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Journal articleDickinson R, Campos-Pires R, Ong BE, et al., 2023,
Repetitive, but not single, mild blast TBI causes persistent neurological impairments and selective cortical neuronal loss in rats
, Brain Sciences, Vol: 13, Pages: 1-24, ISSN: 2076-3425Exposure to repeated mild blast traumatic brain injury (mbTBI) is common in combat soldiers and the training of Special Forces. Evidence suggests that repeated exposure to a mild or subthreshold blast can cause serious and long-lasting impairments, but the mechanisms causing these symptoms are unclear. In this study, we characterise the effects of single and tightly coupled repeated mbTBI in Sprague–Dawley rats exposed to shockwaves generated using a shock tube. The primary outcomes are functional neurologic function (unconsciousness, neuroscore, weight loss, and RotaRod performance) and neuronal density in brain regions associated with sensorimotor function. Exposure to a single shockwave does not result in functional impairments or histologic injury, which is consistent with a mild or subthreshold injury. In contrast, exposure to three tightly coupled shockwaves results in unconsciousness, along with persistent neurologic impairments. Significant neuronal loss following repeated blast was observed in the motor cortex, somatosensory cortex, auditory cortex, and amygdala. Neuronal loss was not accompanied by changes in astrocyte reactivity. Our study identifies specific brain regions particularly sensitive to repeated mbTBI. The reasons for this sensitivity may include exposure to less attenuated shockwaves or proximity to tissue density transitions, and this merits further investigation. Our novel model will be useful in elucidating the mechanisms of sensitisation to injury, the temporal window of sensitivity and the evaluation of new treatments.
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Book chapterCampos-Pires R, Dickinson R, 2023,
Modelling Blast Brain Injury
, Blast Injury Science and Engineering: A Guide for Clinicians and Researchers, Editors: Bull, Clasper, Mahoney, Publisher: Springer Cham, Pages: 315-331, ISBN: 978-3-031-10354-4The consequences of blast traumatic braininjury (blast-TBI) in humans are largely determinedby the characteristics of the traumainsult and, within certain limits, the individualresponses to the lesions inflicted (Maas et al.,Lancet Neurol. 2008;7:728–41). In blast-TBI,the mechanisms of brain vulnerability to thedetonation of an explosive device are not completelyunderstood. They most likely resultfrom a combination of the different physicalaspects of the blast phenomenon, specificallyextreme pressure oscillations (blast overpressurewave), projectile penetrating fragmentsand acceleration–deceleration forces, creatinga spectrum of brain injury that ranges frommild to severe blast-TBI(Hicks et al., JTrauma. 2010; 68:1257-63).The pathophysiologyof penetrating and inertially drivenblast-TBI has been extensively investigatedfor many years. However, the brain damagecaused by blast overpressure is much lessunderstood and is unique to this type of TBI(Chen et al., J Neurotrauma. 2009; 26:861–76). Indeed, there continues to be debate abouthow the pressure wave is transmitted andreflected through the brain and how it causescellular damage (Nakagawa et al., JNeurotrauma. 2011; 28:1101–19). No singlemodel can mimic the clinical and mechanicalcomplexity resulting from a real-lifeblast-TBI (Chen et al., J Neurotrauma. 2009;26:861–76). The different models, non-biological(in silico or surrogate physical) andbiological (ex vivo, in vitro or in vivo), tend tocomplement each other.
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Journal articleLiang M, Ahmad F, Dickinson R, 2022,
A preclinical systematic review and meta-analysis of the noble gases argon and xenon as treatments for acquired brain injury
, British Journal of Anaesthesia, Vol: 129, Pages: 200-218, ISSN: 0007-0912BackgroundThe noble gases argon and xenon are potential novel neuroprotective treatments for acquired brain injuries. Xenon has already undergone early-stage clinical trials in the treatment of ischaemic brain injuries, with mixed results. Argon has yet to progress to clinical trials as a treatment for brain injury. Here, we aim to synthesise the results of preclinical studies evaluating argon and xenon as neuroprotective therapies for brain injuries.MethodsAfter a systematic review of the MEDLINE and Embase databases, we carried out a pairwise and stratified meta-analysis. Heterogeneity was examined by subgroup analysis, funnel plot asymmetry, and Egger's regression.ResultsA total of 32 studies were identified, 14 for argon and 18 for xenon, involving measurements from 1384 animals, including murine, rat, and porcine models. Brain injury models included ischaemic brain injury after cardiac arrest (CA), neurological injury after cardiopulmonary bypass (CPB), traumatic brain injury (TBI), and ischaemic stroke. Both argon and xenon had significant (P<0.001), positive neuroprotective effect sizes. The overall effect size for argon (CA, TBI, stroke) was 18.1% (95% confidence interval [CI], 8.1–28.1%), and for xenon (CA, TBI, stroke) was 34.1% (95% CI, 24.7–43.6%). Including the CPB model, only present for xenon, the xenon effect size (CPB, CA, TBI, stroke) was 27.4% (95% CI, 11.5–43.3%). Xenon, both with and without the CPB model, was significantly (P<0.001) more protective than argon.ConclusionsThese findings provide evidence to support the use of xenon and argon as neuroprotective treatments for acquired brain injuries. Current evidence suggests that xenon is more efficacious than argon overall.
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Conference paperCampos-Pires R, Onggradito H, Ujvari E, et al., 2021,
The noble gas xenon is neuroprotective and promotes beneficial neuroinflammation following severe neurotrauma in rats
, 38th National Neurotrauma Symposium, Publisher: Mary Ann Liebert, Pages: A114-A114, ISSN: 0897-7151 -
Conference paperCampos-Pires R, Onggradito H, Ujvari E, et al., 2021,
Xenon is neuroprotective and promotes beneficial early neuroinflammation in a rat model of severe traumatic brain injury
, Society for Neuroscience -
Conference paperCampos-Pires R, Onggradito H, Ujvari E, et al., 2021,
Xenon is neuroprotective and promotes beneficial early neuroinflammation in a rat model of severe traumatic brain injury
, Society for Neuroscience -
Journal articleEdge C, Dickinson R, 2021,
Argon: a noble, but not inert, treatment for brain trauma?
, British Jourmal of Anaesthesia, Vol: 126, Pages: 41-43 -
Journal articleCampos-Pires R, Onggradito H, Ujvari E, et al., 2020,
Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study
, Critical Care (UK), Vol: 24, Pages: 1-18, ISSN: 1364-8535BackgroundTraumatic brain injury (TBI) is a major cause of morbidity and mortality, but there are no clinically proven treatments that specifically target neuronal loss and secondary injury development following TBI. In this study, we evaluate the effect of xenon treatment on functional outcome, lesion volume, neuronal loss and neuroinflammation after severe TBI in rats.MethodsYoung adult male Sprague Dawley rats were subjected to controlled cortical impact (CCI) brain trauma or sham surgery followed by treatment with either 50% xenon:25% oxygen balance nitrogen, or control gas 75% nitrogen:25% oxygen. Locomotor function was assessed using Catwalk-XT automated gait analysis at baseline and 24 h after injury. Histological outcomes were assessed following perfusion fixation at 15 min or 24 h after injury or sham procedure.ResultsXenon treatment reduced lesion volume, reduced early locomotor deficits, and attenuated neuronal loss in clinically relevant cortical and subcortical areas. Xenon treatment resulted in significant increases in Iba1-positive microglia and GFAP-positive reactive astrocytes that was associated with neuronal preservation.ConclusionsOur findings demonstrate that xenon improves functional outcome and reduces neuronal loss after brain trauma in rats. Neuronal preservation was associated with a xenon-induced enhancement of microglial cell numbers and astrocyte activation, consistent with a role for early beneficial neuroinflammation in xenon’s neuroprotective effect. These findings suggest that xenon may be a first-line clinical treatment for brain trauma.
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Journal articleTurner S, McGregor A, 2020,
Perceived impact of socket fit on major lower limb prosthetic rehabilitation: a clinician and amputee perspective
, Archives of Rehabilitation Research and Clinical Translation, Vol: 2, Pages: 1-8, ISSN: 2590-1095ObjectiveTo determine amputees’ and rehabilitation clinicians’ perspectives on the impact of socket fit and issues caused by ill-fitting sockets throughout lower limb prosthetic rehabilitation.DesignA survey was developed to identify rehabilitation factors and issues for prosthesis wearers and rehabilitation clinicians. Participants opted to participate in a further telephone interview.SettingOnline and across the United Kingdom.ParticipantsLower limb prosthetic wearers and clinicians that are part of a lower limb prosthetic rehabilitation team.InterventionsNot applicable.Main Outcome Measure(s)A survey and an interview to measure the perceived impact of socket fit on lower limb rehabilitation.Results48.0% of amputees and 65.7% of clinicians identified socket fit related issues as the biggest factor impacting rehabilitation. Amputee interviewees focused on the impact of fit on quality of life and the ability to complete daily tasks, whilst clinicians focused on the lack of widespread ability to adjust the socket and gait re-education.ConclusionsSocket fit has a large impact on and is a large source of frustration to amputees and their clinical teams throughout rehabilitation. From the interviews, it became clear that the interpretation of socket fit is different for each person; thus “socket fit” does not mean the same for all.
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Journal articleNguyen TT, Carpanen D, Rankin I, et al., 2020,
Mapping the risk of fracture of the tibia from penetrating fragments
, Frontiers in Bioengineering and Biotechnology, Vol: 8, Pages: 1-11, ISSN: 2296-4185Penetrating injuries are commonly inflicted in attacks with explosive devices. The extremities, and especially the leg, are the most commonly affected body areas, presenting high risk of infection, slow recovery, and threat of amputation. The aim of this study was to quantify the risk of fracture to the anteromedial, posterior, and lateral aspects of the tibia from a metal fragment-simulating projectile (FSP). A gas gun system and a 0.78-g cylindrical FSP were employed to perform tests on an ovine tibia model. The results from the animal study were subsequently scaled to obtain fracture-risk curves for the human tibia using the cortical thickness ratio. The thickness of the surrounding soft tissue was also taken into account when assessing fracture risk. The lateral cortex of the tibia was found to be most susceptible tofracture,whose impact velocity at 50% risk of EF1+, EF2+, EF3+, and EF4+ fracture types –according to the modified Winquist-Hansen classification –were 174, 190, 212,and 282 m/s respectively. The findings of this study will be used to increase the fidelity of predictive models of projectile penetration.
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Journal articleRankin I, Nguyen TT, Carpanen D, et al., 2020,
A new understanding of the mechanism of injury to the pelvis and lower limbs in blast
, Frontiers in Bioengineering and Biotechnology, Vol: 8, ISSN: 2296-4185Dismounted complex blast injury (DCBI) has been one of the most severe forms of trauma sustained in recent conflicts. This injury has been partially attributed to limb flail; however, the full causative mechanism has not yet been fully determined. Soil ejecta has been hypothesized as a significant contributor to the injury but remains untested. In this study, a small-animal model of gas-gun mediated high velocity sand blast was used to investigate this mechanism. The results demonstrated a correlation between increasing sand blast velocity and injury patterns of worsening severity across the trauma range. This study is the first to replicate high velocity sand blast and the first model to reproduce the pattern of injury seen in DCBI. These findings are consistent with clinical and battlefield data. They represent a significant change in the understanding of blast injury, producing a new mechanistic theory of traumatic amputation. This mechanism of traumatic amputation is shown to be high velocity sand blast causing the initial tissue disruption, with the following blast wind and resultant limb flail completing the amputation. These findings implicate high velocity sand blast, in addition to limb flail, as a critical mechanism of injury in the dismounted blast casualty.
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ReportFoss L, Belli A, Brody D, et al., 2020,
Setting a national consensus for managing mild and blast traumatic brain injury: post-meeting consensus report
A meeting was held on Wednesday 15 January 2020 to examine the current evidence for non-routine imaging and for neuroendocrine screening in the management of military personnel with brain injury and overlapping symptom domains. The Summit aimed to specifically address the relative utility of magnetoencephalography (MEG), diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI) in the UK context. This Consensus Report discusses points of consensus, points for further discussion/points of equipoise and recommendations that arose during, and following, the meeting.
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Journal articleStewart S, Tenenbaum O, Masouros S, et al., 2020,
Fracture non-union rates across a century of war: a systematic review of the literature
, BMJ Military Health, Vol: 166, Pages: 271-276, ISSN: 2633-3767IntroductionFractures have been a common denominator of the injury patterns observed over the past century of warfare. The fractures typified by the blast and ballistic injuries of war lead to high rates of bone loss, soft tissue injury and infection, greatly increasing the likelihood of non-union. Despite this, no reliable treatment strategy for non-union exists. This literature review aims to explore the rates of non-union across a century of conflict and war, in order to determine whether our ability to heal the fractures of war has improved.MethodsA systematic review of the literature was conducted, evaluating the rates of union in fractures sustained in a combat environment over a one hundred year period. Only those fractures sustained through a ballistic or blast mechanism were included. The review was in accordance with the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA). Quality and bias assessment was also undertaken. ResultsThirty studies met the inclusion criteria, with a total of 3232 fractures described across fifteen different conflicts from the period 1919-2019. Male subjects made up 96% of cases, and tibial fractures predominated (39%). The lowest fracture union rate observed in a series was 50%. Linear regression analysis demonstrated that increasing years had no statistically significant impact on union rate.ConclusionFailure to improve fracture union rates is likely a result of numerous factors, including greater use of blast weaponry and better survivability of casualties. Finding novel strategies to promote fracture healing is a key defence research priority, in order to improve the rates of fractures sustained in a combat environment.
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Conference paperValeo F, Campos-Pires R, Soumalias P, et al., 2020,
Serum metabolic profiling following traumatic brain injury in rats using ¹H nuclear magnetic resonance spectroscopy
, Federation of European Neuroscience Societies -
Journal articleSaiz-Alia M, Reichenbach T, 2020,
Computational modeling of the auditory brainstem response to continuous speech.
, Journal of Neural Engineering, Vol: 17, Pages: 1-12, ISSN: 1741-2552OBJECTIVE: The auditory brainstem response can be recorded non-invasively from scalp electrodes and serves as an important clinical measure of hearing function. We have recently shown how the brainstem response at the fundamental frequency of continuous, non-repetitive speech can be measured, and have used this measure to demonstrate that the response is modulated by selective attention. However, different parts of the speech signal as well as several parts of the brainstem contribute to this response. Here we employ a computational model of the brainstem to elucidate the influence of these different factors. APPROACH: We developed a computational model of the auditory brainstem by combining a model of the middle and inner ear with a model of globular bushy cells in the cochlear nuclei and with a phenomenological model of the inferior colliculus. We then employed the model to investigate the neural response to continuous speech at different stages in the brainstem, following the methodology developed recently by ourselves for detecting the brainstem response to running speech from scalp recordings. We compared the simulations with recordings from healthy volunteers. MAIN RESULTS: We found that the auditory-nerve fibers, the cochlear nuclei and the inferior colliculus all contributed to the speech-evoked brainstem response, although the dominant contribution came from the inferior colliculus. The delay of the response corresponded to that observed in experiments. We further found that a broad range of harmonics of the fundamental frequency, up to about 8 kHz, contributed to the brainstem response. The response declined with increasing fundamental frequency, although the signal-to-noise ratio was largely unaffected. SIGNIFICANCE: Our results suggest that the scalp-recorded brainstem response at the fundamental frequency of speech originates predominantly in the inferior colliculus. They further show that the response is shaped by a large number of higher harmonics of
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Journal articleYu X, Azor A, Sharp DJ, et al., 2020,
Mechanisms of tensile failure of cerebrospinal fluid in blast traumatic brain injury
, Extreme Mechanics Letters, Vol: 38, Pages: 1-9, ISSN: 2352-4316Mechanisms of blast-induced Traumatic Brain Injury (BTBI), particularly those linked to the primary pressure wave, are still not fully understood. One possible BTBI mechanism is cavitation in the cerebrospinal fluid (CSF) caused by CSF tensile failure, which is likely to increase strain and strain rate in the brain tissue near the CSF. Blast loading of the head can generate rarefaction (expansion) waves and rapid head motion, which both can produce tensile forces in the CSF. However, it is not clear which of these mechanisms is more likely to cause CSF tensile failure. In this study, we used a high-fidelity 3-dimensional computational model of the human head to test whether the CSF tensile failure increases brain deformation near the brain/CSF boundary and to determine the key failure mechanisms. We exposed the head model to a frontal blast wave and predicted strain and strain rate distribution in the cortex. We found that CSF tensile failure significantly increased strain and strain rate in the cortex. We then studied whether the rapid head motion or the rarefaction wave causes strain and strain rate concentration in cortex. We isolated these two effects by conducting simulations with pure head motion loading (i.e. prescribing the skull velocity but eliminating the pressure wave) and pure blast wave loading (i.e. eliminating head motion by fixing the skull base). Our results showed that the strain increase in the cortex was mainly caused by head motion. In contrast, strain rate increase was caused by both rapid head motion and rarefaction waves, but head motion had a stronger effect on elevating strain rate. Our results show that rapid motion of the head produced by blast wave is the key mechanism for CSF tensile failure and subsequent concentration of strain and strain rate in cortex. This finding suggests that mitigation of rapid head motion caused by blast loading needs to be addressed in the design of protective equipment in order to prevent the tensile failure
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Journal articleNguyen TT, Meek G, Breeze J, et al., 2020,
Gelatine backing affects the performance of single-layer ballistic-resistant materials against blast fragments
, Frontiers in Bioengineering and Biotechnology, Vol: 8, Pages: 1-10, ISSN: 2296-4185Penetrating trauma by energized fragments is the most common injury from explosive devices, the main threat in the contemporary battlefield. Such devices produce projectiles dependent upon their design, including preformed fragments, casings, glass, or stones; these are subsequently energized to high velocities and cause serious injuries to the body. Current body armor focuses on the essential coverage, which is mainly the thoracic and abdominal area, and can be heavy and cumbersome. In addition, there may be coverage gaps that can benefit from the additional protection provided by one or more layers of lightweight ballistic fabrics. This study assessed the performance of single layers of commercially available ballistic protective fabrics such as Kevlar®, Twaron®, and Dyneema®, in both woven and knitted configurations. Experiments were carried out using a custom-built gas-gun system, with a 0.78-g cylindrical steel fragment simulating projectile (FSP) as the impactor, and ballistic gelatine as the backing material. FSP velocity at 50% risk of material perforation, gelatine penetration, and high-risk wounding to soft tissue, as well as the depth of penetration (DoP) against impact velocity and the normalized energy absorption were used as metrics to rank the performance of the materials tested. Additional tests were performed to investigate the effect of not including a soft-tissue simulant backing material on the performance of the fabrics. The results show that a thin layer of ballistic material may offer meaningful protection against the penetration of this FSP. Additionally, it is essential to ensure a biofidelic boundary condition as the protective efficacy of fabrics was markedly altered by a gelatine backing.
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Conference paperCampos-Pires R, Mohamed-Ali N, Franks N, et al., 2020,
Hypothermia combined with xenon reduces secondary injury development and enhances neuroprotection by preventing neuronal cell loss in a rat model of traumatic brain injury
, European Journal of Anaesthesia vol e37, Pages: 300-300 -
Journal articleRankin IA, Webster CE, Gibb I, et al., 2020,
Pelvic injury patterns in blast: Morbidity and mortality
, JOURNAL OF TRAUMA AND ACUTE CARE SURGERY, Vol: 88, Pages: 832-838, ISSN: 2163-0755- Author Web Link
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Journal articleReichenbach J, Keshavarzi M, 2020,
Transcranial alternating current stimulation with the theta-band portion of the temporally-aligned speech envelope improves speech-in-noise comprehension
, Frontiers in Human Neuroscience, Vol: 14, Pages: 1-8, ISSN: 1662-5161Transcranial alternating current stimulation with the speech envelope can modulate the comprehension of speech in noise. The modulation stems from the theta- but not the delta-band portion of the speech envelope, and likely reflects the entrainment of neural activity in the theta frequency band, which may aid the parsing of the speech stream. The influence of the current stimulation on speech comprehension can vary with the time delay between the current waveform and the audio signal. While this effect has been investigated for current stimulation based on the entire speech envelope, it has not yet been measured when the current waveform follows the theta-band portion of the speech envelope. Here, we show that transcranial current stimulation with the speech envelope filtered in the theta frequency band improves speech comprehension as compared to a sham stimulus. The improvement occurs when there is no time delay between the current and the speech stimulus, as well as when the temporal delay is comparatively short, 90 ms. In contrast, longer delays, as well as negative delays, do not impact speech-in-noise comprehension. Moreover, we find that the improvement of speech comprehension at no or small delays of the current stimulation is consistent across participants. Our findings suggest that cortical entrainment to speech is most influenced through current stimulation that follows the speech envelope with at most a small delay. They also open a path to enhancing the perception of speech in noise, an issue that is particularly important for people with hearing impairment.
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