Closed-loop optogenetic control of the dynamics of neural activity in non-human primates

Abstract

Electrical neurostimulation is effective in the treatment of neurological disorders, but associated recording artefacts generally limit its applications to open-loop stimuli. Real-time and continuous closed-loop control of brain activity can however be achieved by pairing concurrent electrical recordings and optogenetics. Here we show that closed-loop optogenetic stimulation with excitatory opsins enables the precise manipulation of neural dynamics in brain slices from transgenic mice and in anesthetized non-human primates. The approach generates oscillations in quiescent tissue, enhances or suppresses endogenous patterns in active tissue, and modulates seizure-like bursts elicited by the convulsant 4-aminopyridine. A nonlinear model of the phase-dependent effects of optical stimulation reproduced the modulation of cycles of local-field potentials associated with seizure oscillations, as evidenced by the systematic changes in the variability and entropy of the phase-space trajectories of seizures, which correlated with changes in their duration and intensity. We also show that closed-loop optogenetic neurostimulation could be delivered using intracortical optrodes incorporating light-emitting diodes. Closed-loop optogenetic approaches may have translational therapeutic applications.

Electronic Neurons for a New Learning Paradigm

“…More precise and non-destructive neuron stimulation methods are expected to play a better role of the electronic axon in future work, such as optogenetics. [26,27] As a nerve electrode with high electrical conductivity, a fiber neural electrode can also be used as an electrical stimulation electrode. Three juxtaposed fiber neural electrodes were used as electronic axons and implanted into the dorsolateral periaqueductal gray (dlPAG) to verify their ability to guide mouse behavior when used as electronic axons (Figure 3g,h).…”

“…More precise and non‐destructive neuron stimulation methods are expected to play a better role of the electronic axon in future work, such as optogenetics. [ 26,27 ]…”

Can in vitro studies aid in the development and use of antiseizure therapies? A report of the ILAE/AES Joint Translational Task Force

“…This is much more laborious using electrophysiology and, in the case of patch‐clamp approaches, it is more technically challenging and limited by the number of micropipettes that can be physically placed into the preparation. Indeed, closed‐loop systems have been developed that use optogenetic mediators to manipulate circuit‐level excitability in response to input from electrically recorded network activity 138,139 . The authors of the study 138 argue that such an approach provides benefit for mechanistic studies and also offers translational benefit, although others have noted that challenges may remain with delivery of light to deep brain structures in a clinical setting 140 .…”

“…Indeed, closedloop systems have been developed that use optogenetic mediators to manipulate circuit-level excitability in response to input from electrically recorded network activity. 138,139 The authors of the study 138 argue that such an approach provides benefit for mechanistic studies and also offers translational benefit, although others have noted that challenges may remain with delivery of light to deep brain structures in a clinical setting. 140 This concept was developed initially using in vitro in brain slice preparations, 138,139 demonstrating the utility of in vitro approaches for developing optogenetic-based therapies.…”

Topological Hydrogels for Long‐Term Brain Signal Monitoring, Neuromodulation, and Stroke Treatment

“…It has been reported that the M1 region comprises somatotopic organization, involving the control of limb movement. [44,56,57] Therefore, it is possible to regulate brain neural circuits by optogenetic neuromodulation of the M1 region to control animal behaviors. It is extremely important to investigate the causal relationship of neuronal activity with behavior and explore approaches for treating locomotor disorders.…”