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    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

    , IEEE/EMBS Conference on Neural Engineering (NER), Pages: 1-6

    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.

    Soor NS, Quicke P, Howe CL, Pang KT, Neil MAA, Schultz SR, Foust AJet al., 2019,

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

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

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

    , Frontiers in Cellular Neuroscience, ISSN: 1662-5102
    Ahmadi N, Constandinou TG, Bouganis C-S, 2018,

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

    , PLOS ONE, Vol: 13, ISSN: 1932-6203
    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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 enormouspotential for the development of portable, low-cost and easy-to-use devices for monitoring the cardiovascular system. Usingbody coupled antennas, electromagnetic energy can be directedinto the body to measure arterial pulsation and cardiac motion,and estimate arterial stiffness as well as blood pressure. Inthe current study we validate that heart rate signals, obtainedusing multiple UWB radar-on-chip modules and body coupledantennas, do indeed originate from arterial pulsation. ThroughECG-aligned averaging, pulse arrival time at a number oflocations in the body could be measured with high precision,and arterial pulse propagation through the femoral and carotidartery was demonstrated. In addition, cardiac dynamics weremeasured from the chest. Onset and offset of ventricular systolewere clearly distinguishable, as well as onset of atrial systole.Although further validation is required, these results show thatUWB radar-on-chip is highly suitable for monitoring of vascularhealth as well as the heart’s mechanical functioning.

    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

    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.

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

    Chip-Scale Coils for Millimeter-Sized Bio-Implants

    Leene LB, Constandinou TG, 2018,

    A 0.006 mm(2) 1.2 mu W Analog-to-Time Converter for Asynchronous Bio-Sensors

    , IEEE JOURNAL OF SOLID-STATE CIRCUITS, Vol: 53, Pages: 2604-2613, ISSN: 0018-9200
    , 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

    © 1964-2012 IEEE. 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.

    Quicke P, Reynolds S, Neil M, Knopfel T, Schultz SR, Foust AJet al., 2018,

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

    , BIOMEDICAL OPTICS EXPRESS, Vol: 9, ISSN: 2156-7085
    Luan S, Williams I, Maslik M, Liu Y, De Carvalho F, Jackson A, Quiroga RQ, Constandinou TGet al., 2018,

    Compact standalone platform for neural recording with real-time spike sorting and data logging.

    , J Neural Eng, Vol: 15

    OBJECTIVE: Longitudinal observation of single unit neural activity from large numbers of cortical neurons in awake and mobile animals is often a vital step in studying neural network behaviour and towards the prospect of building effective brain-machine interfaces (BMIs). These recordings generate enormous amounts of data for transmission and storage, and typically require offline processing to tease out the behaviour of individual neurons. Our aim was to create a compact system capable of: (1) reducing the data bandwidth by circa 2 to 3 orders of magnitude (greatly improving battery lifetime and enabling low power wireless transmission in future versions); (2) producing real-time, low-latency, spike sorted data; and (3) long term untethered operation. APPROACH: We have developed a headstage that operates in two phases. In the short training phase a computer is attached and classic spike sorting is performed to generate templates. In the second phase the system is untethered and performs template matching to create an event driven spike output that is logged to a micro-SD card. To enable validation the system is capable of logging the high bandwidth raw neural signal data as well as the spike sorted data. MAIN RESULTS: The system can successfully record 32 channels of raw neural signal data and/or spike sorted events for well over 24 h at a time and is robust to power dropouts during battery changes as well as SD card replacement. A 24 h initial recording in a non-human primate M1 showed consistent spike shapes with the expected changes in neural activity during awake behaviour and sleep cycles. SIGNIFICANCE: The presented platform allows neural activity to be unobtrusively monitored and processed in real-time in freely behaving untethered animals-revealing insights that are not attainable through scheduled recording sessions. This system achieves the lowest power per channel to date and provides a robust, low-latency, low-bandwidth and verifiable outp

    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.

    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
    Ahmadi N, Constandinou TG, Bouganis C-S, 2018,

    Spike Rate Estimation Using Bayesian Adaptive Kernel Smoother (BAKS) and Its Application to Brain Machine Interfaces.

    , Pages: 2547-2550, ISSN: 1557-170X

    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 offline BMI decoding performance using Kalman filter. The results reveal that BAKS can improve the decoding performance compared to the binning method. This suggests the feasibility and the potential use of BAKS for real-time BMIs.

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

    On-Probe Neural Interface ASIC for Combined Electrical Recording and Optogenetic Stimulation

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

    Continuous-Time Acquisition of Biosignals Using a Charge-Based ADC Topology

    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.

    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.

    Kegler M, Etard OE, Forte AE, Reichenbach JDTet al., 2018,

    Complex Statistical Model for Detecting the Auditory Brainstem Response to Natural Speech and for Decoding Attention from High-Density EEG Recordings

    , ARO 2018
    Forte AE, Etard OE, Reichenbach JDT, 2018,

    Selective Auditory Attention At The Brainstem Level

    , ARO 2018
    Saiz Alia M, Askari A, Forte AE, Reichenbach JDTet al., 2018,

    A model of the human auditory brainstem response to running speech

    , ARO 2018
    Etard OE, Kegler M, Braiman C, Forte AE, Reichenbach JDTet al., 2018,

    Real-time decoding of selective attention from the human auditory brainstem response to continuous speech

    , BioRxiv
    Sherlock B, Warren SC, Alexandrov Y, Yu F, Stone J, Knight J, Neil MAA, Paterson C, French PMW, Dunsby Cet al., 2018,

    In vivo multiphoton microscopy using a handheld scanner with lateral and axial motion compensation

    , JOURNAL OF BIOPHOTONICS, Vol: 11, ISSN: 1864-063X

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