Andrew G. Richardson

Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging

Calcium imaging is a versatile experimental approach capable of resolving single neurons with single-cell spatial resolution in the brain. Electrophysiological recordings provide high temporal, but limited spatial resolution, because of the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technology based on graphene, which enables simultaneous optical imaging and electrophysiological recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artefacts in the electrical recordings. Graphene electrodes record high-frequency bursting activity and slow synaptic potentials that are hard to resolve by multicellular calcium imaging. This transparent electrode technology may pave the way for high spatio-temporal resolution electro-optic mapping of the dynamic neuronal activity.

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include post-operative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, that record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.

Reducing surgical site infections following craniotomy: examination of the use of topical vancomycin

OBJECT Although the use of topical vancomycin has been shown to be safe and effective for reducing postoperative infection rates in patients after spine surgery, its use in cranial wounds has not been studied systematically. The authors hypothesized that topical vancomycin, applied in powder form directly to the subgaleal space during closure, would reduce cranial wound infection rates. METHODS A cohort of 150 consecutive patients who underwent craniotomy was studied retrospectively. Seventy-five patients received 1 g of vancomycin powder applied in the subgaleal space at the time of closure. This group was compared with 75 matched-control patients who were accrued over the same time interval and did not receive vancomycin. The primary outcome measure was the presence of surgical site infection within 3 months. Secondary outcome measures included tissue pH from a subgaleal drain and vancomycin levels from the subgaleal space and serum. RESULTS Vancomycin was associated with significantly fewer surgical site infections (1 of 75) than was standard antibiotic prophylaxis alone (5 of 75; p < 0.05). Cultures were positive for typical skin flora species. As expected, local measured vancomycin concentrations peaked immediately after surgery (mean ± SD 499 ± 37 μg/ml) and gradually decreased over 12 hours. Vancomycin in the circulating serum remained undetectable. Subgaleal topical vancomycin was associated with a lower incidence of surgical site infections after craniotomy. The authors attribute this reduction in the infection rate to local vancomycin concentrations well above the minimum inhibitory concentration for antimicrobial efficacy. CONCLUSIONS Topical vancomycin is safe and effective for reducing surgical site infections after craniotomy. These data support the need for a prospective randomized examination of topical vancomycin in the setting of cranial surgery.

Flexible Neural Electrode Array Based-on Porous Graphene for Cortical Microstimulation and Sensing

Neural sensing and stimulation have been the backbone of neuroscience research, brain-machine interfaces and clinical neuromodulation therapies for decades. To-date, most of the neural stimulation systems have relied on sharp metal microelectrodes with poor electrochemical properties that induce extensive damage to the tissue and significantly degrade the long-term stability of implantable systems. Here, we demonstrate a flexible cortical microelectrode array based on porous graphene, which is capable of efficient electrophysiological sensing and stimulation from the brain surface, without penetrating into the tissue. Porous graphene electrodes show superior impedance and charge injection characteristics making them ideal for high efficiency cortical sensing and stimulation. They exhibit no physical delamination or degradation even after 1 million biphasic stimulation cycles, confirming high endurance. In in vivo experiments with rodents, same array is used to sense brain activity patterns with high spatio-temporal resolution and to control leg muscles with high-precision electrical stimulation from the cortical surface. Flexible porous graphene array offers a minimally invasive but high efficiency neuromodulation scheme with potential applications in cortical mapping, brain-computer interfaces, treatment of neurological disorders, where high resolution and simultaneous recording and stimulation of neural activity are crucial.

A Fully Integrated Wireless Compressed Sensing Neural Signal Acquisition System for Chronic Recording and Brain Machine Interface

Reliable, multi-channel neural recording is critical to the neuroscience research and clinical treatment. However, most hardware development of fully integrated, multi-channel wireless neural recorders to-date, is still in the proof-of-concept stage. To be ready for practical use, the trade-offs between performance, power consumption, device size, robustness, and compatibility need to be carefully taken into account. This paper presents an optimized wireless compressed sensing neural signal recording system. The system takes advantages of both custom integrated circuits and universal compatible wireless solutions. The proposed system includes an implantable wireless system-on-chip (SoC) and an external wireless relay. The SoC integrates 16-channel low-noise neural amplifiers, programmable filters and gain stages, a SAR ADC, a real-time compressed sensing module, and a near field wireless power and data transmission link. The external relay integrates a 32 bit low-power microcontroller with Bluetooth 4.0 wireless module, a programming interface, and an inductive charging unit. The SoC achieves high signal recording quality with minimized power consumption, while reducing the risk of infection from through-skin connectors. The external relay maximizes the compatibility and programmability. The proposed compressed sensing module is highly configurable, featuring a SNDR of 9.78 dB with a compression ratio of 8×. The SoC has been fabricated in a 180 nm standard CMOS technology, occupying 2.1 mm × 0.6 mm silicon area. A pre-implantable system has been assembled to demonstrate the proposed paradigm. The developed system has been successfully used for long-term wireless neural recording in freely behaving rhesus monkey.

The PennBMBI: Design of a General Purpose Wireless Brain-Machine-Brain Interface System

In this paper, a general purpose wireless Brain- Machine -Brain Interface (BMBI) system is presented. The system integrates four battery-powered wireless devices for the implementation of a closed-loop sensorimotor neural interface, including a neural signal analyzer, a neural stimulator, a body-area sensor node and a graphic user interface implemented on the PC end. The neural signal analyzer features a four channel analog front-end with configurable bandpass filter, gain stage, digitization resolution, and sampling rate. The target frequency band is configurable from EEG to single unit activity. A noise floor of 4.69 μVrms is achieved over a bandwidth from 0.05 Hz to 6 kHz . Digital filtering, neural feature extraction, spike detection, sensing-stimulating modulation, and compressed sensing measurement are realized in a central processing unit integrated in the analyzer. A flash memory card is also integrated in the analyzer. A 2-channel neural stimulator with a compliance voltage up to ±12 V is included. The stimulator is capable of delivering unipolar or bipolar, charge-balanced current pulses with programmable pulse shape, amplitude, width, pulse train frequency and latency. A multi-functional sensor node, including an accelerometer, a temperature sensor, a flexiforce sensor and a general sensor extension port has been designed. A computer interface is designed to monitor, control and configure all aforementioned devices via a wireless link, according to a custom designed communication protocol. Wireless closed-loop operation between the sensory devices, neural stimulator, and neural signal analyzer can be configured. The proposed system was designed to link two sites in the brain, bridging the brain and external hardware, as well as creating new sensory and motor pathways for clinical practice. Bench test and in vivo experiments are performed to verify the functions and performances of the system.

A chronic neural interface to the macaque dorsal column nuclei

The dorsal column nuclei (DCN) of the brain stem contain secondary afferent neurons, which process ascending somatosensory information. Most of the known physiology of the DCN in primates has been acquired in acute experiments with anesthetized animals. Here, we developed a technique to implant a multielectrode array (MEA) chronically in the DCN of macaque monkeys to enable experiments with the animals awake. Two monkeys were implanted with brain-stem MEAs for 2-5 mo with no major adverse effects. Responses of the cuneate and gracile nuclei were quantified at the level of both field potentials and single units. Tactile receptive fields (RFs) were identified for 315 single units. A subset of these units had very regular spiking patterns with spike frequencies predominantly in the alpha band (8-14 Hz). The stability of the neuronal recordings was assessed with a novel analysis that identified units by their mean spike waveform and by the spike-triggered average of activity on all other electrodes in the array. Fifty-six identified neurons were observed over two or more sessions and in a few cases for as long as 1 mo. RFs of stable neurons were largely consistent across days. The results demonstrate that a chronic DCN implant in a macaque can be safe and effective, yielding high-quality unit recording for several months. The unprecedented access to these nuclei in awake primates should lead to a better understanding of their role in sensorimotor behavior.

Design of a low-noise, high power efficiency neural recording front-end with an integrated real-time compressed sensing unit

This paper presents a 12-channel, low-power, high efficiency neural signal acquisition front-end for local field potential and action potential signals recording. The proposed neural front-end integrates low noise instrumentation amplifiers, low-power filter stages with configurable gain and cut-off frequencies, a successive approximation register (SAR) ADC, and a realtime compressed sensing processing unit. A capacitor coupled instrumentation amplifier integrated input impedance boosting has been designed, dissipating 1μA quiescent current. An input referred noise of 1.63μV was measured in the frequency band of 1Hz to 7kHz. The noise efficiency factor (NEF) of the amplifier is 0.76. The SAR ADC achieves an ENOB of 10.6-bit at a sampling rate of 1MS/s. A compressed sensing processing unit with configurable compression ratio, up to 8x, was integrated in the design. The design has been fabricated in 180nm CMOS, occupying 4.5mm×1.5mm silicon area. A portable neural recorder has been built with the custom IC and a commercial low-power wireless module. A 4.6g lithium battery supports the device for a continuous compressed sensing recording up to 70 hours.

The PennBMBI: A general purpose wireless Brain-Machine-Brain Interface system for unrestrained animals

In this paper, a general purpose wireless Brain-Machine-Brain Interface (BMBI) system is proposed. The system provides all the necessary hardware for a closed-loop sensorimotor neural interface. The system integrates a neural signal analyzer, two neural stimulators with different specifications, multiple body area sensory devices and a user-friendly computer interface. The neural signal analyzer features four channel analog frontend with configurable bandpass filter, gain stage, digitization resolution, and sampling rate. Digital filtering, neural feature extraction, spike detection, sensing-stimulating modulation, and compressed sensing measurement are realized in a central processing unit integrated in the analyzer. Flash memory card is activated for low power operation, compressed sensing recovery verification and/or data backup. An 8-channel stimulator with high driving capability (±10 mA with compliance voltage ±22V), and a 2-channel stimulator for deep brain stimulation are included in the proposed system. Both stimulators are capable of delivering bipolar, biphasic capacitive coupled current pulses in programmable pulse shape, amplitude, width, pulse train frequency and latency. Multi-functional wireless sensor node, including an accelerometer, a temperature sensor, and a general sensor extension port has been designed. Surveillance camera is implemented for the monitoring of the animals behavior. A userfriendly computer interface is designed to monitor, control and configure all aforementioned devices via wireless link. Wireless closed-loop operation between the sensory devices, neural stimulators, and neural signal analyzer can be configured. Bench test and in vivo experiments are performed to verify the functions and performance of the system.

Dissolution of Monocrystalline Silicon Nanomembranes and Their Use as Encapsulation Layers and Electrical Interfaces in Water-Soluble Electronics

The chemistry that governs the dissolution of device-grade, monocrystalline silicon nanomembranes into benign end products by hydrolysis serves as the foundation for fully eco/biodegradable classes of high-performance electronics. This paper examines these processes in aqueous solutions with chemical compositions relevant to groundwater and biofluids. The results show that the presence of Si(OH)4 and proteins in these solutions can slow the rates of dissolution and that ion-specific effects associated with Ca2+ can significantly increase these rates. This information allows for effective use of silicon nanomembranes not only as active layers in eco/biodegradable electronics but also as water barriers capable of providing perfect encapsulation until their disappearance by dissolution. The time scales for this encapsulation can be controlled by introduction of dopants into the Si and by addition of oxide layers on the exposed surfaces.The former possibility also allows the doped silicon to serve as an electrical interface for measuring biopotentials, as demonstrated in fully bioresorbable platforms for in vivo neural recordings. This collection of findings is important for further engineering development of water-soluble classes of silicon electronics.