Serum Histidine is Lower in Fatigued Women with Multiple Sclerosis.

BACKGROUND: Disabling persistent perceived fatigue occurs in 50% of people with multiple sclerosis (MS), but mechanisms are poorly understood. Low histidine could contribute to fatigue since it is the neurotransmitter histamine precursor and low serum levels are reported in other diseases where fatigue is common (e.g., breast cancer, kidney disease, diabetes). Serum histidine is also inversely correlated with proinflammatory cytokines (e.g., TNF, IFN-y), which have been linked to MS fatigue. PURPOSE: To determine if serum histidine is low in fatigued women with MS, and if histidine is related to differences in proinflammatory cytokines. METHODS: Participants were classified as having elevated (n = 19) or normal (n = 18) perceived fatigue based on a median sample split using Profile of Mood States fatigue scale scores, with the elevated fatigue group having scores >7. Histidine and gene-expression of TNF, IFN-y, and leptin were assayed from a serum sample. RESULTS: After adjustment for depression, serum histidine was significantly lower in women with MS with elevated fatigue, compared to normal fatigue (64.57 vs. 70.48 nmol/ml, p = .048, g = 0.75). There were no differences between groups in cytokine expression (all p > .24). Gene expression of TNF correlated with histidine only in people with normal fatigue (r = .51, p = .034), while no other cytokines related to histidine levels. CONCLUSIONS: These results provide evidence that serum histidine is lower in fatigued women with MS, but the study did not find a relationship between histidine and TNF, IFN-y, or leptin gene expression.

Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis.

BACKGROUND: Gait and balance impairment is common in secondary progressive multiple sclerosis (SPMS). Lipoic acid (LA), an over-the-counter antioxidant, is effective in MS animal models and may improve walking speed, but effects on mobility are unreported. OBJECTIVE: Examine the effects of 1200 mg daily oral dose of LA versus placebo (PLA) on gait and balance in a 2-year, randomized, double-blind pilot study. METHODS: 134 participants were screened for eligibility before assignment to LA (n = 28) or PLA (n = 26). Included here were, 21 participants with SPMS who took LA (N = 11) or PLA (N = 10) capsules for 2 years (enrolled May 2, 2011 - August 14, 2015) and completed all tasks without the use of an assistive device. Participants completed the Timed Up and Go (TUG) and quiet standing tasks every 6 months while wearing inertial sensors (APDM Opals) to quantify mobility. RESULTS: LA had a medium effect on time to complete TUG at 2 years (g = 0.51; 95% CI = -0.35, 1.38). In a subset of 18 participants with less disability (EDSS < 6, no use of ambulatory device), turning time was significantly shorter with LA (p = 0.048, Δ= 0.48 s). No differences in balance metrics were found between groups. CONCLUSIONS: LA had an effect on walking performance in people with SPMS, particularly in those with lower baseline disability. TRIAL REGISTRATION: Lipoic Acid for Secondary Progressive Multiple Sclerosis https://clinicaltrials.gov/ct2/show/NCT01188811?term=spain+lipoic+acid&rank=1 NCT0118881.

Perceived fatigue and energy are independent unipolar states: Supporting evidence.

Persistent fatigue is a common problem (∼20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as "a lack of energy", thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes.

Adenosine A2A receptor gene polymorphisms (ADORA2A) are associated with maximal concentric contraction pain.

Objectives: To test associations of adenosine A2A receptor gene (ADORA2A) polymorphisms with maximal concentric contraction pain, caffeine-induced perceptual changes, and responses to mild eccentric injury. Design: Targeted candidate gene association study. Methods: ADORA2A (rs5751876) was genotyped in 26 adults. Pain of a maximal elbow flexor contraction was assessed. Participants performed 18 eccentric actions of the elbow flexors. Arm volume was measured before and 24- and 48-h post-injury. At 24- and 48-h post-injury, caffeine or placebo capsules were given using a randomized cross-over design and effort and pain were assessed. Results: Maximal concentric contraction pain was higher for the CC compared to the CT/TT group (effect size d = 0.89) and lower for the TT compared to the CT/CC group (d = 0.62). There were moderate sized differences between CC and TT/CT groups for post-injury exertion and arm volume 24-h post injury. Conclusions: ADORA2A polymorphisms are moderately associated with muscle pain during maximal contractions in uninjured muscle.

Relationship between perceived fatigue and performance fatigability in people with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Perceived fatigue (i.e., subjective perception of reduced capacity) is one of the most common and disabling symptoms for people with multiple sclerosis (MS). Perceived fatigue may also be related to performance fatigability (i.e., decline in physical performance over time), although study findings have been inconsistent. OBJECTIVE: To locate all studies reporting the relationship between perceived fatigue and fatigability in people with MS, determine the population correlation, and examine moderating variables of the correlation size. METHODS: In accordance with PRISMA guidelines, systematic searches were completed in Medline, PsychInfo, Google Scholar, and the Cochrane Library for peer-reviewed articles published between March 1983 and August 2016. Included articles measured perceived fatigue and performance fatigability in people with MS and provided a correlation between measures. Moderator variables expected to influence the relationship were also coded. Searches located 19 studies of 848 people with MS and a random-effects model was used to pool correlations. RESULTS: The mean correlation between fatigue and fatigability was positive, "medium" in magnitude, and statistically significant, r=0.31 (95% CI=0.21, 0.42), p<0.001. Despite moderate between-study heterogeneity (I2=46%) no statistically significant moderators were found, perhaps due to the small number of studies per moderator category. CONCLUSION: There is a significant relationship between perceived fatigue and fatigability in MS, such that people reporting elevated fatigue also are highly fatigable. The size of the relationship is not large enough to suggest fatigue and fatigability are the same construct, and both should continue to be assessed independently.

Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis.

PURPOSE: A prominent symptom of myalgic encephalomyelitis, chronic fatigue syndrome, or systemic exertion intolerance disease (ME/CFS/SEID) is persistent fatigue that is worsened by physical exertion. Here the population effect of a single bout of exercise on fatigue symptoms in people with ME/CFS/SEID was estimated and effect moderators were identified. METHODS: Google Scholar was systematically searched for peer-reviewed articles published between February 1991 and May 2015. Studies were included where people diagnosed with ME/CFS/SEID and matched control participants completed a single bout of exercise and fatigue self-reports were obtained before and after exercise. Fatigue means, standard deviations, and sample sizes were extracted to calculate effect sizes and the 95% confidence interval. Effects were pooled using a random-effects model and corrected for small sample bias to generate mean Δ. Multilevel regression modeling adjusted for nesting of effects within studies. Moderators identified a priori were diagnostic criteria, fibromyalgia comorbidity, exercise factors (intensity, duration, and type), and measurement factors. RESULTS: Seven studies examining 159 people with ME/CFS/SEID met inclusion criteria, and 47 fatigue effects were derived. The mean fatigue effect was Δ = 0.73 (95% confidence interval = 0.24-1.23). Fatigue increases were larger for people with ME/CFS/SEID when fatigue was measured 4 h or more after exercise ended rather than during or immediately after exercise ceased. CONCLUSIONS: This preliminary evidence indicates that acute exercise increases fatigue in people with ME/CFS/SEID more than that in control groups, but effects were heterogeneous between studies. Future studies with no-exercise control groups of people with ME/CFS/SEID are needed to obtain a more precise estimate of the effect of exercise on fatigue in this population.

The effect of histamine on changes in mental energy and fatigue after a single bout of exercise.

The purpose of this research was to determine if histamine, acting on brain H1 receptors, influences changes in feelings of energy and fatigue or cognitive test performance after acute exercise. Women (n=20) with low vigor and high fatigue were administered the H1 antagonist drug doxepin hydrocholoride (6 mg) in tomato juice and tomato juice alone (placebo) in a randomized, double-blinded, cross-over experiment before performing 30 min of light intensity cycling exercise and completing energy, fatigue, sleepiness, and motivation scales, and cognitive tasks. After exercise, mental fatigue increased for the doxepin condition (p=0.014) but not placebo (p=0.700), while mental energy decreased for both PLA and DOX (p<0.001) and cognitive task performance was unaffected. It is inferred that histamine binding to H1 receptors in the brain has a role in exercise-induced reductions in mental fatigue, but not increases in energy.

Short-term effects of black pepper (Piper nigrum) and rosemary (Rosmarinus officinalis and Rosmarinus eriocalyx) on sustained attention and on energy and fatigue mood states in young adults with low energy.

The purpose was to test whether a single dose of black pepper or rosemary produced short-term enhancements in sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and fatigue. Outcomes were measured in 40 young adults with below average feelings of energy before and twice after they orally consumed capsules containing either black pepper (2.0 g), rosemary (1.7 g), or a placebo (3.1 g rice flour). Sustained attention was measured using a 16-min dual task, in which, single-digit numbers were presented every second on a screen and the participant performed both a primary task [detection of three successive, different odd digits] and a secondary task [detection of the number 6]. Feelings of energy and fatigue were measured using the vigor and fatigue subscales of the Profile of Mood States and visual analog scales (VAS). Analysis of variance showed nonsignificant condition (spice versus placebo)×time (T1, T2, & T3) effects for motivation, measured with a VAS, and the intensity of energy and fatigue feelings. Unadjusted effect sizes revealed that rosemary induced small, transient reductions in false alarm errors (d=0.21) and mental fatigue (d=0.40) at isolated time periods. Time-varying analysis of covariance, controlling for motivation to perform cognitive tasks, showed no significant effects on the primary or secondary task outcomes of correct responses (hits), errors (false alarms, misses), speed of response (reaction time), and signal detection sensitivity. It is concluded that black pepper and rosemary, consumed in a capsule form, in the doses used and while wearing a nose clip to block olfactory effects, do not induce consistent short-term improvements in sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and fatigue in young adults with low energy.