Publications
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Cole JH, underwood J, Caan MWA, et al., 2017, Increased brain-predicted ageing in treated HIV disease, Neurology, Vol: 88, Pages: 1349-1357, ISSN: 0028-3878
Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent “brain age” using neuroimaging and exploring whether these estimates related to HIV-status, age, cognitive performance and HIV-related clinical parameters.Methods: A large sample of virologically-suppressed HIV-positive adults (N = 162, aged 45-82 years) and highly-comparable HIV-negative controls (N = 105) were recruited as part of the COBRA collaboration. Using T1-MRI scans, a machine-learning model of healthy brain ageing was defined in an independent cohort (N = 2001, aged 18-90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age - chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out.Results: HIV-positive individuals had greater brain-PAD score (mean ± SD = 2.15 ± 7.79 years) compared to HIV-negative individuals (-0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV-infection or other HIV-related measures.Conclusions: Increased apparent brain ageing, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain ageing related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV-infection, suggesting that HIV disease may accentuate, rather than accelerate brain ageing.
Arshad Q, Roberts RE, Ahmad H, et al., 2017, Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction, CLINICAL NEUROLOGY AND NEUROSURGERY, Vol: 155, Pages: 17-19, ISSN: 0303-8467
Benoit MPMH, Diaz-Valencia DJ, Asenjo AB, et al., 2017, Exploring the Mechanism of Microtubule Depolymerization by the Kinesin 13 KLP10A and it's Phosphoregulation, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 428A-428A, ISSN: 0006-3495
Ghajari M, Hellyer P, Sharp D, 2017, Computational modelling of traumatic brain injury predicts the location of chronic traumatic encephalopathy pathology, Brain, Vol: 140, Pages: 333-343, ISSN: 0006-8950
Traumatic brain injury can lead to the neurodegenerative disease chronic traumatic encephalopathy. This condition has a clear neuropathological definition but the relationship between the initial head impact and the pattern of progressive brain pathology is poorly understood. We test the hypothesis that mechanical strain and strain rate are greatest in sulci, where neuropathology is prominently seen in chronic traumatic encephalopathy, and whether human neuroimaging observations converge with computational predictions. Three distinct types of injury were simulated. Chronic traumatic encephalopathy can occur after sporting injuries, so we studied a helmet-to-helmet impact in an American football game. In addition, we investigated an occipital head impact due to a fall from ground level and a helmeted head impact in a road traffic accident involving a motorcycle and a car. A high fidelity 3D computational model of brain injury biomechanics was developed and the contours of strain and strain rate at the grey matter–white matter boundary were mapped. Diffusion tensor imaging abnormalities in a cohort of 97 traumatic brain injury patients were also mapped at the grey matter–white matter boundary. Fifty-one healthy subjects served as controls. The computational models predicted large strain most prominent at the depths of sulci. The volume fraction of sulcal regions exceeding brain injury thresholds were significantly larger than that of gyral regions. Strain and strain rates were highest for the road traffic accident and sporting injury. Strain was greater in the sulci for all injury types, but strain rate was greater only in the road traffic and sporting injuries. Diffusion tensor imaging showed converging imaging abnormalities within sulcal regions with a significant decrease in fractional anisotropy in the patient group compared to controls within the sulci. Our results show that brain tissue deformation induced by head impact loading is greatest in sulcal
Su T, Mutsaerts HJMM, Caan MWA, et al., 2017, Cerebral blood flow and cognitive function in HI-infected men with sustained suppressed viremia on combination antiretroviral therapy, AIDS, Vol: 31, Pages: 847-856, ISSN: 0269-9370
Matamoros AJ, Wu D, Baker LA, et al., 2017, A new microtubule-based approach for augmenting nerve regeneration., Annual Joint Meeting of the American-Society-for-Cell-Biology and the European-Molecular-Biology-Organization (ASCB/EMBO), Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Kramer AH, Paulino V, Wang Y, et al., 2017, An investigation on the potential of Fidgetin-like 2, a microtubule severing enzyme, as a target to induce angiogenesis and heart regeneration., Annual Joint Meeting of the American-Society-for-Cell-Biology and the European-Molecular-Biology-Organization (ASCB/EMBO), Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Austin TO, Matamoros AJ, Friedman JM, et al., 2017, Nanoparticle delivery of fidgetin siRNA as a microtubule-based therapy to augment nerve regeneration., Annual Joint Meeting of the American-Society-for-Cell-Biology and the European-Molecular-Biology-Organization (ASCB/EMBO), Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Roberts RE, Arshad Q, Patel M, et al., 2016, Functional neuroimaging of visuo-vestibular interaction, Brain Structure & Function, Vol: 222, Pages: 2329-2343, ISSN: 1863-2661
The brain combines visual, vestibular and proprioceptive information to distinguish between self-and world-motion. Often these signals are complementary and indicate that the individual is moving or stationary with respect to the surroundings. However, conflicting visual motion and vestibular cues can lead to ambiguous or false sensations of motion. In this study, we used functional magnetic resonance imaging to explore human brain activation when visual and vestibular cues were either complementary or in conflict. We combined a horizontally moving optokinetic stimulus with caloric irrigation of the right ear to produce conditions where the vestibular activation and visual motion indicatedthe same (congruent) or opposite directions of self-motion (incongruent). Visuo-vestibular conflict was associated with increased activation in a network of brain regions including posterior insular and transverse temporal areas, cerebellar tonsil, cingulate and medial frontal gyri. In the congruent condition there was increased activation in primary and secondary visual cortex. These findings suggest that when sensory information regarding self-motion is contradictory, there is preferential activation of multisensoryvestibular areas to resolve this ambiguity. When cues are congruent there is a bias towards visual cortical activation. The data support the view thata network of brain areas including the posterior insular cortex may play animportant role in integrating and disambiguating visual and vestibular cues.
Jenkins PO, De Simoni S, Fleminger J, et al., 2016, Disruption to the dopaminergic system after traumatic brain injury, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ Publishing Group, ISSN: 1468-330X
Li L, Violante I, Ross E, et al., 2016, BRAIN NETWORK MODULATION WITH NON-INVASIVE BRAIN STIMULATION, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Ahmad H, Arshad Q, Roberts R, et al., 2016, CHRONIC DIZZINESS POST TRAUMATIC BRAIN INJURY: A CROSS-SECTIONAL STUDY, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Scott G, Jolly A, Jenkins PO, et al., 2016, THE EFFECT OF MINOCYCLINE ON NEUROINFLAMMATION AFTER BRAIN TRAUMA, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
von Rosenberg W, Chanwimalueang T, Goverdovsky V, et al., 2016, Smart helmet: wearable multichannel ECG & EEG, IEEE Journal of Translational Engineering in Health and Medicine, Vol: 4, ISSN: 2168-2372
Modern wearable technologies have enabled continuous recording of vital signs, however, for activities such as cycling, motor-racing, or military engagement, a helmet with embedded sensors would provide maximum convenience and the opportunity to monitor simultaneously both the vital signs and the electroencephalogram (EEG). To this end, we investigate the feasibility of recording the electrocardiogram (ECG), respiration, and EEG from face-lead locations, by embedding multiple electrodes within a standard helmet. The electrode positions are at the lower jaw, mastoids, and forehead, while for validation purposes a respiration belt around the thorax and a reference ECG from the chest serve as ground truth to assess the performance. The within-helmet EEG is verified by exposing the subjects to periodic visual and auditory stimuli and screening the recordings for the steady-state evoked potentials in response to these stimuli. Cycling and walking are chosen as real-world activities to illustrate how to deal with the so-induced irregular motion artifacts, which contaminate the recordings. We also propose a multivariate R-peak detection algorithm suitable for such noisy environments. Recordings in real-world scenarios support a proof of concept of the feasibility of recording vital signs and EEG from the proposed smart helmet.
De Simoni S, Grover PJ, Jenkins PO, et al., 2016, Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia, Brain, Vol: 139, Pages: 3137-3150, ISSN: 0006-8950
Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterised by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the Default Mode Network. Interactions within the Default Mode Network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the Default Mode Network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. 19 traumatic brain injury patients were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normal
Charafeddine RA, Nosanchuk JD, Sharp DJ, 2016, Targeting Microtubules for Wound Repair, ADVANCES IN WOUND CARE, Vol: 5, Pages: 444-454, ISSN: 2162-1918
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- Citations: 9
Record C, De Simoni S, Feeney C, et al., 2016, Improved cerebral blood flow after natalizumab treatment in multiple sclerosis, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE Publications, Pages: 669-669, ISSN: 1352-4585
Peress L, Violante IR, Scott G, et al., 2016, Thalamic magnetic resonance spectroscopy in highly active multiple sclerosis, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 210-211, ISSN: 1352-4585
O'Shea T, Feeney C, Wise R, et al., 2016, Post-traumatic amnesia, but not acute CT findings is predictive of pituitary dysfunction following traumatic brain injury, IRISH JOURNAL OF MEDICAL SCIENCE, Vol: 185, Pages: 400-401, ISSN: 0021-1265
Sariaslan A, Sharp DJ, D'Onofrio BM, et al., 2016, Long-Term Outcomes Associated with Traumatic Brain Injury in Childhood and Adolescence: A Nationwide Swedish Cohort Study of a Wide Range of Medical and Social Outcomes, PLOS Medicine, Vol: 13, ISSN: 1549-1277
BACKGROUND: Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes. METHODS AND FINDINGS: In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers. We subsequently assessed these individuals for the following outcomes using multiple national registries: disability pension, specialist diagnoses of psychiatric disorders and psychiatric inpatient hospitalisation, premature mortality (before age 41 y), low educational attainment (not having achieved secondary school qualifications), and receiving means-tested welfare benefits. We used logistic and Cox regression models to quantify the association between TBI and specified adverse outcomes on the individual level. We further estimated population attributable fractions (PAF) for each outcome measure. We also compared differentially exposed siblings to account for unobserved genetic and environmental confounding. In addition to relative risk estimates, we examined absolute risks by calculating prevalence and Kaplan-Meier estimates. In complementary analyses, we tested whether the findings were moderated by injury severity, recurrence, and age at first injury (ages 0-4, 5-9, 6-10, 15-19, and 20-24 y). TBI exposure was associated with elevated risks of impaired adult functioning across all outcome measures. After a median follow-up period of 8 y from age 26 y, we found that TBI contributed to absolute risks of over 10% for specialist diagnoses of psychiatric disorders and low educational attainment, approximately 5% for disability pension, and 2% for premature mortality. The highest relative risks, adjusted for sex, birth year, and birth order
Shamshiri EA, Tierney TM, Centeno M, et al., 2016, Interictal activity is an important contributor to abnormal intrinsic network connectivity in paediatric focal epilepsy, Human Brain Mapping, ISSN: 1097-0193
Patients with focal epilepsy have been shown to have reduced functional connectivity in intrinsic connectivity networks (ICNs), which has been related to neurocognitive development and outcome. However, the relationship between interictal epileptiform discharges (IEDs) and changes in ICNs remains unclear, with evidence both for and against their influence. EEG-fMRI data was obtained in 27 children with focal epilepsy (mixed localisation and aetiologies) and 17 controls. A natural stimulus task (cartoon blocks verses blocks where the subject was told "please wait") was used to enhance the connectivity within networks corresponding to ICNs while reducing potential confounds of vigilance and motion. Our primary hypothesis was that the functional connectivity within visual and attention networks would be reduced in patients with epilepsy. We further hypothesized that controlling for the effects of IEDs would increase the connectivity in the patient group. The key findings were: (1) Patients with mixed epileptic foci showed a common connectivity reduction in lateral visual and attentional networks compared with controls. (2) Having controlled for the effects of IEDs there were no connectivity differences between patients and controls. (3) A comparison within patients revealed reduced connectivity between the attentional network and basal ganglia associated with interictal epileptiform discharges. We also found that the task activations were reduced in epilepsy patients but that this was unrelated to IED occurrence. Unexpectedly, connectivity changes in ICNs were strongly associated with the transient effects of interictal epileptiform discharges. Interictal epileptiform discharges were shown to have a pervasive transient influence on the brain's functional organisation. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Fagerholm ED, Scott G, Shew WL, et al., 2016, Cortical Entropy, Mutual Information and Scale-Free Dynamics in Waking Mice, Cerebral Cortex, Vol: 26, Pages: 3945-3952, ISSN: 1460-2199
Some neural circuits operate with simple dynamics characterized by one or a few well-defined spatiotemporal scales (e.g. central pattern generators). In contrast, cortical neuronal networks often exhibit richer activity patterns in which all spatiotemporal scales are represented. Such "scale-free" cortical dynamics manifest as cascades of activity with cascade sizes that are distributed according to a power-law. Theory and in vitro experiments suggest that information transmission among cortical circuits is optimized by scale-free dynamics. In vivo tests of this hypothesis have been limited by experimental techniques with insufficient spatial coverage and resolution, i.e., restricted access to a wide range of scales. We overcame these limitations by using genetically encoded voltage imaging to track neural activity in layer 2/3 pyramidal cells across the cortex in mice. As mice recovered from anesthesia, we observed three changes: (a) cortical information capacity increased, (b) information transmission among cortical regions increased and (c) neural activity became scale-free. Our results demonstrate that both information capacity and information transmission are maximized in the awake state in cortical regions with scale-free network dynamics.
Feeney C, Scott G, Raffel J, et al., 2016, Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 43, Pages: 2201-2210, ISSN: 1619-7089
PURPOSE: PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [(11)C]PK-11195 limits accurate quantification. [(18)F]GE-180, a novel TSPO ligand, displays superior binding to [(11)C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [(18)F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. METHODS: Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [(18)F]GE-180. Kinetic modelling of time-activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. RESULTS: The two-tissue compartment model was the best model. The average regional delivery rate constant (K 1) was 0.01 mL cm(-3) min(-1) indicating low extraction across the blood-brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm(-3) in the striatum to 0.38 mL cm(-3) in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. CONCLUSION: A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [(18)F]GE-180 in populations with neuroinflammatory disease is nee
Jenkins PO, Mehta MA, Sharp DJ, 2016, Catecholamines and cognition after traumatic brain injury, Brain, Vol: 139, Pages: 2345-2371, ISSN: 1935-2875
Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury. The heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits makes treating these problems difficult. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems is common after traumatic brain injury and is an important cause of cognitive impairment. Here, we discuss the evidence implicating disruption of the catecholamines (dopamine and noradrenaline) and review the efficacy of catecholaminergic drugs in treating post-traumatic brain injury cognitive impairments. The response to these therapies is often variable, a likely consequence of the heterogeneous patterns of injury as well as a non-linear relationship between catecholamine levels and cognitive functions. This individual variability means that measuring the structure and function of a person’s catecholaminergic systems is likely to allow more refined therapy. Advanced structural and molecular imaging techniques offer the potential to identify disruption to the catecholaminergic systems and to provide a direct measure of catecholamine levels. In addition, measures of structural and functional connectivity can be used to identify common patterns of injury and to measure the functioning of brain ‘networks’ that are important for normal cognitive functioning. As the catecholamine systems modulate these cognitive networks, these measures could potentially be used to stratify treatment selection and monitor response to treatment in a more sophisticated manner.
Whittington A, Iturria-Medina Y, Evans A, et al., 2016, MODEL TO DESCRIBE THE SPATIOTEMPORAL DISTRIBUTION OF MISFOLDED PROTEINS IN ALZHEIMER'S DISEASE, 27th International Symposium on Cerebral Blood Flow, Metabolism and Function / 12th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 79-80, ISSN: 0271-678X
Zimmerman K, Scott G, Violante I, et al., 2016, Magnetic resonance spectroscopy of the thalamus in chronic traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor &; Francis, Pages: 660-661, ISSN: 1362-301X
Scott G, Gunn RN, Matthews PM, et al., 2016, Minocycline reduces microglial activation after traumatic brain injury measured using [11C]-PBR28 positron emission tomography, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 686-687, ISSN: 1362-301X
Sharp D, Hellyer P, Ghanjari M, 2016, The distribution of neuropathology seen in chronic traumatic encephalopathy can be predicted by finite element modelling of impact biomechanics and can be observed in human neuroimaging data, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 662-662, ISSN: 1362-301X
Mirzaei N, de Burgh R, Sharp D, et al., 2016, Evaluation of [3H]PBR28 as a marker of microglial activation in the rat controlled cortical impact model of traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 608-608, ISSN: 1362-301X
De Simoni S, Kochaj R, Jenkins P, et al., 2016, Changes in cerebral blood flow and their relationship to cognition following traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 605-605, ISSN: 1362-301X
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