ). Therefore, our observation that AAV9‐mediated ChR2 expression was biased to large‐sized cells suggests that light stimulation preferentially recruits fast‐conducting afferents at a specific stimulation intensity.…”

“…First, unlike electrical stimulation, the response sensitivity for light stimulation was suppressed within a short ISI (<10 ms). This desensitization might be attributed to the temporal dynamics of neuronal activity, which is determined by the ChR2 conducting state (four-state photocycle kinetics; two open and two closed) (Hegemann & Moglich, 2011;Srinivasan et al 2018). When the second stimulation was applied before closing the light-gated channels (Lin, 2011), some neurons may be shifted to the low-conductance open state, leading to a low probability of neuronal depolarization.…”

“…To date, most optogenetic applications have focused on the central nervous system (CNS) (Galvan et al 2017;Rost et al 2017) and it has rarely been applied to the peripheral nervous system (PNS). Although the application of optogenetics to the PNS has clear advantages for both therapeutic (Llewellyn et al 2010;Daou et al 2013;Liske et al 2013;Copits et al 2016;Iyer et al 2016;Srinivasan et al 2018) and physiological (Park et al 2016;Abe & Yawo, 2017;Arcourt et al 2017) perspectives, a number of technical difficulties have precluded the application (Montgomery et al 2016).…”