MRS studies of the effects of dietary interventions on hepatic metabolism

Magnetic Resonance Spectroscopy is a powerful non-invasive tool for investigating liver metabolism in vivo. PRESS and STEAM localized 1H MRS can be used to provide liver lipid measurements calculated from the fat to water peak ratios. Surface coils can also be used to measure other metabolites using multinuclear MRS, 13C MRS directly measures glycogen levels and 31PMRS measures ATP and other phosphate metabolites. This thesis reports on studies undertaken to develop these techniques and describes a number of in vivo investigations that explored the effects of dietary interventions on hepatic metabolism

Current and future magnetic resonance technologies for assessing liver disease in clinical and experimental medicine

Background: In the past decades, a number of non-invasive methods have emerged for detecting and estimating liver fibrosis; these include both serum-based panels and imaging-based technology. Some of these methods are now being incorporated in clinical practice. However, the limitations of the current techniques include lack of organ specificity, sampling errors and limited ability to reflect the efficacy of interventions. Key Messages: Novel magnetic resonance (MR)-based techniques provide an opportunity to bring about further changes in the investigations and management of patients with liver diseases. Multimodal quantitative MR techniques enable the estimation of fat, iron accumulation, degree of liver injury/inflammation and fibrosis within the whole liver without the need for administering contrast agents. Architectural changes within the liver can be evaluated concurrently with portal haemodynamic changes allowing non-invasive assessment of portal hypertension and effects of interventions. A combination ultra-high field (7T) provides greater sensitivity with a potential to distinguish inflammation from fibrosis on imaging and determine specific types of fats (saturated vs. unsaturated) present within the liver using MR spectroscopy. 13 C MR spectroscopy can estimate glutathione flux and rate of beta oxidation in-vivo providing novel tools for experimental studies that evaluate the efficacy of interventions as well as underlying mechanisms. Conclusions: Translational research should focus on converting the potentials of these innovative methodologies into clinical applications for the benefit of patients

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively,in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate fluxin vivo. Thus, a vast range of key metabolic events inthe natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population leve

1H MRS assessment of lipid composition at 3T and 7T

1H MRS assessment of lipid composition at 3T and 7

Corticotrophin releasing factor increases ascending colon volume after a fructose test meal in healthy humans: a randomised control trial

Background: Poorly absorbed, fermentable carbohydrates can provoke irritable bowel syndrome (IBS) symptoms by escaping absorption in the small bowel and being rapidly fermented in the colon in some susceptible subjects. IBS patients are often anxious and stressed and stress accelerates small bowel transit which may exacerbate malabsorption. Objective: In this study we investigated the effect of intravenous injection of corticotrophin releasing factor (CRF) on fructose malabsorption and the resulting volume of water in the small bowel. Design: We performed a randomised, placebo controlled, cross-over study of CRF versus saline injection in 11 male and 10 female healthy subjects, examining the effect on the malabsorption of a 40 g fructose test meal and its transit through the gut which was assessed by serial Magnetic Resonance imaging (MRI) and breath hydrogen measurement. Orocaecal transit was assessed using the lactose-ureide C13 breath test and the adrenal response to CRF assessed by serial salivary cortisol measurements. Results: (Mean ± SD) CRF injection caused a significant rise in salivary cortisol which lasted 135 minutes. Small bowel water content (SBWC) rose from baseline, peaking at 45 minutes after fructose ingestion while breath hydrogen peaked later at 75 minutes. The area under the curve (AUC) for SBWC from -15 - 135 minutes was significantly lower after CRF versus saline (mean difference [95% CI] 7433 [275, 14591] mL.min, P = 0.04). Ascending colon volume rose after CRF, significantly more for male volunteers than female (P = 0.025). Conclusions: CRF constricts the small bowel and increases fructose malabsorption as shown by increased ascending colon volumes. This mechanism may help to explain the increased sensitivity of some stressed individuals to fructose malabsorption. This trial was registered at ClinicalTrials.gov as NCT0176328

Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging.

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy

The impact of variations in subject geometry, respiration and coil repositioning on the specific absorption rate in parallel transmit abdominal imaging at 7 T

Parallel transmit MRI at 7 T has increasingly been adopted in research projects and provides increased signal‐to‐noise ratios and novel contrasts. However, the interactions of fields in the body need to be carefully considered to ensure safe scanning. Recent advances in physically flexible body coils have allowed for high‐field abdominal imaging, but the effects of increased variability on energy deposition need further exploration. The aim of this study was to assess the impact of subject geometry, respiration phase and coil positioning on the specific absorption rate (SAR). Ten healthy subjects (body mass index [BMI] = 25 ± 5 kg m−2) were scanned (at 3 T) during exhale breath‐hold and images used to generate body models. Seven of these subjects were also scanned during inhale. Simplifications of the coil and body models were first explored, and then finite‐difference time‐domain simulations were run with a typical eight‐channel parallel transmit coil positioned over the abdomen. Simulations were used to generate 10 g averaged SAR (SAR10g) maps across 100,000 phase settings, and the worst‐case scenario 10 g averaged SAR (wocSAR10g) was identified using trigonometric maximisation. The average maximum SAR10g across the 10 subjects with 1 W input power per channel was 1.77 W kg−1. Hotspots were always close to the body surface near the muscle wall boundary. The wocSAR10g across the 10 subjects ranged from 2.3 to 3.2 W kg−1 and was inversely correlated to fat volume percentage (R = 8) and BMI (R = 0.6). The coefficient of variation values in SAR10g due to variations in subject geometry, respiration phase and realistic coil repositioning were 12%, 4% and 12%, respectively. This study found that the variability due to realistic coil repositioning was similar to the variability due to differing healthy subject geometries for abdominal imaging. This is important as it suggests that population‐based modelling is likely to be more useful than individual modelling in setting safe thresholds for abdominal imaging

Effects of an isoenergetic low Glycaemic Index (GI) diet on liver fat accumulation and gut microbiota composition in patients with non-alcoholic fatty liver disease (NAFLD): A study protocol of an efficacy mechanism evaluation

Introduction A Low Glycaemic Index (LGI) diet is a proposed lifestyle intervention in non-alcoholic fatty liver diseases (NAFLD) which is designed to reduce circulating blood glucose levels, hepatic glucose influx, insulin resistance and de novo lipogenesis. A significant reduction in liver fat content through following a 1-week LGI diet has been reported in healthy volunteers. Changes in dietary fat and carbohydrates have also been shown to alter gut microbiota composition and lead to hepatic steatosis through the gut-liver axis. There are no available trials examining the effects of an LGI diet on liver fat accumulation in patients with NAFLD; nor has the impact of consuming an LGI diet on gut microbiota composition been studied in this population. The aim of this trial is to investigate the effects of LGI diet consumption on liver fat content and its effects on gut microbiota composition in participants with NAFLD compared with a High Glycaemic Index (HGI) control diet. Methods and analysis A 2×2 cross-over randomised mechanistic dietary trial will allocate 16 participants with NAFLD to a 2-week either HGI or LGI diet followed by a 4-week wash-out period and then the LGI or HGI diet, alternative to that followed in the first 2 weeks. Baseline and postintervention (four visits) outcome measures will be collected to assess liver fat content (using MRI/S and controlled attenuation parameter-FibroScan), gut microbiota composition (using 16S RNA analysis) and blood biomarkers including glycaemic, insulinaemic, liver, lipid and haematological profiles, gut hormones levels and short-chain fatty acids. Ethics and dissemination Study protocol has been approved by the ethics committees of The University of Nottingham and East Midlands Nottingham-2 Research Ethics Committee (REC reference 19/EM/0291). Data from this trial will be used as part of a Philosophy Doctorate thesis. Publications will be in peer-reviewed journals. Trial registration number NCT04415632

Calibration-free regional RF shims for MRS

Purpose: Achieving a desired RF transmit field (B1+) in small regions-of-interest (ROIs) is critical for single-voxel MR spectroscopy at ultra-high field. RF shimming, using parallel transmission, requires B1+ mapping and optimisation, which limits its ease-of-use. This work aimed to generate calibration-free RF shims for pre-defined target ROIs, which can be applied to any participant, to produce a desired absolute magnitude B1+ (|B1+|).Methods: RF shims were found offline by joint-optimisation on a database, comprising B1+ maps from 11 subjects, considering ROIs in occipital cortex (OCC), hippocampus (Hippo.) and posterior-cingulate (PCC), as well as whole brain. The |B1+| achieved was compared to a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free shims in 4 participants. Global and local 10g specific absorption rate (SAR) deposition were estimated using Duke and Ella dielectric models.Results: There was no difference in the mean |B1+| produced using calibration-free vs. tailored RF shimming in OCC (p=0.15), Hippo. (p=0.5) or PCC (p=0.98) although differences were observed in the root-mean-square error (RMSE) |B1+|. Spectra acquired using calibration-free shims had similar SNR and low residual water signal. Under identical power settings, SAR deposition was lower compared to operating in quadrature mode. For example, total head SAR was around 35% less for OCC.Conclusion: This work demonstrates that static RF shims, optimised offline for small regions, avoid the need for B1+ mapping and optimisation for each ROI and participant. Furthermore, power settings may be increased when using calibration-free shims to better take advantage of RF shimming

Using social media to support small group learning

Abstract Background Medical curricula are increasingly using small group learning and less didactic lecture-based teaching. This creates new challenges and opportunities in how students are best supported with information technology. We explored how university-supported and external social media could support collaborative small group working on our new undergraduate medical curriculum. Methods We made available a curation platform (Scoop.it) and a wiki within our virtual learning environment as part of year 1 Case-Based Learning, and did not discourage the use of other tools such as Facebook. We undertook student surveys to capture perceptions of the tools and information on how they were used, and employed software user metrics to explore the extent to which they were used during the year. Results Student groups developed a preferred way of working early in the course. Most groups used Facebook to facilitate communication within the group, and to host documents and notes. There were more barriers to using the wiki and curation platform, although some groups did make extensive use of them. Staff engagement was variable, with some tutors reviewing the content posted on the wiki and curation platform in face-to-face sessions, but not outside these times. A small number of staff posted resources and reviewed student posts on the curation platform. Conclusions Optimum use of these tools depends on sufficient training of both staff and students, and an opportunity to practice using them, with ongoing support. The platforms can all support collaborative learning, and may help develop digital literacy, critical appraisal skills, and awareness of wider health issues in society