John H. Kindred

Core muscle characteristics during walking of patients with multiple sclerosis.

The purpose of this study was to investigate core muscle characteristics during walking in patients with multiple sclerosis (MS). Eight patients (4 men) with relapsing-remitting MS (aged 44.9 +/- 8.6 yr) and sex-matched controls (37.9 +/- 8.4 yr) walked on a treadmill for 15 min at a self-selected speed. Positron emission tomography/computed tomography imaging was used to measure core muscle activity immediately after walking based on glucose uptake. Activity was not different between the MS and control group for any of the identified muscles (p > 0.28). Within the MS group, side differences in activity were identified in the lateral flexor group, the external and internal obliques, and the rectus abdominis (p < 0.05), with the less-affected side being activated more. Furthermore, greater muscle volume was found on the more-affected side of the transversus abdominis, quadratus lumborum, and the low-back extensor group (p < 0.03). These muscle characteristics suggest patients with MS utilize compensatory mechanisms during walking to maintain balance and posture. These strategies likely result in increased muscle energy cost and early fatigability.

Fatigue in Multiple Sclerosis: Misconceptions and Future Research Directions

Fatigue is one of the most disabling side effects in people with multiple sclerosis. While this fact is well known, there has been a remarkable lack of progress in determining the pathophysiological mechanisms behind fatigue and the establishment of effective treatments. The main barrier has been the lack of a unified definition of fatigue that can be objectively tested with validated experimental models. In this “perspective article” we propose the use of the following model and definition of fatigue: the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors. These changes depend on the task being performed, the environmental conditions it is performed in, and the physical and mental capacity of the individual. Our definition and model of fatigue outlines specific causes of fatigue and how it affects task performance. We also outline the strengths and weaknesses of commonly used measures of fatigue and suggest, based on our model and definition, new research strategies, which should include multiple measures. These studies should be mechanistic with validated experimental models to determine changes in central, psychological, and/or peripheral factors that explain fatigue. The proposed new research strategies may lead to the identification of the origins of MS related fatigue and the development of new, more effective treatments.

Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking

BACKGROUND Difficulties in ambulation are one of the main problems reported by patients with multiple sclerosis. A previous study by our research group showed increased recruitment of muscle groups during walking, but the influence of skeletal muscle properties, such as muscle fiber activity, has not been fully elucidated. The purpose of this investigation was to use the novel method of calculating glucose uptake heterogeneity in the leg muscles of patients with multiple sclerosis and compare these results to healthy controls. METHODS Eight patients with multiple sclerosis (4 men) and 8 healthy controls (4 men) performed 15 min of treadmill walking at a comfortable self-selected speed following muscle strength tests. Participants were injected with ≈ 8 mCi of [(18)F]-fluorodeoxyglucose during walking after which positron emission tomography/computed tomography imaging was performed. FINDINGS No differences in muscle strength were detected between multiple sclerosis and control groups (P>0.27). Within the multiple sclerosis, group differences in muscle volume existed between the stronger and weaker legs in the vastus lateralis, semitendinosus, and semimembranosus (P<0.03). Glucose uptake heterogeneity between the groups was not different for any muscle group or individual muscle of the legs (P>0.16, P≥0.05). INTERPRETATIONS Patients with multiple sclerosis and healthy controls showed similar muscle fiber activity during walking. Interpretations of these results, with respect to our previous study, suggest that walking difficulties in patients with multiple sclerosis may be more associated with altered central nervous system motor patterns rather than alterations in skeletal muscle properties.

Walking Speed and Brain Glucose Uptake are Uncoupled in Patients with Multiple Sclerosis.

Motor impairments of the upper and lower extremities are common symptoms of multiple sclerosis (MS). While some peripheral effects like muscle weakness and loss of balance have been shown to influence these symptoms, central nervous system activity has not been fully elucidated. The purpose of this study was to determine if alterations in glucose uptake were associated with motor impairments in patients with multiple sclerosis. Eight patients with multiple sclerosis (four men) and eight sex matched healthy controls performed 15 min of treadmill walking at a self-selected pace, during which ≈322 MBq of the positron emission tomography (PET) glucose analog [18F]-fluorodeoxyglucose (FDG) was injected. Immediately after the cessation of walking, participants underwent PET imaging. Patients with MS had lower FDG uptake in ≈40% of the brain compared to the healthy controls (pFWE-corr < 0.001, qFDR-corr < 0.001, ke = 93851) and walked at a slower speed [MS, 1.1 (0.2), controls 1.4 (0.1), m/s, P = 0.014]. Within the area of lower FDG uptake 15 regions were identified. Of these 15 regions, 13 were found to have strong to moderate correlations to walking speed within the healthy controls (r > −0.75, P < 0.032). Within patients with MS only 3 of the 15 regions showed significant correlations: insula (r = −0.74, P = 0.036), hippocampus (r = −0.72, P = 0.045), and calcarine sulcus (r = −0.77, P = 0.026). This data suggest that walking impairments in patients with MS may be due to network wide alterations in glucose metabolism. Understanding how brain activity and metabolism are altered in patients with MS may allow for better measures of disability and disease status within this clinical population.

[18F]-FDG positron emission tomography—an established clinical tool opening a new window into exercise physiology

Positron emission tomography (PET) with [(18)F]-fluorodeoxyglucose (FDG) is an established clinical tool primarily used to diagnose and evaluate disease status in patients with cancer. PET imaging using FDG can be a highly valuable tool to investigate normal human physiology by providing a noninvasive, quantitative measure of glucose uptake into various cell types. Over the past years it has also been increasingly used in exercise physiology studies to identify changes in glucose uptake, metabolism, and muscle activity during different exercise modalities. Metabolically active cells transport FDG, an (18)fluorine-labeled glucose analog tracer, from the blood into the cells where it is then phosphorylated but not further metabolized. This metabolic trapping process forms the basis of this methods use during exercise. The tracer is given to a participant during an exercise task, and the actual PET imaging is performed immediately after the exercise. Provided the uptake period is of sufficient duration, and the imaging is performed shortly after the exercise; the captured image strongly reflects the metabolic activity of the cells used during the task. When combined with repeated blood sampling to determine tracer blood concentration over time, also known as the input function, glucose uptake rate of the tissues can be quantitatively calculated. This synthesis provides an accounting of studies using FDG-PET to measure acute exercise-induced skeletal muscle activity, describes the advantages and limitations of this imaging technique, and discusses its applications to the field of exercise physiology.

Greater glucose uptake heterogeneity in knee muscles of old compared to young men during isometric contractions detected by [18F]-FDG PET/CT

We used positron emission tomography/computed tomography (PET/CT) and [18F]-FDG to test the hypothesis that glucose uptake (GU) heterogeneity in skeletal muscles as a measure of heterogeneity in muscle activity is greater in old than young men when they perform isometric contractions. Six young (26 ± 6 years) and six old (77 ± 6 years) men performed two types of submaximal isometric contractions that required either force or position control. [18F]-FDG was injected during the task and PET/CT scans were performed immediately after the task. Within-muscle heterogeneity of knee muscles was determined by calculating the coefficient of variation (CV) of GU in PET image voxels within the muscles of interest. The average GU heterogeneity (mean ± SD) for knee extensors and flexors was greater for the old (35.3 ± 3.3%) than the young (28.6 ± 2.4%) (P = 0.006). Muscle volume of the knee extensors were greater for the young compared to the old men (1016 ± 163 vs. 598 ± 70 cm3, P = 0.004). In a multiple regression model, knee extensor muscle volume was a predictor (partial r = −0.87; P = 0.001) of GU heterogeneity for old men (R2 = 0.78; P < 0.001), and MVC force predicted GU heterogeneity for young men (partial r = −0.95, P < 0.001). The findings demonstrate that GU is more spatially variable for old than young men and especially so for old men who exhibit greater muscle atrophy.

Regional differences of [18F]‐FDG uptake within the brain during fatiguing muscle contractions

Many studies have shown that a position task is more difficult than a force task although both are performed at a similar net muscle force. Thus, the time to task failure is consistently shown to be briefer during the position task. The contributions of the central nervous system to these two types of fatiguing contractions are not completely understood. The purpose of this pilot study was to examine differences in regional brain activity between force and position tasks using positron emission tomography (PET) with [18F]‐Fluorodeoxyglucose (FDG).

Cannabis use in people with Parkinson's disease and Multiple Sclerosis: A web-based investigation.

OBJECTIVES Cannabis has been used for medicinal purpose for thousands of years; however the positive and negative effects of cannabis use in Parkinsons disease (PD) and Multiple Sclerosis (MS) are mostly unknown. Our aim was to assess cannabis use in PD and MS and compare results of self-reported assessments of neurological disability between current cannabis users and non-users. METHODS An anonymous web-based survey was hosted on the Michael J. Fox Foundation and the National Multiple Sclerosis Society webpages from 15 February to 15 October 2016. The survey collected demographic and cannabis use information, and used standardized questionnaires to assess neurological function, fatigue, balance, and physical activity participation. Analysis of variance and chi-square tests were used for the analysis. RESULTS The survey was viewed 801 times, and 595 participants were in the final data set. Seventy-six percent and 24% of the respondents reported PD and MS respectively. Current users reported high efficacy of cannabis, 6.4 (SD 1.8) on a scale from 0 to 7 and 59% reported reducing prescription medication since beginning cannabis use. Current cannabis users were younger and less likely to be classified as obese (P < 0.035). Cannabis users reported lower levels of disability, specifically in domains of mood, memory, and fatigue (P<0.040). CONCLUSIONS Cannabis may have positive impacts on mood, memory, fatigue, and obesity status in people with PD and MS. Further studies using clinically and longitudinally assessed measurements of these domains are needed to establish if these associations are causal and determine the long-term benefits and consequences of cannabis use in people with PD and MS.

FDG‐PET detects nonuniform muscle activity in the lower body during human gait

Introduction: Nonuniform muscle activity has been partially explained by anatomically defined neuromuscular compartments. The purpose of this study was to investigate the uniformity of skeletal muscle activity during walking. Methods: Eight participants walked at a self‐selected speed, and muscle activity was quantified using [18F]‐fluorodeoxyglucose positron emission tomography imaging. Seventeen muscles were divided into 10 equal length sections, and within muscle activity was compared. Results: Nonuniform activity was detected in 12 of 17 muscles (ƒ > 4.074; P < 0.046), which included both uni‐ and multi‐articular muscles. Greater proximal activity was detected in 6 muscles (P < 0.049), and greater distal versus medial activity was found in the iliopsoas (P < 0.042). Conclusions: Nonuniform muscle activity is likely related to recruitment of motor units located within separate neuromuscular compartments. These findings indicate that neuromuscular compartments are recruited selectively to allow for efficient energy transfer, and these patterns may be task‐dependent. Muscle Nerve 54: 959–966, 2016

Cognitive-Motor Related Brain Activity During Walking: Differences Between Men and Women With Multiple Sclerosis

OBJECTIVE To determine if sex differences in glucose uptake, a marker of brain activity, are present in brain regions that facilitate walking performance in persons with multiple sclerosis (MS). DESIGN Cross-sectional, observational pilot. SETTING University laboratory. PARTICIPANTS Positron emission tomography with fluorine-18-labeled deoxyglucose (FDG) was performed on persons with MS and healthy controls (4 men and 4 women per group; N=16) after a 15-minute walking test. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Brain activity was quantified as the mean standardized uptake value (SUV). RESULTS The mean SUV was significantly lower in the thalamus (P=.029) and cerebellum (P=.029) for men with MS compared with women with MS, but not for the prefrontal (P=.057) or frontal (P=.057) cortices. Similar nonsignificant trends were found for healthy controls. No mean SUV group × sex interaction effects were found between the MS and healthy control groups (all P>.05). CONCLUSIONS To our knowledge, this is the first study of brain activity sex differences based on FDG uptake in persons with MS during walking. Significantly less FDG uptake in the thalamus and cerebellum brain regions important for walking performance was found in men with MS compared with women with MS; however, these comparisons were not significantly different in the healthy control group. No differences in FDG uptake were found between the MS and healthy control groups in any of the brain regions examined. Results from this study provide pilot data for larger studies aimed at identifying underlying mechanisms responsible for accelerated disability in men with MS.