Fatigue in primary Sjögren's syndrome is associated with an objective decline in physical performance, pain and depression.

OBJECTIVES: Fatigue is a major complaint in primary Sjögren's syndrome (pSS). To acquire a better understanding of fatigue in pSS, we investigated objective measures of performance decline (performance fatigability). Furthermore, we evaluated the relationship of self-reported fatigue with performance fatigability and factors modulating perceptions of fatigability (perceived fatigability). METHODS: Thirty-nine pSS patients and 27 healthy controls were included. To assess performance fatigability, force decline was measured during a sustained (124s) maximal voluntary contraction (MVC) with the index finger abductor muscle, and voluntary muscle activation was indexed using peripheral nerve stimulation. Self-reported fatigue was quantified using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). Pain, depression, and anxiety assessed using questionnaires and inflammatory biomarkers measured in blood were used as factors relating to perceived fatigability. RESULTS: Voluntary muscle activation was reduced in pSS (p=0.030), but force decline during the sustained MVC did not differ between groups. Self-reported fatigue was significantly higher in pSS than in controls (FSS: 4.4 vs. 2.6, p<0.001). Multivariable linear regression showed that both performance fatigability (force decline) and perceived fatigability (pain and depression) were associated with the MFIS physical domain in pSS (total explained variance of 47%). Negative associations with fatigue were observed for two interferon-associated proteins: MxA and CXCL10. CONCLUSIONS: This study demonstrates that performance fatigability in pSS was compromised by a reduced capacity of the central nervous system to drive the muscle. Furthermore, self-reported fatigue is a multifactorial symptom associated with both performance fatigability and perceived fatigability in patients with pSS.

Fatigue following mild traumatic brain injury relates to visual processing and effort perception in the context of motor performance.

INTRODUCTION: Following mild traumatic brain injury (mTBI), a substantial number of patients experience disabling fatigue for months after the initial injury. To date, the underlying mechanisms of fatigue remain unclear. Recently, it was shown that mTBI patients with persistent fatigue do not demonstrate increased performance fatigability (i.e., objective performance decline) during a sustained motor task. However, it is not known whether the neural activation required to sustain this performance is altered after mTBI. METHODS: Blood oxygen level-dependent (BOLD) fMRI data were acquired from 19 mTBI patients (>3 months post-injury) and 19 control participants during two motor tasks. Force was recorded from the index finger abductors of both hands during submaximal contractions and a 2-minute maximal voluntary contraction (MVC) with the right hand. Voluntary muscle activation (i.e., CNS drive) was indexed during the sustained MVC using peripheral nerve stimulation. Fatigue was quantified using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). Questionnaire, task, and BOLD data were compared across groups, and linear regression was used to evaluate the relationship between BOLD-activity and fatigue in the mTBI group. RESULTS: The mTBI patients reported significantly higher levels of fatigue (FSS: 5.3 vs. 2.6, p < 0.001). Both mTBI- and control groups demonstrated significant performance fatigability during the sustained MVC, but no significant differences in task performance or BOLD-activity were observed between groups. However, mTBI patients reporting higher FSS scores showed increased BOLD-activity in the bilateral visual cortices (mainly extrastriate) and the left midcingulate gyrus. Furthermore, across all participants mean voluntary muscle activation during the sustained MVC correlated with long lasting post-contraction BOLD-activation in the right insula and midcingulate cortex. CONCLUSION: The fMRI findings suggest that self-reported fatigue in mTBI may relate to visual processing and effort perception. Long lasting activation associated with high levels of CNS drive might be related to changes in cortical homeostasis in the context of high effort.

Increased Ipsilateral M1 Activation after Incomplete Spinal Cord Injury Facilitates Motor Performance.

Incomplete spinal cord injury (SCI) may result in muscle weakness and difficulties with force gradation. Although these impairments arise from the injury and subsequent changes at spinal levels, changes have also been demonstrated in the brain. Blood-oxygen-level dependent (BOLD) imaging was used to investigate these changes in brain activation in the context of unimanual contractions with the first dorsal interosseous muscle. BOLD- and force data were obtained in 19 individuals with SCI (AISA Impairment Scale [AIS] C/D, level C4-C8) and 24 able-bodied controls during maximal voluntary contractions (MVCs). To assess force modulation, participants performed 12 submaximal contractions with each hand (at 10, 30, 50, and 70% MVC) by matching their force level to a visual target. MVCs were weaker in the SCI group (both hands p < 0.001), but BOLD activation did not differ between SCI and control groups. For the submaximal contractions, force (as %MVC) was similar across groups. However, SCI participants showed increased activity of the ipsilateral motor cortex and contralateral cerebellum across all contractions, with no differential effect of force level. Activity of ipsilateral M1 was best explained by force of the target hand (vs. the non-target hand). In conclusion, the data suggest that after incomplete cervical SCI, individuals remain capable of producing maximal supraspinal drive and are able to modulate this drive adequately. Activity of the ipsilateral motor network appears to be task related, although it remains uncertain how this activity contributes to task performance and whether this effect could potentially be harnessed to improve motor functioning.

Self-Reported Fatigue After Mild Traumatic Brain Injury Is Not Associated With Performance Fatigability During a Sustained Maximal Contraction.

Patients with mild traumatic brain injury (mTBI) are frequently affected by fatigue. However, hardly any data is available on the fatigability of the motor system. We evaluated fatigue using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) questionnaires in 20 participants with mTBI (>3 months post injury; 8 females) and 20 age- and sex matched controls. Furthermore, index finger abduction force and electromyography of the first dorsal interosseous muscle of the right hand were measured during brief and sustained maximal voluntary contractions (MVC). Double pulse stimulation (100 Hz) was applied to the ulnar nerve to evoke doublet-forces before and after the sustained contraction. Seven superimposed twitches were evoked during the sustained MVC to quantify voluntary muscle activation. mTBI participants reported higher FSS scores (mTBI: 5.2 ± 0.8 SD vs. control: 2.8 ± 0.8 SD; P < 0.01). During the sustained MVC, force declined to similar levels in mTBI (30.0 ± 9.9% MVC) and control participants (32.7 ± 9.8% MVC, P = 0.37). The decline in doublet-forces after the sustained MVC (mTBI: to 37.2 ± 12.1 vs. control: to 41.4 ± 14.0% reference doublet, P = 0.32) and the superimposed twitches evoked during the sustained MVC (mTBI: median 9.3, range: 2.2-32.9 vs. control: median 10.3, range: 1.9-31.0% doubletpre, P = 0.34) also did not differ between groups. Force decline was associated with decline in doublet-force (R 2 = 0.50, P < 0.01) for both groups. Including a measure of voluntary muscle activation resulted in more explained variance for mTBI participants only. No associations between self-reported fatigue and force decline or voluntary muscle activation were found in mTBI participants. However, the physical subdomain of the MFIS was associated with the decline in doublet-force after the sustained MVC (R 2 = 0.23, P = 0.04). These results indicate that after mTBI, increased levels of self-reported physical fatigue reflected increased fatigability due to changes in peripheral muscle properties, but not force decline or muscle activation. Additionally, muscle activation was more important to explain the decline in voluntary force (performance fatigability) after mTBI than in control participants.

Age- and Sex-Related Differences in Motor Performance During Sustained Maximal Voluntary Contraction of the First Dorsal Interosseous.

Age and sex affect the neuromuscular system including performance fatigability. Data on performance fatigability and underlying mechanisms in hand muscles are scarce. Therefore, we determined the effects of age and sex on force decline, and the mechanisms contributing to force decline, during a sustained isometric maximal voluntary contraction (MVC) with the index finger abductor (first dorsal interosseous, FDI). Subjects (n = 51, age range: 19-77 years, 25 females) performed brief and a 2-min sustained MVC with the right FDI. Abduction force and root mean squared electromyographic activity (rms-EMG) were recorded in both hands. Double-pulse stimulation was applied to the ulnar nerve during (superimposed twitch) and after (doublet-force) the brief and sustained MVCs. Compared to females, males were stronger (134%, p < 0.001) and exhibited a greater decline in voluntary (difference: 8%, p = 0.010) and evoked (doublet) force (difference: 12%, p = 0.010) during and after the sustained MVC. Age did not affect MVC, force decline and superimposed twitch. The ratio between the doublet- and MVC-force was greater in females (0.33, p = 0.007) and in older (0.38, p = 0.06) individuals than in males (0.30) and younger (0.30) individuals; after the sustained MVC this ratio increased with age and the increase was larger for females compared to males (p = 0.04). The inadvertent contralateral, left force and rms-EMG activity increased over time (2.7-13.6% MVC and 5.4-17.7% MVC, respectively). Males had higher contralateral forces than females (p = 0.012) and contralateral force was higher at the start of the contralateral contraction in older compared with young subjects (difference: 29%, p = 0.008). In conclusion, our results suggest that the observed sex-differences in performance fatigability were mainly due to differences in peripheral muscle properties. Yet the reduced amount of contralateral activity and the larger difference in evoked versus voluntary force in female subjects indicate that sex-differences in voluntary activation should not be overlooked. These data obtained in neurological healthy adults provides a framework and help the interpretation and referencing of neurophysiological measures in patients suffering from neuromuscular diseases, who often present with symptoms of performance fatigability.

Reduced voluntary drive during sustained but not during brief maximal voluntary contractions in the first dorsal interosseous weakened by spinal cord injury.

In able-bodied (AB) individuals, voluntary muscle activation progressively declines during sustained contractions. However, few data are available on voluntary muscle activation during sustained contractions in muscles weakened by spinal cord injury (SCI), where greater force declines may limit task performance. SCI-related impairment of muscle activation complicates interpretation of the interpolated twitch technique commonly used to assess muscle activation. We attempted to estimate and correct for the SCI-related-superimposed twitch. Seventeen participants, both AB and with SCI (American Spinal Injury Association Impairment Scale C/D) produced brief and sustained (2-min) maximal voluntary contractions (MVCs) with the first dorsal interosseous. Force and electromyography were recorded together with superimposed (doublet) twitches. MVCs of participants with SCI were weaker than those of AB participants (20.3 N, SD 7.1 vs. 37.9 N, SD 9.5; P < 0.001); MVC-superimposed twitches were larger in participants with SCI (SCI median 10.1%, range 2.0-63.2%; AB median 4.7%, range 0.0-18.4% rest twitch; P = 0.007). No difference was found after correction for the SCI-related-superimposed twitch (median 6.7%, 0.0-17.5% rest twitch, P = 0.402). Thus during brief contractions, the maximal corticofugal output that participants with SCI could exert was similar to that of AB participants. During the sustained contraction, force decline (SCI, 58.0%, SD 15.1; AB, 57.2% SD 13.3) was similar (P = 0.887) because participants with SCI developed less peripheral (P = 0.048) but more central fatigue than AB participants. The largest change occurred at the start of the sustained contraction when the (corrected) superimposed twitches increased more in participants with SCI (SCI, 16.3% rest twitch, SD 20.8; AB, 2.7%, SD 4.7; P = 0.01). The greater reduction in muscle activation after SCI may relate to a reduced capacity to overcome fast fatigue-related excitability changes at the spinal level.