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  • Journal article
    Li L, Ribeiro Violante I, Leech R, Ross E, Hampshire A, Opitz A, Rothwell J, Carmichael D, Sharp Det al., 2019,

    Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation

    , Human Brain Mapping, Vol: 40, Pages: 904-915, ISSN: 1065-9471

    Despite its widespread use in cognitive studies, there is still limited understanding of whether and how transcranial direct current stimulation (tDCS) modulates brain network function. To clarify its physiological effects, we assessed brain network function using functional magnetic resonance imaging (fMRI) simultaneously acquired during tDCS stimulation. Cognitive state was manipulated by having subjects perform a Choice Reaction Task or being at “rest.” A novel factorial design was used to assess the effects of brain state and polarity. Anodal and cathodal tDCS were applied to the right inferior frontal gyrus (rIFG), a region involved in controlling activity large‐scale intrinsic connectivity networks during switches of cognitive state. tDCS produced widespread modulation of brain activity in a polarity and brain state dependent manner. In the absence of task, the main effect of tDCS was to accentuate default mode network (DMN) activation and salience network (SN) deactivation. In contrast, during task performance, tDCS increased SN activation. In the absence of task, the main effect of anodal tDCS was more pronounced, whereas cathodal tDCS had a greater effect during task performance. Cathodal tDCS also accentuated the within‐DMN connectivity associated with task performance. There were minimal main effects of stimulation on network connectivity. These results demonstrate that rIFG tDCS can modulate the activity and functional connectivity of large‐scale brain networks involved in cognitive function, in a brain state and polarity dependent manner. This study provides an important insight into mechanisms by which tDCS may modulate cognitive function, and also has implications for the design of future stimulation studies.

  • Conference paper
    Chen C, Bai W, Rueckert D, 2019,

    Multi-task learning for left atrial segmentation on GE-MRI

    , International Workshop on Statistical Atlases and Computational Models of the Heart, Publisher: Springer Verlag, Pages: 292-301, ISSN: 0302-9743

    Segmentation of the left atrium (LA) is crucial for assessing its anatomy in both pre-operative atrial fibrillation (AF) ablation planning and post-operative follow-up studies. In this paper, we present a fully automated framework for left atrial segmentation in gadolinium-enhanced magnetic resonance images (GE-MRI) based on deep learning. We propose a fully convolutional neural network and explore the benefits of multi-task learning for performing both atrial segmentation and pre/post ablation classification. Our results show that, by sharing features between related tasks, the network can gain additional anatomical information and achieve more accurate atrial segmentation, leading to a mean Dice score of 0.901 on a test set of 20 3D MRI images. Code of our proposed algorithm is available at

  • Journal article
    Thayyil S, Liow N, Montaldo P, Lally P, Teiserskas J, Bassett P, Oliveira V, Mendoza J, Slater R, Shankaran Set al., 2019,

    Pre-emptive morphine during therapeutic hypothermia after neonatal encephalopathy: a secondary analysis

    , Therapeutic Hypothermia and Temperature Management, Vol: 10, Pages: 45-52, ISSN: 2153-7658

    Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate (n = 150) or severe NE (n = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion (n = 141) were more hypotensive (49% vs. 25%, p = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days, p = 0.009) than those who did not (n = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group (p > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5; p = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12–0.21] vs. 0.13 [0.11–0.18]; p = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10; p = 0.98), language (89 ± 22 vs. 93 ± 

  • Journal article
    Gilbert K, Bai W, Mauger C, Medrano-Gracia P, Suinesiaputra A, Lee AM, Sanghvi MM, Aung N, Piechnik SK, Neubauer S, Petersen SE, Rueckert D, Young AAet al., 2019,

    Independent left ventricular morphometric atlases show consistent relationships with cardiovascular risk factors: A UK Biobank study

    , Scientific Reports, Vol: 9, ISSN: 2045-2322

    Left ventricular (LV) mass and volume are important indicators of clinical and pre-clinical disease processes. However, much of the shape information present in modern imaging examinations is currently ignored. Morphometric atlases enable precise quantification of shape and function, but there has been no objective comparison of different atlases in the same cohort. We compared two independent LV atlases using MRI scans of 4547 UK Biobank participants: (i) a volume atlas derived by automatic non-rigid registration of image volumes to a common template, and (ii) a surface atlas derived from manually drawn epicardial and endocardial surface contours. The strength of associations between atlas principal components and cardiovascular risk factors (smoking, diabetes, high blood pressure, high cholesterol and angina) were quantified with logistic regression models and five-fold cross validation, using area under the ROC curve (AUC) and Akaike Information Criterion (AIC) metrics. Both atlases exhibited similar principal components, showed similar relationships with risk factors, and had stronger associations (higher AUC and lower AIC) than a reference model based on LV mass and volume, for all risk factors (DeLong p < 0.05). Morphometric variations associated with each risk factor could be quantified and visualized and were similar between atlases. UK Biobank LV shape atlases are robust to construction method and show stronger relationships with cardiovascular risk factors than mass and volume.

  • Journal article
    Creese B, Brooker H, Ismail Z, Wesnes KA, Hampshire A, Khan Z, Megalogeni M, Corbett A, Aarsland D, Ballard Cet al., 2019,

    Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults

    , American Journal of Geriatric Psychiatry, ISSN: 1064-7481

    © 2019 American Association for Geriatric Psychiatry Objective: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment. Methods: A total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance. Results: A total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001). Conclusion: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.

  • Journal article
    Sandrone S, Berthaud JV, Chuquilin M, Cios J, Ghosh P, Gottlieb-Smith RJ, Kushlaf H, Mantri S, Masangkay N, Menkes DL, Nevel KS, Sarva H, Schneider LDet al., 2019,

    Neurologic and neuroscience education Mitigating neurophobia to mentor health care providers

    , NEUROLOGY, Vol: 92, Pages: 174-179, ISSN: 0028-3878
  • Journal article
    Li L, Ribeiro Violante I, Leech R, Hampshire A, Opitz A, McArhur D, Carmichael D, Sharp Det al., 2019,

    Cognitive enhancement with Salience Network electrical stimulation is influenced by network structural connectivity

    , NeuroImage, Vol: 185, Pages: 425-433, ISSN: 1053-8119

    The Salience Network (SN) and its interactions are important for cognitive control. We have previously shown that structural damage to the SN is associated with abnormal functional connectivity between the SN and Default Mode Network (DMN), abnormal DMN deactivation, and impaired response inhibition, which is an important aspect of cognitive control. This suggests that stimulating the SN might enhance cognitive control. Here, we tested whether non-invasive transcranial direct current stimulation (TDCS) could be used to modulate activity within the SN and enhance cognitive control. TDCS was applied to the right inferior frontal gyrus/anterior insula cortex during performance of the Stop Signal Task (SST) and concurrent functional (f)MRI. Anodal TDCS improved response inhibition. Furthermore, stratification of participants based on SN structural connectivity showed that it was an important influence on both behavioural and physiological responses to anodal TDCS. Participants with high fractional anisotropy within the SN showed improved SST performance and increased activation of the SN with anodal TDCS, whilst those with low fractional anisotropy within the SN did not. Cathodal stimulation of the SN produced activation of the right caudate, an effect which was not modulated by SN structural connectivity. Our results show that stimulation targeted to the SN can improve response inhibition, supporting the causal influence of this network on cognitive control and confirming it as a target to produce cognitive enhancement. Our results also highlight the importance of structural connectivity as a modulator of network to TDCS, which should guide the design and interpretation of future stimulation studies.

  • Journal article
    Azor AM, Cole JH, Holland AJ, Dumba M, Patel MC, Sadlon A, Goldstone AP, Manning KEet al., 2019,

    Increased brain age in adults with Prader-Willi syndrome

    , NeuroImage: Clinical, Vol: 21, ISSN: 2213-1582

    Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging. In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging. Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8-27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5-47.7; n = 19 paternal chromosome 15q11-13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6-29.0; 65.0% male; BMI 24.1 kg/m2, 19.2-34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5-33.7 kg/m2, and n = 29 controls with BMI 21.7-34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive

  • Journal article
    Brooker H, Wesnes KA, Ballard C, Hampshire A, Aarsland D, Khan Z, Stenton R, Megalogeni M, Corbett Aet al., 2019,

    The relationship between the frequency of number-puzzle use and baseline cognitive function in a large online sample of adults aged 50 and over

    , International Journal of Geriatric Psychiatry, ISSN: 0885-6230

    © 2019 John Wiley & Sons, Ltd. Objective: Establishing affordable lifestyle interventions that might preserve cognitive function in the aging population and subsequent generations is a growing area of research focus. Data from the PROTECT study has been utilised to examine whether number-puzzle use is related to cognitive function in older adults. Methods: Data from 19 078 healthy volunteers aged 50 to 93 years old enrolled on the online PROTECT study were evaluated for self-reported frequency of performing number puzzles. Two cognitive-test batteries were employed to assess core aspects of cognitive function including reasoning, focussed and sustained attention, information processing, executive function, working memory, and episodic memory. Analysis of covariance was used to establish the differences between the six frequency groups. Results: Highly statistically significant main effects of the frequency of performing number puzzles were seen on all 14 cognitive measures, with P values of less than 0.0004. Interestingly, participants who reported engaging in number puzzles more than once a day had superior cognitive performance on 10 core measures compared with all other frequency groups, although not all were statistically significant. Conclusions: This study has identified a close relationship between frequency of number-puzzle use and the quality of cognitive function in adults aged 50 to 93 years old. In order to determine the value of these findings as a potential intervention, further research should explore the type and difficulty of the number puzzles. These findings further contribute to the growing evidence that engaging in mentally stimulating activities could benefit the brain function of the ageing population.

  • Journal article
    Montaldo P, Kaforou M, Pollara G, Hervás-Maríne D, Calabria I, Panadero J, Pedrola L, Lally PJ, Oliveira V, Kage A, Atreja G, Mendoza J, Soe A, Pattnayak S, Shankaranh S, Vento M, Herberg J, Thayyil Set al., 2019,

    Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy

    , Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800

    BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.

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