Title: Electrophysiological-mechanical coupled pulses in neural membranes: a new paradigm for clinical therapy of SCI and TBI (NeuroPulse)
Funder: Engineering and Physical Sciences Research Council

Abstract: Traumatic Brain Injury (TBI) is a major public health issue with over 10m incidents resulting in death or in hospitalisation annually occurring worldwide. In Europe, an average incidence of 235/100,000 per year is estimated, with most countries experiencing an incidence in the range of 150-300/100,000, leading to a direct healthcare cost of EUR2.9b per year. The World Health Organization estimates that TBI will surpass many diseases as the major cause of death and disability by 2020. The other constituent of the central nervous system is the spinal cord. Damage to the spinal cord, or Spinal Cord Injury (SCI), thus shares many similarities with TBI, but also independently leads to pain and/or motor impairments ranging from incontinence to paralysis. In addition to potentially occurring simultaneously with TBI in many situations, mild SCI alone can cost in the US as much as $334,170 the first year followed by $40,589 the subsequent years. Severe SCIs reach the staggering figure of $1m for the first year alone. In the UK, this corresponds to an overall cost of £1b per year. A direct consequence of TBI and SCI, but of a much wider scope, pain management is discretely posing itself as one of the most important healthcare costs in the UK, reaching an evaluated £774m in direct cost and £4,338m in employment related cost for back pain alone in 1998, which, extrapolated to this decade, implies a total current cost of back pain in excess of £10b a year. The recent increase in the number of research campaigns on TBI and SCI has drastically improved the understanding of the coupled role of micromechanics and electrophysiology at the neuron level. More particularly, the PI of this proposal has focussed his recent research on the development of in silico models aimed at capturing the electrophysiological alterations of neurons when submitted to a mechanical insult. In parallel to this, recent findings suggesting a direct coupling between mechanical vibration and electrical pulses in healthy neuron action potential propagation open the door to a new series of evolution for this simulation platform, as well as potentially a novel approach for the understanding of TBI and SCI. However, the intrinsic relationship between mechanical vibrations (among which ultrasounds) and their biophysical implications is still widely ignored in this context. Said otherwise, whereas the effect of mechanical damage on the neuronal functional properties is currently heavily studied, the intrinsic coupling between mechanics and electrophysiology in healthy neurons is still not fully understood. As a direct consequence, the effect of functional alteration due to a mechanical insult on the vibrational mechanical properties of a neuron has so far been fully ignored. NeuroPulse thus aims at developing and utilising state of the art modelling approaches for the study of electrophysiological and mechanical coupling in a healthy and mechanically damaged axon, nerve and eventually spinal cord and brain white matter tract. The resulting in silico platform will be calibrated and validated by means of a comprehensive experimental programme in collaboration with the Department of Physics of the University of Oxford. Two teams of clinical project partners in Oxford and Cambridge will participate to the analysis of the results for direct applications in a clinical setting. More specifically, the project will aim at a) evaluating the role of this newly identified electrophysiological-mechanical coupling in pulses in TBI/SCI related functional deficits and, as a pilot application, b) at posing the bases for the design of a device leveraging this coupling for spinal cord pain management by cancelling effect (and reversibly, for signal enhancement). Both objectives will considerably benefit the medical community in the diagnosis, prognosis, and treatment of TBI and SCI, while providing new avenues for non-invasive electrophysiological control.

Lay abstract: NeuroPulse is tackling three of the four pillars of the Healthcare Technologies Grand Challenges: a) the development of future therapies aimed at leveraging neuron electrophysiological-mechanical coupling (EMC) to modify or quantify electrophysiological properties by control over the mechanical properties, b) treatment optimisation by non-invasive pain treatment and functional deficit detection in Traumatic Brain Injuries (TBI) and Spinal Cord Injuries (SCI), and c) transforming community health and care by alleviating the need for primary care to "second guess" the patients' symptoms (as is unfortunately often the case in TBI), and provide an objective roadmap for damage quantification. These challenges will be achieved by reaching the following set of project, personal, and clinical objectives: -Project objectives: 1. Design an in silico platform constituted of scale dedicated models linked together through multiscale methods: a) A Molecular Dynamics model of membrane EMC during pulse propagation b) An axon model based on in-house code Neurite able to capture propagation of electrophysiological-mechanical pulses in individual axons (with and without damage) calibrated from Model 1.a c) Extension of Model 1.b to nerves (with and without damage) by statistical behaviour averaging d) Development of a novel homogenised constitutive model of EMC at the brain and spinal cord tissue level (with and without damage) calibrated from Model 1.c e) Continuum model with and without damage using constitutive Model 1.d of: i.spinal cord signal propagation (embedded in neighbouring organs) based on medical images ii.brain white matter tracts based on "connectomically" correct head model 2. Calibrate and validate the healthy models with a thorough experimental programme making use of: a) Artificial lipid membranes to measure the mechanical response when submitted to mechanical vibrations by use of Atomic Force Microscopy b) An electrophysiologically stimulated neuron with simultaneous mechanical vibration measurements by defocussing microscopy c) A mechanically stimulated neuron (by use of optical tweezer) with simultaneous electrophysiological measurements 3. Evaluate the relevance of EMC in pulses in an in vivo setting by use of Model 1.e 4. Complement current studies by evaluating EMC for damaged membranes as resulting from TBI and/or SCI using Model 1.e and Experiments 2 when possible -Clinical objectives: 1. Enhance knowledge of the role of mechanics in electrophysiological signal propagation (e.g., in ion channels) 2. Study the effect of mechanical waves in TBI/SCI context, and review current knowledge in light of findings 3. Pave the road for a subsequent project aimed at designing an electrical signal cancelling device by dynamic mechanical stimulation (the chosen pilot application is spinal cord pain therapy, but signal enhancement or epilepsy control in the brain will also be considered) 4. Identify a set of other applications potentially benefiting from the project outcomes 5. If the state of advancement of project allows, make use of Model 1.e for comparison/validation against Research Tissue Bank tissue (e.g., ODB) experimental tests in collaboration with Oxford and Cambridge medical partners -Personal objectives: 1. Establish myself as a leader in engineering-driven TBI and SCI research, and a new player in pain therapy 2. Establish new expertise and network for medical solution by engineering medical device design and development 3. Leverage NeuroPulse to transform the recently (and so far virtual) founded International Brain Mechanics and Trauma Lab into a physical multisciplinary lab in collaboration with the Department of Engineering Science, and by ensuring a long term collaboration with Oxford and Cambridge Medical partners, especially with the Cambridge NIHR Healthcare Technology Cooperative for Acute Brain Injury

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL