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.

Electrical neurostimulation is effective in treating neurological disorders, but associated recording artefacts generally limit applications to ‘open-loop’ stimuli. Since light does not prevent concurrent electrical recordings, optogenetics enables real-time, continuous ‘closed-loop’ control of brain activity. Here we show that closed-loop optogenetic stimulation with excitatory opsins (CLOSe) affords precise manipulation of neural dynamics, both in vitro, in brain slices from transgenic mice, and in vivo, with anesthetised monkeys. We demonstrate the generation of oscillations in quiescent tissue, enhancement or suppression of endogenous patterns in active tissue, and modulation of seizure-like bursts elicited by 4-aminopyridine. New network properties, emergent under CLOSe, depended on the phase-shift imposed between neural activity and optical stimulation, and could be modelled with a nonlinear dynamical system. In particular, CLOSe could stabilise or destabilise limit cycles associated with seizure oscillations, evident from systematic changes in the variability and entropy of seizure trajectories that correlated with their altered duration and intensity. Furthermore, CLOSe was achieved using intracortical optrodes incorporating light-emitting diodes, paving the way for translation of closed-loop optogenetics towards therapeutic applications in humans.

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface. We include commercial components to validate performance, with the ultimate aim of translating this approach to humans. In the meantime our system is flexible and expandable for use in a variety of preclinical neuroscientific applications. The platform consists of a Controlling Abnormal Network Dynamics using Optogenetics (CANDO) Control System (CS) that interfaces with up to four CANDO headstages responsible for electrical recording and optical stimulation through custom CANDO LED optrodes. Control of the hardware, inbuilt algorithms and data acquisition is enabled via the CANDO GUI (Graphical User Interface). Here we describe the design and implementation of this system, and demonstrate how it can be used to modulate neuronal oscillations in vitro and in vivo.

Brain-machine Interfaces (BMI) hold great potential for treating neurological disorders such as epilepsy. Technological progress is allowing for a shift from open-loop, pacemaker-class, intervention towards fully closed-loop neural control systems. Low power programmable processing systems are therefore required which can operate within the thermal window of 2O C for medical implants and maintain long battery life. In this work, we have developed a low power neural engine with an optimized set of algorithms which can operate under a power cycling domain. We have integrated our system with a custom-designed brain implant chip and demonstrated the operational applicability to the closedloop modulating neural activities in in-vitro and in-vivo brain tissues: the local field potentials can be modulated at required central frequency ranges. Also, both a freely-moving non-human primate (24-hour) and a rodent (1-hour) in-vivo experiments were performed to show system reliable recording performance. The overall system consumes only 2.93mA during operation with a biological recording frequency 50Hz sampling rate (the lifespan is approximately 56 hours). A library of algorithms has been implemented in terms of detection, suppression and optical intervention to allow for exploratory applications in different neurological disorders. Thermal experiments demonstrated that operation creates minimal heating as well as battery performance exceeding 24 hours on a freely moving rodent. Therefore, this technology shows great capabilities for both neuroscience invitro/in-vivo applications and medical implantable processing units.