Global intravascular and local hyperoxia contrast phase-based blood oxygenation measurements

AbstractThe measurement of venous cerebral blood oxygenation (Yv) has potential applications in the study of patient groups where oxygen extraction and/or metabolism are compromised. It is also useful for fMRI studies to assess the stimulus-induced changes in Yv, particularly since basal Yv partially accounts for inter-subject variation in the haemodynamic response to a stimulus. A range of MRI-based methods of measuring Yv have been developed recently. Here, we use a method based on the change in phase in the MR image arising from the field perturbation caused by deoxygenated haemoglobin in veins. We build on the existing phase based approach (Method I), where Yv is measured in a large vein (such as the superior sagittal sinus) based on the field shift inside the vein with assumptions as to the vein's shape and orientation. We demonstrate two novel modifications which address limitations of this method. The first modification (Method II), maps the actual form of the vein, rather than assume a given shape and orientation. The second modification (Method III) uses the intra and perivascular phase change in response to a known change in Yv on hyperoxia to measure normoxic Yv in smaller veins. Method III can be applied to veins whose shape, size and orientation are not accurately known, thus allowing more localised measures of venous oxygenation. Results demonstrate that the use of an overly fine spatial filter caused an overestimation in Yv for Method I, whilst the measurement of Yv using Method II was less sensitive to this bias, giving Yv=0.62±0.03. Method III was applied to mapping of Yv in local veins across the brain, yielding a distribution of values with a mode of Yv=0.661±0.008

The effect of isocapnic hyperoxia on neurophysiology as measured with MRI and MEG

The physiological effect of hyperoxia has been poorly characterised, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirActTM system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3 ± 0.8 % change during hyperoxia, p = 0.8), whilst Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3 ± 0.4 %, -0.5 ± 5 % change during hyperoxia). These are in contrast to significant changes in blood flow observed for hypercapnia (6.8 ± 1.5 %/mmHg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibrated BOLD using hyperoxia or combined hyperoxia and hypercapnia needs further investigation

Calibrated BOLD using direct measurement of changes in venous oxygenation

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO2 due to the stimulus. CMRO2 changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches

Glycemic, Gastrointestinal, Hormonal and Appetitive Responses to Pearl Millet or Oats Porridge Breakfasts: a Randomized, Crossover Trial in Healthy Humans

Whole grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. This study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomized, two way crossover trial, 26 healthy participants consumed two iso-energetic/volumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, GLP-1, GIP and PYY, gastric volumes and appetite ratings were collected for two hours postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental area under the curve (iAUC2h) for blood glucose was not significantly different between the porridges (p ˃ 0.05). The iAUC2h gastric volume was larger for PMP compared with SOP (p = 0.045). The iAUC2h GIP concentration was significantly lower for PMP compared with SOP (p = 0.001). Other hormones and appetite responses were similar between meals. In conclusion, this study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable, alternative, with health-promoting characteristics comparable to oats. GIP is an incretin hormone linked to triacylglycerol absorption in adipose tissue, therefore the lower GIP response for PMP may be an added health benefit

Field strength dependence of grey matter R2* on venous oxygenation

The relationship between venous blood oxygenation and change in transverse relaxation rate (ΔR2 *) plays a key role in calibrated BOLD fMRI. This relationship, defined by the parameter β, has previously been determined using theoretical simulations and experimental measures. However, these earlier studies have been confounded by the change in venous cerebral blood volume (CBV) in response to functional tasks. This study used a double-echo gradient echo EPI scheme in conjunction with a graded isocapnic hyperoxic sequence to assess quantitatively the relationship between the fractional venous blood oxygenation (1-Yv) and transverse relaxation rate of grey matter (ΔR2 * GM), without inducing a change in vCBV. The results demonstrate that the relationship between ΔR2 * and fractional venous oxygenation at all magnet field strengths studied was adequately described by a linear relationship. The gradient of this relationship did not increase monotonically with field strength, which may be attributed to the relative contributions of intravascular and extravascular signals which will vary with both field strength and blood oxygenation

Assessing the impact of posture on diaphragm morphology and function using an open upright MRI system – a pilot study

PurposeThe diaphragm is the most important muscle of respiration. Disorders of the diaphragm can have a deleterious impact on respiratory function. We aimed to evaluate the use of an open-configuration upright low-field MRI system to assess diaphragm morphology and function in patients with bilateral diaphragm weakness (BDW) and chronic obstructive pulmonary disease (COPD) with hyperinflation.MethodThe study was approved by the National Research Ethics Committee, and written consent was obtained. We recruited 20 healthy adult volunteers, six subjects with BDW, and five subjects with COPD with hyperinflation. We measured their vital capacity in the upright and supine position, after which they were scanned on the 0.5 T MRI system during 10-second breath-holds at end-expiration and end-inspiration in both positions. We developed and applied image analysis methods to measure the volume under the dome, maximum excursion of hemidiaphragms, and anterior-posterior and left-right extension of the diaphragm.ResultsAll participants were able to complete the scanning protocol. The patients found scanning in the upright position more comfortable than the supine position. All differences in the supine inspiratory-expiratory parameters, excluding left-right extension, were significantly smaller in the BDW and COPD groups compared with healthy volunteers. No significant correlation was found between the postural change in diaphragm morphology and vital capacity in either group.ConclusionOur combined upright-supine MR imaging approach facilitates the assessment of the impact of posture on diaphragm morphology and function in patients with BDW and those with COPD with hyperinflation

Liver glycogen stores via 13C magnetic resonance spectroscopy in healthy children: randomized, controlled study

BackgroundOwing to its role in glucose homeostasis, liver glycogen concentration ([LGly]) can be a marker of altered metabolism seen in disorders which impact health of children. However, there is a paucity of normative data for this measure in children to allow comparison with patients, and time-course assessment of [LGly] in response to feeding has not been reported. 13C-magnetic resonance spectroscopy (13C-MRS) is used extensively in research to non-invasively assess liver metabolites in adult health and disease, but similar measurements in children are lacking.ObjectiveThe main objectives were to quantify the depletion of [LGly] after overnight fasting, and the subsequent response to feeding.DesignIn a randomized, open-label, incomplete block design study, healthy, normal-weight children (8-12y) attended 2 evening visits, each separated by ≥5 days and directly followed by a morning visit. An individually tailored, standardized meal was consumed 3-hours prior to evening assessments. Participants then remained fasted until the morning visit. [LGly] was assessed once in the fed (20:00hrs) and fasted state (08:00hrs) using 13C-MRS. After the 8:00hrs assessment, 200ml of a mixed-macronutrient drink containing 15.5g (402kJ) or 31g carbohydrate (804kJ), or water only, was consumed, with 13C-MRS measurements then performed hourly for 4h. Each child was randomized to 2 of 3 drink options across the 2 mornings. Data are expressed as mean (SD).ResultsTwenty-four children (13F:11M) completed the study (9.9(1.1)y, BMI percentile 45.7(25.9)). [LGly] decreased from 377.9(141.3) to 277.3(107.4) mmol·l-1 overnight; depletion rate 0.14(0.15) mmol·l-1·min-1. Incremental responses of [LGly] to test drinks differed (P<0.001), with incremental net AUC of [LGly] over 4h (i.netAUC240min) being higher for 15.5g (-67.1(205.8) mmol·l-1·240min; P<0.01) and 31g carbohydrate (101.6(180.9) mmol·l-1·240min; P<0.005) compared to water (-253.1(231.2) mmol·l-1·240min).ConclusionAfter overnight fasting, [LGly] decreased by 22.9(25.1)%, and [LGly] i.netAUC240min was higher after subsequent consumption of 15.5g and 31g carbohydrate, compared to water.Clinical Trial Registry number: NCT04278209 (www.clinicaltrials.gov

Glycaemic, gastrointestinal and appetite responses to breakfast porridges from ancient cereal grains: a MRI pilot study in healthy humans

Cereal grain based porridges are commonly consumed throughout the world. Whilst some data are available for varieties that are popular in the Western world such as oats and rye, other ‘ancient’ grains used in the East and in Africa such as millets are thought to have beneficial health effects, such as a suppression of post prandial hunger and circulating glucose levels. These grains, a sustainable food source due to their tolerance of extreme weather and growing conditions, are commonly found throughout Asia and Africa. However, knowledge of the physiological responses to these grain varieties is very limited. This study aimed to collect initial pilot data on the physiological and gastrointestinal responses to breakfast porridges made with two millet varieties and oats and rye grains. A total of n = 15 completed the oats and rye, n = 9 the finger millet n = 12 the pearl millet meals. MRI scans were undertaken at baseline, immediately after consumption and then hourly postprandially. Blood glucose was measured at baseline, immediately after consumption and then every 15 min until t = 80 min, then every 20 min until t = 120 min, followed on each occasion by completion of VAS. Seven participants completed the entire protocol and were included in the final analysis. A subgroup analysis with the n = 10 paired comparison between the same individuals that completed the oats, rye and pearl millet was also considered. The gastric volume AUC was higher for pearl millet than oats and rye (n = 10, p<0.001). The incremental area under the curve (iAUC) for blood glucose was not significantly different between the meals although this showed a trend to be lower for pearl millet. Hunger was lower for pearl millet compared to oats and rye (n = 10, p = 0.01). There was a significant correlation between total gastric volume AUC and average appetite AUC r = -0.47, p < 0.010. Isoenergetic breakfast porridges from ‘ancient’ varieties of millet grains showed physiological responses that were comparable with those from common Western varieties known to have beneficial health effects. Pearl millet appeared to induce lower postprandial blood glucose response and appetite scores though the differences were not conclusive compared with the other porridges and further work is needed. Improved knowledge of the effects of different cereal grains could help direct dietary advice and ultimately improve health outcomes in the general population worldwide

Histological basis of laminar MRI patterns in high resolution images of fixed human auditory cortex

Functional magnetic resonance imaging (fMRI) studies of the auditory region of the temporal lobe would benefit from the availability of image contrast that allowed direct identification of the primary auditory cortex, as this region cannot be accurately located using gyral landmarks alone. Previous work has suggested that the primary area can be identified in magnetic resonance (MR) images because of its relatively high myelin content. However, MR images are also affected by the iron content of the tissue and in this study we sought to confirm that different MR image contrasts did correlate with the myelin content in the grey matter and were not primarily affected by iron content as is the case in the primary visual and somatosensory areas. By imaging blocks of fixed post-mortem cortex in a 7 Tesla scanner and then sectioning them for histological staining we sought to assess the relative contribution of myelin and iron to the grey matter contrast in the auditory region. Evaluating the image contrast in T2*-weighted images and quantitative R2* maps showed a reasonably high correlation between the myelin density of the grey matter and the intensity of the MR images. The correlation with T1-weighted phase sensitive inversion recovery (PSIR) images was better than with the previous two image types, and there were clearly differentiated borders between adjacent cortical areas in these images. A significant amount of iron was present in the auditory region, but did not seem to contribute to the laminar pattern of the cortical grey matter in MR images. Similar levels of iron were present in the grey and white matter and although iron was present in fibres within the grey matter, these fibres were fairly uniformly distributed across the cortex. Thus we conclude that T1- and T2*-weighted imaging sequences do demonstrate the relatively high myelin levels that are characteristic of the deep layers in primary auditory cortex and allow it and some of the surrounding areas to be reliably distinguished

The Ser82 RAGE variant affects lung function and serum RAGE in smokers and sRAGE production in vitro

Introduction: Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model. Methods: Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified. Results: Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production. Conclusions: This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism