Phosphorus MR Spectroscopy as a biomarker of improved tissue metabolism after aerobic exercise in Multiple Sclerosis at 7T
Manoj K Sammi1, Rebecca Spain2, Bharti Garg3, Kerry Kuehl3, and William D Rooney1

1Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States, 2Department of Neurology, Oregon Health & Science University, Portland, OR, United States, 3Department of Medicine, Oregon Health & Science University, Portland, OR, United States


Moderate exercise has been shown to benefit several aspects of brain health. We investigate the feasibility of aerobic exercise in subjects with Multiple Sclerosis and use of 31P MR spectroscopic imaging as a biomarker.


Study the feasibility of aerobic exercise in subjects with mild Relapsing Remitting Multiple Sclerosis (RRMS) and investigate use of 31P MR spectroscopic imaging as a biomarker for improvement in tissue metabolism.


Exercise has been linked and shown to be effective in slowing aging process and increasing brain neurogenesis1,2. Our hypothesis is that moderate aerobic exercise will improve the brain health manifested by improved brain metabolism. Human subjects with relapsing-remitting MS were recruited under an IRB approved protocol to study the effect of aerobic exercise. Each subject underwent a series of physiological and cognitive measures (including walking tests, Modified Fatigue Impact Scale (MFIS) and Symbol Digits Modality Test (SDMT)). Subjects were studied on a 7T Siemens Magnetom system (Erlangen, Germany) for MRI and MRS measures. High resolution MPRAGE (0.8 mm isotropic, TR/TI/FA/TAT= 2.3 s/1.05 s/8°/10.8 min) were acquired for tissue segmentation using an 8‑channel proton RF array coil (Rapid Biomedical, Germany)3. Brain 31P magnetic resonance spectroscopic imaging was performed using a 31P head coil with a 1Halo coil3,4 setup. A low-resolution phosphorus B1 maps were acquired for RF coil inhomogeneity correction. Phosphate metabolite level were also measured following a rest, exercise and recovery protocol in tibialis anterior (TA) of the right leg using a dual-tuned 31P/1H surface coil (4 cm x 9.5 cm oval, with longer axis aligned to the muscle length). Subject’s right leg was positioned in a home-built exercise setup that isolated dorsi-flexion of the ankle against a fixed load. Spectra (TR/TE/FA/NS/SW/NP = 300 ms/0.225 ms/~20°/4/8000 Hz/2048) were acquired continuously during the rest (1.5-3.0 min), exercise (2-3 min) synchronized to a metronome beats of 40 beats/min and recovery period of 4-10 min. A hard pulse of 250 μs was used for excitation centered at PCr resonance frequency. Subjects underwent an aerobic exercise regimen (AER) of 30 minutes at a target heart rate four times per week for eight weeks under supervised training. The above measurements were repeated to measure any post-aerobic exercise regimen changes. Brain phosphorus spectra were fit for phosphocreatine (PCr), adenosine triphosphate (α, β and γ-ATP), phosphoethanolamine (PE), phosphocholine (PC), glycerol-3-phosphoethanolamine (GPE), glycerol‑3‑phosphocholine (GPC) and inorganic phosphate (Pi) peaks using AMARES algorithm3,5. Spectra from TA muscle were fit for PCr, α, β and γ-ATP, Pi and GPC peaks. Phosphocreatine recovery was modeled as a single exponential6 and a non-linear fit was performed using Levenberg-Marquardt algorithm. Measured values were assessed statistically using paired t-test.


10 subjects (age = 44.7 ± 9.4 years, EDSS = 3.4 [mean, range: 2.5-4.0] and mean disease duration of 14.6 ± 6.5 years) participated and finished the study. Resting heart rate, fat mass, lean mass and VO2 max showed a significant improvement (-16.8%, -6.4%, 2.6% and 13.2% respectively, P< 0.05, Table 1). Subjects’ spent significantly more time exercising (21%, P<0.01) and SDMT scores (15%, P<0.05) were improved after post-AER. MFIS cognitive component showed significant improvement (26%, P<0.05). There were no significant changes in brain phosphorus metabolite levels in a volume of interest in superatentorial region (Table 2). Post-aerobic exercise regimen value for PCr recovery constant was significantly improved in TA muscle (Table 3, Figure 1). In addition, ATP/PCr ratio was increased in post-exercise (4.1%, P<0.01, Table 3).


While physiological measures of fitness, fatigue and cognition showed an improvement in subjects with MS, brain metabolite levels did not show a significant change after an eight week long aerobic exercise intervention. PCr recovery time decreased post-AER in TA muscle and shows that 31P MRS can be used to monitor improvement in muscle health. The small number of subjects and short duration of this pilot study precludes any extensive conclusions about brain metabolism.


Aerobic exercise is feasible and beneficial in MS subjects’ fitness and cognitive measures. While 31P MRS can be used in leg muscle successfully to monitor improved metabolic function, significant changes in brain metabolite levels were not observed following an 8-week intense aerobic exercise challenge. However, such changes could be apparent following longer duration exercise intervention2. Magnetization transfer studies or functional exercise studies that elucidate kinetic parameters of Creatine-Kinase reaction may be a more sensitive measure of tissue metabolism.


GRANTS: NIH R01-NS40801, S10 OD018224 01, Collaborative MS Research Center Award from the National Multiple Sclerosis Society, Race to Erase MS Foundation

The authors would like to thank Eric Shankland, Mark Mathis and Tim Wilbur (University of Washington) for providing a dual tuned 31P/1H surface coil.


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6. Kent-Braun JA, Sharma KR, Miller RG, Weiner MW. Postexercise phosphocreatine resynthesis is slowed in multiple sclerosis. Muscle Nerve 1994; 17: 835-841.


Figure 1: Integrated PCr signal during rest, exercise and recovery period with corresponding representative spectrum from TA muscle during ~2 min paced exercise in the magnet. The signal spike at 530 s is due to the initial steady state after the second experiment starts due to software limit of 512 acquisitions per experiment. Blue curve is a non-linear fit to PCr recovery data (red points).

Table 1: Physiological measures pre and post-exercise intervention

Table 2: Measured metabolite concentrations and pH in human brain (160 mL volume of interest) at pre- and post- aerobic exercise regimen (8 weeks period)

Measured metabolite ratios at baseline and PCr recovery rate during localized tibialis anterior muscle exercise

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)