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Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level. Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282. 29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6-14.2) and 40.6% (95% CI: 26.2-56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0-15.8) and 64.8% (95% CI: 54.3-74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS). In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.

Preterm birth is closely associated with diffuse white matter dysmaturation inferred from diffusion MRI and neurocognitive impairment in childhood. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are distinct dMRI modalities, yet metrics derived from these two methods share variance across tracts. This raises the hypothesis that dimensionality reduction approaches may provide efficient whole-brain estimates of white matter microstructure that capture (dys)maturational processes. To investigate the optimal model for accurate classification of generalised white matter dysmaturation in preterm infants we assessed variation in DTI and NODDI metrics across 16 major white matter tracts using principal component analysis and structural equation modelling, in 79 term and 141 preterm infants at term equivalent age. We used logistic regression models to evaluate performances of single-metric and multimodality general factor frameworks for efficient classification of preterm infants based on variation in white matter microstructure. Single-metric general factors from DTI and NODDI capture substantial shared variance (41.8-72.5%) across 16 white matter tracts, and two multimodality factors captured 93.9% of variance shared between DTI and NODDI metrics themselves. General factors associate with preterm birth and a single model that includes all seven DTI and NODDI metrics provides the most accurate prediction of microstructural variations associated with preterm birth. This suggests that despite global covariance of dMRI metrics in neonates, each metric represents information about specific (and additive) aspects of the underlying microstructure that differ in preterm compared to term subjects.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre ‘FutureMS’ study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration (HCC), is associated with microstructure, structural connectivity, and volume of the infant amygdala. In 78 mother-infant dyads, maternal hair was sampled postnatally, and infants underwent magnetic resonance imaging at term-equivalent age. We found a relationship between maternal HCC and amygdala development that differed according to infant sex. Higher HCC was associated with higher left amygdala fractional anisotropy (β = 0.677, p=0.010), lower left amygdala orientation dispersion index (β = −0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (β = 0.475, p=0.007) in girls compared to boys. Furthermore, altered amygdala microstructure was only observed in boys, with connectivity changes restricted to girls. Maternal cortisol during pregnancy is related to newborn amygdala architecture and connectivity in a sexually dimorphic manner. Given the fundamental role of the amygdala in the emergence of emotion regulation, these findings offer new insights into mechanisms linking maternal health with neuropsychiatric outcomes of children. Stress during pregnancy, for example because of mental or physical disorders, can have long-term effects on child development. Epidemiological studies have shown that individuals exposed to stress in the womb are at higher risk of developmental and mood conditions, such as ADHD and depression. This effect is different between the sexes, and the biological mechanisms that underpin these observations are poorly understood. One possibility is that a baby’s developing amygdala, the part of the brain that processes emotions, is affected by a signal known as cortisol. This hormone is best known for its role in coordinating the stress response, but it also directs the growth of a fetus. Tracking fetal amygdala changes as well as cortisol levels in the pregnant individual could explain how stress during pregnancy affects development. To investigate, Stoye et al. recruited nearly 80 volunteers and their newborn children. MRI scans were used to examine the structure of the amygdala, and how it is connected to other parts of the brain. In parallel, the amount of cortisol was measured in hair samples collected from the volunteers around the time of birth, which reflects stress levels during the final three months of pregnancy. Linking the brain imaging results to the volunteers’ cortisol levels showed that being exposed to higher cortisol levels in the womb affected babies in different ways based on their sex: boys showed alterations in the fine structure of their amygdala, while girls displayed changes in the way that brain region connected to other neural networks. The work by Stoye et al. potentially reveals a biological mechanism by which early exposure to stress could affect brain development differently between the sexes, potentially informing real-world interventions.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies. [Display omitted]

Background Bipolar disorder is a serious mental illness, which requires new strategies for prevention and management. Recent evidence suggests that a ketogenic diet may be an effective intervention. This research aimed to explore the feasibility and acceptability of a ketogenic diet intervention for bipolar disorder, fidelity to its behavioural components and the experiences of the participants and research clinicians involved. Methods A mixed-methods process evaluation was conducted. Semi-structured telephone interviews were carried out with 15 participants 1–2 months after completing a 6–8 week modified ketogenic diet intervention, and 4 research clinicians from the study team following the completion of data collection. Data were thematically analysed. Fidelity checklists completed by research dietitians were analysed using descriptive count and percentage statistics. Findings are reported post-hoc, following the analysis and publication of the main pilot study findings. Reporting was guided by the COREQ checklist. Results Five themes were identified in the qualitative data: (1) ‘ Encouraging entry and supporting exit’ (e.g. recognising and managing participants’ varied motives and expectations, including around weight loss and symptom alleviation); (2) ‘ Challenging but potentially transformational ,’ which reflects that while it can be difficult to initiate and maintain a ketogenic diet day-to-day, many participants perceived physical and psychological benefits (e.g. significant weight loss, mood stability and enhanced ability to focus); (3) ‘Intervention facilitators ,’ including a range of behavioural (e.g. goal setting), social (e.g. family and dietitians) and technological (e.g. apps for monitoring) support mechanisms; (4) ‘Intervention barriers’ (e.g. dietary preferences, concerns about the diet and its impact, the testing burden and capacity of the delivery team); and (5) ‘The wider context’ (e.g. the cost of living and sociocultural expectations) was a crucial factor explaining differential experiences. Overall, descriptive analyses indicated moderate-to-good fidelity to the behaviour change components of the study. Conclusion We provide novel insight into the experiences of people living with bipolar disorder initiating and following a ketogenic diet, as well as those of research clinicians who support the intervention. Future trials may benefit from increased clinical research capacity, better-defined entry and exit routes, additional interpersonal support, and greater understanding of how social and societal factors impact participation. Trial registration Study registration number: ISRCTN61613198 (02/03/22).

Purpose Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing–remitting MS (RRMS). Methods Subjects ( n  = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. Results Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with ‘subject’ as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions ( p  = 0.0350 and p  = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability ( p  > 0.05). Conclusion We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice.

IntroductionPreterm birth is closely associated with altered brain development and is a leading cause of neurodevelopmental, cognitive and behavioural impairments across the life course. We aimed to investigate neuroanatomic variation and adverse outcomes associated with preterm birth by studying a cohort of preterm infants and controls born at term using brain MRI linked to biosamples and clinical, environmental and neuropsychological data.Methods and analysisTheirworld Edinburgh Birth Cohort is a prospective longitudinal cohort study at the University of Edinburgh. We plan to recruit 300 infants born at <33 weeks of gestational age (GA) and 100 healthy control infants born after 37 weeks of GA. Multiple domains are assessed: maternal and infant clinical and demographic information; placental histology; immunoregulatory and trophic proteins in umbilical cord and neonatal blood; brain macrostructure and microstructure from structural and diffusion MRI (dMRI); DNA methylation; hypothalamic–pituitary–adrenal axis activity; social cognition, attention and processing speed from eye tracking during infancy and childhood; neurodevelopment; gut and respiratory microbiota; susceptibility to viral infections; and participant experience. Main analyses include creation of novel methods for extracting information from neonatal structural and dMRI, regression analyses of predictors of brain maldevelopment and neurocognitive outcome associated with preterm birth, and determination of the quantitative predictive performance of MRI and other early life factors for childhood outcome.Ethics and disseminationEthical approval has been obtained from the National Research Ethics Service (NRES), South East Scotland Research Ethics Committee (NRES numbers 11/55/0061 and 13/SS/0143 (phase I) and 16/SS/0154 (phase II)), and NHS Lothian Research and Development (2016/0255). Results are disseminated through open access journals, scientific meetings, social media, newsletters anda study website (www.tebc.ed.ac.uk), and we engage with the University of Edinburgh public relations and media office to ensure maximum publicity and benefit.

Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6-8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.