Publications

Conference paper

Manatchinapisit V, Rapeaux A, Williams I, Constandinou TGet al., 2022,

Accelerated testing of electrode degradation for validation of new implantable neural interfaces

, Pages: 534-538

Neural prostheses, such as cochlear implants or deep brain stimulators, can modulate neural activity and restore lost physiological function by performing electrical stimulation and neural recordings. However, prolonged stimulation can degrade electrodes and adversely affect their performance over long-term implantation. Therefore, integrating the electrodes' health monitoring system is required for new implantable neural interface designs. However, validating the electrode degradation monitoring system with in-vivo experiment is slow and highly challenging. Furthermore, artificially generating the degradation of electrodes in in-vitro analysis is also time-consuming. This paper proposes an experimental setup for accelerated electrode degradation by elevating temperature and electrical stimulation. In order to demonstrate feasibility, a previous generation electrode material (tungsten) was used, and Electrochemical Impedance Spectroscopy (EIS) was measured every hour to analyse the electrochemical properties. As a result, optical microscopy images, before and after testing, show the morphology changes of the tungsten wire electrodes. The minimum accelerated testing to create electrode failure was 6 hours. Following prolonged stimulation, the results show electrode erosion possibly exacerbated by the evolution of hydrogen gas, while the EIS plots illustrate the slight increase of impedance over time in certain frequency bands, likely due to the progressive decline of the electrode surface area.

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Conference paper

Jaccottet A, Feng P, Szostak-Lipowicz KM, Keeble L, Constandinou TGet al., 2022,

Towards a wireless micropackaged implant with hermeticity monitoring

, Pages: 500-504

The development of reliable hermetic chip-scale micropackaging is one of the major challenges in the miniaturization of implantable medical devices. Protecting the patient from the implanted foreign body and the implant itself from the biological environment is crucial. This paper presents an implantable micropackaging concept to protect a microelectronic system-on-chip. A hermetic chamber is formed by bonding the active CMOS chip to a silicon cover using a gold-tin eutectic sealant. The cover's fabrication method and the die's post-processing steps are presented. A humidity sensor inside the chamber monitors the humidity to assess permeability. To power the sensor and read its data, interconnections in the CMOS chip have been designed; these metal tracks pass underneath the cover and thus create a connection between the inside and the outside of the cavity. As an alternative to these connections, an on-chip wireless power management and data communication system is presented with simulated results.

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Conference paper

Oprea A, Zhang Z, Constandinou TG, 2022,

Hardware evaluation of spike detection algorithms towards wireless brain machine interfaces

, Pages: 60-64

The current trend for implantable Brain Machine Interfaces (BMIs) is to increase the channel count, towards next generation devices that improve on information transfer rate. This however increases the raw data bandwidth for wired or wireless systems that ultimately impacts the power budget (and thermal dissipation). On-implant feature extraction and/or compression are therefore becoming essential to reduce the data rate, however the processing power is of concern. One common feature extraction technique for intracortical BMIs is spike detection. In this work, we have empirically compared the performance, resource utilization, and power consumption of three hardware efficient spike emphasizers: Non-linear Energy Operator (NEO), Amplitude Slope Operator (ASO) and Energy of Derivative (ED), and two common statistical thresholding mechanisms (using mean or median). We also propose a novel median approximation to address the issue of the median operator not being hardware-efficient to implement. These have all been implemented and evaluated on reconfigurable hardware (FPGA) to estimate their hardware efficiency in an ultimate ASIC design. Our results suggest that ED with average thresholding provides the most hardware efficient (low power/resource) choice, while using median has the advantage of improved detection accuracy and higher robustness on threshold multiplier settings. This work is significant because it is the first to implement and compare the hardware and algorithm trade-offs that have to be made before translating the algorithms into hardware instances to design wireless implantable BMIs.

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Citations: 6

Conference paper

Stanchieri GDP, De Marcellis A, Faccio M, Palange E, Constandinou TGet al., 2022,

A 180 nm CMOS Integrated System based on a Multilevel Synchronized Pulsed Modulation for High Efficiency Implantable Optical Biotelemetry

, Pages: 302-306

This paper reports on the design of a fully integrated UWB-inspired optical biotelemetry system for high efficiency implantable devices in biomedical applications. The communication link implements a multilevel data coding combined to a synchronized pulse position modulation technique operating with serial bitstreams having data rates from 60 Mbps to 240 Mbps and symbols composed by 1 up to 6 bits (configurable operating modes). The optical biotelemetry system takes advantage of the use of 300 ps laser pulses as the data transmitter and of a Si photodiode as the data receiver so guaranteeing reliable operations, wide bandwidth, high efficiency, electromagnetic compatibility, and signal integrity. The proposed system has been designed in TSMC 180 nm standard CMOS technology requiring a total Si area of about 0.044 mm2. Post-layout simulations demonstrate the correctness of the system functionalities and operations for transmission data rates up to 240 Mbps, symbol lengths up to 6 bits, and overall energy efficiencies lower than 22 pJ/bit. The comparison with results of similar solutions in the Literature demonstrates that the proposed system achieves the best performances in terms of data rate and energy efficiency.

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Journal article

Antoniadis D, Mifsud A, Feng P, Constandinou TGet al., 2022,

An Open-Source RRAM Compiler

, 2022 20TH IEEE INTERREGIONAL NEWCAS CONFERENCE (NEWCAS), Pages: 465-469

Journal article

Burdett A, Toumazou C, Sahoo R, Mujan A, Hon T-K, Bedzo-Nutakor J, Casali N, Karvela M, Sohbati M, Cooke GS, Davies GW, Moore LSPet al., 2021,

Pooled sputum to optimise the efficiency and utility of rapid, point-of-care molecular SARS-CoV-2 testing

, BMC Infectious Diseases, Vol: 21, Pages: 1-10, ISSN: 1471-2334

BackgroundAs SARS-CoV-2 testing expands, particularly to widespread asymptomatic testing, high sensitivity point-of-care PCR platforms may optimise potential benefits from pooling multiple patients’ samples.MethodWe tested patients and asymptomatic citizens for SARS-CoV-2, exploring the efficiency and utility of CovidNudge (i) for detection in individuals’ sputum (compared to nasopharyngeal swabs), (ii) for detection in pooled sputum samples, and (iii) by modelling roll out scenarios for pooled sputum testing.ResultsAcross 295 paired samples, we find no difference (p = 0.1236) in signal strength for sputum (mean amplified replicates (MAR) 25.2, standard deviation (SD) 14.2, range 0–60) compared to nasopharyngeal swabs (MAR 27.8, SD 12.4, range 6–56). At 10-sample pool size we find some drop in absolute strength of signal (individual sputum MAR 42.1, SD 11.8, range 13–60 vs. pooled sputum MAR 25.3, SD 14.6, range 1–54; p < 0.0001), but only marginal drop in sensitivity (51/53,96%). We determine a limit of detection of 250 copies/ml for an individual test, rising only four-fold to 1000copies/ml for a 10-sample pool. We find optimal pooled testing efficiency to be a 12–3-1-sample model, yet as prevalence increases, pool size should decrease; at 5% prevalence to maintain a 75% probability of negative first test, 5-sample pools are optimal.ConclusionWe describe for the first time the use of sequentially dipped sputum samples for rapid pooled point of care SARS-CoV-2 PCR testing. The potential to screen asymptomatic cohorts rapidly, at the point-of-care, with PCR, offers the potential to quickly identify and isolate positive individuals within a population “bubble”.

Journal article

Rapeaux AB, Constandinou TG, 2021,

Implantable brain machine interfaces: first-in-human studies, technology challenges and trends

, CURRENT OPINION IN BIOTECHNOLOGY, Vol: 72, Pages: 102-111, ISSN: 0958-1669

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Citations: 27

Journal article

Maheshwari S, Stathopoulos S, Wang J, Serb A, Pan Y, Mifsud A, Leene LB, Shen J, Papavassiliou C, Constandinou TG, Prodromakis Tet al., 2021,

Design flow for hybrid CMOS/memristor systems--Part II: circuit schematics and layout

, IEEE Transactions on Circuits and Systems I: Regular Papers, Vol: 68, Pages: 4876-4888, ISSN: 1549-8328

\normalsize The capability of in-memory computation, reconfigurability, low power operation as well as multistate operation of the memristive device deems them a suitable candidate for designing electronic circuits with a broad range of applications. Besides, the integrability of memristor with CMOS enables it to use in logic circuits too. In this work, we demonstrate with examples the design flow for memristor-based electronics, after the custom memristor model already being integrated and validated into our chosen Computer-Aided Design (CAD) tool to performing layout-versus-schematic and post-layout checks including the memristive device. We envisage that this step-by-step guide to introducing memristor into the standard integrated circuit design flow will be a useful reference document for both device developers who wish to benchmark their technologies and circuit designers who wish to experiment with memristive-enhanced systems.

Journal article

Maheshwari S, Stathopoulos S, Wang J, Serb A, Pan Y, Mifsud A, Leene LB, Shen J, Papavassiliou C, Constandinou TG, Prodromakis Tet al., 2021,

Design flow for hybrid CMOS/memristor systems--Part I: modeling and verification steps

, IEEE Transactions on Circuits and Systems I: Regular Papers, Vol: 68, Pages: 4862-4875, ISSN: 1549-8328

Memristive technology has experienced explosive growth in the last decade, with multiple device structures being developed for a wide range of applications. However, transitioning the technology from the lab into the marketplace requires the development of an accessible and user-friendly design flow, supported by an industry-grade toolchain. In this work, we demonstrate the behaviour of our in-house fabricated custom memristor model and its integration into the Cadence Electronic Design Automation (EDA) tools for verification. Various input stimuli were given to record the memristive device characteristics both at the device level as well as the schematic level for verification of the memristor model. This design flow from device to industrial level EDA tools is the first step before the model can be used and integrated with Complementary Metal-Oxide Semiconductor (CMOS) in applications for hybrid memristor/CMOS system design.

Journal article

Harding EC, Ba W, Zahir R, Yu X, Yustos R, Hsieh B, Lignos L, Vyssotski AL, Merkle FT, Constandinou TG, Franks NP, Wisden Wet al., 2021,

Nitric oxide synthase neurons in the preoptic hypothalamus are NREM and REM sleep-active and lower body temperature

, Frontiers in Neuroscience, Vol: 15, ISSN: 1662-453X

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 and REM active, especially at the boundary of wake to NREM transitions, and in the later parts of REM bouts, with lower activity during wakefulness. 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 h, 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 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.

Journal article

Ahmadi N, Constandinou T, Bouganis C, 2021,

Inferring entire spiking activity from local field potentials

, Scientific Reports, Vol: 11, Pages: 1-13, ISSN: 2045-2322

Extracellular recordings are typically analysed by separating them into two distinct signals: local field potentials (LFPs) andspikes. Previous studies have shown that spikes, in the form of single-unit activity (SUA) or multiunit activity (MUA), can beinferred solely from LFPs with moderately good accuracy. SUA and MUA are typically extracted via threshold-based techniquewhich may not be reliable when the recordings exhibit a low signal-to-noise ratio (SNR). Another type of spiking activity, referredto as entire spiking activity (ESA), can be extracted by a threshold-less, fast, and automated technique and has led to betterperformance in several tasks. However, its relationship with the LFPs has not been investigated. In this study, we aim toaddress this issue by inferring ESA from LFPs intracortically recorded from the motor cortex area of three monkeys performingdifferent tasks. Results from long-term recording sessions and across subjects revealed that ESA can be inferred from LFPswith good accuracy. On average, the inference performance of ESA was consistently and significantly higher than those of SUAand MUA. In addition, local motor potential (LMP) was found to be the most predictive feature. The overall results indicate thatLFPs contain substantial information about spiking activity, particularly ESA. This could be useful for understanding LFP-spikerelationship and for the development of LFP-based BMIs.

Conference paper

Antoniadis DD, Feng P, Mifsud A, Constandinou TGet al., 2021,

Open-source memory compiler for automatic RRAM generation and verification

, 2021 IEEE International Midwest Symposium on Circuits and Systems (MWSCAS), Publisher: IEEE, Pages: 97-100

The lack of open-source memory compilers in academia typically causes significant delays in research and design implementations. This paper presents an open-source memory compiler that is directly integrated within the Cadence Virtuoso environment using physical verification tools provided by Mentor Graphics (Calibre). It facilitates the entire memory generation process from netlist generation to layout implementation, and physical implementation verification. To the best of our knowledge, this is the first open-source memory compiler that has been developed specifically to automate Resistive Random Access Memory (RRAM) generation. RRAM holds the promise of achieving high speed, high density and non-volatility. A novel RRAM architecture, additionally is proposed, and a number of generated RRAM arrays are evaluated to identify their worst case control line parasitics and worst case settling time across the memristors of their cells. The total capacitance of lines SEL, N and P is 5.83 fF/cell, 3.31 fF/cell and 2.48 fF/cell respectively, while the total calculated resistance for SEL is 1.28 Ω/cell and 0.14 Ω/cell for both N and P lines.

Journal article

Firfilionis D, Hutchings F, Tamadoni R, Walsh D, Turnbull M, Escobedo-Cousin E, Bailey RG, Gausden J, Patel A, Haci D, Liu Y, LeBeau FEN, Trevelyan A, Constandinou TG, O'Neill A, Kaiser M, Degenaar P, Jackson Aet al., 2021,

A closed-loop optogenetic platform

, Frontiers in Neuroscience, Vol: 15, Pages: 1-10, ISSN: 1662-453X

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface. We include commercial components to validate performance, with the ultimate aim of translating this approach to humans. In the meantime our system is flexible and expandable for use in a variety of preclinical neuroscientific applications. The platform consists of a Controlling Abnormal Network Dynamics using Optogenetics (CANDO) Control System (CS) that interfaces with up to four CANDO headstages responsible for electrical recording and optical stimulation through custom CANDO LED optrodes. Control of the hardware, inbuilt algorithms and data acquisition is enabled via the CANDO GUI (Graphical User Interface). Here we describe the design and implementation of this system, and demonstrate how it can be used to modulate neuronal oscillations in vitro and in vivo.

Journal article

Constandinou TG, Tang KT, Wang G, 2021,

Editorial special section on selected papers from ISICAS 2020

, IEEE Transactions on Biomedical Circuits and Systems, Vol: 15, Pages: 646-646, ISSN: 1932-4545

Journal article

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

Alexandrou G, Moser N, Mantikas K-T, Rodriguez-Manzano J, Ali S, Coombes RC, Shaw J, Georgiou P, Toumazou C, Kalofonou Met al., 2021,

Detection of Multiple Breast Cancer ESR1 mutations on an ISFET based Lab-on-Chip Platform.

, IEEE Trans Biomed Circuits Syst, Vol: PP

ESR1 mutations are important biomarkers in metastatic breast cancer. Specifically, p.E380Q and p.Y537S mu- tations arise in response to hormonal therapies given to patients with hormone receptor positive (HR+) breast cancer (BC). This paper demonstrates the efficacy of an ISFET based CMOS integrated Lab-on-Chip (LoC) system, coupled with variant- specific isothermal amplification chemistries, for detection and discrimination of wild type (WT) from mutant (MT) copies of the ESR1 gene. Hormonal resistant cancers often lead to increased chances of metastatic disease which leads to high mortality rates, especially in low-income regions and areas with low healthcare coverage. Design and optimization of bespoke primers was carried out and tested on a qPCR instrument and then benchmarked versus the LoC platform. Assays for detection of p.Y537S and p.E380Q were developed and tested on the LoC platform, achieving amplification in under 25 minutes and sensitivity of down to 1000 copies of DNA per reaction for both target assays. The LoC system hereby presented, is cheaper and smaller than other standard industry equivalent technologies such as qPCR and sequencing. The LoC platform proposed, has the potential to be used at a breast cancer point-of-care testing setting, offering mutational tracking of circulating tumour DNA in liquid biopsies to assist patient stratification and metastatic monitoring.

Journal article

Rawson TM, Hernandez B, Moore L, Herrero P, Charani E, Ming D, Wilson R, Blandy O, Sriskandan S, Toumazou C, Georgiou P, Holmes Aet al., 2021,

A real-world evaluation of a case-based reasoning algorithm to support antimicrobial prescribing decisions in acute care

, Clinical Infectious Diseases, Vol: 72, Pages: 2103-2111, ISSN: 1058-4838

BackgroundA locally developed Case-Based Reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated.MethodsPrescribing recommendations made by a CBR algorithm were compared to decisions made by physicians in clinical practice. Comparisons were examined in two patient populations. Firstly, in patients with confirmed Escherichia coli blood stream infections (‘E.coli patients’), and secondly in ward-based patients presenting with a range of potential infections (‘ward patients’). Prescribing recommendations were compared against the Antimicrobial Spectrum Index (ASI) and the WHO Essential Medicine List Access, Watch, Reserve (AWaRe) classification system. Appropriateness of a prescription was defined as the spectrum of the prescription covering the known, or most-likely organism antimicrobial sensitivity profile.ResultsIn total, 224 patients (145 E.coli patients and 79 ward patients) were included. Mean (SD) age was 66 (18) years with 108/224 (48%) female gender. The CBR recommendations were appropriate in 202/224 (90%) compared to 186/224 (83%) in practice (OR: 1.24 95%CI:0.392-3.936;p=0.71). CBR recommendations had a smaller ASI compared to practice with a median (range) of 6 (0-13) compared to 8 (0-12) (p<0.01). CBR recommendations were more likely to be classified as Access class antimicrobials compared to physicians’ prescriptions at 110/224 (49%) vs. 79/224 (35%) (OR: 1.77 95%CI:1.212-2.588 p<0.01). Results were similar for E.coli and ward patients on subgroup analysis.ConclusionsA CBR-driven decision support system provided appropriate recommendations within a narrower spectrum compared to current clinical practice. Future work must investigate the impact of this intervention on prescribing behaviours more broadly and patient outcomes.

Conference paper

Chen Z, Bannon A, Rapeaux A, Constandinou TGet al., 2021,

Towards robust, unobtrusive sensing of respiration using UWB impulse Radar for the care of people living with dementia

, 10th International IEEE-EMBS Conference on Neural Engineering (NER), Publisher: IEEE, Pages: 866-871, ISSN: 1948-3546

The unobtrusive monitoring of vital signals and behaviour can be used to gather intelligence to support the care of people living with dementia. This can provide insights into the person's wellbeing and the neurogenerative process, as well as enable them to continue to live safely at home, thereby improving their quality of life. Within this context, this study investigated the deployability of non-contact respiration rate (RR) measurement based on an Ultra-Wideband (UWB) radar System-on-Chip (SoC). An algorithm was developed to simultaneously and continuously extract the respiration signal, together with the confidence level of the respiration signal and the target position, without needing any prior calibration. The radar-measured RR results were compared to the RR results obtained from a ground truth measure based on the breathing sound, and the error rates were within 8% with a mean value of 2.5%. The target localisation results match to the radar-to-chest distances with a mean error rate of 5.8%. The tested measurement range was up to 5m. The results suggest that the algorithm could perform sufficiently well in non-contact stationary respiration rate detection.

Conference paper

Zhang Z, Constandinou TG, 2021,

A robust and automated algorithm that uses single-channel spike sorting to label multi-channel Neuropixels data

, 10th International IEEE-EMBS Conference on Neural Engineering (NER), Publisher: IEEE, Pages: 783-787, ISSN: 1948-3546

This paper describes preliminary work towards an automated algorithm for labelling Neuropixel data that exploits the fact that adjacent recording sites are spatially oversampled. This is achieved by combining classical single channel spike sorting with spatial spike grouping, resulting in an improvement in both accuracy and robustness. This is additionally complemented by an automated method for channel selection that determines which channels contain high quality data. The algorithm has been applied to a freely accessible dataset, produced by Cortex Lab, UCL. This has been evaluated to have a accuracy of over 77% compared to a manually curated ground truth.

Conference paper

Savolainen OW, Constandinou TG, 2021,

Investigating the effects of macaque primary motor cortex multi-unit activity binning period on behavioural decoding performance

, 10th International IEEE-EMBS Conference on Neural Engineering (NER), Publisher: IEEE, Pages: 436-439, ISSN: 1948-3546

This paper investigates the relationship between Multi-Unit Activity (MUA) Binning Period (BP) and Brain-Computer Interface (BCI) decoding performance using Long-Short Term Memory decoders. The motivation is to determine whether lossy compression of MUA via increasing BP has any adverse consequences for BCI Behavioral Decoding Performance (BDP). The Neural data originates from intracortical recordings from Macaque Primary Motor cortex. The BDP is measured by the Pearson correlation r between the observed and predicted velocity of the subject's X- Y hand coordinates in reaching tasks. The results suggest a statistically significant but slight linear relationship between increasing MUA BP and decreasing BDP. For example, when using a 100 ms moving average window, increasing the BP by 10 ms on average reduces the BDP r by approximately 0.85%. This relationship may be due to the reduced number of training examples, or due to the loss of Behavioral information because of reduced MUA temporal resolution.

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