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  • Journal article
    Khan S, Anderson W, Constandinou T, 2024,

    Surgical Implantation of Brain Computer Interfaces.

    , JAMA Surg, Vol: 159, Pages: 219-220
  • Journal article
    Alexandrou G, Mantikas K-T, Allsopp R, Yapeter CA, Jahin M, Melnick T, Ali S, Coombes RC, Toumazou C, Shaw JA, Kalofonou Met al., 2023,

    The evolution of affordable technologies in liquid biopsy diagnostics: the key to clinical implementation

    , Cancers, Vol: 15, ISSN: 2072-6694

    Cancer remains a leading cause of death worldwide, despite many advances in diagnosis and treatment. Precision medicine has been a key area of focus, with research providing insights and progress in helping to lower cancer mortality through better patient stratification for therapies and more precise diagnostic techniques. However, unequal access to cancer care is still a global concern, with many patients having limited access to diagnostic tests and treatment regimens. Noninvasive liquid biopsy (LB) technology can determine tumour-specific molecular alterations in peripheral samples. This allows clinicians to infer knowledge at a DNA or cellular level, which can be used to screen individuals with high cancer risk, personalize treatments, monitor treatment response, and detect metastasis early. As scientific understanding of cancer pathology increases, LB technologies that utilize circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) have evolved over the course of research. These technologies incorporate tumour-specific markers into molecular testing platforms. For clinical translation and maximum patient benefit at a wider scale, the accuracy, accessibility, and affordability of LB tests need to be prioritized and compared with gold standard methodologies in current use. In this review, we highlight the range of technologies in LB diagnostics and discuss the future prospects of LB through the anticipated evolution of current technologies and the integration of emerging and novel ones. This could potentially allow a more cost-effective model of cancer care to be widely adopted.

  • Journal article
    Tossell K, Yu X, Giannos P, Anuncibay Soto B, Nollet M, Yustos R, Miracca G, Vicente M, Miao A, Hsieh B, Ma Y, Vysstoski A, Constandinou T, Franks N, Wisden Wet al., 2023,

    Somatostatin neurons in prefrontal cortex initiate sleep preparatory behavior and sleep via the preoptic and lateral hypothalamus

    , Nature Neuroscience, Vol: 26, Pages: 1805-1819, ISSN: 1097-6256

    The prefrontal cortex (PFC) enables mammals to respond to situations, including internal states, with appropriate actions. One such internal state could be ‘tiredness’. Here, using activity tagging in the mouse PFC, we identified particularly excitable, fast-spiking, somatostatin-expressing, γ-aminobutyric acid (GABA) (PFCSst-GABA) cells that responded to sleep deprivation. These cells projected to the lateral preoptic (LPO) hypothalamus and the lateral hypothalamus (LH). Stimulating PFCSst-GABA terminals in the LPO hypothalamus caused sleep-preparatory behavior (nesting, elevated theta power and elevated temperature), and stimulating PFCSst-GABA terminals in the LH mimicked recovery sleep (non-rapid eye-movement sleep with higher delta power and lower body temperature). PFCSst-GABA terminals had enhanced activity during nesting and sleep, inducing inhibitory postsynaptic currents on diverse cells in the LPO hypothalamus and the LH. The PFC also might feature in deciding sleep location in the absence of excessive fatigue. These findings suggest that the PFC instructs the hypothalamus to ensure that optimal sleep takes place in a suitable place.

  • Journal article
    Zhang Z, Feng P, Oprea A, Constandinou Tet al., 2023,

    Calibration-free and hardware-efficient neural spike detection for brain machine interfaces

    , IEEE Transactions on Biomedical Circuits and Systems, Vol: 17, Pages: 725-740, ISSN: 1932-4545

    Recent translational efforts in brain-machine interfaces (BMI) are demonstrating the potential to help people with neurological disorders. The current trend in BMI technology is to increase the number of recording channels to the thousands, resulting in the generation of vast amounts of raw data. This in turn places high bandwidth requirements for data transmission, which increases power consumption and thermal dissipation of implanted systems. On-implant compression and/or feature extraction are therefore becoming essential to limiting this increase in bandwidth, but add further power constraints – the power required for data reduction must remain less than the power saved through bandwidth reduction. Spike detection is a common feature extraction technique used for intracortical BMIs. In this paper, we develop a novel firing-rate-based spike detection algorithm that requires no external training and is hardware efficient and therefore ideally suited for real-time applications. Key performance and implementation metrics such as detection accuracy, adaptability in chronic deployment, power consumption, area utilization, and channel scalability are benchmarked against existing methods using various datasets. The algorithm is first validated using a reconfigurable hardware (FPGA) platform and then ported to a digital ASIC implementation in both 65 nm and 0.18MU m CMOS technologies. The 128-channel ASIC design implemented in a 65 nm CMOS technology occupies 0.096 mm2 silicon area and consumes 4.86MU W from a 1.2 V power supply. The adaptive algorithm achieves a 96% spike detection accuracy on a commonly used synthetic dataset, without the need for any prior training.

  • Journal article
    Cavallo FR, Toumazou C, 2023,

    Personalised lifestyle recommendations for type 2 diabetes: Design and simulation of a recommender system on UK Biobank Data.

    , PLOS Digit Health, Vol: 2

    Mobile health applications, which employ wireless technology for healthcare, can aid behaviour change and subsequently improve health outcomes. Mobile health applications have been developed to increase physical activity, but are rarely grounded on behavioural theory and employ simple techniques for personalisation, which has been proven effective in promoting behaviour change. In this work, we propose a theoretically driven and personalised behavioural intervention delivered through an adaptive knowledge-based system. The behavioural system design is guided by the Behavioural Change Wheel and the Capability-Opportunity-Motivation behavioural model. The system exploits the ever-increasing availability of health data from wearable devices, point-of-care tests and consumer genetic tests to issue highly personalised physical activity and sedentary behaviour recommendations. To provide the personalised recommendations, the system firstly classifies the user into one of four diabetes clusters based on their cardiometabolic profile. Secondly, it recommends activity levels based on their genotype and past activity history, and finally, it presents the user with their current risk of developing cardiovascular disease. In addition, leptin, a hormone involved in metabolism, is included as a feedback biosignal to personalise the recommendations further. As a case study, we designed and demonstrated the system on people with type 2 diabetes, since it is a chronic condition often managed through lifestyle changes, such as physical activity increase and sedentary behaviour reduction. We trained and simulated the system using data from diabetic participants of the UK Biobank, a large-scale clinical database, and demonstrate that the system could help increase activity over time. These results warrant a real-life implementation of the system, which we aim to evaluate through human intervention.

  • Journal article
    Wong SS, Malik A, Ekanayake J, Constandinou TGet al., 2023,

    Towards Real-time Multiplexed Bioimpedance Tumour-Tissue Margin Analysis.

    , Annu Int Conf IEEE Eng Med Biol Soc, Vol: 2023, Pages: 1-5

    Bioimpedance varies with physical tissue characteristics. As such it can be used for real-time tissue discrimination. This has led to its application as a surgical mapping tool to differentiate between healthy and abnormal tissue intraoperatively during tumour resection. Here, we build on previous work implementing a probe-based tetrapolar bioimpedance systems demonstrator, now extracting additional information for margin analysis with imperfect bioimpedance visibility. Through finite element analysis, we show preliminary findings using a single measurement with a multiplexed tetrapolar bioimpedance probe for identifying tissue boundaries, applied to porcine tissue as a surrogate for a tumour-tissue interface.

  • Journal article
    Zhang Z, Constandinou TG, 2023,

    Firing-rate-modulated spike detection and neural decoding co-design

    , JOURNAL OF NEURAL ENGINEERING, Vol: 20, ISSN: 1741-2560
  • Journal article
    Martinez S, Veirano F, Constandinou TGG, Silveira Fet al., 2023,

    Trends in Volumetric-Energy Efficiency of Implantable Neurostimulators: A Review From a Circuits and Systems Perspective

    , IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, Vol: 17, Pages: 2-20, ISSN: 1932-4545
  • Journal article
    Zhang Z, Constandinou TG, 2023,

    Firing-rate-modulated spike detection and neural decoding co-design

    <jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Translational efforts on spike-signal-based implantable brain-machine interfaces (BMIs) are increasingly aiming to minimise bandwidth while maintaining decoding performance. Developing these BMIs requires advances in neuroscience and electronic technology, as well as using low-complexity spike detection algorithms and high-performance machine learning models. While some state-of-the-art BMI systems jointly design spike detection algorithms and machine learning models, it remains unclear how the detection performance affects decoding.</jats:p></jats:sec><jats:sec><jats:title>Approach</jats:title><jats:p>We propose the co-design of the neural decoder with an ultra-low complexity spike detection algorithm. The detection algorithm is designed to attain a target firing rate, which the decoder uses to modulate the input features preserving statistical invariance.</jats:p></jats:sec><jats:sec><jats:title>Main results</jats:title><jats:p>We demonstrate a multiplication-free fixed-point spike detection algorithm with nearly perfect detection accuracy and the lowest complexity among studies we have seen. By co-designing the system to incorporate statistically invariant features, we observe significantly improved long-term stability, with decoding accuracy degrading by less than 10% after 80 days of operation. Our analysis also reveals a nonlinear relationship between spike detection and decoding performance. Increasing the detection sensitivity improves decoding accuracy and long-term stability, which means the activity of more neurons is beneficial despite the detection of more noise. Reducing the spike detection sensitivity still provides acceptable decoding accuracy whilst reducing the bandwidth by at least 30%.</jats:p></jats:sec><jats:sec><jats:title>Signifi

  • Conference paper
    Hyanda MH, Ahmadi N, Charlton PH, Constandinou TG, Purwarianti A, Adiono Tet al., 2023,

    A Comparative Evaluation of Video Codecs for rPPG-based Heart Rate Estimation

    , Pages: 243-247

    Remote photoplethysmography (rPPG) is a noninvasive technology that can be used to extract heart rate (HR) from video data. Video codecs are typically used for compressing video, which allows for efficient data storage, but could negatively impact the accuracy of HR estimation. To date, only limited number of studies investigate the impact of video codecs on rPPG-based HR estimation. In this paper, we present a comprehensive comparative evaluation of video codecs for rPPG-based HR estimation. Several factors being compared include video encoders, video containers, quality rate mode, and resolution. Experimental results using in-house dataset show that the lossy encoder like VP9 yield good performance nearly similar to the lossless counterparts. Additionally, the.avi container is preferable because it can contain all encoders tested except x265 (HEVC). Varying the resolution significantly affects the file size and accuracy of HR estimation. This study provides useful information for the creation of rPPG dataset and development of rPPG algorithm.

  • Conference paper
    Wong SS, Radford J, Faccio D, Constandinou TG, Ekanayake Jet al., 2023,

    Multielectrode Multiplexing for Bioimpedance Surface Topography Mapping

    Traditional bioimpedance point scanning for tissue identification successively measures tissue electrical properties at discrete locations; this process is not optimised for developing a bioimpedance map with sufficient spatial resolution in a short time frame to reflect the underlying tissue topography. We build on previous work implementing a tetrapolar bioimpedance measuring system, with a novel combination of computational bioimpedance multiplexing and a multi-electrode architecture. Experimental results were obtained from porcine tissue, using a 12-electrode probe with 14.3 seconds of recorded data sampled at 1MSPS. The reconstructed bioimpedance image resembles the tissue sample RGB image and can provide mesoscopic tissue structural information, surpassing the spatial resolution previously limited by electrode pitch size. The spatial resolution obtained with our approach scales exponentially with the number of electrodes, with an adaptable electrode geometry to achieve optimal reconstructed bioimpedance maps for real-time tissue identification.

  • Conference paper
    Meimandi A, Feng P, Carminati M, Constandinou TG, Carrara Set al., 2023,

    Implantable Biosensor for Brain Dopamine using Microwire-Based Electrodes

    This paper systematically demonstrates the feasibility of wirelessly monitoring dopamine concentration in the brain with an implantable biosensor. The biosensor was realized using microwires, and then, the dopamine concentration was measured in-vitro ranging from 0.3 μ M to 2 μ M, corresponding to the physio-pathological concentration range in human brain. The obtained results were used to design and optimise a full-custom CMOS sensor interface for in-vivo dopamine monitoring. The key component of this interface is a potentiostat with a maximum power consumption of 10.24 μ W in a 10kHz sampling frequency. The CMOS interface automatically subtracts the background current up to 2.34 μ A. The obtained sensitivity in dopamine detection has been evaluated in 150μ A/μ M, with a Limit of Detection (LoD) of 33 nM, thus being suitable for dopamine monitoring in human brain.

  • Conference paper
    Wong SS, Radford J, Binner P, Gradauskas V, Constandinou TG, Ekanayake J, Faccio Det al., 2023,

    Multimodal Approaches for Real-time Mesoscopic Tissue Differentiation

    Multi-modality imaging techniques that integrate sensor data from different domains have shown immense potential in the field of clinical diagnostics. This paper aims to provide a comprehensive approach to delineating surface topology and tissue boundaries resolved at the mesoscopic scale with electrical (bioimpedance), mechanical (force-related haptics) and optical technologies (diffuse correlation spectroscopy and time-domain near-infrared spectroscopy). This preliminary work lays the foundations for comparing and combining next-generation approaches for real-time tissue identification.

  • Conference paper
    Alexandrou G, Moser N, Ali S, Coombes C, Shaw J, Georgiou P, Toumazou C, Kalofonou Met al., 2023,

    Distinguishing <i>PIK3CA</i> p.E545K mutational status from pseudogene DNA with a next-generation ISFET sensor array

    , 56th IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, ISSN: 0271-4302
  • Conference paper
    Nairac Z, Constandinou TG, 2023,

    Design of a Novel, Low-Cost System for Neural Electrical Impedance Tomography

    , 11th International IEEE EMBS Conference on Neural Engineering (IEEE/EMBS NER), Publisher: IEEE, ISSN: 1948-3546
  • Conference paper
    Ozbek B, Constandinou TG, 2023,

    An Autonomous Zero-Mask Unique ID Generation System for Next-Generation Neural Interfaces

    , 21st IEEE Interregional NEWCAS Conference (NEWCAS), Publisher: IEEE, ISSN: 2472-467X
  • Conference paper
    Mifsud A, Constandinou TG, 2023,

    Towards a CMOS-Process-Portable ReRAM PDK

    , 21st IEEE Interregional NEWCAS Conference (NEWCAS), Publisher: IEEE, ISSN: 2472-467X
  • Journal article
    Stanchieri GDP, De Marcellis A, Battisti G, Faccio M, Palange E, Constandinou TGet al., 2022,

    A Multilevel Synchronized Optical Pulsed Modulation for High Efficiency Biotelemetry

    , IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, Vol: 16, Pages: 1313-1324, ISSN: 1932-4545
  • Journal article
    Savolainen OW, Zhang Z, Constandinou TG, 2022,

    Ultra Low Power, Event-Driven Data Compression of Multi-Unit Activity

    <jats:title>Abstract</jats:title><jats:p>Recent years have demonstrated the feasibility of using intracortical Brain-Machine Interfaces (iBMIs), by decoding thoughts, for communication and cursor control tasks. iBMIs are increasingly becoming wireless due to the risk of infection and mechanical failure, typically associated with percutaneous connections. The wireless communication itself, however, increases the power consumption further; with the total dissipation being strictly limited due to safety heating limits of cortical tissue. Since wireless power is typically proportional to the communication bandwidth, the output Bit Rate (BR) must be minimised. Whilst most iBMIs utilise Multi-Unit activity (MUA), i.e. spike events, and this in itself significantly reduces the output BR (compared to raw data), it still limits the scalability (number of channels) that can be achieved. As such, additional compression for MUA signals are essential for fully-implantable, high-information-bandwidth systems. To meet this need, this work proposes various hardware-efficient, ultra-low power MUA compression schemes. We investigate them in terms of their BRs and hardware requirements as a function of various on-implant conditions such as MUA Binning Period (BP) and number of channels. It was found that for BPs ≤ 10 ms, the delta-asynchronous method had the lowest total power and reduced the BR by almost an order of magnitude relative to classical methods (e.g. to approx. 151 bps/channel for a BP of 1 ms and 1000 channels on-implant.). However, at larger BPs the synchronous method performed best (e.g. approx. 29 bps/channel for a BP of 50 ms, independent of channel count). As such, this work can guide the choice of MUA data compression scheme for BMI applications, where the BR can be significantly reduced in hardware efficient ways. This enables the next generation of wireless iBMIs, with small implant sizes, high channel counts, low-power, and small hardware foo

  • Conference paper
    Mifsud A, Shen J, Feng P, Xie L, Wang C, Pan Y, Maheshwari S, Agwa S, Stathopoulos S, Wang S, Serb A, Papavassiliou C, Prodromakis T, Constandinou TGet al., 2022,

    A CMOS-based characterisation platform for emerging RRAM technologies

    , 2022 IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, Pages: 75-79

    Mass characterisation of emerging memory devices is an essential step in modelling their behaviour for integration within a standard design flow for existing integrated circuit designers. This work develops a novel characterisation platform for emerging resistive devices with a capacity of up to 1 million devices on-chip. Split into four independent sub-arrays, it contains on-chip column-parallel DACs for fast voltage programming of the DUT. On-chip readout circuits with ADCs are also available for fast read operations covering 5-decades of input current (20nA to 2mA). This allows a device’s resistance range to be between 1kΩ and 10MΩ with a minimum voltage range of ±1.5V on the device.

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