Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson’s disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple “reversible lesion” effect to augment network communication. Specifically, we examined the modulation of beta band (14–30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson’s. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

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Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit

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.

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A Closed-Loop Optogenetic Platform.

With its potential of single cell specificity, optogenetics has made the investigation into the brain circuits more controllable. Closed loop optogenetic brain stimulation enhances the efficacy of the stimulation by adjusting the stimulation parameters based on direct feedback from the target area of the brain. It combines the principles of genetics, physiology, electrical engineering, optics, signal processing and control theory to create an efficient brain stimulation system. To read the underlying neuronal condition from the electrical activity of neurons, a sensor, sensor interface circuit, and signal conditioning are needed. Also, efficient feature extraction, classification, and control algorithms should be in place to interpret and use the sensed data for closing the feedback loop. Finally, a stimulation circuitry is required to effectively control a light source to deliver light based stimulation according to the feedback signal. Thus, the backbone to a functioning closed loop optogenetic brain stimulation device is a well-built electronic circuitry for sensing and processing of brain signals, running efficient signal processing and control algorithm, and delivering timed light stimulations. This paper presents a review of electronic and software concepts and components used in recent closed-loop optogenetic devices based on neuro-electrophysiological reading and an outlook on the future design possibilities with the aim of providing a compact and easy reference for developing closed loop optogenetic brain stimulation devices. 

Electrophysiology-Based Closed Loop Optogenetic Brain Stimulation Devices: Recent Developments and Future Prospects

In the intact brain, neural activity can be recorded using sensing electrodes and manipulated using light stimulation. Silicon probes with integrated electrodes and µLEDs enable the detection and control of neural activity using a single implanted device. Miniaturized solutions for recordings from small freely moving animals are commercially available, but stimulation is driven by large, stationary current sources. We designed and fabricated a current source chip and integrated it into a headstage PCB that weighs 1.37 g. The proposed system provides 10-bit resolution current control for 32 channels, driving µLEDs with up to 4.6 V and sourcing up to 0.9 mA at a refresh rate of 5 kHz per channel. When calibrated against a µLED probe, the system allows linear control of light output power, up to 10 µW per µLED. To demonstrate the capabilities of the system, synthetic sequences of neural spiking activity were produced by driving multiple µLEDs implanted in the hippocampal CA1 area of a freely moving mouse. The high spatial, temporal, and amplitude resolution of the system provides a rich variety of stimulation patterns. Combined with commercially available sampling headstages, the system provides an easy to use back-end, fully utilizing the bi-directional potential of integrated opto-electronic arrays.

Outan: An On-Head System for Driving µLED Arrays Implanted in Freely Moving Mice

Closed-loop Modulation of the Self-regulating Brain: A Review on Approaches, Emerging Paradigms, and Experimental Designs

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 2° 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 closed-loop 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 2.93 mA during operation with a biological recording frequency 50 Hz 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 in-vitro/in-vivo applications and medical implantable processing units.

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The Neural Engine: A Reprogrammable Low Power Platform for Closed-Loop Optogenetics


 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.

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Mark Turnbull

Papers

The Neural Engine: A Reprogrammable Low Power Platform for Closed-Loop Optogenetics

Closed-loop optogenetic control of normal and pathological network dynamics

A Closed-Loop Optogenetic Platform.