VLSI Circuits for Bidirectional Neural Interfaces

Medical devices that deliver electrical stimulation to neural tissue are important clinical tools that can augment or replace pharmacological therapies. The success of such devices has led to an explosion of interest in the field, termed neuromodulation, with a diverse set of disorders being targeted for device-based treatment. Nevertheless, a large degree of uncertainty surrounds how and why these devices are effective. This uncertainty limits the ability to optimize therapy and gives rise to deleterious side effects. An emerging approach to improve neuromodulation efficacy and to better understand its mechanisms is to record bioelectric activity during stimulation. Understanding how stimulation affects electrophysiology can provide insights into disease, and also provides a feedback signal to autonomously tune stimulation parameters to improve efficacy or decrease side-effects. The aims of this work were taken up to advance the state-of-the-art in neuro-interface technology to enable closed-loop neuromodulation therapies. Long term monitoring of neuronal activity in awake and behaving subjects can provide critical insights into brain dynamics that can inform system-level design of closed-loop neuromodulation systems. Thus, first we designed a system that wirelessly telemetered electrocorticography signals from awake-behaving rats. We hypothesized that such a system could be useful for detecting sporadic but clinically relevant electrophysiological events. In an 18-hour, overnight recording, seizure activity was detected in a pre-clinical rodent model of global ischemic brain injury. We subsequently turned to the design of neurostimulation circuits. Three critical features of neurostimulation devices are safety, programmability, and specificity. We conceived and implemented a neurostimulator architecture that utilizes a compact on-chip circuit for charge balancing (safety), digital-to-analog converter calibration (programmability) and current steering (specificity). Charge balancing accuracy was measured at better than 0.3%, the digital-to-analog converters achieved 8-bit resolution, and physiological effects of current steering stimulation were demonstrated in an anesthetized rat. Lastly, to implement a bidirectional neural interface, both the recording and stimulation circuits were fabricated on a single chip. In doing so, we implemented a low noise, ultra-low power recording front end with a high dynamic range. The recording circuits achieved a signal-to-noise ratio of 58 dB and a spurious-free dynamic range of better than 70 dB, while consuming 5.5 μW per channel. We demonstrated bidirectional operation of the chip by recording cardiac modulation induced through vagus nerve stimulation, and demonstrated closed-loop control of cardiac rhythm

A Multi-Channel Stimulator With High-Resolution Time-to-Current Conversion for Vagal-Cardiac Neuromodulation

This paper presents an integrated stimulator for a cardiac neuroprosthesis aiming to restore the parasympathetic control after heart transplantation. The stimulator is based on time-to-current conversion. Instead of the conventional current mode digital-to-analog converter (DAC) that uses ten of microamp for biasing, the proposed design uses a novel capacitor time-based DAC offering close to 10 bit of current amplitude resolution while using only a bias current 250 nA. The stimulator chip was design in a 0.18 m CMOS high-voltage (HV) technology. It consists of 16 independent channels, each capable of delivering 550 A stimulus current under a HV output stage that can be operated up to 30 V. Featuring both power efficiency and high-resolution current amplitude stimulation, the design is suitable for multi-channel neural simulation applications

Feasibility Assessment of an Optically Powered Digital Retinal Prosthesis Architecture for Retinal Ganglion Cell Stimulation

Clinical trials previously demonstrated the notable capacity to elicit visual percepts in blind patients affected with retinal diseases by electrically stimulating the remaining neurons on the retina. However, these implants restored very limited visual acuity and required transcutaneous cables traversing the eyeball, leading to reduced reliability and complex surgery with high postoperative infection risks. To overcome the limitations imposed by cables, a retinal implant architecture in which near-infrared illumination carries both power and data through the pupil to a digital stimulation controller is presented. A high efficiency multi-junction photovoltaic cell transduces the optical power to a CMOS stimulator capable of delivering flexible interleaved sequential stimulation through a diamond microelectrode array. To demonstrate the capacity to elicit a neural response with this approach while complying with the optical irradiance limit at the pupil, fluorescence imaging with a calcium indicator is used on a degenerate rat retina. The power delivered by the laser at the permissible irradiance of 4 mW/mm2 at 850 nm is shown to be sufficient to both power the stimulator ASIC and elicit a response in retinal ganglion cells (RGCs), with the ability to generate of up to 35 000 pulses per second at the average stimulation threshold. This confirms the feasibility of generating a response in RGCs with an infrared-powered digital architecture capable of delivering complex sequential stimulation patterns at high repetition rates, albeit with some limitations.Comment: 11 pages, 13 figure

A Closed-Loop Bidirectional Brain-Machine Interface System For Freely Behaving Animals

A brain-machine interface (BMI) creates an artificial pathway between the brain and the external world. The research and applications of BMI have received enormous attention among the scientific community as well as the public in the past decade. However, most research of BMI relies on experiments with tethered or sedated animals, using rack-mount equipment, which significantly restricts the experimental methods and paradigms. Moreover, most research to date has focused on neural signal recording or decoding in an open-loop method. Although the use of a closed-loop, wireless BMI is critical to the success of an extensive range of neuroscience research, it is an approach yet to be widely used, with the electronics design being one of the major bottlenecks. The key goal of this research is to address the design challenges of a closed-loop, bidirectional BMI by providing innovative solutions from the neuron-electronics interface up to the system level. Circuit design innovations have been proposed in the neural recording front-end, the neural feature extraction module, and the neural stimulator. Practical design issues of the bidirectional neural interface, the closed-loop controller and the overall system integration have been carefully studied and discussed.To the best of our knowledge, this work presents the first reported portable system to provide all required hardware for a closed-loop sensorimotor neural interface, the first wireless sensory encoding experiment conducted in freely swimming animals, and the first bidirectional study of the hippocampal field potentials in freely behaving animals from sedation to sleep. This thesis gives a comprehensive survey of bidirectional BMI designs, reviews the key design trade-offs in neural recorders and stimulators, and summarizes neural features and mechanisms for a successful closed-loop operation. The circuit and system design details are presented with bench testing and animal experimental results. The methods, circuit techniques, system topology, and experimental paradigms proposed in this work can be used in a wide range of relevant neurophysiology research and neuroprosthetic development, especially in experiments using freely behaving animals

An ASIC for Recording and Stimulation in Stacked Microchannel Neural Interfaces

This paper presents an active microchannel neural interface (MNI) using seven stacked application specific integrated circuits (ASIC). The approach provides a solution to the present problem of interconnect density in 3-dimensional MNIs. The 4 mm2 ASIC is implemented in 0.35 μm high-voltage CMOS technology. Each ASIC is the base for seven microchannels each with three electrodes in a pseudo-tripolar arrangement. Multiplexing allows stimulating or recording from any one of 49 channels, across 7 ASICs. Connections to the ASICs are made with a 5-line parallel bus. Current controlled biphasic stimulation from 5 μA to 500 μA has been demonstrated with switching between channels and ASICs. The high-voltage technology gives a compliance of 40 V for stimulation, appropriate for the high impedances within microchannels. High frequency biphasic stimulation, up to 40 kHz is achieved, suitable for reversible high frequency nerve blocks. Recording has been demonstrated with mV level signals; common-mode inputs are differentially distorted and limit the CMRR to 40dB. The ASIC has been used in vitro in conjunction with an oversize (2 mm diameter) microchannel in phosphate buffered saline, demonstrating attenuation of interference from outside the microchannel and tripolar recording of signals from within the microchannel. By using 5-lines for 49 active microchannels the device overcomes limitations with connecting many electrodes in a 3-dimensional miniaturised nerve interface

Enhancing selectivity of minimally invasive peripheral nerve interfaces using combined stimulation and high frequency block: from design to application

The discovery of the excitable property of nerves was a fundamental step forward in our knowledge of the nervous system and our ability to interact with it. As the injection of charge into tissue can drive its artificial activation, devices have been conceived that can serve healthcare by substituting the input or output of the peripheral nervous system when damage or disease has rendered it inaccessible or its action pathological. Applications are far-ranging and transformational as can be attested by the success of neuroprosthetics such as the cochlear implant. However, the body’s immune response to invasive implants have prevented the use of more selective interfaces, leading to therapy side-effects and off-target activation. The inherent tradeoff between the selectivity and invasiveness of neural interfaces, and the consequences thereof, is still a defining problem for the field. More recently, continued research into how nervous tissue responds to stimulation has led to the discovery of High Frequency Alternating Current (HFAC) block as a stimulation method with inhibitory effects for nerve conduction. While leveraging the structure of the peripheral nervous system, this neuromodulation technique could be a key component in efforts to improve the selectivity-invasiveness tradeoff and provide more effective neuroprosthetic therapy while retaining the safety and reliability of minimally invasive neural interfaces. This thesis describes work investigating the use of HFAC block to improve the selectivity of peripheral nerve interfaces, towards applications such as bladder control or vagus nerve stimulation where selective peripheral nerve interfaces cannot be used, and yet there is an unmet need for more selectivity from stimulation-based therapy. An overview of the underlying neuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Original contributions are the design of a custom multi-channel stimulator able to combine conventional and high frequency stimulation, establishing a suitable experimental platform for ex-vivo electrophysiology of the rat sciatic nerve model for HFAC block, and exploratory experiments to determine the feasibility of using HFAC block in combination with conventional stimulation to enhance the selectivity of minimally-invasive peripheral nerve interfaces.Open Acces

Wired, wireless and wearable bioinstrumentation for high-precision recording of bioelectrical signals in bidirectional neural interfaces

It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Furthermore, electrical stimulation of specific target brain regions has been shown to alleviate symptoms of neurological disorders, such as Parkinson’s disease, essential tremor, dystonia, epilepsy etc. In recent years, the traditional practice of continuously stimulating the brain using static stimulation parameters has shifted to the use of disease biomarkers to determine the intensity and timing of stimulation. The main motivation behind closed-loop stimulation is minimization of treatment side effects by providing only the necessary stimulation required within a certain period of time, as determined from a guiding biomarker. Hence, it is clear that high-quality recording of local field potentials (LFPs) or electrocorticographic (ECoG) signals during deep brain stimulation (DBS) is necessary to investigate the instantaneous brain response to stimulation, minimize time delays for closed-loop neurostimulation and maximise the available neural data. To our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording ECoG signals, which are of particular importance in closed-loop DBS and epilepsy DBS. In addition, existing recording systems lack the ability to provide artefact-free high-frequency (> 100 Hz) LFP recordings during DBS in real time primarily because of the contamination of the neural signals of interest by the stimulation artefacts. To address the problem of limited mobility often encountered by patients in the clinic and to provide a wide variety of high-precision sensor data to a closed-loop neurostimulation platform, a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless multi-instrument (55 × 80 mm2) was designed and developed. The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile tool to be utilized in a wide range of applications and environments. Moreover, in order to offer the capability of sensing and stimulating via the same electrode, novel real-time artefact suppression methods that could be used in bidirectional (recording and stimulation) system architectures are proposed and validated. More specifically, a novel, low-noise and versatile analog front-end (AFE), which uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency, is presented. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, the performance of the realised AFE is assessed by conducting both in vitro and in vivo experiments using unipolar and bipolar DBS (monophasic pulses, amplitude ranging from 3 to 6 V peak-to-peak, frequency 140 Hz and pulse width 100 µs). Under both in vitro and in vivo experimental conditions, the proposed AFE provided real-time, low-noise and artefact-free LFP recordings (in the frequency range 0.5 – 250 Hz) during stimulation. Finally, a family of tunable hardware filter designs and a novel method for real-time artefact suppression that enables wide-bandwidth biosignal recordings during stimulation are also presented. This work paves the way for the development of miniaturized research tools for closed-loop neuromodulation that use a wide variety of bioelectrical signals as control signals.Open Acces

Design, Fabrication, and Validation of a Highly Miniaturized Wirelessly Powered Neural Implant

We have recently witnessed an explosion in the number of neurons that can be recorded and/or stimulated simultaneously during neurophysiological experiments. Experiments have progressed from recording or stimulation with a single electrode to Micro-Electrode Array (MEA) such as the Utah Array. These MEAs can be instrumented with current drivers, neural amplifiers, digitizers and wireless communication links. The broad interest in these MEAs suggests that there is a need for large scale neural recording and stimulation. The ultimate goal is to coordinate the recordings and stimulation of potentially thousands of neurons from many brain areas. Unfortunately, current state-of-the-art MEAs are limited by their scalability and long-term stability because of their physical size and rigid configuration. Furthermore, some applications prioritize a distributed neural interface over one that offers high resolution. Examples of biomedical applications that necessitate an interface with neurons from many sites in the brain include: i) understanding and treating neurological disorders that affect distributed locations throughout the CNS; ii) revolutionizing our understanding of the brain by studying the correlations between neural networks from different regions of the brain and the mechanisms of cognitive functions; and iii) covering larger area in the sensorimotor cortex of amputees to more accurately control robotic prosthetic limbs or better evoke a sense of touch. One solution to make large scale, fully specifiable, electrical stimulation and recording possible, is to disconnect the electrodes from the base, so that they can be arbitrarily placed, using a syringe, freely in the nervous system. To overcome the challenges of system miniaturization, we propose the “microbead”, an ultra-small neural stimulating implant, that is currently implemented in a 130nm CMOS technology with the following characteristics: 200 μm × 200 μm × 80 μm size; optimized wireless powering, all micro-electronics on single chip; and integrated electrodes and coil. The stimulating microbead is validated in a sciatic nerve by generating leg movements. A recording microbead is also investigated with following characteristics: wireless powering using steerable phased coil array, miniaturized front-end, and backscattering telemetry. These microbeads could eventually replace the rigid arrays that are currently the state-of-the-art in electrophysiology set-ups