MRI-derived arterial input functions for PET kinetic modelling in rats

Simultaneous PET–MR acquisition provides the high temporal and spatial resolution of MRI with the specificity of PET. In PET, accurate modelling of physiological function in vivo requires the time-activity curve of tracer in blood plasma, known as the arterial input function (AIF). As the gold standard method of blood sampling is inherently prohibitive in the small animal case, here we discuss how we prepare to rapidly sample MRI signals from gadolinium-doped tracer to obtain the tracer input functions from a simultaneous PET-MR measurement. ΔR2⁎ measurements taken from EPI images were used to obtain first pass bolus AIFs in the rat brain from DSC-MRI datasets of 5 rats. AIFs obtained using our automatic algorithm were found to be consistent between animals and compared well with manual methods without need for a priori voxel selection. A variable flip angle FLASH sequence used for T1 mapping was successfully tested in a phantom study, providing accurate measurements of Gd concentration.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org10.1016/j.nima.2012.08.08

Glucose metabolism following human traumatic brain injury: methods of assessment and pathophysiological findings.

The pathophysiology of traumatic brain (TBI) injury involves changes to glucose uptake into the brain and its subsequent metabolism. We review the methods used to study cerebral glucose metabolism with a focus on those used in clinical TBI studies. Arterio-venous measurements provide a global measure of glucose uptake into the brain. Microdialysis allows the in vivo sampling of brain extracellular fluid and is well suited to the longitudinal assessment of metabolism after TBI in the clinical setting. A recent novel development is the use of microdialysis to deliver glucose and other energy substrates labelled with carbon-13, which allows the metabolism of glucose and other substrates to be tracked. Positron emission tomography and magnetic resonance spectroscopy allow regional differences in metabolism to be assessed. We summarise the data published from these techniques and review their potential uses in the clinical setting.This is the final published version. It originally appeared at http://dx.doi.org/10.1007/s11011-014-9628-y

A survey of patient motion in disorders of consciousness and optimization of its retrospective correction.

Functional magnetic resonance imaging (fMRI) can be seriously impaired by patient motion. The purpose of this study was to characterize the typical motion in a clinical population of patients in disorders of consciousness and compare the performance of retrospective correction with rigid-body realignment as implemented in widely used software packages. 63 subjects were scanned with an fMRI visual checkerboard paradigm using a 3T scanner. Time series were corrected for motion, and the resulting transformations were used to calculate a motion score. SPM, FSL, AFNI and AIR were evaluated by comparing the motion obtained by re-running the tool on the corrected data. A publicly available sample fMRI dataset was modified with the motion detected in each patient with each tool. The performance of each tool was measured by comparing the number of supra-threshold voxels after standard fMRI analysis, both in the sample dataset and in simulated fMRI data. We assessed the effect of user-changeable parameters on motion correction in SPM. We found the equivalent motion in the patient population to be 1.4mm on average. There was no significant difference in performance between SPM, FSL and AFNI. AIR was considerably worse, and took more time to run. We found that in SPM the quality factor and interpolation method have no effect on the cluster size, while higher separation and smoothing reduce it. We showed that the main packages SPM, FSL and AFNI are equally suitable for retrospective motion correction of fMRI time series. We show that typically only 80% of activated voxels are recovered by retrospective motion correction

Huntington's disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy.

Magnetic resonance imaging (MRI) has proved to be an ideal modality for non-destructive and highly detailed assessment of structural morphology in biological tissues. Here we used MRI to make a dataset of ex vivo brains from two different rodent models of Huntington's disease (HD), the R6/2 line and the YAC 128 mouse. We are making the whole dataset (399 transgenic HD and wildtype (WT) brains, from mice aged 9-80 weeks) publicly available. These data will be useful, not only to investigators interested in the study of HD, but also to researchers of computational neuroanatomy who may not have access to such large datasets from mouse models. Here we demonstrate a number of uses of such data, for example to produce maps of grey and white matter and cortical thickness. As an example of how the library might provide insights in mouse models of HD, we calculated whole brain grey matter volumes across different age groups with different numbers of cytosine-adenine-guanine (CAG) repeats in a fragment of the gene responsible for HD in humans. (The R6/2 dataset was obtained from an allelic series of R6/2 mice carrying a range of CAG repeat lengths between 109 and 464.) This analysis revealed different trajectories for each fragment length. In particular there was a gradient of decreasing pathology with longer CAG repeat lengths, reflecting our previous findings with behavioural and histological studies. There will be no constraints placed on the use of the datasets included here. The original data will be easily and permanently accessible via the University of Cambridge data repository (http://www.dspace.cam.ac.uk/handle/1810/243361)

Additional sampling directions improve detection range of wireless probes

PURPOSE: While MRI is enhancing our knowledge about the structure and function of the human brain, subject motion remains a problem in many clinical applications. Recently, the use of wireless radiofrequency markers with three one-dimensional (1D) navigators for prospective correction was demonstrated. This method is restricted in the range of motion that can be corrected, however, because of limited information in the 1D readouts. METHODS: Here, the limitation of techniques for disambiguating marker locations was investigated. It was shown that including more sampling directions extends the tracking range for head rotations. The efficiency of trading readout resolution for speed was explored. RESULTS: Tracking of head rotations was demonstrated from -19.2 to 34.4°, -2.7 to 10.0°, and -60.9 to 70.9° in the x-, y-, and z-directions, respectively. In the presence of excessive head motion, the deviation of marker estimates from SPM8 was reduced by 17.1% over existing three-projection methods. This was achieved by using an additional seven directions, extending the time needed for readouts by a factor of 3.3. Much of this increase may be circumvented by reducing resolution, without compromising accuracy. CONCLUSION: Including additional sampling directions extends the range in which markers can be used, for patients who move a lot. Magn Reson Med 76:913-918, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.The project was supported by funding from the Isaac Newton Trust, the Wellcome Trust ISSF, and the Cusanuswerk funding body (Bonn, Germany).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/mrm.2599

Comparison of first pass bolus AIFs extracted from sequential 18F-FDG PET and DSC-MRI of mice.

Accurate kinetic modelling of in vivo physiological function using positron emission tomography (PET) requires determination of the tracer time-activity curve in plasma, known as the arterial input function (AIF). The AIF is usually determined by invasive blood sampling methods, which are prohibitive in murine studies due to low total blood volumes. Extracting AIFs from PET images is also challenging due to large partial volume effects (PVE). We hypothesise that in combined PET with magnetic resonance imaging (PET/MR), a co-injected bolus of MR contrast agent and PET ligand can be tracked using fast MR acquisitions. This protocol would allow extraction of a MR AIF from MR contrast agent concentration-time curves, at higher spatial and temporal resolution than an image-derived PET AIF. A conversion factor could then be applied to the MR AIF for use in PET kinetic analysis. This work has compared AIFs obtained from sequential DSC-MRI and PET with separate injections of gadolinium contrast agent and 18F-FDG respectively to ascertain the technique's validity. An automated voxel selection algorithm was employed to improve MR AIF reproducibility. We found that MR and PET AIFs displayed similar character in the first pass, confirmed by gamma variate fits (p<0.02). MR AIFs displayed reduced PVE compared to PET AIFs, indicating their potential use in PET/MR studies.This work was funded by an MRC studentship and travel to PSMR 2013 was funded by the EU COST action for PET/MR.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.nima.2013.08.07

Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy.

The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable. The device exploits an MR-compatible high-density material (BaSO4) to form a weight which is attached directly to the ankle, and a one-minute dynamic knee extension protocol produced highly reproducible measurements of post-exercise PCr recovery kinetics in both healthy subjects and patients. As sophisticated exercise equipment is unnecessary for this measurement, our extremely simple design provides an effective and easy-to-implement apparatus that is readily translatable across sites. Its design, being tailored to the needs of the patient, makes it particularly well suited to clinical applications, and we argue the potential of this method for investigating in vivo mitochondrial function in new cohorts of growing clinical interest.We are grateful to all the participants. This work was funded by the Clinical Research Infrastructure Grant. We thank the National Institute for Health Research (NIHR) Cambridge BioResource and S. Nutland, for facilitating the recruitment of the 24 BioResource volunteers. We thank the NIHR Cambridge Biomedical Research Centre for funding the BioResource and we also acknowledge research grants from Addenbrooke's Charitable Trust and the British Society for Pediatric Endocrinology and Diabetes. D.B.S. is supported by the Wellcome Trust [091551] and the U.K. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. A.S. and the Siemens MAGNETOM 3T Verio scanner are funded by the NIHR via an award to the Cambridge NIHR/Wellcome Trust Clinical Research Facility. A.T. and D.B.D. are supported by the U.K. NIHR Cambridge Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep19057

Further evidence for a non-cortical origin of mirror movements after stroke.

Ejaz et al. (2018) are to be commended for showing no evidence for a cortical origin of post-stroke mirror movements. Using functional MRI during affected-finger presses in recovering adult-onset stroke patients, they found no consistent relationship between contralesional sensorimotor cortex (cSM1) activation and quantitative indices of mirror movements; specifically, mirror movements were not linked to the presence of cSM1 overactivation, arguing against the classic ‘transcallosal’ mechanism heretofore widely believed to cause mirror movements (Di Pino et al., 2014). We wish to report findings—previously published in abstract form (Calautti, 2008)—that further support the idea that mirror movements are not cortically mediated. We also present data that confirm that mirror movements can involve the affected (i.e. paretic) hand during movement of the unaffected (i.e. non-paretic) hand, also arguing in favour of disruption of a bilaterally-organized system

Defective Mitochondrial Function In Vivo in Skeletal Muscle in Adults with Down's Syndrome: A P-31-MRS Study

Down’s syndrome (DS) is a developmental disorder associated with intellectual disability (ID). We have previously shown that people with DS engage in very low levels of exercise compared to people with ID not due to DS. Many aspects of the DS phenotype, such as dementia, low activity levels and poor muscle tone, are shared with disorders of mitochondrial origin, and mitochondrial dysfunction has been demonstrated in cultured DS tissue. We undertook a phosphorus magnetic resonance spectroscopy ((31)P-MRS) study in the quadriceps muscle of 14 people with DS and 11 non-DS ID controls to investigate the post-exercise resynthesis kinetics of phosphocreatine (PCr), which relies on mitochondrial respiratory function and yields a measure of muscle mitochondrial function in vivo. We found that the PCr recovery rate constant was significantly decreased in adults with DS compared to non-DS ID controls (1.7±0.1 min(−1) vs 2.1±0.1 min(−1) respectively) who were matched for physical activity levels, indicating that muscle mitochondrial function in vivo is impaired in DS. This is the first study to investigate mitochondrial function in vivo in DS using (31)P-MRS. Our study is consistent with previous in vitro studies, supporting a theory of a global mitochondrial defect in DS

P-31 magnetization transfer measurements of P-i -> ATP flux in exercising human muscle

Fundamental criticisms have been made over the use of (31)P magnetic resonance spectroscopy (MRS) magnetization transfer estimates of inorganic phosphate (P(i))→ATP flux (V(Pi-ATP)) in human resting skeletal muscle for assessing mitochondrial function. Although the discrepancy in the magnitude of V(Pi-ATP) is now acknowledged, little is known about its metabolic determinants. Here we use a novel protocol to measure V(Pi-ATP) in human exercising muscle for the first time. Steady-state V(Pi-ATP) was measured at rest and over a range of exercise intensities and compared with suprabasal oxidative ATP synthesis rates estimated from the initial rates of postexercise phosphocreatine resynthesis (V(ATP)). We define a surplus P(i)→ATP flux as the difference between V(Pi-ATP) and V(ATP). The coupled reactions catalyzed by the glycolytic enzymes GAPDH and phosphoglycerate kinase (PGK) have been shown to catalyze measurable exchange between ATP and P(i) in some systems and have been suggested to be responsible for this surplus flux. Surplus V(Pi-ATP) did not change between rest and exercise, even though the concentrations of P(i) and ADP, which are substrates for GAPDH and PGK, respectively, increased as expected. However, involvement of these enzymes is suggested by correlations between absolute and surplus P(i)→ATP flux, both at rest and during exercise, and the intensity of the phosphomonoester peak in the (31)P NMR spectrum. This peak includes contributions from sugar phosphates in the glycolytic pathway, and changes in its intensity may indicate changes in downstream glycolytic intermediates, including 3-phosphoglycerate, which has been shown to influence the exchange between ATP and P(i) catalyzed by GAPDH and PGK