Motor Unit Magnetic Resonance Imaging (MUMRI) In Skeletal Muscle.

Magnetic resonance imaging (MRI) is routinely used in the musculoskeletal system to measure skeletal muscle structure and pathology in health and disease. Recently, it has been shown that MRI also has promise for detecting the functional changes, which occur in muscles, commonly associated with a range of neuromuscular disorders. This review focuses on novel adaptations of MRI, which can detect the activity of the functional sub-units of skeletal muscle, the motor units, referred to as "motor unit MRI (MUMRI)." MUMRI utilizes pulsed gradient spin echo, pulsed gradient stimulated echo and phase contrast MRI sequences and has, so far, been used to investigate spontaneous motor unit activity (fasciculation) and used in combination with electrical nerve stimulation to study motor unit morphology and muscle twitch dynamics. Through detection of disease driven changes in motor unit activity, MUMRI shows promise as a tool to aid in both earlier diagnosis of neuromuscular disorders and to help in furthering our understanding of the underlying mechanisms, which proceed gross structural and anatomical changes within diseased muscle. Here, we summarize evidence for the use of MUMRI in neuromuscular disorders and discuss what future research is required to translate MUMRI toward clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Whole Muscle and Single Motor Unit Twitch Profiles in a Healthy Adult Cohort Assessed With Phase Contrast Motor Unit MRI (PC-MUMRI).

BACKGROUND: Motor units (MUs) control the contraction of muscles and degenerate with age. It is therefore of interest to measure whole muscle and MU twitch profiles in aging skeletal muscle. PURPOSE: Apply phase contrast MU MRI (PC-MUMRI) in a cohort of healthy adults to measure whole anterior compartment, individual muscles, and single MU twitch profiles in the calf. Assess the effect of age and sex on contraction and relaxation times. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Sixty-one healthy participants (N = 32 male; age 55 ± 16 years [range: 26-82]). FIELD STRENGTH/SEQUENCES: 3 T, velocity encoded gradient echo and single shot spin echo pulsed gradient spin echo, echo-planar imaging. ASSESSMENT: Anterior shin compartment (N = 47), individual muscle (tibialis anterior, extensor digitorum longus, peroneus longus; N = 47) and single MU (N = 34) twitch profiles were extracted from the data to calculate contraction and relaxation times. STATISTICAL TESTS: Multivariable linear regression to investigate relationships between age, sex and contraction and relaxation times of the whole anterior compartment. Pearson correlation to investigate relationships between age and contraction and relaxation times of individual muscles and single MUs. A P value <0.05 was considered statistically significant. RESULTS: Age and sex predicted significantly increased contraction and relaxation time for the anterior compartment. Females had significantly longer contraction times than males (females 86 ± 8 msec, males 80 ± 9 msec). Relaxation times were longer, not significant (females 204 ± 36 msec, males 188 ± 34 msec, P = 0.151). Contraction and relaxation times of single MUs showed no change with age (P = 0.462, P = 0.534, respectively). DATE CONCLUSION: Older participants had significantly longer contraction and relaxation times of the whole anterior compartment compared to younger participants. Females had longer contraction and relaxation times than males, significant for contraction time. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

The muscle twitch profile assessed with motor unit magnetic resonance imaging.

Localised signal voids in diffusion-weighted (DW) images of skeletal muscle have been postulated to occur as a result of muscle fibre contraction and relaxation. We investigated the contrast mechanism of these signal voids using a combination of modelling and experimental measurements by employing DW and phase contrast (PC) imaging sequences. The DW signal and PC signal were simulated for each time point of a theoretical muscle twitch. The model incorporated compaction (simulating actively contracting muscle fibres) and translation (simulating passively moving surrounding fibres). The model suggested that the DW signal depended on contraction time and compaction whereas the PC signal depended on contraction time, compaction and translation. In a retrospective study, we tested this model with subgroup analyses on 10 healthy participants. Electrical nerve stimulation was used to generate muscle twitches in lower leg muscles; the resulting force was measured using an MR-compatible force transducer. At current levels causing a visible muscle twitch (~13 mA), the width of the first signal drop in the DW signal (mean ± SD: 103 ± 20 ms) was comparable with the force contraction time (93 ± 34 ms; intraclass correlation coefficient [ICC] = 0.717, P = .010). At current levels activating single motor units (~9 mA), the contraction time determined from the DW signal was 75 ± 13 ms and comparable with the PC contraction time (81 ± 15 ms; ICC = 0.925, P = .001). The maximum positive velocity was 0.55 ± 0.26 cm/s and the displacement was 0.20 ± 0.10 mm. Voxel-wise analysis revealed localised DW changes occurring together with more widespread phase changes. In conclusion, local signal attenuations in DW images following muscle fibre activation are primarily caused by compaction. The PC sequence also detects translating muscle tissue being passively pulled. The magnitude of the changes in DW and PC images depends on the twitch's contractile properties and percentage contraction. DW imaging and PC imaging can therefore measure twitch profiles of skeletal muscle fibres.

Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI.

OBJECTIVE: Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG). METHODS: Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]). RESULTS: MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm-3min-1vs. 0.04 ± 0.10 cm-3min-1, p = 0.004), paraspinals (1.14 ± 1.61 cm-3min-1vs. 0.02 ± 0.02 cm-3min-1, p = 0.016) and lower legs (1.42 ± 1.27 cm-3min-1vs. 0.13 ± 0.10 cm-3min-1, p = 0.004), but not tongue (1.41 ± 1.94 cm-3min-1vs. 0.18 ± 0.18 cm-3min-1, p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006). CONCLUSION: MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients. SIGNIFICANCE: MUMRI has potential as diagnostic tool for ALS.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations. METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection. ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21. TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

In vivo 3D imaging of human motor units in upper and lower limb muscles.

OBJECTIVE: To assess in-vivo cross-sectional and 3D morphology of human motor units in hand, forearm and lower leg muscles using magnetic resonance imaging (MRI). METHODS: Diffusion weighted MRI was used with in-scanner electrical stimulation in healthy controls to image motor units at a single slice in lower leg, forearm and hand muscles (n = 6) and multiple slices in the lower leg for 3D assessment (n = 7). RESULTS: Motor unit cross-sectional area (CSA) and maximum Feret diameter (FDmax) did not differ between the lower leg (CSA: 22.4 ± 8.4 mm2; FDmax: 8.7 ± 2.4 mm), forearm (CSA: 23.6 ± 14.1 mm2; FDmax: 9.0 ± 3.3 mm) and hand (CSA: 26.8 ± 12.8 mm2 and FDmax: 9.6 ± 2.7 mm) (ANOVA; p = 0.487 and p = 0.587, respectively). Lower leg motor units were 8.0 ± 3.8 cm long with largest CSA in the motor unit's middle section. 3D motor unit imaging revealed a complex structure with several units splitting and re-forming along their length. CONCLUSIONS: Motor unit MRI (MUMRI) can be applied to upper limb muscles, and can reveal the 3D structure of human motor units in-vivo. SIGNIFICANCE: MUMRI provides the first in-vivo 2D images of upper limb motor units and 3D images of lower leg motor units. 3D imaging suggest a more complex human motor unit structure than previously thought.

The role of novel motor unit magnetic resonance imaging to investigate motor unit activity in ageing skeletal muscle.

Sarcopenia is a progressive and generalized disease, more common in older adults, which manifests as a loss of muscle strength and mass. The pathophysiology of sarcopenia is still poorly understood with many mechanisms suggested. Age associated changes to the neuromuscular architecture, including motor units and their constituent muscle fibres, represent one such mechanism. Electromyography can be used to distinguish between different myopathies and produce counts of motor units. Evidence from electromyography studies suggests that with age, there is a loss of motor units, increases to the sizes of remaining units, and changes to their activity patterns. However, electromyography is invasive, can be uncomfortable, does not reveal the exact spatial position of motor units within muscle and is difficult to perform in deep muscles. We present a novel diffusion-weighted magnetic resonance imaging technique called 'motor unit magnetic resonance imaging (MUMRI)'. MUMRI aims to improve our understanding of the changes to the neuromuscular system associated with ageing, sarcopenia and other neuromuscular diseases. To date, we have demonstrated that MUMRI can be used to detect statistically significant differences in fasciculation rate of motor units between (n = 4) patients with amyotrophic lateral sclerosis (mean age ± SD: 53 ± 15) and a group of (n = 4) healthy controls (38 ± 7). Patients had significantly higher rates of fasciculation compared with healthy controls (mean = 99.1/min, range = 25.7-161.0 in patients vs. 7.7/min, range = 4.3-9.7 in controls; P < 0.05. MUMRI has detected differences in size, shape, and distribution of single human motor units between (n = 5) young healthy volunteers (29 ± 2.2) and (n = 5) healthy older volunteers (65.6 ± 14.8). The maximum size of motor unit territories in the older group was 12.4 ± 3.3 mm and 9.7 ± 2.7 mm in the young group; P < 0.05. MUMRI is an entirely non-invasive tool, which can be used to detect physiological and pathological changes to motor units in neuromuscular diseases. MUMRI also has the potential to be used as an intermediate outcome measure in sarcopenia trials.

Non-invasive imaging of single human motor units.

OBJECTIVE: To determine the size, shape and distribution of single human motor units in-vivo in healthy controls of different ages. METHODS: A novel diffusion-weighted magnetic resonance imaging (MRI) technique was used in combination with in-scanner electrical stimulation to quantify the shape, cross-sectional area, and dimensions of individual motor units in 10 healthy subjects. RESULTS: Thirty-one discrete motor units were studied. The majority were elliptical or crescent shaped, but occasional split motor units were observed. The mean motor unit cross sectional area was 26.7 ± 11.2 mm2, the mean maximum dimension was 10.7 ± 3.3 mm, and the mean minimum dimension was 4.5 ± 1.2 mm. Subjects aged over 40 had significantly larger maximum dimensions than those below this age (p < 0.05). CONCLUSIONS: Motor unit MRI (MUMRI) is a novel technique capable of revealing the size, shape and position of multiple motor units in human muscles. It is reproducible, non-invasive, and sufficiently sensitive to detect physiologically relevant changes in motor unit morphology with age. SIGNIFICANCE: To our knowledge, these results provide the first imaging assessment of human motor unit morphology. The technique shows promise both as a diagnostic tool and as a biomarker in longitudinal studies of disease progression.