In a recent study published within the Brain Communications Journal, researchers investigated the neural mechanisms underlying post-coronavirus disease (COVID) fatigue (pCF).

Study: Neural dysregulation in post-COVID fatigue. Image Credit: VitaliiVodolazskyi/Shutterstock.com

Background

COVID 2019 (COVID-19) symptoms may persist beyond the acute phase of the disease [referred to as long COVID or post-COVID-19 condition (PCC)].

Such patients regularly present with fatigue, a symptom that affects the performance of routine activities. Fatigue seems to involve multiple systems, leading to immunological, hormonal, and metabolic abnormalities, especially affecting neurocognitive functions and resulting in a sense of weakness. Nonetheless, the pathophysiology of long COVID fatigue just isn’t well-characterized and warrants further investigation.

In regards to the study

In the current cross-sectional study, researchers investigated the pathophysiology of fatigue within the post-acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

The study comprised 37 adults, aged ≤65.0 years, reporting fatigue six to 26 weeks following mild SARS-CoV-2 infection and no prior history of neurological diseases.

For comparison, 52 sex- and age-matched individuals without fatigue (controls) were included, amongst whom six had suffered from mild COVID-19 and recovered from it without pCF.

Several non-invasive neurophysiological and behavioral tests evaluating the autonomic (ANS), central (CNS), and peripheral nervous systems (PNS) were performed, followed by K-means cluster K-and gap evaluation.

Transcranial magnetic stimulation (TMS) was performed to evaluate primary motor cortex function, and sensory nerves were stimulated to evaluate for dysfunctions in sensory circuit feedback to the CNS.

As well as, the muscles were electrically stimulated to guage peripheral and central fatigue levels, and heart rates (HR) and galvanic cutaneous responses were recorded for evaluating ANS functions.

Further, high-density-type surface electromyography was performed to guage muscle motor units’ activity, from which the neuromodulatory system metrics were derived.

Moreover, the participants filled out online fatigue impact scale (FIS) questionnaires, and a machine learning-based classifier was used to categorise individuals as pCF patients and controls using multi-variable data.

Results

Among the many study participants, 73% (n=27) and 71% (n=37) of the pCF and control group individuals were female. In comparison with sex- and age-matched controls, long COVID patients experiencing fatigue demonstrated under-activity specifically cortical circuits, dysregulated autonomic functions, and myopathic changes within the skeletal muscles. Nonetheless, abnormalities in sensory functions and descending neuromodulatory drive were unlikely to contribute to pCF.

Further, no sub-groups were found, indicating that long COVID fatigue is a definite entity with individual-level variations as a substitute of a mix of various syndromes.

The mean FIS rating amongst pCF patients was 83, indicating that fatigue moderately impacted day by day lives. The duration between COVID-19 diagnosis and laboratory testing for SARS-CoV-2 was 121 days. No correlation was observed between fatigue severity and days elapsed because the SARS-CoV-2 infection.

Based on the previously published relative SARS-CoV-2 variants of concern (VOC) incidence rates in the UK (UK), the team estimated that 83.0% of the pCF group were infected with the SARS-CoV-2 Alpha VOC.

The TMS findings showed that intracortical facilitation (ICF), a measure of intracortical glutamatergic function, was significantly lower amongst pCF patients than controls (conditioned motor evoked potential versus unconditioned was 171% versus 258%), indicating reduced cortical excitability.

The pCF patients showed increased peripheral fatigue levels and greater visual response times. The maximal twitch evoked by direct electrical stimulation of muscles following sustained muscle contractions was 49% and 67% in pCF and controls, respectively.

Indicating that pCF patients develop metabolic alterations in muscle fibers following prolonged activities that lead to lowered force output. Post-COVID fatigue patients had normal grip strength, with none evidence of fatiguing transmission on the neuromuscular junction (NMJ), and normal intrinsic excitability of motoneurons.

The mean values for resting heart rate were significantly greater amongst pCF patients than controls (75 versus 68 beats per minute, respectively). Quite the opposite, post-COVID fatigue patients had significantly lower blood oxygen saturation (SaO2) values than controls (95% versus 97%, respectively), probably attributable to sustained pulmonary damage and/or vasculopathy.

The findings indicated reduced vagal (relative to sympathetic) tone amongst pCF patients, indicating that at the very least a number of pCF group individuals suffered from dysautonomia.

As well as, pCF patients had lower HR variability, indicating increased sympathetic nervous system activity. Habituation of galvanic skin responses to loud (startling) sounds was also lower amongst pCF subjects, further supporting sympathetic output excess.

Further, pCF patients had elevated core body temperatures, indicating long-term effects of acute COVID-19 on immunological activation and pulmonary function and/or a generalized enhanced sympathetic drive in pCF. The mean ML classifier accuracy was 70.0%.

Conclusions

Overall, the study findings highlighted the neural aspect of pCF pathogenesis. Essentially the most regularly reported pCF symptoms include exhaustion following slight cognitive or physical activity, depending on neural circuits.

Post-COVID fatigue doesn’t result from a generalized deficit but particular alterations in specific neural circuits. The findings could aid in a more accurate pCF diagnosis based on signs moderately than symptoms only.

As well as, objective assessments can discover high-risk individuals for whom more prompt management of otherwise mild COVID-19 could also be required.

Nonetheless, further research must be conducted, including longitudinal evaluations of post-COVID fatigue patients, to find out whether the changes occurred before the onset of fatigue or alongside fatigue.