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  • Journal article
    Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil Set al., 2019,

    Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study

    , Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422

    BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after

  • Journal article
    Peers PV, Astle DE, Duncan J, Murphy FC, Hampshire A, Das T, Manly Tet al., 2018,

    Dissociable effects of attention vs working memory training on cognitive performance and everyday functioning following fronto-parietal strokes

    , Neuropsychological Rehabilitation, ISSN: 0960-2011

    © 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Difficulties with attention are common following stroke, particularly in patients with frontal and parietal damage, and are associated with poor outcome. Home-based online cognitive training may have the potential to provide an efficient and effective way to improve attentional functions in such patients. Little work has been carried out to assess the efficacy of this approach in stroke patients, and the lack of studies with active control conditions and rigorous evaluations of cognitive functioning pre and post-training means understanding is limited as to whether and how such interventions may be effective. Here, in a feasibility pilot study, we compare the effects of 20 days of cognitive training using either novel Selective Attention Training (SAT) or commercial Working Memory Training (WMT) programme, versus a waitlist control on a range of attentional and working memory tasks. We demonstrate separable effects of each training condition, with SAT leading to improvements in spatial and non-spatial aspects of attention and WMT leading to improvements on closely related working memory tasks. In addition, both training groups reported improvements in everyday functioning, which were associated with improvements in attention, suggesting that improving attention may be of particular importance in maximising functional improvements in this patient group.

  • Journal article
    Balaban G, Halliday BP, Costa CM, Bai W, Porter B, Rinaldi CA, Plank G, Rueckert D, Prasad SK, Bishop MJet al., 2018,

    Fibrosis Microstructure Modulates Reentry in Non-ischemic Dilated Cardiomyopathy: Insights From Imaged Guided 2D Computational Modeling

    , Frontiers in Physiology, Vol: 9, ISSN: 1664-042X

    Aims: Patients who present with non-ischemic dilated cardiomyopathy (NIDCM) andenhancement on late gadolinium magnetic resonance imaging (LGE-CMR), are at highrisk of sudden cardiac death (SCD). Further risk stratification of these patients basedon LGE-CMR may be improved through better understanding of fibrosis microstructure.Our aim is to examine variations in fibrosis microstructure based on LGE imaging, andquantify the effect on reentry inducibility and mechanism. Furthermore, we examine therelationship between transmural activation time differences and reentry.Methods and Results: 2D Computational models were created from a single short axisLGE-CMR image, with 401 variations in fibrosis type (interstitial, replacement) and density,as well as presence or absence of reduced conductivity (RC). Transmural activationtimes (TAT) were measured, as well as reentry incidence and mechanism. Reentrieswere inducible above specific density thresholds (0.8, 0.6 for interstitial, replacementfibrosis). RC reduced these thresholds (0.3, 0.4 for interstitial, replacement fibrosis) andincreased reentry incidence (48 no RC vs. 133 with RC). Reentries were classified as rotor,micro-reentry, or macro-reentry and depended on fibrosis micro-structure. Differencesin TAT at coupling intervals 210 and 500ms predicted reentry in the models (sensitivity89%, specificity 93%). A sensitivity analysis of TAT and reentry incidence showed thatthese quantities were robust to small changes in the pacing location.Conclusion: Computational models of fibrosis micro-structure underlying areas ofLGE in NIDCM provide insight into the mechanisms and inducibility of reentry, andtheir dependence upon the type and density of fibrosis. Transmural activation times,measured at the central extent of the scar, can potentially differentiate microstructureswhich support reentry.

  • Journal article
    Zetterberg H, Winblad B, Bernick C, Yaffe K, Majdan M, Johansson G, Newcombe V, Nyberg L, Sharp D, Tenovuo O, Blennow Ket al., 2018,

    Head trauma in sports - clinical characteristics, epidemiology and biomarkers.

    , J Intern Med

    Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt nonpenetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop postconcussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers.

  • Journal article
    Montaldo P, Lally PJ, Oliveira V, Thayyil Set al., 2018,

    Hypothermic neuroprotection for neonatal encephalopathy in low-and middle-income countries: a new approach to an old problem

    ,, Vol: 19, Pages: e735-e741, ISSN: 1526-9906

    Little progress has been made over the past decade in improving the outcomes of infants with neonatal encephalopathy in low-and middle-income countries (LMICs), and millions of infants still die or sustain permanent neurodisability every year. One of the key reasons for this lack of progress is a disconnect between encephalopathy research in high-income countries and LMICs. The majority of the neonatal encephalopathy research has been conducted in high-income countries with a low disease burden, without the involvement of LMICs. Here we discuss how a collaborative approach—particularly between middle-income countries and high-income countries—enables the use of state-of-the-art magnetic resonance biomarkers and host gene expression profiling for effective disease stratification. Using the example of the Hypothermia for Encephalopathy in Low-and middle-Income countries (HELIX) trial, we describe how this approach may result in a paradigm shift in global perinatal brain research over the next decade.

  • Conference paper
    Duan J, Schlemper J, Bai W, Dawes TJW, Bello G, Biffi C, Doumou G, De Marvao A, O’Regan DP, Rueckert Det al., 2018,

    Combining deep learning and shape priors for bi-ventricular segmentation of volumetric cardiac magnetic resonance images

    , MICCAI ShapeMI Workshop, Publisher: Springer Verlag, Pages: 258-267, ISSN: 0302-9743

    In this paper, we combine a network-based method with image registration to develop a shape-based bi-ventricular segmentation tool for short-axis cardiac magnetic resonance (CMR) volumetric images. The method first employs a fully convolutional network (FCN) to learn the segmentation task from manually labelled ground truth CMR volumes. However, due to the presence of image artefacts in the training dataset, the resulting FCN segmentation results are often imperfect. As such, we propose a second step to refine the FCN segmentation. This step involves performing a non-rigid registration with multiple high-resolution bi-ventricular atlases, allowing the explicit shape priors to be inferred. We validate the proposed approach on 1831 healthy subjects and 200 subjects with pulmonary hypertension. Numerical experiments on the two datasets demonstrate that our approach is capable of producing accurate, high-resolution and anatomically smooth bi-ventricular models, despite the artefacts in the input CMR volumes.

  • Journal article
    Haijen ECHM, Kaelen M, Roseman L, Timmermann C, Russ S, Nutt D, Daws R, Hampshire A, Lorenz R, Carhart-Harris Ret al., 2018,

    Predicting responses to psychedelics: a prospective study

    , Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812

    Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey ( Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding

  • Journal article
    Oliveira V, Martins R, Liow N, Teiserskas J, von Rosenberg W, Adjei T, Shivamurthappa V, Lally PJ, Mandic D, Thayyil Set al., 2018,

    Prognostic accuracy of heart rate variability analysis in neonatal encephalopathy: a systematic review

    , Neonatology, Vol: 115, Pages: 59-67, ISSN: 1661-7800

    BACKGROUND: Heart rate variability analysis offers real-time quantification of autonomic disturbance after perinatal asphyxia, and may therefore aid in disease stratification and prognostication after neonatal encephalopathy (NE). OBJECTIVE: To systematically review the existing literature on the accuracy of early heart rate variability (HRV) to predict brain injury and adverse neurodevelopmental outcomes after NE. DESIGN/METHODS: We systematically searched the literature published between May 1947 and May 2018. We included all prospective and retrospective studies reporting HRV metrics, within the first 7 days of life in babies with NE, and its association with adverse outcomes (defined as evidence of brain injury on magnetic resonance imaging and/or abnormal neurodevelopment at ≥1 year of age). We extracted raw data wherever possible to calculate the prognostic indices with confidence intervals. RESULTS: We retrieved 379 citations, 5 of which met the criteria. One further study was excluded as it analysed an already-included cohort. The 4 studies provided data on 205 babies, 80 (39%) of whom had adverse outcomes. Prognostic accuracy was reported for 12 different HRV metrics and the area under the curve (AUC) varied between 0.79 and 0.94. The best performing metric reported in the included studies was the relative power of high-frequency band, with an AUC of 0.94. CONCLUSIONS: HRV metrics are a promising bedside tool for early prediction of brain injury and neurodevelopmental outcome in babies with NE. Due to the small number of studies available, their heterogeneity and methodological limitations, further research is needed to refine this tool so that it can be used in clinical practice.

  • Journal article
    Roberts R, Ahmad H, Patel M, Danai D, Ibitoye R, Sharif M, Leech R, Arshad Q, Bronstein Aet al., 2018,

    An fMRI study of visuo-vestibular interaction in Vestibular Neuritis

    , NeuroImage: Clinical, Vol: 20, Pages: 1010-1017, ISSN: 2213-1582

    Vestibular neuritis (VN) is characterised by acute vertigo due to a sudden loss of unilateral vestibular function. A considerable proportion of VN patients proceed to develop chronic symptoms of dizziness, including visually induced dizziness, specifically during head turns. Here we investigated whether the development of such poor clinical outcomes following VN, is associated with abnormal visuo-vestibular cortical processing. Accordingly, we applied functional magnetic resonance imaging to assess brain responses of chronic VN patients and compared these to controls during both congruent (co-directional) and incongruent (opposite directions) visuo-vestibular stimulation (i.e. emulating situations that provoke symptoms in patients). We observed a focal significant difference in BOLD signal in the primary visual cortex V1 between patients and controls in the congruent condition (small volume corrected level of p < .05 FWE). Importantly, this reduced BOLD signal in V1 was negatively correlated with functional status measured with validated clinical questionnaires. Our findings suggest that central compensation and in turn clinical outcomes in VN are partly mediated by adaptive mechanisms associated with the early visual cortex.

  • Conference paper
    Li W, Lao-Kaim N, Roussakis A, Martin-Bastida A, Valle-Guzman N, Paul G, Soreq E, Daws R, Foltynie T, Barker R, Hampshire A, Piccini Pet al., 2018,

    Functional connectivity changes in relation to dopaminergic decline in Parkinson's over time: A resting-state fMRI and 11C-PE2I PET imaging study

    , International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S682-S683, ISSN: 0885-3185

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