Highlights: 21• A CBV-sensitive fMRI method is developed for high resolution fMRI in humans. 22• Lamina-dependent CBV fMRI responses are shown in humans. 23• VASO cortical profiles are validated with Fe-contrast agent fMRI in animals. 24• Sensitivity to large veins can be minimized using VASO-CBV instead of BOLD fMRI. 25• Ipsilateral fMRI responses to finger-tapping are positive in M1 and negative in S1. 26 27 Abstract 28Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging 29 (fMRI) in human or animal brain can be used to address questions regarding the functioning of 30 cortical circuits, such as the effect of different afferent and efferent connectivity on activity in 31 specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level dependent 32 (BOLD) responses to large draining veins reduces its local specificity and can render the 33 interpretation of the underlying laminar neural activity impossible. Application of the more spatially 34 specific cerebral blood volume (CBV) based fMRI in humans has been hindered by the low sensitivity 35 of the non-invasive modalities available. Here, a Vascular Space Occupancy (VASO) variant, adapted 36 for use at high field, is further optimized to capture layer-dependent activity changes in human 37 motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that 38 the VASO signal peaks in grey matter at 0.8 -1.6 mm depth, and deeper compared to the superficial 39 and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-40 established iron-oxide contrast agent based fMRI methods in animals showed the same cortical 41 profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate 42 its potential of revealing small lamina-dependent signal differences due to modulations of the input-43 output characteristics, layer-dependent VASO responses were investigated in the ipsilateral 44 hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex 45 *7. Manuscript Click here to view linked References 2 and negative activation in ipsilateral primary sensory cortex were observed. This feature is only 1 visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently 2 because of a lack of partial volume effects. Based on the results presented here we conclude that 3 VASO offers good reproducibility, high sensitivity, and lower sensitivity than GE-BOLD to changes in 4 larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans. 5Abbreviations: BOLD = blood oxygenation level dependent; CBV = cerebral blood volume; CNR = 6 contrast-to-noise ratio; CSF = cerebrospinal fluid; ΔCBV = change in CBV; EPI = echo planar imaging; 7 Fe = iron; fMRI = functional magnetic resonance imaging; GE = gradient echo; GM = grey matter; ROI 8 = region of interest; SNR = signal-to-noise ratio; SS-SI-VASO = slice-selective slab-inversion VASO...

The concentration of sodium ions (Na +) is raised in solid tumours and can be measured at the cellular, tissue and patient levels. At the cellular level, the Na + gradient across the membrane powers the transport of H + ions and essential nutrients for normal activity. The maintenance of the Na + gradient requires a large proportion of the cell's ATP. Na + is a major contributor to the osmolarity of the tumour microenvironment, which affects cell volume and metabolism as well as immune function. Here, we review evidence indicating that Na + handling is altered in tumours, explore our current understanding of the mechanisms that may underlie these alterations and consider the potential consequences for cancer progression. Dysregulated Na + balance in tumours may open opportunities for new imaging biomarkers and re-purposing of drugs for treatment.

Redgrave P, Mayhew JE. Fine detail of neurovascular coupling revealed by spatiotemporal analysis of the hemodynamic response to single whisker stimulation in rat barrel cortex.

Modern neuroimaging techniques rely on neurovascular coupling to show regions of increased brain activation. However, little is known of the neurovascular coupling relationships that exist for inhibitory signals. To address this issue directly we developed a preparation to investigate the signal sources of one of these proposed inhibitory neurovascular signals, the negative blood oxygen level-dependent (BOLD) response (NBR), in rat somatosensory cortex. We found a reliable NBR measured in rat somatosensory cortex in response to unilateral electrical whisker stimulation, which was located in deeper cortical layers relative to the positive BOLD response. Separate optical measurements (two-dimensional optical imaging spectroscopy and laser Doppler flowmetry) revealed that the NBR was a result of decreased blood volume and flow and increased levels of deoxyhemoglobin. Neural activity in the NBR region, measured by multichannel electrodes, varied considerably as a function of cortical depth. There was a decrease in neuronal activity in deep cortical laminae. After cessation of whisker stimulation there was a large increase in neural activity above baseline. Both the decrease in neuronal activity and increase above baseline after stimulation cessation correlated well with the simultaneous measurement of blood flow suggesting that the NBR is related to decreases in neural activity in deep cortical layers. Interestingly, the magnitude of the neural decrease was largest in regions showing stimulus-evoked positive BOLD responses. Since a similar type of neural suppression in surround regions was associated with a negative BOLD signal, the increased levels of suppression in positive BOLD regions could importantly moderate the size of the observed BOLD response.

Hyperpolarisation methods that premagnetise agents such as pyruvate are currently receiving significant attention because they produce sensitivity gains that allowd isease tracking and interrogation of cellular metabolism by magnetic resonance.Here,wecommunicate how signal amplification by reversible exchange (SABRE) can providestrong 13 Cpyruvate signal enhancements in seconds through the formation of the novel polarisation transfer catalyst [Ir(H) 2 (h 2 -pyruvate)-(DMSO)(IMes)].B yh arnessing SABRE, strong signals for [1-13 C]-and [2-13 C]pyruvate in addition to along-lived singlet state in the [1,2-13 C 2 ]form are readily created;the latter can be observed five minutes after the initial hyperpolarisation step. We also demonstrate how this development may help with future studies of chemical reactivity.

The human SOD1G93A 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) SOD1G93A 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.

Hyperpolarisation methods that premagnetise agents such as pyruvate are currently receiving significant attention because they produce sensitivity gains that allowd isease tracking and interrogation of cellular metabolism by magnetic resonance.Here,wecommunicate how signal amplification by reversible exchange (SABRE) can providestrong 13 Cpyruvate signal enhancements in seconds through the formation of the novel polarisation transfer catalyst [Ir(H) 2 (h 2 -pyruvate)-(DMSO)(IMes)].B yh arnessing SABRE, strong signals for [1-13 C]-and [2-13 C]pyruvate in addition to along-lived singlet state in the [1,2-13 C 2 ]form are readily created;the latter can be observed five minutes after the initial hyperpolarisation step. We also demonstrate how this development may help with future studies of chemical reactivity.

Mathematical models are required to estimate kinetic parameters of [1-(13)C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method for direct measurement of the AIF in the rat. The hyperpolarized [1-(13)C] pyruvate signal was measured in arterial blood as it was continuously withdrawn through a small chamber. The measured signal was corrected for T1 relaxation of pyruvate, RF pulses and dispersion of blood in the chamber to allow for the estimation of the direct AIF. Using direct AIF, rather than the commonly used box-car AIF, provided realistic estimates of the rate constant of conversion of pyruvate to lactate, kpl, the rate constant of conversion of lactate to pyruvate klp, the clearance rate constant of pyruvate from blood to tissue, Kip, and the relaxation rate of lactate T1la. Since no lactate signal was present in blood, it was possible to use a simple precursor-product relationship, with the tumor tissue pyruvate time-course as the input for the lactate time-course. This provided a robust estimate of kpl, similar to that obtained using a directly measured AIF.