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In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac 31P-MRS, and 16 aged 60-75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p ≪ 0.001; -28.2%, p = 0.02; and -49.1%, p ≪ 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function., This study was funded by a combination of seed funding awarded to D.C. by Norwich Medical School, University of East Anglia, and funding from TdeltaS., Ltd. L.V is a Sir Henry Dale Fellow supported jointly by the Wellcome Trust and the Royal Academy (#221805/Z/20/Z), and he also acknowledges the support of the Slovak Grant Agencies VEGA (#2/0003/20) and APVV (#19-0032). A.I.S. was supported by The Austrian Science Fund (FWF) Schrödinger Fellowship (J 4043). C.T.R. is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (#098436/Z/12/B) and acknowledges support from the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. J.E. was funded by the Medical Research Council.

The article of Lopez et al describes the use of a multi-parametric MR approach to study muscle T-2 relaxation times and P-31-MRS indices of energetics and sarcolemma integrity in a mouse model of DMD, the mdx mouse. Muscular dystrophies have a multi-factorial disease cascade, and there are several MR methods used to assess these. Aspects that reflect disease progression are outlined on the left, while features that are more related to disease activity are outlined on the right.

Skeletal muscle phosphorus-31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Skeletal muscle phosphorus-31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross‐sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non‐fat‐replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T 2 relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat‐replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three‐point Dixon, multi‐spin‐echo and diffusion‐weighted spin‐echo echo planar imaging) and 2D chemical shift imaging 31P MRS data were acquired in 24 patients with BMD (age 18.8‐66.2 years) and 13 healthy controls (age 21.3‐63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T 2 relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T 2 SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T 2 relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T 2 heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups., In this study, diffusion measures and the means and standard deviations of the water T 2 relaxation time and 31P metabolic indices were explored as early markers for muscle tissue changes in the lower leg muscles of patients with Becker muscular dystrophy. Primarily muscles that were further along in the disease process as defined by elevated fat fractions showed increased T 2 heterogeneity in the majority of lower leg muscles and some changes in 31P metabolic indices.

In recent years a paradigm shift in therapy evaluations for oncology is apparent. Focusing on the morphological changes with the variety of imaging modalities is not sufficient to assess therapy efficacy during treatment. In the first part of this thesis the changes of relaxation times were quantified in ex vivo porcine recta during formaldehyde fixation and in human specimen. Chapter 2 concludes that T1 of the circular muscle, mucosa and submucosa, and T2 of the circular muscle decreased. Consequently, fixation, prior to imaging, progressively decreases image contrast. The human specimens were therefore imaged during the first few hours of fixation, in search for a suitable diagnostic marker. However, no conclusive parameter resulted as a significant diagnostic parameter for therapy evaluation. First step towards bringing metabolic imaging to patients is good magnetic field (B0) uniformity. Improvements of the B0-field homogeneity by simulating a local array of shim coils on liver MRI during different respiratory states are investigated in chapter 3. From simulations it is apparent that the increased degree of freedom improves homogeneity to a greater extent (10%) than using conventional shim hardware. Shimming B0 dependent on respiratory states reduces the effects of the respiratory motion with improvements ranging from 21 to 44 %. Chapter 4 facilitates the next step by integrating a 31P whole-body birdcage coil in 7T MR system, to enable 31P MRS over large fields of views. The design allows use of rectangular RF-pulses which decreases overall SAR compared to adiabatic RF-pulses while maintaining flip-angle homogeneity. It permits exchange in SNR for an increase in resolution and/or MR-weighting in 31P MRSI. The number of RF-pulses/dt can be increased as is demonstrated by fast 3D CSI of the liver with a short TR and low flip-angle excitation to acquire optimal SNR/dt. Furthermore, T2 of PCr in the gluteal muscle was quantified using a MESING protocol, something previously not possible large volumes. Interpretation of accompanied data required development of a software tool, CSIgui as explained in chapter 5. The large data sets have a high number of dimensionalities and are therefore not handled well by current software solutions. The tool is compatible with conventional MRS and raw file types. Data can be processed using a variety of MR algorithms and saved for analysis. Chapter 6 focuses on the feasibility of acquiring 3D CSI of tumor tissue in four lung carcinoma patients using the 31P whole-body birdcage coil in combination with a dual-Rx coil or a Rx array setup. Simulations proved the loss in SNR/dt with imperfect flip-angles is minimal using a short TR low flip angle protocol, eliminating a time-consuming calibration process. However, use of the receiver array favored SNR over a larger FOV compared to the dual coil setup. Detected metabolites were ATP and Pi, but also the phospholipid metabolites including the individual PME, PE and PC, and PDE, GPC and GPE which are not detectable at 3T. 31P MRSI of lung tumors at 7T is feasible and warrants further research as a non-invasive method for therapy evaluation.

Skeletal muscle phosphorus-31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Skeletal muscle phosphorus-31 P-31 MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of P-31 MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how P-31 MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with P-31 MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and H-1 MRS measurements) can help in the physiological/metabolic interpretation of P-31 MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Skeletal muscle phosphorus-31 31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31 P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31 P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31 P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1 H MRS measurements) can help in the physiological/metabolic interpretation of 31 P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Skeletal muscle phosphorus‐31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal‐acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near‐infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology., 31P MRS can usefully probe skeletal muscle cellular energy metabolism. Choice of methodology depends on the research question. The recommendations given here will help researchers experienced in general MRS with the application of 31P MRS in skeletal muscle, covering the practicalities of data acquisition and muscle exercise as well as the physiological interpretation of the measurements. We also give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting results and acquisition parameters.

Skeletal muscle phosphorus-31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Purpose In vivo MRS is often characterized by a spectral signal‐to‐noise ratio (SNR) that varies highly between experiments. A common design for spectroscopic studies is to compare the ratio of two spectral peak amplitudes between groups, e.g. individual PCr/γ‐ATP ratios in 31P‐MRS. The uncertainty on this ratio is often neglected. We wished to explore this assumption. Theory The canonical theory for the propagation of uncertainty on the ratio of two spectral peaks and its incorporation in the Frequentist hypothesis testing framework by weighted averaging is presented. Methods Two retrospective re‐analyses of studies comparing spectral peak ratios and one prospective simulation were performed using both the weighted and unweighted methods. Results It was found that propagating uncertainty correctly improved statistical power in all cases considered, which could be used to reduce the number of subjects required to perform an MR study. Conclusion The variability of in vivo spectroscopy data is often accounted for by requiring it to meet an SNR threshold. A theoretically sound propagation of the variable uncertainty caused by quantifying spectra of differing SNR is therefore likely to improve the power of in vivo spectroscopy studies. Magn Reson Med 78:2082–2094, 2017. © 2017 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.

Phosphorus magnetic resonance spectroscopy (MRS) was used to study muscle phosphates metabolism in several brain disorders. Those with primary mitochondrial encephalomyopathies showed the typical pattern of impaired oxidative metabolism at rest and during recovery after exercise. In migraine, Parkinson's disease and alternating hemiplegia muscle MRS observations lend support to a possible mitochondrial dysfunction. Similar observations in multiple sclerosis are probably the result of secondary deconditioning. In post polio syndrome and in some of the hereditary ataxias, elevated intracellular inorganic phosphates may be the result of another, yet unknown, metabolic impairment. Thus, muscle phosphate metabolism may be altered in various central nervous system (CNS) disorders by different metabolic impairments. All these possibilities should be taken into account when evaluating MRS results in brain diseases.