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1.  Fatigue and fatigability in neurologic illnesses 
Neurology  2013;80(4):409-416.
Fatigue is commonly reported in many neurologic illnesses, including multiple sclerosis, Parkinson disease, myasthenia gravis, traumatic brain injury, and stroke. Fatigue contributes substantially to decrements in quality of life and disability in these illnesses. Despite the clear impact of fatigue as a disabling symptom, our understanding of fatigue pathophysiology is limited and current treatment options rarely lead to meaningful improvements in fatigue. Progress continues to be hampered by issues related to terminology and assessment. In this article, we propose a unified taxonomy and a novel assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings. This taxonomy is based on our current knowledge of the pathophysiology and phenomenology of fatigue and fatigability. Application of our approach indicates that the assessment and reporting of fatigue can be clarified and improved by utilizing this taxonomy and creating measures to address distinct aspects of fatigue and fatigability. We review the strengths and weaknesses of several common measures of fatigue and suggest, based on our model, that many research questions may be better addressed by using multiple measures. We also provide examples of how to apply and validate the taxonomy and suggest directions for future research.
doi:10.1212/WNL.0b013e31827f07be
PMCID: PMC3589241  PMID: 23339207
2.  Influence of Amplitude Cancellation on the Accuracy of Determining the Onset of Muscle Activity from the Surface Electromyogram 
The purpose of the study was to quantify the influence of amplitude cancellation on the accuracy of detecting the onset of muscle activity based on an analysis of simulated surface electromyographic (EMG) signals. EMG activity of a generic lower limb muscle was simulated during the stance phase of human gait. Surface EMG signals were generated with and without amplitude cancellation by summing simulated motor unit potentials either before (cancellation EMG) or after (no-cancellation EMG) the potentials had been rectified. The two sets of EMG signals were compared at forces of 30 and 80% of maximum voluntary contraction (MVC) and with various low-pass filter cut-off frequencies. Onset time was determined both visually and by an algorithm that identified when the mean amplitude of the signal within a sliding window exceeded a specified standard deviation (SD) above the baseline mean. Onset error was greater for the no-cancellation conditions when determined automatically and by visual inspection. However, the differences in onset error between the two cancellation conditions appear to be clinically insignificant. Therefore, amplitude cancellation does not appear to limit the ability to detect the onset of muscle activity from the surface EMG.
doi:10.1016/j.jelekin.2012.01.011
PMCID: PMC3357456  PMID: 22330887
EMG onset; Amplitude cancellation; Computer simulation
3.  Timing variability and not force variability predicts the endpoint accuracy of fast and slow isometric contractions 
The purpose of the study was to determine the contributions of endpoint variance and trajectory variability to the endpoint accuracy of goal-directed isometric contractions when the target force and contraction speed were varied. Thirteen young adults (25 ± 6 years) performed blocks of 15 trials at each of 2 contraction speeds and 4 target forces. Subjects were instructed to match the peak of a parabolic force trajectory to a target force by controlling the abduction force exerted by the index finger. The time to peak force was either 150 ms (fast) or 1 s (slow). The target forces were 20, 40, 60, and 80% of the maximal force that could be achieved in 150 ms during an MVC. The same absolute forces were required for both contraction speeds. Endpoint accuracy and variability in force and time along with intramuscular EMG activity of the agonist (first dorsal interosseus) and antagonist (second palmar interosseus) muscles were quantified for each block of trials. The principal dependent variables were endpoint error (shortest distance between the coordinates of the target and the peak force), endpoint variance (sum of the variance in peak force and time to peak force), trial-to-trial variability (SD of peak force and time to peak force), SD of the force trajectory (SD of the detrended force from force onset to peak force), normalized peak EMG amplitude, and the SD of normalized peak EMG amplitude. Stepwise multiple linear regression models were used to determine the EMG activity parameters that could explain the differences observed in endpoint error and endpoint variance. Endpoint error increased with target force for the fast contractions, but not for the slow contractions. In contrast, endpoint variance was greatest at the lowest force and was not associated with endpoint error at either contraction speed. Furthermore, force trajectory SD was not associated with endpoint error or endpoint variance for either contraction speed. Only the trial-to-trial variability of the timing predicted endpoint accuracy for fast and slow contractions. These findings indicate that endpoint error in tasks that require force and timing accuracy is minimized by controlling timing variability but not force variability, and that endpoint error is not related to the amplitude of the activation signal.
doi:10.1007/s00221-009-2126-5
PMCID: PMC3631579  PMID: 20033680
Hand; First dorsal interosseus; Force control; Neural noise
4.  Addressing the gaps: sex differences in osteoarthritis of the knee 
An introduction to the accompanying three papers.
doi:10.1186/2042-6410-4-4
PMCID: PMC3571922  PMID: 23374401
Sex differences in response to sex steroids; Knee biomechanics and osteoarthritis; Pain perception in knee osteoarthritis; Musculoskeletal tissues; Estrogen; Testosterone; Rapid actions; Ligaments; Tendons; Bones; Animal models of osteoarthritis; Knee as an organ
5.  Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee 
Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.
doi:10.1186/2042-6410-4-3
PMCID: PMC3583799  PMID: 23374322
Bone; Estrogen; Ligaments; Osteoarthritis; Sex differences; Sex steroids; Tendon; Testosterone
6.  Mechanical contributors to sex differences in idiopathic knee osteoarthritis 
The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.
doi:10.1186/2042-6410-3-28
PMCID: PMC3560206  PMID: 23259740
Knee joint; Limb alignment; Muscle function; Obesity; Osteoarthritis; Sex differences
7.  Neural and psychosocial contributions to sex differences in knee osteoarthritic pain 
People with osteoarthritis (OA) can have significant pain that interferes with function and quality of life. Women with knee OA have greater pain and greater reductions in function and quality of life than men. In many cases, OA pain is directly related to sensitization and activation of nociceptors in the injured joint and correlates with the degree of joint effusion and synovial thickening. In some patients, however, the pain does not match the degree of injury and continues after removal of the nociceptors with a total joint replacement. Growth of new nociceptors, activation of nociceptors in the subchondral bone exposed after cartilage degradation, and nociceptors innervating synovium sensitized by inflammatory mediators could all augment the peripheral input to the central nervous system and result in pain. Enhanced central excitability and reduced central inhibition could lead to prolonged and enhanced pain that does not directly match the degree of injury. Psychosocial variables can influence pain and contribute to pain variability. This review explores the neural and psychosocial factors that contribute to knee OA pain with an emphasis on differences between the sexes and gaps in knowledge.
doi:10.1186/2042-6410-3-26
PMCID: PMC3583673  PMID: 23244577
Osteoarthritis; Pain; Sex differences; Gender; Nociceptor; Central sensitization; Psychosocial; Catastrophizing
8.  Aging and movement errors when lifting and lowering light loads 
Age  2010;33(3):393-407.
The purpose was to determine the influence of movement variability and level of muscle activation on the accuracy of targeted movements performed with the index finger by young and older adults. Twelve young (27.4 ± 4.4 years) and 12 older adults (74.5 ± 8.9 years) attempted to match the end position of an index finger movement to a target position when lifting and lowering a light load (10% of the maximum). Visual feedback was provided after each trial. Movement error was calculated as the absolute distance from the target. Movement variability was quantified as the standard deviation of finger acceleration and the variability of end position across trials. The EMG activity of first dorsal interosseus (FDI) and second palmar interosseus (SPI) muscles was measured with intramuscular electrodes. Older adults exhibited greater spatial and temporal errors and greater variability in finger acceleration and end position during both the lifting and lowering tasks. Older adults lifted the load by activating FDI less but SPI the same as young adults, whereas they lowered the load by activating SPI less and FDI the same as young adults. In addition, older adults exhibited lower variability across trials in SPI activation when lifting the load and lower variability for FDI activation when lowering the load. The findings demonstrate that the decrease in spatial and temporal accuracy observed in older adults when lifting and lowering a light load to a target position was due to greater movement variability and differences in antagonistic muscle activity.
doi:10.1007/s11357-010-9190-4
PMCID: PMC3168598  PMID: 20945163
Motor output variability; Older adults; Movement control; EMG; Muscle synergy; Antagonist muscles
9.  Comparison of the influence of two stressors on steadiness during index finger abduction 
Physiology & behavior  2010;99(4):515-520.
Although several stressors have been used to examine the influence of arousal on motor performance, including noxious electrical stimulation, cold pressor test, and mental math calculations, no study has compared the influence of different physical stressors on motor output. The purpose of the study was to compare the influence of two stressors (cold pressor test and electrical stimulation) on the steadiness of the abduction force exerted by the index finger. Sixteen subjects (22.8 ± 3.5 yrs, 8 women) performed steadiness trials before (anticipatory phase), during (stressor phase), and after (recovery phase) each stressor. The steadiness task involved isometric contractions with the first dorsal interosseus muscle, which is the muscle that produces most of the abduction force exerted by the index finger. Subjects were required to match the abduction force on a monitor to a target force set to 5% of the maximal voluntary contraction (MVC) force for 60 s. In contrast to previous studies that examined the influence of stressors on pinch grip steadiness, the two stressors did not decrease steadiness. Furthermore, the absence of a change in steadiness contrasted with the increases in cognitive (State-Trait Anxiety Index, Visual Analog Scale) and physiological (heart rate) arousal during the stressor phase and the subsequent decline during recovery. The null effect of the stressors on index finger steadiness may be due to the relative simplicity of the task compared with those examined previously.
doi:10.1016/j.physbeh.2010.01.002
PMCID: PMC2826591  PMID: 20079364
10.  Pronation-supination torque and associated electromyographic activity varies during a sustained elbow flexor contraction but does not influence the time to task failure 
Muscle & nerve  2009;40(2):231-239.
This study measured the pronation-supination torque, the flexion force, and the EMG activity in elbow flexor muscles during an isometric contraction in which a submaximal elbow flexion force was kept constant for as long as possible. Ten subjects performed the contraction at 20% of maximal voluntary contraction (MVC) torque until failure. Electromyographic (EMG) activity of the long and short heads of biceps brachii, brachialis, brachioradialis, and triceps brachii was recorded with surface and intramuscular electrodes. The mean time to failure was 8.2 ± 6.2 min. The fluctuations in flexion force and pronation-supination torque were correlated (r range: 0.68 to 0.92), and subjects exhibited a range of pronation-torque profiles that were not associated with the time to failure. Knowing the influence of concurrent actions about the pronation-supination axis during a submaximal fatiguing contraction with the elbow flexor muscles has implications for the design of workstations in ergonomic settings and in the prescription of activities for rehabilitation programs.
doi:10.1002/mus.21224
PMCID: PMC2758423  PMID: 19358235
isometric contraction; muscle activity; muscle fatigue; neural strategy
11.  A spinal pathway between synergists can modulate activity in human elbow flexor muscles 
Electrical stimulation of the brachioradialis branch of the radial nerve has been shown to inhibit the discharge of voluntarily activated motor units in biceps brachii during weak contractions with the elbow flexor muscles. The purpose of the present study was to characterise the inhibitory reflex by comparing its strength in the short and long heads of the biceps brachii and examining the influence of forearm position on the strength of the reflex. Spike-triggered stimulation was used to assess the influence of radial nerve stimulation on the discharge of single motor units in the biceps brachii of 15 subjects. Stimulation of the radial nerve prolonged the interspike interval (P < 0.001) of motor units in the long (n = 31, 4.8 ± 5.6 ms) and short heads (n = 26, 8.1 ± 12.3 ms) of biceps brachii with no difference between the two heads (P = 0.11). The strength of inhibition varied with forearm position for motor units in both heads (n = 18, P < 0.05). The amount of inhibition was greatest in pronation (7.9 ± 8.9 ms), intermediate in neutral (5.8 ± 7.1 ms), and least in supination (2.8 ± 3.4 ms). These findings indicate that the inhibition evoked by afferent feedback from brachioradialis to low-threshold motor units (mean force 3–5% MVC) in biceps brachii varied with forearm posture yet was similar for the two heads of biceps brachii. This reflex pathway provides a mechanism to adjust the activation of biceps brachii with changes in forearm position, and represents a spinal basis for a muscle synergy in humans.
doi:10.1007/s00221-008-1479-5
PMCID: PMC2570337  PMID: 18597082
Motor unit; Inhibition; Biceps brachii; Brachioradialis; Synergy
12.  Fluctuations in motor output of a hand muscle can be altered by the mechanical properties of the position sensor 
Journal of neuroscience methods  2007;168(1):164-173.
Fluctuations in motor output are typically quantified by the standard deviation (SD) of displacement or acceleration. The aim of the study was to determine the influence of a linear variable-displacement transducer (LVDT) on the SDs and spectral content of displacement and acceleration during steady isometric and anisometric contractions performed with the first dorsal interosseus muscle. Thirteen young adults supported six loads when performing position-holding and position-tracking tasks when the LVDT either was or was not attached to the index finger. The LVDT reduced the magnitude of the SDs in displacement and acceleration and disrupted the load-dependent modulation of the spectral properties of these signals. When the LVDT was not connected to the finger, the displacement SD was greatest during concentric contractions, the acceleration SD was greatest during eccentric contractions, and there were load-dependent changes in the power density spectra. Although the LVDT may be used for assessing relative changes in displacement, its ability to provide absolute measures of fluctuations in motor output is limited. The results provide baseline measures of the fluctuations in motor output during steady contractions with a hand muscle and how the method used to detect displacement alters these measures.
doi:10.1016/j.jneumeth.2007.09.015
PMCID: PMC2253721  PMID: 17964659
First dorsal interosseus muscle; Steadiness; Displacement; Acceleration
13.  Reflex Responsiveness of a Human Hand Muscle When Controlling Isometric Force and Joint Position 
Objective
This study compared reflex responsiveness of the first dorsal interosseus muscle during two tasks that employ different strategies to stabilize the finger while exerting the same net muscle torque.
Methods
Healthy human subjects performed two motor tasks that involved either pushing up against a rigid restraint to exert a constant isometric force equal to 20% of maximum, or maintaining a constant angle at the metacarpophalangeal joint while supporting an equivalent inertial load. Each task consisted of six 40-s contractions during which electrical and mechanical stimuli were delivered.
Results
The amplitude of short and long latency reflex responses to mechanical stretch did not differ significantly between tasks. In contrast, reflexes evoked by electrical stimulation were significantly greater when supporting the inertial load.
Conclusions
Agonist motor neurons exhibited heightened reflex responsiveness to synaptic input from heteronymous afferents when controlling the position of an inertial load. Task differences in the reflex response to electrical stimulation were not reflected in the response to mechanical perturbation, indicating a difference in the efficacy of the pathways that mediate these effects.
Significance
Results from this study suggest that modulation of spinal reflex pathways may contribute to differences in the control of force and position during isometric contractions of the first dorsal interosseus muscle.
doi:10.1016/j.clinph.2007.06.009
PMCID: PMC2020450  PMID: 17646129
spinal reflexes; isometric contraction; motor control; muscle spindle afferents; presynaptic inhibition
14.  Tirasemtiv amplifies skeletal muscle response to nerve activation in humans 
Muscle & Nerve  2014;50(6):925-931.
Introduction: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. Methods: Healthy men received tirasemtiv and placebo in a randomized, double-blind, 4-period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force–frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. Results: Tirasemtiv increased force produced by the tibialis anterior in a dose-, concentration-, and frequency-dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz). Conclusions: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input. Muscle Nerve 50: 925–931, 2014
doi:10.1002/mus.24239
PMCID: PMC4260123  PMID: 24634285
fast skeletal muscle troponin activator; force–frequency relationship; Phase 1; skeletal muscle; tirasemtiv

Results 1-14 (14)