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  • Journal article
    Ritzau-Reid K, Spicer C, Gelmi A, Grigsby CL, Ponder Jr J, Bemmer V, Creamer A, Vilar R, Serio A, Stevens Met al., 2020,

    An electroactive oligo-EDOT platform for neural tissue engineering

    , Advanced Functional Materials, Vol: 30, Pages: 1-11, ISSN: 1616-301X

    The unique electrochemical properties of the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) make it an attractive material for use in neural tissue engineering applications. However, inadequate mechanical properties, and difficulties in processing and lack of biodegradability have hindered progress in this field. Here, we have improved the functionality of PEDOT:PSS for neural tissue engineering by incorporating 3,4-ethylenedioxythiophene (EDOT) oligomers, synthesised using a novel end-capping strategy, into block co-polymers. By exploiting end-functionalised oligoEDOT constructs as macroinitiators for the polymerization of poly(caprolactone) (PCL), we produce a block co-polymer that is electroactive, processable, and bio-compatible. By combining these properties, we were able to produce electroactive fibrous mats for neuronal culture via solution electrospinning and melt electrospinning writing (MEW). Importantly, we also show that neurite length and branching of neural stem cells can be enhanced on our materials under electrical stimulation, demonstrating the promise of these scaffolds for neural tissue engineering.

  • Journal article
    Bashford J, Masood U, Wickham A, Iniesta R, Drakakis E, Boutelle M, Mills K, Shaw Cet al., 2020,

    Fasciculations demonstrate daytime consistency in amyotrophic lateral sclerosis

    , Muscle and Nerve, Vol: 61, Pages: 745-750, ISSN: 0148-639X

    IntroductionFasciculations represent early neuronal hyperexcitability in amyotrophic lateral sclerosis (ALS). To aid calibration as a disease biomarker, we set out to characterize the daytime variability of fasciculation firing.MethodsFasciculation awareness scores were compiled from 19 ALS patients. In addition, 10 ALS patients prospectively underwent high‐density surface electromyographic (HDSEMG) recordings from biceps and gastrocnemius at three time‐points during a single day.ResultsDaytime fasciculation awareness scores were low (mean: 0.28 muscle groups), demonstrating significant variability (coefficient of variation: 303%). Biceps HDSEMG recordings were highly consistent for fasciculation potential frequency (intraclass correlation coefficient [ICC] = 95%, n = 19) and the interquartile range of fasciculation potential amplitude (ICC = 95%, n = 19). These parameters exhibited robustness to observed fluctuations in data quality parameters. Gastrocnemius demonstrated more modest levels of consistency overall (44% to 62%, n = 20).DiscussionThere was remarkable daytime consistency of fasciculation firing in the biceps of ALS patients, despite sparse and intermittent awareness among patients’ accounts.

  • Conference paper
    Ahmadi N, Cavuto ML, Feng P, Leene LB, Maslik M, Mazza F, Savolainen O, Szostak KM, Bouganis C-S, Ekanayake J, Jackson A, Constandinou TG, Ahmadi N, Cavuto M, Feng P, Leene L, Maslik M, Mazza F, Savolainen O, Szostak K, Bouganis C, Ekanayake J, Jackson A, Constandinou Tet al., 2019,

    Towards a distributed, chronically-implantable neural interface

    , 9th IEEE/EMBS International Conference on Neural Engineering (NER), Publisher: IEEE, Pages: 719-724, ISSN: 1948-3546

    We present a platform technology encompassing a family of innovations that together aim to tackle key challenges with existing implantable brain machine interfaces. The ENGINI (Empowering Next Generation Implantable Neural Interfaces) platform utilizes a 3-tier network (external processor, cranial transponder, intracortical probes) to inductively couple power to, and communicate data from, a distributed array of freely-floating mm-scale probes. Novel features integrated into each probe include: (1) an array of niobium microwires for observing local field potentials (LFPs) along the cortical column; (2) ultra-low power instrumentation for signal acquisition and data reduction; (3) an autonomous, self-calibrating wireless transceiver for receiving power and transmitting data; and (4) a hermetically-sealed micropackage suitable for chronic use. We are additionally engineering a surgical tool, to facilitate manual and robot-assisted insertion, within a streamlined neurosurgical workflow. Ongoing work is focused on system integration and preclinical testing.

  • Journal article
    Morse SV, Pouliopoulos AN, Chan TG, Copping MJ, Lin J, Long NJ, Choi JJet al., 2019,

    Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption

    , Radiology, Vol: 291, Pages: 459-466, ISSN: 0033-8419

    Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally

  • Journal article
    Quicke P, Song C, McKimm EJ, Milosevic MM, Howe CL, Neil M, Schultz SR, Antic SD, Foust AJ, Knopfel Tet al., 2019,

    Single-neuron level one-photon voltage imaging with sparsely targeted genetically encoded voltage indicators

    , Frontiers in Cellular Neuroscience, Vol: 13, ISSN: 1662-5102

    Voltage imaging of many neurons simultaneously at single-cell resolution is hampered by the difficulty of detecting small voltage signals from overlapping neuronal processes in neural tissue. Recent advances in genetically encoded voltage indicator (GEVI) imaging have shown single-cell resolution optical voltage recordings in intact tissue through imaging naturally sparse cell classes, sparse viral expression, soma restricted expression, advanced optical systems, or a combination of these. Widespread sparse and strong transgenic GEVI expression would enable straightforward optical access to a densely occurring cell type, such as cortical pyramidal cells. Here we demonstrate that a recently described sparse transgenic expression strategy can enable single-cell resolution voltage imaging of cortical pyramidal cells in intact brain tissue without restricting expression to the soma. We also quantify the functional crosstalk in brain tissue and discuss optimal imaging rates to inform future GEVI experimental design.

  • Journal article
    Soor N, Quicke P, Howe C, Pang KT, Neil M, Schultz S, Foust Aet al., 2019,

    All-optical crosstalk-free manipulation and readout of Chronos-expressing Neurons

    , Journal of Physics D: Applied Physics, Vol: 52, ISSN: 0022-3727

    All optical neurophysiology allows manipulation and readout of neural network activity with single-cell spatial resolution and millisecond temporal resolution. Neurons can be made to express proteins that actuate transmembrane currents upon light absorption, enabling optical control of membrane potential and action potential signalling. In addition, neurons can be genetically or synthetically labelled with fluorescent reporters of changes in intracellular calcium concentration or membrane potential. Thus, to optically manipulate and readout neural activity in parallel, two spectra are involved: the action spectrum of the actuator, and the absorption spectrum of the fluorescent reporter. Due to overlap in these spectra, previous all-optical neurophysiology paradigms have been hindered by spurious activation of neuronal activity caused by the readout light. Here, we pair the blue-green absorbing optogenetic actuator, Chronos, with a deep red-emitting fluorescent calcium reporter CaSiR-1. We show that cultured Chinese hamster ovary cells transfected with Chronos do not exhibit transmembrane currents when illuminated with wavelengths and intensities suitable for exciting one-photon CaSiR-1 fluorescence. We then demonstrate crosstalk-free, high signal-to-noise ratio CaSiR-1 red fluorescence imaging at 100 frames s−1 of Chronos-mediated calcium transients evoked in neurons with blue light pulses at rates up to 20 Hz. These results indicate that the spectral separation between red light excited fluorophores, excited efficiently at or above 640 nm, with blue-green absorbing opsins such as Chronos, is sufficient to avoid spurious opsin actuation by the imaging wavelengths and therefore enable crosstalk-free all-optical neuronal manipulation and readout.

  • Conference paper
    Moly A, Luan S, Zoltan M, Salimpour Y, Anderson W, Constandinou TG, Grand Let al., 2018,

    Embedded phase-amplitude coupling based closed-loop platform for Parkinson's Disease

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 527-530, ISSN: 2163-4025

    Deep Brain Stimulation (DBS) is a widely used clin-ical therapeutic modality to treat Parkinsons disease refractorysymptoms and complications of levodopa therapy. Currentlyavailable DBS systems use continuous, open-loop stimulationstrategies. It might be redundant and we could extend the batterylife otherwise. Recently, robust electrophysiological signaturesof Parkinsons disease have been characterized in motor cortexof patients undergoing DBS surgery. Reductions in the beta-gamma Phase-Amplitude coupling (PAC) correlated with symp-tom improvement, and the therapeutic effects of DBS itself. Weaim to develop a miniature, implantable and adaptive system,which only stimulates the neural target, when triggered by theoutput of the appropriate PAC algorithm. As a first step, in thispaper we compare published PAC algorithms by using humandata intra-operatively recorded from Parkinsonian patients. Wethen introduce IIR masking for later achieving fast and low-power FPGA implementation of PAC mapping for intra-operativestudies. Our closed-loop application is expected to consumesignificantly less power than current DBS systems, thereforewe can increase the battery life, without compromising clinicalbenefits.

  • Conference paper
    Moly A, Luan S, Mari Z, Anderson WS, Salimpour Y, Constandinou TG, Grand Let al., 2018,

    Embedded phase-amplitude coupling based closed-loop platform forParkinson’s Disease

    , 40th International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Publisher: IEEE, ISSN: 2163-4025

    Deep Brain Stimulation (DBS) is a widely used clinical therapeutic modality to treat Parkinsons disease refractory symptoms and complications of levodopa therapy. Currently available DBS systems use continuous, open-loop stimulation strategies. It might be redundant and we could extend the battery life otherwise. Recently, robust electrophysiological signatures of Parkinsons disease have been characterized in motor cortex of patients undergoing DBS surgery. Reductions in the beta-gamma Phase-Amplitude coupling (PAC) correlated with symptom improvement, and the therapeutic effects of DBS itself. We aim to develop a miniature, implantable andadaptive system, which only stimulates the neural target, when triggered by the output of the appropriate PAC algorithm. As a first step, in this paper we compare published PAC algorithms by using human data intra-operatively recorded from Parkinsonian patients. We then introduce IIR maskingfor later achieving fast and low-power FPGA implementation of PAC mapping for intra-operative studies. Our closed-loop application is expected to consume significantly less power than current DBS systems, therefore we can increase the battery life, without compromising clinical benefits.

  • Conference paper
    De Marcellis A, Di Patrizio Stanchieri G, Palange E, Faccio M, Constandinou TGet al., 2018,

    An ultra-wideband-inspired system-on-chip for an optical bidirectional transcutaneous biotelemetry

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 351-354

    This paper describes an integrated communicationsystem, implementing a UWB-inspired pulsed coding technique,for an optical transcutaneous biotelemetry. The system consistsof both a transmitter and a receiver facilitating a bidirectionallink. The transmitter includes a digital data coding circuit and iscapable of generating sub-nanosecond current pulses and directlydriving an off-chip semiconductor laser diode including all biasand drive circuits. The receiver includes an integrated compactPN-junction photodiode together with signal conditioning, de-tection and digital data decoding circuits to enable a high bitrate, energy efficient communication. The proposed solution hasbeen implemented in a commercially available 0.35μm CMOStechnology provided by AMS. The circuit core occupies a compactsilicon footprint of less than 0.13 mm2(only 113 transistors and1 resistor). Post-layout simulations have validated the overallsystem operation demonstrating the ability to operate at bit ratesup to 500 Mbps with pulse widths of 300 ps with a total powerefficiency (transmitter + receiver) lower than 74 pJ/bit. Thismakes the system ideally suited for demanding applications thatrequire high bit rates at extremely low energy levels. One suchapplication is implantable brain machine interfaces requiringhigh uplink bitrates to transmit recorded data externally througha transcutaneous communication channel.

  • Conference paper
    Lauteslager T, Tommer M, Lande TS, Constandinou TGet al., 2018,

    Cross-body UWB radar sensing of arterial pulse propagation and ventricular Dynamics

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 165-168

    Single-chip UWB radar systems have enormous potential for the development of portable, low-cost and easy-to-use devices for monitoring the cardiovascular system. Using body coupled antennas, electromagnetic energy can be directed into the body to measure arterial pulsation and cardiac motion, and estimate arterial stiffness as well as blood pressure. In the current study we validate that heart rate signals, obtained using multiple UWB radar-on-chip modules and body coupled antennas, do indeed originate from arterial pulsation. Through ECG-aligned averaging, pulse arrival time at a number of locations in the body could be measured with high precision, and arterial pulse propagation through the femoral and carotid artery was demonstrated. In addition, cardiac dynamics were measured from the chest. Onset and offset of ventricular systole were clearly distinguishable, as well as onset of atrial systole. Although further validation is required, these results show that UWB radar-on-chip is highly suitable for monitoring of vascular health as well as the heart's mechanical functioning.

  • Conference paper
    Maslik M, Lande TS, Constandinou TG, 2018,

    A clockless method of flicker noise suppression in continuous-time acquisition of biosignals

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 491-494

    This paper presents a novel chopping method allow-ing suppression of 1/f flicker noise in continuous-time acquisitionsystems without the need for a fixed-frequency clock, stochasti-cally deriving the chopping signal from the input and henceachieving completely signal-dependent power consumption. Themethod is analysed, its basis of operation explained and a proof-of-concept implementation presented alongside simulated resultsdemonstrating an increase in achieved SNR of more than 8 dBduring acquisition of ECG, EAP and EEG signals.

  • Conference paper
    Leene L, Constandinou TG, 2018,

    Direct digital wavelet synthesis for embedded biomedical microsystems

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 77-80

    This paper presents a compact direct digital waveletsynthesizer for extracting phase and amplitude data from corticalrecordings using a feed-forward recurrent digital oscillator.These measurements are essential for accurately decoding local-field-potentials in selected frequency bands. Current systemsextensively to rely large digital cores to efficiently performFourier or wavelet transforms which is not viable for manyimplants. The proposed system dynamically controls oscillation togenerate frequency selective quadrature wavelets instead of usingmemory intensive sinusoid/cordic look-up-tables while retainingrobust digital operation. A MachXO3LF Lattice FPGA is used topresent the results for a 16 bit implementation. This configurationrequires 401 registers combined with 283 logic elements andalso accommodates real-time reconfigurability to allow ultra-low-power sensors to perform spectroscopy with high-fidelity.

  • Conference paper
    Feng P, Constandinou TG, 2018,

    Robust wireless power transfer to multiple mm-scale freely-positioned Neural implants

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 363-366

    This paper presents a novel wireless power transfer(WPT) scheme that consists of a two-tier hierarchy of near-field inductively coupled links to provide efficient power transferefficiency (PTE) and uniform energy distribution for mm-scalefree-positioned neural implants. The top tier facilitates a tran-scutaneous link from a scalp-worn (cm-scale) primary coil toa subcutaneous array of smaller, parallel-connected secondarycoils. These are then wired through the skull to a correspondingset of parallel connected primary coils in the lower tier, placedepidurally. These then inductively couple to freely positioned(mm-scale) secondary coils within each subdural implant. Thisarchitecture has three key advantages: (1) the opportunity toachieve efficient energy transfer by utilising two short-distanceinductive links; (2) good uniformity of the transdural powerdistribution through the multiple (redundant) coils; and (3) areduced risk of infection by maintaining the dura protecting theblood-brain barrier. The functionality of this approach has beenverified and optimized through HFSS simulations, to demonstratethe robustness against positional and angular misalignment. Theaverage 11.9% PTE and 26.6% power distribution deviation(PDD) for horizontally positioned Rx coil and average 2.6% PTEand 62.8% power distribution deviation for the vertical Rx coilhave been achieved.

  • Conference paper
    Haci D, Liu Y, Ghoreishizadeh S, Constandinou TGet al., 2018,

    Design considerations for ground referencing in multi-module neural implants

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 563-566

    Implantable neural interfaces have evolved in thepast decades from stimulation-only devices to closed-loop record-ing and stimulation systems, allowing both for more targetedtherapeutic techniques and more advanced prosthetic implants.Emerging applications require multi-module active implantabledevices with intrabody power and data transmission. Thisdistributed approach poses a new set of challenges relatedto inter-module connectivity, functional reliability and patientsafety. This paper addresses the ground referencing challenge inactive multi-implant systems, with a particular focus on neuralrecording devices. Three different grounding schemes (passive,drive, and sense) are presented and evaluated in terms of bothrecording reliability and patient safety. Considerations on thepractical implementation of body potential referencing circuitryare finally discussed, with a detailed analysis of their impact onthe recording performance.

  • Conference paper
    Mazza F, Liu Y, Donaldson N, Constandinou TGet al., 2018,

    Integrated devices for micro-package integrity monitoring in mm-scale neural implants

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference 2018, Publisher: IEEE, Pages: 295-298

    Recent developments in the design of active im-plantable devices have achieved significant advances, for example,an increased number of recording channels, but too oftenpractical clinical applications are restricted by device longevity.It is important however to complement efforts for increased func-tionality with translational work to develop implant technologiesthat are safe and reliable to be hosted inside the human bodyover long periods of time. This paper first examines techniquescurrently used to evaluate micro-package hermeticity and keychallenges, highlighting the need for new,in situinstrumentationthat can monitor the encapsulation status over time. Two novelcircuits are then proposed to tackle the specific issue of moisturepenetration inside a sub-mm, silicon-based package. They bothshare the use of metal tracks on the different layers of the CMOSstack to measure changes in impedance caused by moisturepresent in leak cracks or diffused into the oxide layers.

  • Conference paper
    Haci D, Liu Y, Nikolic K, Demarchi D, Constandinou TG, Georgiou Pet al., 2018,

    Thermally controlled lab-on-PCB for biomedical applications

    , IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 655-658

    This paper reports on the implementation andcharacterisation of a thermally controlled device forin vitrobiomedical applications, based on standard Printed Circuit Board(PCB) technology. This is proposed as a low cost alternativeto state-of-the-art microfluidic devices and Lab-on-Chip (LoC)platforms, which we refer to as the thermal Lab-on-PCB concept.In total, six different prototype boards have been manufacturedto implement as many mini-hotplate arrays. 3D multiphysicssoftware simulations show the thermal response of the modelledmini-hotplate boards to electrical current stimulation, highlight-ing their versatile heating capability. A comparison with theresults obtained by the characterisation of the fabricated PCBsdemonstrates the dual temperature sensing/heating property ofthe mini-hotplate, exploitable in a larger range of temperaturewith respect to the typical operating range of LoC devices. Thethermal system is controllable by means of external off-the-shelfcircuitry designed and implemented on a single-channel controlboard prototype.

  • Journal article
    Braiman C, Fridman A, Conte MM, Vosse HU, Reichenbach CS, Reichenbach J, Schiff NDet al., 2018,

    Cortical response to the natural speech envelope correlates with neuroimaging evidence of cognition in severe brain injury

    , Current Biology, Vol: 28, Pages: 3833-3839, ISSN: 1879-0445

    Recent studies identify severely brain-injured patients with limited or no behavioral responses who successfully perform functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG) mental imagery tasks [1, 2, 3, 4, 5]. Such tasks are cognitively demanding [1]; accordingly, recent studies support that fMRI command following in brain-injured patients associates with preserved cerebral metabolism and preserved sleep-wake EEG [5, 6]. We investigated the use of an EEG response that tracks the natural speech envelope (NSE) of spoken language [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22] in healthy controls and brain-injured patients (vegetative state to emergence from minimally conscious state). As audition is typically preserved after brain injury, auditory paradigms may be preferred in searching for covert cognitive function [23, 24, 25]. NSE measures are obtained by cross-correlating EEG with the NSE. We compared NSE latencies and amplitudes with and without consideration of fMRI assessments. NSE latencies showed significant and progressive delay across diagnostic categories. Patients who could carry out fMRI-based mental imagery tasks showed no statistically significant difference in NSE latencies relative to healthy controls; this subgroup included patients without behavioral command following. The NSE may stratify patients with severe brain injuries and identify those patients demonstrating “cognitive motor dissociation” (CMD) [26] who show only covert evidence of command following utilizing neuroimaging or electrophysiological methods that demand high levels of cognitive function. Thus, the NSE is a passive measure that may provide a useful screening tool to improve detection of covert cognition with fMRI or other methods and improve stratification of patients with disorders of consciousness in research studies.

  • Journal article
    Ahmadi N, Constandinou T, Bouganis C, 2018,

    Estimation of neuronal firing rate using Bayesian Adaptive Kernel Smoother (BAKS)

    , PLoS ONE, Vol: 13, ISSN: 1932-6203

    Neurons use sequences of action potentials (spikes) to convey information across neuronal networks. In neurophysiology experiments, information about external stimuli or behavioral tasks has been frequently characterized in term of neuronal firing rate. The firing rate is conventionally estimated by averaging spiking responses across multiple similar experiments (or trials). However, there exist a number of applications in neuroscience research that require firing rate to be estimated on a single trial basis. Estimating firing rate from a single trial is a challenging problem and current state-of-the-art methods do not perform well. To address this issue, we develop a new method for estimating firing rate based on a kernel smoothing technique that considers the bandwidth as a random variable with prior distribution that is adaptively updated under an empirical Bayesian framework. By carefully selecting the prior distribution together with Gaussian kernel function, an analytical expression can be achieved for the kernel bandwidth. We refer to the proposed method as Bayesian Adaptive Kernel Smoother (BAKS). We evaluate the performance of BAKS using synthetic spike train data generated by biologically plausible models: inhomogeneous Gamma (IG) and inhomogeneous inverse Gaussian (IIG). We also apply BAKS to real spike train data from non-human primate (NHP) motor and visual cortex. We benchmark the proposed method against established and previously reported methods. These include: optimized kernel smoother (OKS), variable kernel smoother (VKS), local polynomial fit (Locfit), and Bayesian adaptive regression splines (BARS). Results using both synthetic and real data demonstrate that the proposed method achieves better performance compared to competing methods. This suggests that the proposed method could be useful for understanding the encoding mechanism of neurons in cognitive-related tasks. The proposed method could also potentially improve the performance of brain-mac

  • Conference paper
    Szostak KM, Constandinou TG, 2018,

    Hermetic packaging for implantable microsystems: effectiveness of sequentially electroplated AuSn alloy

    , 40th International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Publisher: IEEE

    With modern microtechnology, there is an aggressive miniaturization of smart devices, despite an increasing level of integration and overall complexity. It is therefore becoming increasingly important to be achieve reliable, compact packaging. For implantable medical devices (IMDs), the package must additionally provide a high quality hermetic environmentto protect the device from the human body. For chip-scale devices, AuSn eutectic bonding offers the possibility of forming compact seals that achieve ultra-low permeability. A key feature is this can be achieved at process temperatures of below 350 C, therefore allowing for the integration of sensors and microsystems with CMOS electronics within a single package. Issueshowever such as solder wetting, void formation and controlling composition make formation of high-quality repeatable seals highly challenging. Towards this aim, this paper presents our experimental work characterizing the eutectic stack deposition. We detail our design methods and process flow, share our experiences in controlling electrochemical deposition of AuSnalloy and finally discuss usability of sequential electroplating process for the formation of hermetic eutectic bonds.

  • Conference paper
    Ahmadi N, Constandinou TG, Bouganis C, 2018,

    Spike rate estimation using Bayesian Adaptive Kernel Smoother (BAKS) and its application to brain machine interfaces

    , 40th International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Publisher: IEEE

    Brain Machine Interfaces (BMIs) mostly utilise spike rate as an input feature for decoding a desired motor output as it conveys a useful measure to the underlying neuronal activity. The spike rate is typically estimated by a using non-overlap binning method that yields a coarse estimate. There exist several methods that can produce a smooth estimate which could potentially improve the decoding performance. However, these methods are relatively computationally heavy for real-time BMIs. To address this issue, we propose a new method for estimating spike rate that is able to yield a smooth estimate and also amenable to real-time BMIs. The proposed method, referred to as Bayesian adaptive kernel smoother (BAKS), employs kernel smoothing technique that considers the bandwidth as a random variable with prior distribution which is adaptively updated through a Bayesian framework. With appropriate selection of prior distribution and kernel function, an analytical expression can be achieved for the kernel bandwidth. We apply BAKS and evaluate its impact on of fline BMI decoding performance using Kalman filter. The results show that overlap BAKS improved the decoding performance up to 3.33% and 12.93% compared to overlap and non-overlapbinning methods, respectively, depending on the window size. This suggests the feasibility and the potential use of BAKS method for real-time BMIs.

  • Conference paper
    Rapeaux A, Brunton E, Nazarpour K, Constandinou TGet al., 2018,

    Preliminary study of time to recovery of rat sciatic nerve from high frequency alternating current nerve block

    , 40th International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Publisher: IEEE

    High-Frequency alternating current nerve block has great potential for neuromodulation-based therapies. However, no precise measurements have been made of the time needed for nerves to recover from block once the signal has been turned off. This study aims to characterise time to recoveryof the rat sciatic nerve after 30 seconds of block at varying amplitudes and frequencies. Experiments were carried out in-vivo to quantify recovery times and recovery completeness within 0.7s from the end of block. The sciatic nerve was blocked with an alternating square wave signal of amplitudeand frequency ranging from 2 to 9mA and 10 to 50 kHz respectively. To determine the recovery dynamics the nerve was stimulated at 100 Hz after cessation of the blocking stimulus. Electromyogram signals were measured from the gastrocnemius medialis and tibialis anterior muscles during trials as indicators of nerve function. This allowed for nerve recovery to bemeasured with a resolution of 10 ms. This resolution is much greater than previous measurements of nerve recovery in the literature. Times for the nerve to recover to a steady state of activity ranged from 20 to 430 milliseconds and final relative recovery activity at 0.7 seconds spanned 0.2 to 1 approximately. Higher blocking signal amplitudes increased recovery time and decreased recovery completeness. These results suggestthat blocking signal properties affect nerve recovery dynamics, which could help improve neuromodulation therapies and allow more precise comparison of results across studies using different blocking signal parameters.

  • Journal article
    Feng P, Yeon P, Cheng Y, Ghovanloo M, Constandinou TGet al., 2018,

    Chip-scale coils for millimeter-sized bio-implants

    , IEEE Transactions on Biomedical Circuits and Systems, Vol: 12, Pages: 1088-1099, ISSN: 1932-4545

    Next generation implantable neural interfaces are targeting devices with mm-scale form factors that are freely floating and completely wireless. Scalability to more recording (or stimulation) channels will be achieved through distributing multiple devices, instead of the current approach that uses a single centralized implant wired to individual electrodes or arrays. In this way, challenges associated with tethers, micromotion and reliability of wiring is mitigated. This concept is now being applied to both central and peripheral nervous system interfaces. One key requirement, however, is to maximize SAR-constrained achievable wireless power transfer efficiency (PTE) of these inductive links with mm-sized receivers. Chip-scale coil structures for microsystem integration that can provide efficient near-field coupling are investigated. We develop near-optimal geometries for three specific coil structures: “in-CMOS”, “above-CMOS” (planar coil post-fabricated on a substrate) and “around-CMOS” (helical wirewound coil around substrate). We develop analytical and simulation models that have been validated in air and biological tissues by fabrications and experimentally measurements. Specifically, we prototype structures that are constrained to a 4mm x 4mm silicon substrate i.e. the planar in-/above-CMOS coils have outer diameter <4mm, whereas the around-CMOS coil has inner diameter of 4mm. The in-CMOS and above-CMOS coils have metal film thicknesses of 3μm aluminium and 25μm gold, respectively, whereas the around-CMOS coil is fabricated by winding a 25μm gold bonding-wire around the substrate. The measured quality factors (Q) of the mm-scale Rx coils are 10.5 @450.3MHz (in-CMOS), 24.61 @85MHz (above-CMOS), and 26.23 @283MHz (around-CMOS). Also, PTE of 2-coil links based on three types of chip-scale coils is measured in air and tissue environment to demonstrate tissue loss for bio-implants. The SAR-constrained maximum PTE are

  • Journal article
    Leene L, Constandinou TG, 2018,

    A 0.006mm² 1.2μW analogue-to-time converter for asynchronous bio-sensors

    , IEEE Journal of Solid-State Circuits, Vol: 53, Pages: 2604-2613, ISSN: 0018-9200

    This work presents a low-power analogue-to-time converter (ATC) for integrated bio-sensors. The proposed circuit facilitates the direct conversion of electrode biopotential recordings into time-encoded digital pulses with high efficiency without prior signal amplification. This approach reduces the circuit complexity for multi-channel instrumentation systems and allows asynchronous digital control to maximise the potential powersavings during sensor inactivity. A prototype fabricated using a 65nm CMOS technology is demonstrated with measured characteristics. Experimental results show an input-referred noise figure of 3.8μ Vrms for a 11kHz signal bandwidth while dissipating 1.2μ W from a 0.5V supply and occupying 60 ×80μ m² silicon area. This compact configuration is enabled by the proposed asynchronous readout that shapes the mismatch componentsarising from the multi-bit quantiser and the use of capacitive feedback.

  • Journal article
    Farina D, Yao, Sheng, Mrachacz-Kersting, Xiangyang, Ninget al., 2018,

    Decoding covert somatosensory attention by a BCI system calibrated with tactile sensation

    , IEEE Transactions on Biomedical Engineering, Vol: 65, Pages: 1689-1695, ISSN: 0018-9294

    Objective: We propose a novel calibration strategy to facilitate the decoding of covert somatosensory attention by exploring the oscillatory dynamics induced by tactile sensation. Methods: It was hypothesized that the similarity of the oscillatory pattern between stimulation sensation (SS, real sensation) and somatosensory attentional orientation (SAO) provides a way to decode covert somatic attention. Subjects were instructed to sense the tactile stimulation, which was applied to the left (SS-L) or the right (SS-R) wrist. The brain-computer interface (BCI) system was calibrated with the sensation data and then applied for online SAO decoding. Results: Both SS and SAO showed oscillatory activation concentrated on the contralateral somatosensory hemisphere. Offline analysis showed that the proposed calibration method led to a greater accuracy than the traditional calibration method based on SAO only. This is confirmed by online experiments, where the online accuracy on 15 subjects was 78.8 ± 13.1%, with 12 subjects >70% and 4 subject >90%. Conclusion: By integrating the stimulus-induced oscillatory dynamics from sensory cortex, covert somatosensory attention can be reliably decoded by a BCI system calibrated with tactile sensation. Significance: Indeed, real tactile sensation is more consistent during calibration than SAO. This brain-computer interfacing approach may find application for stroke and completely locked-in patients with preserved somatic sensation.

  • Journal article
    Song JH, Lucaci D, Calangiu I, Brown MTC, Park JS, Kim J, Brickley SG, Chadderton PTet al., 2018,

    Combining mGRASP and optogenetics enables high-resolution functional mapping of descending cortical projections

    , Cell Reports, Vol: 24, Pages: 1071-1080, ISSN: 2211-1247

    We have applied optogenetics and mGRASP, a light microscopy technique that labels synaptic contacts, to map the number and strength of defined corticocollicular (CC) connections. Using mGRASP, we show that CC projections form small, medium, and large synapses, and both the number and the distribution of synapse size vary among the IC regions. Using optogenetics, we show that low-frequency stimulation of CC axons expressing channelrhodopsin produces prolonged elevations of the CC miniature EPSC (mEPSC) rate. Functional analysis of CC mEPSCs reveals small-, medium-, and large-amplitude events that mirror the synaptic distributions observed with mGRASP. Our results reveal that descending ipsilateral projections dominate CC feedback via an increased number of large synaptic contacts, especially onto the soma of IC neurons. This study highlights the feasibility of combining microscopy (i.e., mGRASP) and optogenetics to reveal synaptic weighting of defined projections at the level of single neurons, enabling functional connectomic mapping in diverse neural circuits.

  • Journal article
    Quicke P, Reynolds S, Neil M, Knopfel T, Schultz S, Foust AJet al., 2018,

    High speed functional imaging with source localized multifocal two-photon microscopy

    , Biomedical Optics Express, Vol: 9, Pages: 3678-3693, ISSN: 2156-7085

    Multifocal two-photon microscopy (MTPM) increases imaging speed over single-focus scanning by parallelizing fluorescence excitation. The imaged fluorescence’s susceptibility to crosstalk, however, severely degrades contrast in scattering tissue. Here we present a source-localized MTPM scheme optimized for high speed functional fluorescence imaging in scattering mammalian brain tissue. A rastered line array of beamlets excites fluorescence imaged with a complementary metal-oxide-semiconductor (CMOS) camera. We mitigate scattering-induced crosstalk by temporally oversampling the rastered image, generating grouped images with structured illumination, and applying Richardson-Lucy deconvolution to reassign scattered photons. Single images are then retrieved with a maximum intensity projection through the deconvolved image groups. This method increased image contrast at depths up to 112 μm in scattering brain tissue and reduced functional crosstalk between pixels during neuronal calcium imaging. Source-localization did not affect signal-to-noise ratio (SNR) in densely labeled tissue under our experimental conditions. SNR decreased at low frame rates in sparsely labeled tissue, with no effect at frame rates above 50 Hz. Our non-descanned source-localized MTPM system enables high SNR, 100 Hz capture of fluorescence transients in scattering brain, increasing the scope of MTPM to faster and smaller functional signals.

  • Journal article
    Troiani F, Nikolic K, Constandinou TG, 2018,

    Simulating optical coherence tomography for observing nerve activity: a finite difference time domain bi-dimensional model

    , PLoS ONE, Vol: 13, Pages: 1-14, ISSN: 1932-6203

    We present a finite difference time domain (FDTD) model for computation of A line scans in time domain optical coherence tomography (OCT). The OCT output signal is created using two different simulations for the reference and sample arms, with a successive computation of the interference signal with external software. In this paper we present the model applied to two different samples: a glass rod filled with water-sucrose solution at different concentrations and a peripheral nerve. This work aims to understand to what extent time domain OCT can be used for non-invasive, direct optical monitoring of peripheral nerve activity.

  • Journal article
    Dall'Orso S, Steinweg J, Allievi AG, Edwards AD, Burdet E, Arichi Tet al., 2018,

    Somatotopic mapping of the developing sensorimotor cortex in the preterm human brain

    , Cerebral Cortex, Vol: 28, Pages: 2507-2515, ISSN: 1047-3211

    In the mature mammalian brain, the primary somatosensory and motor cortices are known to be spatially organized such that neural activity relating to specific body parts can be somatopically mapped onto an anatomical "homunculus". This organization creates an internal body representation which is fundamental for precise motor control, spatial awareness and social interaction. Although it is unknown when this organization develops in humans, animal studies suggest that it may emerge even before the time of normal birth. We therefore characterized the somatotopic organization of the primary sensorimotor cortices using functional MRI and a set of custom-made robotic tools in 35 healthy preterm infants aged from 31 + 6 to 36 + 3 weeks postmenstrual age. Functional responses induced by somatosensory stimulation of the wrists, ankles, and mouth had a distinct spatial organization as seen in the characteristic mature homunculus map. In comparison to the ankle, activation related to wrist stimulation was significantly larger and more commonly involved additional areas including the supplementary motor area and ipsilateral sensorimotor cortex. These results are in keeping with early intrinsic determination of a somatotopic map within the primary sensorimotor cortices. This may explain why acquired brain injury in this region during the preterm period cannot be compensated for by cortical reorganization and therefore can lead to long-lasting motor and sensory impairment.

  • Journal article
    Maslik M, Liu Y, Lande TS, Constandinou TGet al., 2018,

    Continuous-time acquisition of biosignals using a charge-based ADC topology

    , IEEE Transactions on Biomedical Circuits and Systems, Vol: 12, Pages: 471-482, ISSN: 1932-4545

    This paper investigates Continuous-Time (CT) signal acquisition as an activity-dependent and non-uniform sampling alternative to conventional fixed-rate digitisation. We demonstrate the applicability to biosignal representation by quantifying the achievable bandwidth saving by non-uniform quantisation to commonly recorded biological signal fragmentsallowing a compression ratio of 5 and 26 when applied to Electrocardiogram (ECG) and Extracellular Action Potential (EAP) signals respectively. We describe several desirable properties of CT sampling including bandwidth reduction, elimination/reduction of quantisation error and describe its impact on aliasing. This is followed by demonstration of a resource-efficient hardware implementation. We propose a novel circuit topology for a charge-based CT Analogue-to-Digital Converter (CT ADC) that has been optimised for the acquisition of neural signals. This has been implemented in a commercially-available 0.35µm CMOS technology occupying a compact footprint of 0.12mm². Silicon verified measurements demonstrate an 8-bit resolution and a 4kHz bandwidth with static power consumption of 3.75µWfrom a 1.5V supply. The dynamic power dissipation is completely activity-dependent, requiring 1.39pJ energy per conversion.

  • Journal article
    Ramezani R, Liu Y, Dehkhoda F, Soltan A, Haci D, Zhao H, Hazra A, Cunningham M, Firfilionis D, Jackson A, Constandinou TG, Degenaar Pet al., 2018,

    On-probe neural interface ASIC for combined electrical recording and optogenetic stimulation

    , IEEE Transactions on Biomedical Circuits and Systems, Vol: 12, Pages: 576-588, ISSN: 1932-4545

    Neuromodulation technologies are progressing from pacemaking and sensory operations to full closed-loop control. In particular, optogenetics—the genetic modification of light sensitivity into neural tissue allows for simultaneous optical stimulation and electronic recording. This paper presents a neural interface application-specified integrated circuit (ASIC) for intelligent optoelectronic probes. The architecture is designed to enable simultaneous optical neural stimulation and electronic recording. It provides four low noise (2.08 μVrms) recording channels optimized for recording local field potentials (LFPs) (0.1–300 Hz bandwidth, ± 5 mV range, sampled 10-bit@4 kHz), which are more stable for chronic applications. For stimulation, it provides six independently addressable optical driver circuits, which can provide both intensity (8-bit resolution across a 1.1 mA range) and pulse-width modulation for high-radiance light emitting diodes (LEDs). The system includes a fully digital interface using a serial peripheral interface (SPI) protocol to allow for use with embedded controllers. The SPI interface is embedded within a finite state machine (FSM), which implements a command interpreter that can send out LFP data whilst receiving instructions to control LED emission. The circuit has been implemented in a commercially available 0.35 μm CMOS technology occupying a 1.95 mm × 1.10 mm footprint for mounting onto the head of a silicon probe. Measured results are given for a variety of bench-top, in vitro and in vivo experiments, quantifying system performance and also demonstrating concurrent recording and stimulation within relevant experimental models.

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