Imperial College London

Dr Timothy Constandinou

Faculty of EngineeringDepartment of Electrical and Electronic Engineering

Reader in Neural Microsystems
 
 
 
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Contact

 

+44 (0)20 7594 0790t.constandinou Website

 
 
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Assistant

 

Miss Izabela Wojcicka-Grzesiak +44 (0)20 7594 0701

 
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Location

 

B407Bessemer BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

213 results found

Szostak KM, Keshavarz M, Constandinou T, 2021, Hermetic chip-scale packaging using Au:Sn eutectic bonding for implantable devices, Journal of Micromechanics and Microengineering, Vol: 31, Pages: 1-13, ISSN: 0960-1317

Advancements in miniaturisation and new capabilities of implantable devices impose a need for the development of compact, hermetic, and CMOS-compatible micro packaging methods. Gold-tin-based eutectic bonding presents the potential for achieving low-footprint seals with low permeability to moisture at process temperatures below 350 compfnC. This work describes a method for the deposition of Au:Sn eutectic alloy frames by sequential electroplating from commercially available solutions. Frames were bonded on the chip-level in the process of eutectic bonding. Bond quality was characterised through shear force measurements, scanning electron microscopy, visual inspection, and immersion tests. Characterisation of seals geometry, solder thickness, and bonding process parameters was evaluated, along with toxicity assessment of bonding layers to the human fibroblast cells. With a successful bond yield of over 70% and no cytotoxic effect, Au:Sn eutectic bonding appears as a suitable method for the protection of integrated circuitry in implantable applications.

Journal article

Harding EC, Ba W, Zahir R, Yu X, Yustos R, Hsieh B, Lignos L, Vyssotski AL, Constandinou T, Franks NP, Wisden Wet al., 2021, Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature, Publisher: Cold Spring Harbor Laboratory

When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.

Working paper

Zhang Z, Constandinou T, 2021, Adaptive spike detection and hardware optimization towards autonomous, high-channel-count BMIs, Journal of Neuroscience Methods, Vol: 354, ISSN: 0165-0270

BackgroundThe progress in microtechnology has enabled an exponential trend in the number of neurons that can be simultaneously recorded. The data bandwidth requirement is however increasing with channel count. The vast majority of experimental work involving electrophysiology stores the raw data and then processes this offline; to detect the underlying spike events. Emerging applications however require new methods for local, real-time processing.New MethodsWe have developed an adaptive, low complexity spike detection algorithm that combines three novel components for: (1) removing the local field potentials; (2) enhancing the signal-to-noise ratio; and (3) computing an adaptive threshold. The proposed algorithm has been optimised for hardware implementation (i.e. minimising computations, translating to a fixed-point implementation), and demonstrated on low-power embedded targets.Main resultsThe algorithm has been validated on both synthetic datasets and real recordings yielding a detection sensitivity of up to 90%. The initial hardware implementation using an off-the-shelf embedded platform demonstrated a memory requirement of less than 0.1 kb ROM and 3 kb program flash, consuming an average power of 130 μW.Comparison with Existing MethodsThe method presented has the advantages over other approaches, that it allows spike events to be robustly detected in real-time from neural activity in a completely autonomous way, without the need for any calibration, and can be implemented with low hardware resources.ConclusionThe proposed method can detect spikes effectively and adaptively. It alleviates the need for re-calibration, which is critical towards achieving a viable BMI, and more so with future ‘high bandwidth’ systems’ targeting 1000s of channels.

Journal article

Ahmadi N, Constandinou TG, Bouganis C-S, 2021, Robust and accurate decoding of hand kinematics from entire spiking activity using deep learning, Journal of Neural Engineering, Vol: 18, Pages: 1-23, ISSN: 1741-2552

Objective. Brain–machine interfaces (BMIs) seek to restore lost motor functions in individuals with neurological disorders by enabling them to control external devices directly with their thoughts. This work aims to improve robustness and decoding accuracy that currently become major challenges in the clinical translation of intracortical BMIs. Approach. We propose entire spiking activity (ESA)—an envelope of spiking activity that can be extracted by a simple, threshold-less, and automated technique—as the input signal. We couple ESA with deep learning-based decoding algorithm that uses quasi-recurrent neural network (QRNN) architecture. We evaluate comprehensively the performance of ESA-driven QRNN decoder for decoding hand kinematics from neural signals chronically recorded from the primary motor cortex area of three non-human primates performing different tasks. Main results. Our proposed method yields consistently higher decoding performance than any other combinations of the input signal and decoding algorithm previously reported across long-term recording sessions. It can sustain high decoding performance even when removing spikes from the raw signals, when using the different number of channels, and when using a smaller amount of training data. Significance. Overall results demonstrate exceptionally high decoding accuracy and chronic robustness, which is highly desirable given it is an unresolved challenge in BMIs.

Journal article

Ahmadi N, Constandinou T, Bouganis C-S, 2021, Impact of referencing scheme on decoding performance of LFP-based brain-machine interface, Journal of Neural Engineering, Vol: 18, ISSN: 1741-2552

OBJECTIVE: There has recently been an increasing interest in local field potential (LFP) for brain-machine interface (BMI) applications due to its desirable properties (signal stability and low bandwidth). LFP is typically recorded with respect to a single unipolar reference which is susceptible to common noise. Several referencing schemes have been proposed to eliminate the common noise, such as bipolar reference, current source density (CSD), and common average reference (CAR). However, to date, there have not been any studies to investigate the impact of these referencing schemes on decoding performance of LFP-based BMIs. APPROACH: To address this issue, we comprehensively examined the impact of different referencing schemes and LFP features on the performance of hand kinematic decoding using a deep learning method. We used LFPs chronically recorded from the motor cortex area of a monkey while performing reaching tasks. MAIN RESULTS: Experimental results revealed that local motor potential (LMP) emerged as the most informative feature regardless of the referencing schemes. Using LMP as the feature, CAR was found to yield consistently better decoding performance than other referencing schemes over long-term recording sessions. Significance Overall, our results suggest the potential use of LMP coupled with CAR for enhancing the decoding performance of LFP-based BMIs.

Journal article

Toth R, Zamora M, Ottaway J, Gillbe T, Martin S, Benjaber M, Lamb G, Noone T, Taylor B, Deli A, Kremen V, Worrell G, Constandinou TG, Gillbe I, De Wachter S, Knowles C, Sharott A, Valentin A, Green AL, Denison Tet al., 2020, DyNeuMo Mk-2: an investigational circadian-locked neuromodulator with responsive stimulation for applied chronobiology, 2020 IEEE International Conference on Systems, Man, and Cybernetics (SMC), Publisher: IEEE, Pages: 3433-3440, ISSN: 0884-3627

Deep brain stimulation (DBS) for Parkinson's disease, essential tremor and epilepsy is an established palliative treatment. DBS uses electrical neuromodulation to suppress symptoms. Most current systems provide a continuous pattern of fixed stimulation, with clinical follow-ups to refine settings constrained to normal office hours. An issue with this management strategy is that the impact of stimulation on circadian, i.e. sleep-wake, rhythms is not fully considered; either in the device design or in the clinical follow-up. Since devices can be implanted in brain targets that couple into the reticular activating network, impact on wakefulness and sleep can be significant. This issue will likely grow as new targets are explored, with the potential to create entraining signals that are uncoupled from environmental influences. To address this issue, we have designed a new brain-machine-interface for DBS that combines a slow-adaptive circadian-based stimulation pattern with a fast-acting pathway for responsive stimulation, demonstrated here for seizure management. In preparation for first-in-human research trials to explore the utility of multi-timescale automated adaptive algorithms, design and prototyping was carried out in line with ISO risk management standards, ensuring patient safety. The ultimate aim is to account for chronobiology within the algorithms embedded in brain-machine-interfaces and in neuromodulation technology more broadly.

Conference paper

Rapeaux A, 2020, 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 underlyingneuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Origina

Thesis dissertation

Luo J, Firflionis D, Turnball M, Xu W, Walsh D, Escobedo-Cousin E, Soltan A, Ramezani R, Liu Y, Bailey R, O'Neill A, Donaldson N, Constandinou T, Jackson A, Degenaar Pet al., 2020, The neural engine: a reprogrammable low power platform for closed-loop optogenetics, IEEE Transactions on Biomedical Engineering, Vol: 67, Pages: 3004-3015, ISSN: 0018-9294

Brain-machine Interfaces (BMI) hold great potential for treating neurological disorders such as epilepsy. Technological progress is allowing for a shift from open-loop, pacemaker-class, intervention towards fully closed-loop neural control systems. Low power programmable processing systems are therefore required which can operate within the thermal window of 2° C for medical implants and maintain long battery life. In this work, we developed a low power neural engine with an optimized set of algorithms which can operate under a power cycling domain. By integrating with custom designed brain implant chip, we have demonstrated the operational applicability to the closed-loop modulating neural activities in in-vitro brain tissues: the local field potentials can be modulated at required central frequency ranges. Also, both a freely-moving non-human primate (24-hour) and a rodent (1-hour) in-vivo experiments were performed to show system long-term recording performance. The overall system consumes only 2.93mA during operation with a biological recording frequency 50Hz sampling rate (the lifespan is approximately 56 hours). A library of algorithms has been implemented in terms of detection, suppression and optical intervention to allow for exploratory applications in different neurological disorders. Thermal experiments demonstrated that operation creates minimal heating as well as battery performance exceeding 24 hours on a freely moving rodent. Therefore, this technology shows great capabilities for both neuroscience in-vitro/in-vivo applications and medical implantable processing units.

Journal article

Williams I, Brunton E, Rapeaux A, Liu Y, Luan S, Nazarpour K, Constandinou TGet al., 2020, SenseBack-an implantable system for bidirectional neural interfacing, IEEE Transactions on Biomedical Circuits and Systems, Vol: 14, Pages: 1079-1087, ISSN: 1932-4545

Chronic in-vivo neurophysiology experiments require highly miniaturized, remotely powered multi-channel neural interfaces which are currently lacking in power or flexibility post implantation. In this article, to resolve this problem we present the SenseBack system, a post-implantation reprogrammable wireless 32-channel bidirectional neural interfacing that can enable chronic peripheral electrophysiology experiments in freely behaving small animals. The large number of channels for a peripheral neural interface, coupled with fully implantable hardware and complete software flexibility enable complex in-vivo studies where the system can adapt to evolving study needs as they arise. In complementary ex-vivo and in-vivo preparations, we demonstrate that this system can record neural signals and perform high-voltage, bipolar stimulation on any channel. In addition, we demonstrate transcutaneous power delivery and Bluetooth 5 data communication with a PC. The SenseBack system is capable of stimulation on any channel with ±20 V of compliance and up to 315 μA of current, and highly configurable recording with per-channel adjustable gain and filtering with 8 sets of 10-bit ADCs to sample data at 20 kHz for each channel. To the best of our knowledge this is the first such implantable research platform offering this level of performance and flexibility post-implantation (including complete reprogramming even after encapsulation) for small animal electrophysiology. Here we present initial acute trials, demonstrations and progress towards a system that we expect to enable a wide range of electrophysiology experiments in freely behaving animals.

Journal article

Zamora M, Toth R, Morgante F, Ottaway J, Gillbe T, Martin S, Lamb G, Noone T, Benjaber M, Nairac Z, Constandinou T, Herron J, Aziz T, Gillbe I, Green A, Pereira E, Denison Tet al., 2020, DyNeuMo Mk-1: Design and Pilot Validation of an Investigational Motion-Adaptive Neurostimulator with Integrated Chronotherapy, bioRxiv

There is growing interest in using adaptive neuro-modulation to provide a more personalized therapy experience that might improve patient outcomes. Current implant technology, however, can be limited in its adaptive algorithm capability. To enable exploration of adaptive algorithms with chronic implants, we designed and validated the ‘DyNeuMo Mk-1’, a fully-implantable, adaptive research stimulator that titrates stimulation based on circadian rhythms (e.g. sleep, wake) and the patient’s movement state (e.g. posture, activity, shock, free-fall). The design leverages off-the-shelf consumer technology that provides inertial sensing with low-power, high reliability, and relatively modest cost. The DyNeuMo Mk-1 system was designed, manufactured and verified using ISO 13485 design controls, including ISO 14971 risk management techniques to ensure patient safety, while enabling novel algorithms. The system was validated for an intended use case in movement disorders under an emergency-device authorization from the MHRA. The algorithm configurability and expanded stimulation parameter space allows for a number of applications to be explored in both central and peripheral applications. Intended applications include adaptive stimulation for movement disorders, synchronizing stimulation with circadian patterns, and reacting to transient inertial events such as shocks for urinary incontinence. With appropriate design controls in place, first-in-human research trials are now being prepared to explore the utility of automated motion-adaptive algorithms.

Journal article

Rapeaux A, Constandinou TG, 2020, An HFAC block-capable and module-extendable 4-channel stimulator for acute neurophysiology, Journal of Neural Engineering, Vol: 17, ISSN: 1741-2552

Objective. This paper describes the design, testing and use of a novel multichannel block-capable stimulator for acute neurophysiology experiments to study highly selective neural interfacing techniques. This paper demonstrates the stimulator's ability to excite and inhibit nerve activity in the rat sciatic nerve model concurrently using monophasic and biphasic nerve stimulation as well as high-frequency alternating current (HFAC). Approach. The proposed stimulator uses a Howland Current Pump circuit as the main analogue stimulator element. 4 current output channels with a common return path were implemented on printed circuit board using Commercial Off-The-Shelf components. Programmable operation is carried out by an ARM Cortex-M4 Microcontroller on the Freescale freedom development platform (K64F). Main results. This stimulator design achieves ± 10 mA of output current with ± 15 V of compliance and less than 6 µA of resolution using a quad-channel 12-bit external DAC, for four independently driven channels. This allows the stimulator to carry out both excitatory and inhibitory (HFAC block) stimulation. DC Output impedance is above 1 M Ω. Overall cost for materials i.e. PCB boards and electronic components is less than USD 450 or GBP 350 and device size is approximately 9 cm × 6 cm × 5 cm. Significance. Experimental neurophysiology often requires significant investment in bulky equipment for specific stimulation requirements, especially when using HFAC block. Different stimulators have limited means of communicating with each other, making protocols more complicated. This device provides an effective solution for multi-channel stimulation and block of nerves, enabling studies on selective neural interfacing in acute scenarios with an affordable, portable and space-saving design for the laboratory. The stimulator can be further upgraded with additional modules to extend functionality while maintaining straightforward programming

Journal article

Savolainen OW, Constandinou TG, 2020, Predicting single-unit activity from local field potentials with LSTMs, 42nd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (EMBC), Publisher: IEEE, Pages: 884-887, ISSN: 1557-170X

This paper investigates to what extent Long ShortTerm Memory (LSTM) decoders can use Local Field Potentials (LFPs) to predict Single-Unit Activity (SUA) in Macaque Primary Motor cortex. The motivation is to determine to what degree the LFP signal can be used as a proxy for SUA, for both neuroscience and Brain-Computer Interface (BCI) applications. Firstly, the results suggest that the prediction quality varies significantly by implant location or animal. However, within each implant location / animal, the prediction quality seems to be correlated with the amount of power in certain LFP frequency bands (0-10, 10-20 and 40-50 Hz, standardised LFPs). Secondly, the results suggest that bipolar LFPs are more informative as to SUA than unipolar LFPs. This suggests common mode rejection aids in the elimination of non-local neural information. Thirdly, the best individual bipolar LFPs generally perform better than when using all available unipolar LFPs. This suggests that LFP channel selection may be a simple but effective means of lossy data compression in Wireless Intracortical LFP-based BCIs. Overall, LFPs were moderately predictive of SUA, and improvements can likely be made.

Conference paper

Savolainen OW, Constandinou TG, 2020, Lossless compression of intracortical extracellular neural recordings using non-adaptive huffman encoding, 42nd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (EMBC), Publisher: IEEE, Pages: 4318-4321, ISSN: 1557-170X

This paper investigates the effectiveness of four Huffman-based compression schemes for different intracortical neural signals and sample resolutions. The motivation is to find effective lossless, low-complexity data compression schemes for Wireless Intracortical Brain-Machine Interfaces (WI-BMI). The considered schemes include pre-trained Lone 1st and 2nd order encoding [1], pre-trained Delta encoding, and pre-trained Linear Neural Network Time (LNNT) encoding [2]. Maximum codeword-length limited versions are also considered to protect against overfit to training data. The considered signals are the Extracellular Action Potential signal, the Entire Spiking Activity signal, and the Local Field Potential signal. Sample resolutions of 5 to 13 bits are considered. The result show that overfit-protection dramatically improves compression, especially at higher sample resolutions. Across signals, 2nd order encoding generally performed best at lower sample resolutions, and 1st order, Delta and LNNT encoding performed best at higher sample resolutions. The proposed methods should generalise to other remote sensing applications where the distribution of the sensed data can be estimated a priori.

Conference paper

Tossell K, Yu X, Soto BA, Vicente M, Miracca G, Giannos P, Miao A, Hsieh B, Ma Y, Yustos R, Vyssotski A, Constandinou T, Franks N, Wisden Wet al., 2020, Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus, Publisher: bioRxiv

Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.

Working paper

Liu Y, Urso A, Martins da Ponte R, Costa T, Valente V, Giagka V, Serdijn WA, Constandinou TG, Denison Tet al., 2020, Bidirectional bioelectronic interfaces: system design and circuit implications, IEEE Solid-State Circuits Magazine, Vol: 12, Pages: 30-46, ISSN: 1943-0582

The total economic cost of neurological disorders exceeds £100 billion per annum in the United Kingdom alone, yet pharmaceutical companies continue to cut investments due to failed clinical studies and risk [1]. These challenges motivate an alternative to solely pharmacological treatments. The emerging field of bioelectronics suggests a novel alternative to pharmaceutical intervention that uses electronic hardware to directly stimulate the nervous system with physiologically inspired electrical signals [2]. Given the processing capability of electronics and precise targeting of electrodes, the potential advantages of bioelectronics include specificity in the time, method, and location of treatment, with the ability to iteratively refine and update therapy algorithms in software [3]. A primary disadvantage of the current systems is invasiveness due to surgical implantation of the device.

Journal article

De Marcellis A, Di Patrizio Stanchieri G, Faccio M, Palange E, Constandinou Tet al., 2020, A 300 Mbps 37 pJ/bit pulsed optical biotelemetry, IEEE Transactions on Biomedical Circuits and Systems, Vol: 14, Pages: 441-451, ISSN: 1932-4545

This article reports an implantable transcutaneous telemetry for a brain machine interface that uses a novel optical communication system to achieve a highly energy-efficient link. Based on an pulse-based coding scheme, the system uses sub-nanosecond laser pulses to achieve data rates up to 300 Mbps with relatively low power levels when compared to other methods of wireless communication. This has been implemented using a combination of discrete components (semiconductor laser and driver, fast-response Si photodiode and interface) integrated at board level together with reconfigurable logic (encoder, decoder and processing circuits implemented using Xilinx KCU105 board with Kintex UltraScale FPGA). Experimental validation has been performed using a tissue sample that achieves representative level of attenuation/scattering (porcine skin) in the optical path. Results reveal that the system can operate at data rates up to 300 Mbps with a bit error rate (BER) of less than 10 −10 , and an energy efficiency of 37 pJ/bit. This can communicate, for example, 1,024 channels of broadband neural data sampled at 18 kHz, 16-bit with only 11 mW power consumption.

Journal article

Wang G, Constandinou TG, Tang K-T, 2020, Editorial, IEEE Transactions on Biomedical Circuits and Systems, Vol: 14, Pages: 1-1, ISSN: 1932-4545

Journal article

Rapeaux A, Constandinou T, 2020, A block-capable and module-extendable 4-channel stimulator for acute neurophysiology, Publisher: bioRxiv

Objective: This paper describes the design, testing and use of a novel multichannel block-capable stimulator for acute neurophysiology experiments to study highly selective neural interfacing techniques. This paper demonstrates the stimulator's ability to excite and inhibit nerve activity in the rat sciatic nerve model concurrently using monophasic and biphasic nerve stimulation as well as high-frequency alternating current (HFAC). Approach: The proposed stimulator uses a Howland Current Pump circuit as the main analogue stimulator element. 4 current output channels with a common return path were implemented on printed circuit board using Commercial Off-The-Shelf components. Programmable operation is carried out by an ARM Cortex-M4 Microcontroller on the Freescale freedom development platform (K64F). Main Results: This stimulator design achieves +-10 mA of output current with +-15V of compliance and less than 6 uA of resolution using a quad-channel 12-bit external DAC, for four independently driven channels. This allows the stimulator to carry out both excitatory and inhibitory (HFAC block) stimulation. DC Output impedance is above 1 Mohm. Overall cost is less than USD 450 or GBP 350 and device size is approximately 9 cm x 6 cm x 5 cm. Significance: Experimental neurophysiology often requires significant investment in bulky equipment for specific stimulation requirements, especially when using HFAC block. Different stimulators have limited means of communicating with each other, making protocols more complicated. This device provides an effective solution for multi-channel stimulation and block of nerves, enabling studies on selective neural interfacing in acute scenarios with an affordable, portable and space-saving design for the laboratory. The stimulator can be further upgraded with additional modules to extend functionality while maintaining straightforward programming and integration of functions with one controller.

Working paper

Cavuto M, Hallam R, Rapeaux A, Maslik M, Troiani F, Constandinou Tet al., 2019, Live demonstration: a public engagement platform for invasive neural interfaces, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-1

Neural interfaces, and more specifically ones ofthe invasive/implantable variety, today are a topic of muchcontroversy, often making the general public uncomfortable andintimidated. We have thus devised a bespoke interactive demoto help people understand brain implants and their need inthe age of wearable devices, with the secondary objective ofintroducing the wireless cortical neural probe that we, at NGNI(Next Generation Neural Interfaces) lab, are developing.

Conference paper

Haci D, Mifsud A, Liu Y, Ghoreishizadeh S, Constandinou Tet al., 2019, In-body wireline interfacing platform for multi-module implantable microsystems, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

The recent evolution of implantable medical devicesfrom single-unit stimulators to modern implantable microsys-tems, has driven the need for distributed technologies, in whichboth the implant system and functions are partitioned across mul-tiple active devices. This multi-module approach is made possiblethanks to novel network architectures, allowing for in-body powerand data communications to be performed using implantableleads. This paper discusses the challenges in implementing suchinterfacing system and presents a platform based on one centralimplant (CI) and multiple peripheral implants (PIs) using a cus-tom 4WiCS communication protocol. This is implemented in PCBtechnology and tested to demonstrate intrabody communicationcapabilities and power transfer within the network. Measuredresults show CI-to-PI power delivery achieves 70%efficiency inexpected load condition, while establishing full-duplex data linkwith up to 4 PIs simultaneously.

Conference paper

Hsieh B, Harding E, Wisden W, Franks N, Constandinou Tet al., 2019, A miniature neural recording device to investigate sleep and temperature regulation in mice, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

Sleep is an important and ubiquitous process that,despite decades of research, a large part of its underlyingbiological circuity still remain elusive. To conduct research inthis field, many devices capable of recording neural signalssuch as LFP and EEG have been developed. However, most ofthese devices are unsuitable for sleep studies in mice, the mostcommonly used animals, due to their size and weight. Thus, thispaper presents a novel 4 channel, compact ( 2.1cm by 1.7cm )and lightweight ( 3.6g ) neural-logging device that can recordfor 3 days on just two 0.6g zinc air 312 batteries. Instead ofthe typical solution of using multiple platforms, the presenteddevice integrates high resolution EEG, EMG and temperaturerecordings into one platform. The onboard BLE module allowsthe device to be controlled wirelessly as well as stream data in realtime, enabling researchers to check the progress of the recordingwith minimal animal disturbance. The device demonstrates itsability to accurately record EEG and temperature data throughthe long 24 hour in-vivo recordings conducted. The obtainedEEG data could be easily sleep scored and the temperaturesvalues were all within expected physiological range.

Conference paper

De Marcellis A, Stanchieri GDP, Palange E, Faccio M, Constandinou Tet al., 2019, A 0.35μm CMOS UWB-inspired bidirectional communication system-on-chip for transcutaneous optical biotelemetry links, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

In this paper we report on the fabrication, implementation and experimental characterization of an integrated bidirectional communication System-on-Chip (SoC) for transcutaneous bidirectional optical biotelemetry links. The proposed architecture implements a UWB-inspired pulsed coding technique and contains a transmitter and a receiver to achieve a simultaneous bidirectional link. The transmitter generates sub-nanosecond current pulses to directly drive off-chip pulsed vertical cavity semiconductor lasers by means of a digital data coding subsystem and all the needed bias and driving circuits. On the other hand, the receiver manages off-chip fast Si photodiodes and includes signal conditioning, detection and digital data decoding circuits to support high bit rate and energy efficient communication links. The entire solution designed at transistor level has been fabricated in AMS 0.35µm standard CMOS technology into a compact silicon footprint lower than 0.13mm2 employing only 113 transistors and 1 resistor. A specific PCB has been developed together with a suitable test bench implemented on Xilinx Virtex-6 XC6VLX240T FPGA board to properly evaluate the performances and the main characteristics of the ASIC. Furthermore, a 6 GHz, 20 GS/s LeCroy WaveMaster 8600A digital oscilloscope has been employed to investigate the system time response. Preliminary experimental results validated the correct functionality of the overall integrated system demonstrating also its capability to operate, also in a bidirectional mode, at bit rates up to 250 Mbps with pulse widths up to 1.2ns and a minimum total power efficiency of about 160 pJ/bit in the conditions for which the transmitter and the receiver work simultaneously onto the same chip. These results make the developed solution suitable for high performances bidirectional optical biotelemetry links to be applied, e.g., to implantable neural recording/stimulation transcutaneous platforms that generally require communication

Conference paper

Feng P, Maslik M, Constandinou T, 2019, EM-lens enhanced power transfer and multi-node data transmission for implantable medical devices, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

This paper presents a robust EM-lens-enhancedwireless power transmission system and a novel multiple-nodedata communication method for distributed implantable medicaldevices. The proposed techniques can solve the common issuescaused by multiple implanted devices, such as low power transferefficiency through biological tissues, uneven delivered powerfor distributed devices and interference between simultaneouswireless power and data transmission. A prototype system hasbeen manufactured with discrete components on FR4 substrateas a proof of concept. The EM-Lens-enhanced inductive linkscan expand the power coverage of transmitting (Tx) coil from9 mm×5 mm to 14 mm×13 mm, and double the recovered DCvoltage from 1.8 V to 3.2 V at 12.5 mm distance. Data commu-nication is achieved by novel low-power back-scattering CDMAscheme. This permits transmission of data from several nodesall operating with the same carrier frequency simultaneouslyreflecting the power carriers to the primary side. In this paper,we demonstrate simultaneous communication between two nodesat 125 kbps with 1.05 mW power consumption.

Conference paper

Wong S, Ekanayake J, Liu Y, Constandinou Tet al., 2019, An impedance probing system for real-time intra-operative brain tumour tissue discrimination, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

The ability to perform realtime diagnostics of tissueintraoperatively can greatly enhance the precision and effective-ness of the underlying surgery, for example, in tumour resection.To achieve this however would require a miniature tool ableto performin situ, in-vivocharacterisation for distinguishingbetween different types of tissues. In this work, we exploredthe feasibility and requirements of implementing a portableimpedance characterisation system for brain tumour detection.We proposed and implemented a novel system based on PCB-based instrumentation using a square four-electrode microendo-scopic probe. The system uses a digital-to-analogue converterto generate a multi-tone sinusoid waveform, and a floating bi-directional voltage-to-current converter to output the differentialstimulation current to one pair of electrodes. The other pairof electrodes are connected to the sensing circuit based on aninstrumentation amplifier. The recorded data is pre-processed bythe micro-controller and then analysed on a host computer. Toevaluate the system, tetrapolar impedances have been recordedfrom a number of different electrode configurations to sense pre-defined resistance values. The overall system consumes 143 mAcurrent, achieve 0.1% linearity and 15μV noise level, with amaximum signal bandwidth of 100 kHz. Initial experimentalresults on tissue were carried out on a piece of rib-eye steak.Electrical impedance maps (EIM) and contour plots were thenreconstructed to represent the impedance value in different tissue region.

Conference paper

Williams I, Rapeaux A, Pearson J, Nazarpour K, Brunton E, Luan S, Liu Y, Constandinou Tet al., 2019, SenseBack - implant considerations for an implantable neural stimulation and recording device, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4

This paper describes a fully implantable and highlycompact neural interface platform for chronic (>6 month) ratand small rodent experiments. It provides 32 channels of highlyflexible neural stimulation and recording with wireless controland data readout, as well as wireless transcutaneous power. Allthe system firmware is fully upgradeable over the air (even afterimplantation) allowing future enhancements such as closed loopoperation or data filtering. This paper focuses on the implantconsiderations – i.e. design and manufacture of the physicalplatform, encapsulation, wireless connections and testing.

Conference paper

Liu Y, Constandinou TG, Georgiou P, 2019, Ultrafast large-scale chemical sensing with CMOS ISFETs: a level-crossing time-domain approach, IEEE Transactions on Biomedical Circuits and Systems, Vol: 13, Pages: 1201-1213, ISSN: 1932-4545

The introduction of large-scale chemical sensing systems in CMOS which integrate millions of ISFET sensors have allowed applications such as DNA sequencing and fine-pixel chemical imaging systems to be realised. Using CMOS ISFETs provides advantages of digitisation directly at the sensor as well as correcting for non-linearity in its response. However, for this to be beneficial and scale, the readout circuits need to have the minimum possible footprint and power consumption. Within this context, this paper analyses an ISFET based pH-to-time readout using an inverter in the time-domain as a level-crossing detector and presents a 32×32 array with in-pixel digitisation for pH sensing. The inverter-based sensing pixel, controlled by a triangular waveform, converts the pH response into a time-domain signal whilst also compensating for sensor offset and thus resulting in an increase in dynamic range. The sensor pixels interface to a 15-bit asynchronous column-wise time-to-digital converter (TDC), enabling fast asynchronous conversion whilst using minimal silicon area. Parallel outputs of 32 TDC interfaces are serialised to achieve fast data throughput. This system is implemented in a standard 0.18um CMOS technology, with a pixel size of 26μm×26μm and a TDC area of 26μm×180μm. Measured results demonstrate the system is able to sense reliably with an average pH sensitivity of 30mVpH, whilst being able to compensate for sensor offset by up to ±7V. A resolution of 0.013pH is achieved and noise measurements show an integrated noise of 0.08pH within 2-500Hz and SFDR of 42.6dB. Total power consumption is 11.286mW.

Journal article

Chew DJ, Constandinou TG, Gupta I, Hann MM, Porter RA, Witherington Jet al., 2019, Bioelectronic medicines: past, present and future. Highlights from The Society for Medicines Research Symposium, Drugs of the Future, Vol: 44, Pages: 895-902, ISSN: 0377-8282

On October 1, 2019, the Society for Medicines Research (SMR) held its first symposium on "Bioelectronic medicines, past, present and future" at the Royal Academy of Engineering in London. The meeting was attended by 145 participants and was supported by Galvani Bioelectronics, IEEE-CAS Society, IEEE-Brain Initiative, BIOS, Heraeus, CorTec and the IT'IS Foundation.

Journal article

De Marcellis A, Stanchieri GDP, Palange E, Faccio M, Constandinou TGet al., 2019, A 0.35 mu m CMOS UWB-inspired bidirectional communication system-on-chip for transcutaneous optical biotelemetry links, IEEE Biomedical Circuits and Systems Conference (BioCAS), Publisher: IEEE, ISSN: 2163-4025

In this paper we report on the fabrication, implementation and experimental characterization of an integrated bidirectional communication System-on-Chip (SoC) for transcutaneous bidirectional optical biotelemetry links. The proposed architecture implements a UWB-inspired pulsed coding technique and contains a transmitter and a receiver to achieve a simultaneous bidirectional link. The transmitter generates sub- nanosecond current pulses to directly drive offchip pulsed vertical cavity semiconductor lasers by means of a digital data coding subsystem and all the needed bias and driving circuits. The receiver interfaces to off-chip fast Si photodiodes and includes signal conditioning, detection and digital data decoding circuits to support high bit rate and energy efficient communication links. The SoC has been implemented in a commercially-available 0.35 mu m CMOS technology provided by AMS, occupying a compact silicon footprint of less than 0.13 mm2 employing 113 transistors and 1 resistor. This is evaluated using a testbench consisting of a custom PCB and a Xilinx Virtex-6 XC6VLX240T FPGA board. Preliminary experimental results validated the correct functionality of the overall integrated system demonstrating its capability to operate, also in a bidirectional mode, at bit rates up to 250 Mbps with pulse widths down to 1.2 ns and a minimum total power efficiency of about 160 pJ/bit in the conditions for which the transmitter and the receiver work simultaneously on the same chip. This demonstrated performance makes the optical biotelemetry particularly suitable for highly scalable (i.e., high bitrate, low energy per bit) implantable devices such as brain machine interfaces.

Conference paper

Han Y, Lauteslager T, Lande TS, Constandinou TGet al., 2019, UWB radar for non-contact heart rate variability monitoring and mental state classification., Annual Meeting of the IEEE Engineering in Medicine and Biology Society, Pages: 6578-6582, ISSN: 1557-170X

Heart rate variability (HRV), as measured by ultra-wideband (UWB) radar, enables contactless monitoring of physiological functioning in the human body. In the current study, we verified the reliability of HRV extraction from radar data, under limited transmitter power. In addition, we conducted a feasibility study of mental state classification from HRV data, measured using radar. Specifically, arctangent demodulation with calibration and low rank approximation have been used for radar signal pre-processing. An adaptive continuous wavelet filter and moving average filter were utilized for HRV extraction. For the mental state classification task, performance of support vector machine, k-nearest neighbors and random forest classifiers have been compared. The developed system has been validated on human participants, with 10 participants for HRV extraction, and three participants for the proof-of-concept mental state classification study. The results of HRV extraction demonstrate the reliability of time-domain parameter extraction from radar data. However, frequency-domain HRV parameters proved to be unreliable under low SNR. The best average overall mental state classification accuracy achieved was 82.34%, which has important implications for the feasibility of mental health monitoring using UWB radar.

Conference paper

Lauteslager T, Tommer M, Lande TS, Constandinou TGet al., 2019, Coherent UWB radar-on-chip for in-body measurement of cardiovascular dynamics, IEEE Transactions on Biomedical Circuits and Systems, Vol: 13, Pages: 814-824, ISSN: 1932-4545

Coherent ultra-wideband (UWB) radar-on-chip technology shows great promise for developing portable and low-cost medical imaging and monitoring devices. Particularly monitoring the mechanical functioning of the cardiovascular system is of interest, due to the ability of radar systems to track sub-mm motion inside the body at a high speed. For imaging applications, UWB radar systems are required, but there are still significant challenges with in-body sensing using low-power microwave equipment and wideband signals. Recently it was shown for the first time, on a single subject, that the arterial pulse wave can be measured at various locations in the body, using coherent UWB radar-on-chip technology. The current work provides more substantial evidence, in the form of new measurements and improved methods, to demonstrate that cardiovascular dynamics can be measured using radar-on-chip. Results across four participants were found to be robust and repeatable. Cardiovascular signals were recorded using radar-on-chip systems and electrocardiography (ECG). Through ECG-aligned averaging, the arterial pulse wave could be measured at a number of locations in the body. Pulse arrival time could be determined with high precision, and blood pressure pulse wave propagation through different arteries was demonstrated. In addition, cardiac dynamics were measured from the chest. This work serves as a first step in developing a portable and low-cost device for long-term monitoring of the cardiovascular system, and provides the fundamentals necessary for developing UWB radar-on-chip imaging systems.

Journal article

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