Multicohort cross-sectional study of cognitive and behavioural digital biomarkers in neurodegeneration: the Living Lab Study protocol

INTRODUCTION AND AIMS: Digital biomarkers can provide a cost-effective, objective and robust measure for neurological disease progression, changes in care needs and the effect of interventions. Motor function, physiology and behaviour can provide informative measures of neurological conditions and neurodegenerative decline. New digital technologies present an opportunity to provide remote, high-frequency monitoring of patients from within their homes. The purpose of the living lab study is to develop novel digital biomarkers of functional impairment in those living with neurodegenerative disease (NDD) and neurological conditions. METHODS AND ANALYSIS: The Living Lab study is a cross-sectional observational study of cognition and behaviour in people living with NDDs and other, non-degenerative neurological conditions. Patients (n≥25 for each patient group) with dementia, Parkinson's disease, amyotrophic lateral sclerosis, mild cognitive impairment, traumatic brain injury and stroke along with controls (n≥60) will be pragmatically recruited. Patients will carry out activities of daily living and functional assessments within the Living Lab. The Living Lab is an apartment-laboratory containing a functional kitchen, bathroom, bed and living area to provide a controlled environment to develop novel digital biomarkers. The Living Lab provides an important intermediary stage between the conventional laboratory and the home. Multiple passive environmental sensors, internet-enabled medical devices, wearables and electroencephalography (EEG) will be used to characterise functional impairments of NDDs and non-NDD conditions. We will also relate these digital technology measures to clinical and cognitive outcomes. ETHICS AND DISSEMINATION: Ethical approvals have been granted by the Imperial College Research Ethics Committee (reference number: 21IC6992). Results from the study will be disseminated at conferences and within peer-reviewed journals

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

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

HFAC dose repetition and accumulation leads to progressively longer block carryover effect in rat sciatic nerve

This paper describes high-frequency nerve block experiments carried out on rat sciatic nerves to measure the speed of recovery of A fibres from block carryover. Block carryover is the process by which nerve excitability remains suppressed temporarily after High Frequency Alternative (HFAC) block is turned off following its application. In this series of experiments 5 rat sciatic nerves were extracted and prepared for ex-vivo stimulation and recording in a specially designed perfusion chamber. For each nerve repeated HFAC block and concurrent stimulation trials were carried out to observe block carryover after signal shutoff. The nerve was allowed to recover fully between each trial. Time to recovery from block was measured by monitoring for when relative nerve activity returned to within 90% of baseline levels measured at the start of each trial. HFAC block carryover duration was found to be dependent on accumulated dose by statistical test for two different HFAC durations. The carryover property of HFAC block on A fibres could enable selective stimulation of autonomic nerve fibres such as C fibres for the duration of carryover. Block carryover is particularly relevant to potential chronic clinical applications of block as it reduces power requirements for stimulation to provide the blocking effect. This work characterises this process towards the creation of a model describing its behaviour

An HFAC block-capable and module-extendable 4-channel stimulator for acute neurophysiology

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 and integration of functions with one controller. Additionally, all source files including all code and PCB design files are freely available to the community to use and further develop

The crucial role of nerve depolarisation in high frequency conduction block in mammalian nerves: simulation study

Neurostimulations which use High Frequency Alternating Current (HFAC) block show great promise for neuromodulatory therapies. Treatments have been developed for various health conditions including obesity and obesity related health risks, and now even stomach cancer treatments are being considered. However the mechanism of the block is still not completely clear, as well as how various neural and electrode parameters affect it. In order to study conduction block during HF stimulation in mammalian axons, we describe a detailed computational model and perform comprehensive simulations. We establish relationships between the blocking frequency and amplitude versus fibre diameter and the distance between the electrode and fibre. We found that only a certain level of depolarisation will universally create a block irrespective of the fibre size, and it is in the range 24-30mV depending on the stimulus frequency. Our study crucially improves our knowledge about this important technique which is rapidly emerging as a commercially available therapy

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

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

Recovery Dynamics of the High Frequency Alternating Current Nerve Block

Objective: High-Frequency alternating current (HFAC) nerve block has great potential for neuromodulation-based therapies. However nerve function recovery dynamics after a block is highly understudied. This study aims to characterise the recovery dynamics of neural function after an HFAC block. Approach: Experiments were carried out in-vivo to determine blocking efficacy as a function of blocking signal amplitude and frequency, and recovery times as well as recovery completeness was measured within a 0.7s time scale from the end of block. The sciatic nerve was stimulated at 100 Hz during recovery to reduce error to within ±10 ms for measurements of recovery dynamics. The electromyogram (EMG) signals were measured from gastrocnemius medialis and tibialis anterior during trials as an indicator for nerve function. Main Results: The HFAC block was most reliable around 20 kHz, with block thresholds approximately 5 or 6 mA depending on the animal and muscle. Recovery times ranged from 20 to 430 milliseconds and final values spanned relative outputs from approximately 1 to 0.2. Higher blocking signal frequencies and amplitudes increased recovery time and decreased recovery completeness. Significance: These results confirm that recovery dynamics from block depend on blocking signal frequency and amplitude, which is of particular importance for neuromodulation therapies and for comparing results across studies using different blocking signal parameters

A 64-Channel Versatile Neural Recording SoC with Activity Dependant Data Throughput

Modern microtechnology is enabling the channel count of neural recording integrated circuits to scale exponentially. However, the raw data bandwidth of these systems is increasing proportionately, presenting major challenges in terms of power consumption and data transmission (especially for wireless systems). This paper presents a system that exploits the sparse nature of neural signals to address these challenges and provides a reconfigurable low-bandwidth event-driven output. Specifically, we present a novel 64-channel low noise (2.1μVrms, low power (23μW per analogue channel) neural recording system-on-chip (SoC). This features individually-configurable channels, 10-bit analogue-to-digital conversion, digital filtering, spike detection, and an event-driven output. Each channel's gain, bandwidth & sampling rate settings can be independently configured to extract Local Field Potentials (LFPs) at a low data-rate and/or Action Potentials (APs) at a higher data rate. The sampled data is streamed through an SRAM buffer that supports additional on-chip processing such as digital filtering and spike detection. Real-time spike detection can achieve ~2 orders of magnitude data reduction, by using a dual polarity simple threshold to enable an event driven output for neural spikes (16-sample window). The SoC additionally features a latency-encoded asynchronous output that is critical if used as part of a closed-loop system. This has been specifically developed to complement a separate on-node spike sorting co-processor to provide a real-time (low latency) output. The system has been implemented in a commercially-available 0.35μm CMOS technology occupying a silicon area of 19.1mm² (0.3mm² gross per channel), demonstrating a low power & efficient architecture which could be further optimised by aggressive technology and supply voltage scaling