Birmingham Spinal Cord Injury Research

The role of water channel protein, aquaporin-4 in spinal cord injury (Ahmed, Bill)

Impairment of the blood–spinal cord barrier (BSCB) after spinal cord injury is the second most common insult after ischemia reperfusion (IR) injury and it is associated with poor prognosis, such as paralysis or even death. Aquaporins (AQP) are small membrane proteins of epithelial and/or glial cell origin and permit passive water diffusion in the development of cytotoxic as well as vasogenic oedema during various pathophysiological injury such as neuroinflammation, ischemia and trauma. AQP4 is recognized as the major pathway for water homeostasis in the CNS and we have recently shown that inhibitors of AQP4 relocalisation can prevent spinal cord injury-induced oedema and thus improved functional outcomes. We are now exploring these mechanisms to understand how oedema can be controlled in spinal cord injury.

The role of DNA damage inhibitors in spinal cord injury (Ahmed, Tuxworth)

Double strand breaks (DSBs) are the most deleterious type of DNA damage in mitotically active cells and trigger the DNA damage response to arrest the cell cycle and attempt repair via non-homologous end-joining in G1 or G2 phases or homologous recombination in M and S phases. DSBs also feature in acute and long-term neurological disorders, including many forms of neurodegeneration, following neurotrauma and after stroke. Unrepaired DSBs in neurons lead to persistent activation of the DNA damage response which, in turn, causes neural dysfunction and can trigger aberrant re-entry of neurons into G1, leading to apoptosis and senescence.

Our novel work has shown that attenuating the DNA damage response in neurons slows loss of neural function in Drosophila models of neurodegeneration and also prevents neural loss, preserves function after acute trauma to the optic nerve and spinal cord (Tuxworth et al., 2019). These results have enormous implications for SCI patients, suggesting inhibition of this pathway could promote both neuroprotection and axon regeneration. We are currently testing various small molecule inhibitors in this pathway to identify suitable targets for therapeutic intervention in spinal cord injured patients.

Decorin as an anti-scarring agent after spinal cord injury (Ahmed)

In most mammals, progressive tissue necrosis occurs after SCI leading to the formation of fluid filled cavities and is potentially a life-threatening condition in humans. Several lines of evidence suggest that promotion of angiogenesis improved wound healing and reduces cavitation after SCI. We are using state-of-the-art gene detection studies, including microarray and deep sequencing technologies to identify genes involved in angiogenesis/wound healing with the aim of reducing cavitation after spinal cord injury.

Definition of genes that contribute to axon regeneration after SCI (Ahmed, Alhajlah)

In contrast to adult neurons of the peripheral nervous system, damaged CNS axons do not spontaneously regenerate due to limitations that include; neuronal loss by apoptosis, reduced intrinsic growth capacity of neurons and the presence of a non-permissive environment in the injured adult CNS preventing axon growth. There is a plethora of axon growth inhibitory molecules that prevent CNS axons from regenerating. We are trying to identify these with a view to modulating their function to enhance axon regeneration. For example, we have shown that amphoterin-induced gene and ORF3 (AMIGO3) can substitute for LINGO-1 as a binding partner to NgR66 and p75 in blocking axon regeneration (Ahmed et al., 2013). Deletion of AMIGO3 therefore promotes significant axon regeneration and functional recovery after spinal cord injury (Almutiri et al., 2018). We are currently defining other molecules that can be targeted to promote axon regeneration after spinal cord injury.

Age-related changes in brain plasticity and postural control in older adults (Chiou)

Balance deterioration is a consequence of ageing. Poor balance can decrease mobility, reduce confidence of moving around, and increase risk of falling in older people. There are many factors contributing to poor balance and we are particularly interested in finding links between age-related changes in the brain and balance deterioration. Our work has shown that the brain plays a role in anticipating perturbations, such as arm movements generating self-initiated perturbation to the trunk (Chiou et al., 2016; 2018). When people grow older, the ability to be proactive, to anticipate perturbations becomes weaker. We hypothesise that this impairment is due to reduced efficiency in communication between the brain and muscles. We use advanced non-invasive brain stimulation machine to probe the brain-muscle communication in older people, with a view to developing targeted treatment to strengthen the communication.

Neural interaction between upper limbs and the trunk in humans with spinal cord injury – can arms give the trunk a hand? (Chiou)

Core stability (trunk control) is crucial in activities of daily living. Although we are not always conscious about its involvement, core (trunk) muscles are activated in numerous activities involving arms and legs. For example, trunk muscles are co-activated during reaching out for an object and walking. Despite evidence showing that arms and the trunk interact functionally, neural interaction between the arms and the trunk is less understood. We have shown that the physiological pathways controlling the arms and the trunk interact and that activating arm muscles can increase excitability of the neural pathways to the trunk muscles (Chiou et al., 2018, 2020). This highlights the possibility of inducing neuroplasticity in the pathways controlling the trunk muscles via the use of arms. In other words, a new rehabilitation method. We are interested in determining whether upper-limb exercise, such as arm cycling exercise, can help individuals with spinal cord injury (SCI) recover and regain their core (trunk) control. As equipment used for upper-limb exercise is relatively affordable (i.e. low-cost, accessible to publics), this project has a clear pathway to impact health and socioeconomics. This project is funded by the Wellcome Trust ISSF and the INSPIRE Foundation.

Early-initiated arm-crank exercise (ACE) training in enhancing motor recovery after spinal cord injury: an ACE recovery! (Chiou)

The project aims to examine the effects of early-initiated arm-crank exercise training on enhanced motor recovery and its underpinning mechanisms after spinal cord injury. We hypothesise that if ACET is applied much earlier when repair processes have a greater chance of success, the improvements will be much greater, leading to better independence and quality of life. The project is funded by the International Spinal Research Trust and in partnership with a number of spinal units in the West Midlands and Yorkshire regions.

Maximising recovery and enhancing quality of life for individuals within the first year of spinal cord injury via community-based, unsupervised arm-crank exercise training. (Chiou)

The project aims to bridge a gap in the current SCI care pathways, that is to provide continuing rehabilitation programmes for individuals with SCI from a specialised hospital to people’s home. To do so, we will examine the effects and feasibility of the use of technology for supporting individuals with SCI to exercise correctly at home. We will explore how to best use technology to motivate people with SCI to exercise in the community. The project is in collaboration with NHS spinal units and charities supporting people living with SCI.

Cerebrovascular burden and cognitive impairment after spinal cord injury (Nightingale)

SCI is often associated with an increased risk of stroke and cognitive difficulties compared to non-injured individuals. One possible explanation for this is blood pressure instability. Episodes of both extremely low blood pressure (in response to sitting upright: orthostatic hypotension) and sudden, transient episodes of high blood pressure (autonomic dysreflexia) are prevalent in individuals with cervical and upper-thoracic injuries. Such volatile swings in blood pressure can result in structural and functional changes within peripheral blood vessels and lead to the deterioration of organs, including the brain. Indeed, our preliminary data suggests that symptoms of unstable blood pressure were associated with diverse cognitive impairment following SCI (Nightingale et al., 2020). In collaboration with colleagues at the University of British Columbia, this project is utilising magnetic resonance imaging (MRI), transcranial Doppler and a neuropsychological test battery to compare cerebrovascular health (i.e. neurovascular coupling and cerebrovascular reactivity to carbon dioxide), small vessel disease burden and cognitive functioning between individuals with SCI and an age-matched non-injured control group. The long-term goal of this program of work is to better understand the mechanisms behind cerebrovascular decline in persons with SCI.

Improving exercise performance and functional outcomes with non-invasive spinal cord stimulation following spinal cord injury (Nightingale)

Due to disrupted cardiovascular control, individuals with cervical and upper-thoracic SCI do not adapt appropriately to a bout of exercise, resulting in premature fatigue and a reduced physical capacity. It is well established that low fitness is a key risk factor for the development of cardiovascular disease, which is the number one cause of death in this population. Recent findings have demonstrated that epidural spinal cord stimulation (eSCS) can modulate cardiovascular function (i.e. increase blood pressure) after SCI by re-awakening dormant spinal circuits. This resulted in improved exercise performance by a magnitude much greater than weeks or months of exercise training (Nightingale et al., 2019). While promising, a major drawback is that individuals must undergo a highly invasive and expensive surgical procedure to implant a pulse generator and electrodes on top of the spinal cord. However, emerging evidence demonstrates that non-invasive transcutaneous spinal cord stimulation (tSCS) (with electrodes applied over the skin to deliver electrical stimulation) can target the same spinal circuits as eSCS to restore a degree of cardiovascular control. Therefore, with the support of a Wellcome Trust ISSF grant, we are planning to investigate whether tSCS can augment upper-body exercise performance in individuals with SCI.

In collaboration with Dr. Andrei Krassioukov and colleagues at the International Collaboration On Repair Discoveries (ICORD), we are also investigating the application of tSCS to treat bladder, bowel and sexual dysfunctions following SCI.

More information on spinal cord stimulation techniques to help individuals with SCI can be found here.

Therapeutic exercise strategies in people with spinal cord injury (Nightingale)

Individuals with SCI experience numerous environmental and psychosocial barriers that can restrict their engagement in physical activity. Consequently, reduced levels of physical activity and an increased likelihood of central obesity can predispose individuals with SCI to various chronic diseases (i.e. heart disease or type 2 diabetes). Our previous work demonstrated that the prescription of home-based upper-body moderate-intensity exercise improves cardiorespiratory fitness, insulin resistance and health-related quality of life in participants with SCI (Nightingale et al., 2017). We are currently investigating the efficacy of different exercise strategies and complementary approaches to optimise cardiometabolic health outcomes in this population.

Acute intermittent hypoxia and respiratory strength training to improve respiratory function in people with chronic spinal cord injury (Welch)

Despite advances in medical care, respiratory dysfunction remains the leading cause of morbidity and mortality following spinal cord injury (SCI). Thus, it is imperative to develop strategies to restore breathing and improve the quality of life for people with SCI. Based on decades of studies in animal models, recent human investigations have shown that brief exposure to moderate reductions in inspired oxygen, known as acute intermittent hypoxia (AIH), elicits spinal neuroplasticity that enhances limb function in people with SCI (Trumbower et al., 2012). Remarkably, when AIH is paired with task-specific training (e.g. walking practice), the combined effects exceed the sum of individual effects (Hayes et al., 2014)—in other words, AIH and TST are synergistic in their effects on limb locomotor performance (Welch et al., 2020). This study further explores the synergistic relationship between AIH and TST, applying this foundational knowledge to the respiratory system. The study is funded by the United States Department of Defence and tests the hypothesis that combined AIH and respiratory strength training is more effective at restoring breathing function than either treatment alone. The study is ongoing and is a collaboration between the University of Florida and Brooks Rehabilitation, led by Dr. Emily Fox and Professor Gordon Mitchell.

Genetic biomarkers of intermittent hypoxia-induced respiratory motor plasticity in chronic spinal cord injury (Welch)

Exciting outcomes in nine clinical trials completed to date in humans with spinal cord injury (SCI) demonstrate that acute intermittent hypoxia (AIH) can improve respiratory and limb function (Vose et al., 2022). Unfortunately, ~40% of individuals exhibit minimal response to AIH, making it essential to: a) optimize AIH protocols to maximize functional benefits; and b) identify genetic biomarkers distinguishing those most/least likely to benefit from AIH-based treatments. Guided by recent observations that combining hypoxia with hypercapnia enhances respiratory motor plasticity in healthy humans (Welch et al., 2022) and the magnitude of plasticity is dependent upon age, sex and genetic variants in key molecules associated with intracellular mechanisms of intermittent hypoxia-induced plasticity (Nair et al., unpublished), this United States Department of Defence funded clinical trial tests the hypothesis that: a) acute intermittent hypercapnic-hypoxia (AIHH) is a more potent stimulus of respiratory neuroplasticity than AIH alone; and b) dysfunctional genetic variants characterize individuals with minimal respiratory motor plasticity in response to AIH or AIHH in individuals with chronic SCI. The study is expected to commence in 2023 and is a collaboration between the University of Florida and Brooks Rehabilitation, led by Dr. Emily Fox and Professor Gordon Mitchell.

Taylor MJ, Thompson AM, Alhajlah S, Tuxworth RI, Ahmed Z. Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury. Sci Adv 2022; 8:eabq2611.

Ahmed Z, Alhajlah S, Thompson AM, Fairclough RJ. Clinic-ready inhibitor of MMP-9/-12 restores sensory and functional decline in rodent models of spinal cord injury. Clin Transl Med. 2022; 12:e884.

Ahmed Z, Tuxworth RI. The brain-penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in preclinical models of spinal cord injury. Clin Transl Med. 2022; 12: e962.

Welch JF, Nair J, Argento PJ, Mitchell GS & Fox EJ. (2022). Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans. The Journal of Physiology, 600(10), 2515-2533.

Vose AK, Welch JF, Nair J, Dale EA, Fox EJ, Muir GD, Trumbower RD & Mitchell GS. (2022). Therapeutic acute intermittent hypoxia: a translational roadmap to treat spinal cord injury and neuromuscular disease. Experimental Neurology, 347, 113891.

van Helden JFL, Martinez-Valdes E, Strutton PH, Falla D, Chiou SY*. Reliability of high-density surface electromyography for assessing characteristics of the thoracic erector spinae during static and dynamic tasks. J Electromyogr Kinesiol. 2022;67:102703.

Hodgkiss DD, Bhangu GS, Lunny C, Jutzeler CR, Chiou SY, Walter M, Lucas SJE, Krassioukov AV, Nightingale TE. The impact of physical activity and exercise on aerobic capacity in individuals with spinal cord injury: A systematic review with meta-analysis and meta-regression. medRxiv 2022; doi: https://doi.org/10.1101/2022.08.05.22278397

*Chiou SY, Clarke E, Lam C, Harvey T, Nightingale TE (2022). Effects of arm-crank exercise on fitness and health in adults with chronic spinal cord injury: a systematic review. Front. Physiol.13:831372.

Goodyear V.A, Boardley I, Chiou SY, Fenton SA, Makopoulou K, Stathi A, et al (2021). Social media use informing behaviours related to physical activity, diet and quality of life during COVID-19: a mixed methods study. BMC Public Health; 21:1333.

Sutor TW, Cavka K, Vose AK, Welch JF, Davenport PW, Fuller DD, Mitchell GS & Fox EJ. (2021). Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. Experimental Neurology, 342, 113735.

Welch JF, Sutor TW, Vose AK, Perim RR, Fox EJ & Mitchell GS. (2020). Synergy between acute intermittent hypoxia and task-specific training. Exercise and Sport Sciences Reviews, 48(3), 125-132.

Kitchen, P, Salman, MM, Halsey, A, Clarke-Band, C, MacDonald, J, Ishida, H, Vogel, H, Almuitiri, S, Logan, A, Kreida, S, Al-Jubair, T, Missel, J, Gourdon, P, Tornroth-Horsefield, S, Conner, M, Ahmed, Z, Conner, A & Bill, RM 2020, 'Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema', Cell, vol. 181, no. 4, pp. 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

Nightingale, TE, Tejpar, T, O'Connell, C, Krassioukov, AV. 2020. Using Cannabis to Control Blood Pressure After Spinal Cord Injury: A Case Report. Ann Intern Med. doi: 10.7326/L20-0090.

Gee, C*, Nightingale, TE*, West, CR, Krassioukov, AV. 2020. Infographic. Doping without drugs: how para-athletes may self-harm to boost performance. British Journal of Sports Medicine. doi: 10.1136/bjsports-2020-101980

Nabata, K*, Tse, E*, Nightingale, TE*, Lee, AHX, Eng, JJ, Queree, M, Walter, M, Krassioukov, AV. 2020. The therapeutic potential and usage patterns of cannabinoids in people with spinal cord injuries: A systematic review. Current Neuropharmacology. doi: 10.2174/1570159X18666200420085712

Nightingale, TE, Bhangu, GS, Bilzon, JLJ & Krassioukov, AV. 2020. A cross-sectional comparison between cardiorespiratory fitness, level of lesion and red blood cell distribution width in adults with chronic spinal cord injury. Journal of Science and Medicine in Sport, vol. 23, no. 2, pp. 106-111. https://doi.org/10.1016/j.jsams.2019.08.015

Nightingale, T, Zheng, MMZ, Sachdeva, R, Phillips, A & Krassioukov, A. 2020. Diverse cognitive impairment after spinal cord injury is associated with orthostatic hypotension symptom burden. Physiology and Behavior, vol. 213, 112742. https://doi.org/10.1016/j.physbeh.2019.112742

Nightingale, TE, Walter M, Williams, AMM, Lam, T, Krassioukov, AV. 2019. Ergogenic effects of an epidural neuroprosthesis in one individual with spinal cord injury. Neurology. 92(7). doi: 10.1212/WNL.0000000000006923.

Nightingale, TE, Walhin, JP, Thompson, D, Bilzon, JLJ. 2017. Impact of exercise on markers of cardiometabolic component risks in spinal cord injured humans. Medicine & Science in Sports & Exercise. 49(12): 2469-2477. doi: 10.1249/MSS.0000000000001390.

Nightingale, TE,Metcalfe, RS, Vollaard, NBJ,Bilzon, JLJ. 2017. Exercise guidelines to promote cardiometabolic health in spinal cord injured humans: time to raise the intensity? Archives of Physical Medicine and Rehabilitation. 98(8): 1693-1704. doi: 10.1016/j.apmr.2016.12.008.

Tuxworth, R, Taylor, M, Anduaga, AM, Hussien-Ali, A, Chatzimatthaiou, S, Longland, J, Thompson, AM, Almutiri, S, Alifragis, P, Kyriacou, CP, Kysela, B & Ahmed, Z 2019, 'Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration', Brain Communications, vol. 1, no. 1, fcz005. https://doi.org/10.1093/braincomms/fcz005

Almutiri S, Berry M, Logan A, Ahmed Z (2018) Non-viral-mediated suppression of AMIGO3 promotes disinhibited NT3-mediated regeneration of spinal cord dorsal column axons. Sci Rep 8:10707. doi: 10.1038/s41598-018-29124-z

Chiou SY, Hurry M, Reed T, Quek JX, Strutton PH. Cortical contributions to anticipatory postural adjustments in the trunk. J Physiol. 2018; 596:1295-1306.

Chiou SY, Koutsos E, Georgiou P, Strutton PH. Association between spectral characteristics of paraspinal muscles and functional disability in patients with low back pain: a cohort study. BMJ Open. 2018; 8(2):e017091.

Chiou SY, Hellyer PJ, Sharp DJ, Newbould RD, Patel MC, Strutton PH. Relationships between the microstructure and function of lumbar nerve roots as assessed by diffusion tensor imaging and neurophysiology. Neuroradiology. 2017;59(9):893-903.

Ahmed Z, Bansal D, Tizzard K, Surey S, Esmaeili M, Gonzalez AM, Berry M and Logan A (2014) Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds. Neurobiol Dis 64:163-76

Principal Investigators

Professor Zubair Ahmed - Professor of Neuroscience, Institute of Inflammation and Ageing

Dr Richard Tuxworth - Associate Professor in Molecular Genetics, Institute of Cancer and Genomic Sciences

Dr Shin-Yi (Chloe) Chiou - Associate Professor in Motor Control and Rehabilitation, School of Sport, Exercise and Rehabilitation Sciences

Dr Tom Nightingale - Assistant Professor in Exercise Physiology, School of Sport, Exercise and Rehabilitation Sciences

Dr Joseph Welch - Assistant Professor in Respiratory Physiology and Neurobiology, School of Sport, Exercise and Rehabilitation Sciences

Internal Collaborators

Dr Kevin Whitehead - Assistant Professor in Neuropharmacology, Institute of Clinical Sciences

Professor Liam Grover - Professor in Biomaterials Science, School of Chemical Engineering

Professor Roy Bicknell - Professor of Functional Genomics, Institute of Cardiovascular Sciences

Dr Sam Lucas – Associate Professor in Exercise and Environmental Physiology, School of Sport, Exercise and Rehabilitation Sciences and Centre for Human Brain Health

Dr Daniel Fulton – Assistant Professor in Glial Biology, Institute of Inflammation and Ageing

External Collaborators

Mr Navin Furtado – Consultant Neurosurgeon and Spinal Surgeon, QEHB, UK

Dr Sharif Alhajlah – Shaqra University, Saudi Arabia

Dr Andrei Krassioukov – Chair in Rehabilitation Research, International Collaboration On Repair Discoveries, University of British Columbia and Staff Physician, GF Strong Rehabilitation Centre, Vancouver, Canada

Dr Matthias Walter – Consultant, Department of Urology, University Hospital Basel, Switzerland

Professor Roslyn Bill – Aston University, Birmingham, UK