Explore the vast range of titles available.

Using proton magnetic resonance spectroscopy (1H MRS) to determine total creatine (tCr) concentrations will become increasingly prevalent, as the role of creatine (Cr) in supporting brain health gains interest. Methodological limitations and margins of error in repeated 1H MRS, which often surpass reported effects of supplementation, permeate existing literature. We examined the intra‐ and inter‐session reliability and repeatability of 1H MRS for determining tCr concentrations across multiple brain regions (midbrain, visual cortex and frontal cortex). Eighteen healthy adults aged 20–32 years were recruited (50% female; n = 14 intra‐session; n = 15 inter‐session). 1H Magnetic resonance imaging and spectroscopy were completed at 3 T. Intra‐session analyses involved repeated 1H MRS of the midbrain, visual cortex and frontal cortex without participant or voxel repositioning, whereas inter‐session analyses involved measurements of the same regions, but with participant and voxel repositioning between repeated measurements. The 1H MRS data (174 spectra) were analysed using TARQUIN and OSPREY, and voxel fractions (grey/white matter and CSF) were determined using segmentation. Our findings show that tCr concentrations can be determined reliably and repeatably using 1H MRS, within an error of <2%, and that large inter‐regional differences in tCr concentration are present in the human brain. We provide new minimum detectable change data for tCr concentrations, a detailed discussion of the inherent error sources in repeated 1H MRS, including the substantial effect of the analysis package on tCr quantification, and suggestions for how these should be managed to improve the interpretability and clinical value of future research. More studies are needed to determine whether our findings can be replicated in other centres and different populations. What is the central question of this study? What are the intra‐ and inter‐session reliability and repeatability of 1H magnetic resonance spectroscopy for determining total creatine concentrations in the human brain, and does the choice of analysis package matter? What is the main finding and its importance? 1H Magnetic resonance spectroscopy can determine total creatine concentrations accurately and repeatably across multiple brain regions, within an error of <2%, although the inherent error sources in repeated 1H magnetic resonance spectroscopy need to be managed carefully. We discuss these error sources, including the choice of analysis package, and provide suggestions for how these should be managed to improve the interpretability and quality of future work.

•Our goal is to validate layer-specific VASO fMRI with gold standard methods.•Layer-specific VASO sequences are implemented for 7T imaging in humans and rats.•Comparisons of VASO, optical imaging, and MION confirm the expected contrast origin.•We confirm that VASO is a valid measure to estimate layer-specific neural activity. [Display omitted] Cerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (≥7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated for human fMRI and thus interpretation of such data is confounded. Here we validate the signal source of layer-dependent SS-SI VASO fMRI using multi-modal imaging in a rat model in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Quantified cortical layer profiling is demonstrated to be in agreement between VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical processing independent of confounding large draining veins which can hamper BOLD fMRI studies, (depending on slice positioning). Thus, a cross species comparison is enabled using VASO as a common measure. We find increased VASO based CBV reactivity (3.1 ± 1.2 fold increase) in humans compared to rats. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent VASO fMRI as an appropriate method in neuroscience application studies, in which the presence of large draining intracortical and pial veins limits neuroscientific inference with BOLD fMRI.

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms. •We developed an MRI-method to estimate arterial/venous CBV and BOLD signal changes.•Hemodynamics of excitation and inhibition was investigated in human brain at 7T.•We found different timecourses, layer-dependence and arterio-venous interaction.•Our results suggest different neurovascular coupling for excitation and inhibition.

A full understanding of how we see our world remains a fundamental research question in vision neuroscience. While topographic profiling has allowed us to identify different visual areas, the exact functional characteristics and organization of areas up in the visual hierarchy (beyond V1 & V2) is still debated. It is hypothesized that visual area V4 represents a vital intermediate stage of processing spatial and curvature information preceding object recognition. Advancements in magnetic resonance imaging hardware and acquisition techniques (e.g., non-BOLD functional MRI) now permits the capture of cortical layer-specific functional properties and organization of the human brain (including the visual system) at high precision. Here, we use functional cerebral blood volume measures to study the modularity in how responses to contours (curvature) are organized within area V4 of the human brain. To achieve this at 3 Tesla (a clinically relevant field strength) we utilize optimized high-resolution 3D-Echo Planar Imaging (EPI) Vascular Space Occupancy (VASO) measurements. Data here provide the first evidence of curvature domains in human V4 that are consistent with previous findings from non-human primates. We show that VASO and BOLD tSNR maps for functional imaging align with high field equivalents, with robust time series of changes to visual stimuli measured across the visual cortex. V4 curvature preference maps for VASO show strong modular organization compared to BOLD imaging contrast. It is noted that BOLD has a much lower sensitivity (due to known venous vasculature weightings) and specificity to stimulus contrast. We show evidence that curvature domains persist across the cortical depth. The work advances our understanding of the role of mid-level area V4 in human processing of curvature and shape features. Knowledge of how the functional architecture and hierarchical integration of local contours (curvature) contribute to formation of shapes can inform computational models of object recognition. Techniques described here allow for quantification of individual differences in functional architecture of mid-level visual areas to help drive a better understanding of how changes in functional brain organization relate to difference in visual perception.

The human SOD1(G93A) transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1(G93A) transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

Background To study the reproducibility of 23 Na magnetic resonance imaging (MRI) measurements from breast tissue in healthy volunteers. Methods Using a dual-tuned bilateral 23 Na/ 1 H breast coil at 3-T MRI, high-resolution 23 Na MRI three-dimensional cones sequences were used to quantify total sodium concentration (TSC) and fluid-attenuated sodium concentration (FASC). B 1 -corrected TSC and FASC maps were created. Two readers manually measured mean, minimum and maximum TSC and mean FASC values using two sampling methods: large regions of interest (LROIs) and small regions of interest (SROIs) encompassing fibroglandular tissue (FGT) and the highest signal area at the level of the nipple, respectively. The reproducibility of the measurements and correlations between density, age and FGT apparent diffusion coefficient (ADC) values were evaluatedss. Results Nine healthy volunteers were included. The inter-reader reproducibility of TSC and FASC using SROIs and LROIs was excellent (intraclass coefficient range 0.945−0.979, p  < 0.001), except for the minimum TSC LROI measurements ( p  = 0.369). The mean/minimum LROI TSC and mean LROI FASC values were lower than the respective SROI values ( p  < 0.001); the maximum LROI TSC values were higher than the SROI TSC values ( p  = 0.009). TSC correlated inversely with age but not with FGT ADCs. The mean and maximum FGT TSC and FASC values were higher in dense breasts in comparison to non-dense breasts ( p  < 0.020). Conclusions The chosen sampling method and the selected descriptive value affect the measured TSC and FASC values, although the inter-reader reproducibility of the measurements is in general excellent. Relevance statement 23 Na MRI at 3 T allows the quantification of TSC and FASC sodium concentrations. The sodium measurements should be obtained consistently in a uniform manner. Key points • 23 Na MRI allows the quantification of total and fluid-attenuated sodium concentrations (TSC/FASC). • Sampling method (large/small region of interest) affects the TSC and FASC values. • Dense breasts have higher TSC and FASC values than non-dense breasts. • The inter-reader reproducibility of TSC and FASC measurements was, in general, excellent. • The results suggest the importance of stratifying the sodium measurements protocol. Graphical Abstract

Anesthetized rodent models are ubiquitous in pre-clinical neuroimaging studies. However, because the associated cerebral morphology and experimental methodology results in a profound negative brain-core temperature differential, cerebral temperature changes during functional activation are likely to be principally driven by local inflow of fresh, core-temperature, blood. This presents a confound to the interpretation of blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data acquired from such models, since this signal is also critically temperature-dependent. Nevertheless, previous investigation on the subject is surprisingly sparse. Here, we address this issue through use of a novel multi-modal methodology in the urethane anesthetized rat. We reveal that sensory stimulation, hypercapnia and recurrent acute seizures induce significant increases in cortical temperature that are preferentially correlated to changes in total hemoglobin concentration (Hbt), relative to cerebral blood flow and oxidative metabolism. Furthermore, using a phantom-based evaluation of the effect of such temperature changes on the BOLD fMRI signal, we demonstrate a robust inverse relationship between both variables. These findings suggest that temperature increases, due to functional hyperemia, should be accounted for to ensure accurate interpretation of BOLD fMRI signals in pre-clinical neuroimaging studies.

Using proton magnetic resonance spectroscopy ( 1 H MRS) to determine total creatine (tCr) concentrations will become increasingly prevalent, as the role of creatine (Cr) in supporting brain health gains interest. Methodological limitations and margins of error in repeated 1 H MRS, which often surpass reported effects of supplementation, permeate existing literature. We examined the intra‐ and inter‐session reliability and repeatability of 1 H MRS for determining tCr concentrations across multiple brain regions (midbrain, visual cortex and frontal cortex). Eighteen healthy adults aged 20–32 years were recruited (50% female; n  = 14 intra‐session; n  = 15 inter‐session). 1 H Magnetic resonance imaging and spectroscopy were completed at 3 T. Intra‐session analyses involved repeated 1 H MRS of the midbrain, visual cortex and frontal cortex without participant or voxel repositioning, whereas inter‐session analyses involved measurements of the same regions, but with participant and voxel repositioning between repeated measurements. The 1 H MRS data (174 spectra) were analysed using TARQUIN and OSPREY, and voxel fractions (grey/white matter and CSF) were determined using segmentation. Our findings show that tCr concentrations can be determined reliably and repeatably using 1 H MRS, within an error of <2%, and that large inter‐regional differences in tCr concentration are present in the human brain. We provide new minimum detectable change data for tCr concentrations, a detailed discussion of the inherent error sources in repeated 1 H MRS, including the substantial effect of the analysis package on tCr quantification, and suggestions for how these should be managed to improve the interpretability and clinical value of future research. More studies are needed to determine whether our findings can be replicated in other centres and different populations. What is the central question of this study? What are the intra‐ and inter‐session reliability and repeatability of 1 H magnetic resonance spectroscopy for determining total creatine concentrations in the human brain, and does the choice of analysis package matter? What is the main finding and its importance? 1 H Magnetic resonance spectroscopy can determine total creatine concentrations accurately and repeatably across multiple brain regions, within an error of <2%, although the inherent error sources in repeated 1 H magnetic resonance spectroscopy need to be managed carefully. We discuss these error sources, including the choice of analysis package, and provide suggestions for how these should be managed to improve the interpretability and quality of future work.

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans. [Display omitted] •A CBV-sensitive fMRI method is developed for high-resolution fMRI in humans.•Lamina-dependent CBV fMRI responses are shown in humans.•VASO cortical profiles are validated with Fe-contrast agent fMRI in animals.•Sensitivity to large veins can be minimized using VASO-CBV instead of BOLD fMRI.•Ipsilateral fMRI responses to finger tapping are positive in M1 and negative in S1.

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8-1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans.