Electrophysiological-mechanical coupled pulses in neural membranes: a new paradigm for clinical therapy of SCI and TBI (NeuroPulse)

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 ps 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.

NeuroPulse encompasses three of the four pillars of the Healthcare Technologies Grand Challenges: a) the development of future therapies aimed at leveraging neuron electrophysiological-mechanical coupling to modify or quantify electrophysiological properties by control over the mechanical properties, b) treatment optimisation by potentially inexpensive non-invasive pain treatment and possibly functional deficit detection, 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. Doing so, NeuroPulse will help decrease the societal and economic burden of TBI, SCI and pain management in the UK, and worldwide. The tremendous economic implications of these efforts for the UK (see Summary Abstract) and the envisioned translational activity will be achieved as follows.

The current network and team of the PI already involve many scientific disciplines (e.g., Engineering, Mathematics, Physics and Biology), including Co-I Prof Contera from the Department of Physics (in NeuroPulse, Prof Contera will provide her state-of-the-art experimental expertise to support the numerical efforts of the PI). Additionally, over the course of his efforts to create the International Brain Mechanics and Trauma Lab (IBMTL), the PI has consolidated a strong network of neurosurgeons and neuroscientists. With the support of University of Oxford's Department of Engineering Science, NeuroPulse will build the ideal framework (until now merely virtual) to concretise their dedicated interest in clinically driven engineering solutions by transforming the IBMTL into a physical multisciplinary lab.

In addition, so as to guarantee a direct implication of the medical (and military) community into the envisioned pilot application, Dr Jenkins, an Army Medical Officer lecturing in Neurology and a Fellow in Medicine in St Hugh's College was identified as a project partner. He is a member of the University of Oxford Multiple Sclerosis (MS) Neuropathology Research Group focussed on multidisciplinary studies of brain and spinal cord tissue in the context of MS, and aimed at ensuring that the understanding derived from these studies translates into ideas for improved treatments of patients. Dr Jenkins will be in charge of centralising the additional participation of Mr Lawrence, a consultant paediatric neurosurgeon in the John Radcliffe Hospital focussing on biomarkers identification of TBI symptoms, as well as a novel unique collaboration with University of Cambridge Prof Menon, Head of Division of Anaesthesia and Acute Care Lead in the Cambridge NIHR Healthcare Technology Cooperative for Acute Brain Injury, and Dr Ercole, consultant anaesthetist specialised in resuscitation and neurocritical care. Prof Menon is Co-Chair of the European Brain Injury Consortium, one of the coordinators of the current CENTER-TBI study and Co-Chair of the Acute Brain Injury program at Cambridge. Dr Ercole is also part of the CENTER-TBI consortium, and leads a research theme on mechanical, physiological, and metabolic modelling of human brain injury. In addition, Prof Menon's role as Head of the Division of Anaesthesia will provide access to a productive pain research group and facilitate the exploitation of research outputs that relate to pain management or more generally electrophysiological control by mechanical means. His involvement will also provide a means of disseminating NeuroPulse's research to the broader clinical community through his role in the NIHR Cambridge Biomedical Research Centre.

Finally Dr Malboubi will be hired as a Researcher Co-I to leverage the expertise and wide research connectivity of the medical partners by ensuring the dissemination of the research outputs from NeuroPulse, and identifying with the PI opportunities for translational activity and grant funding.