The neural mechanisms causing long-COVID fatigue

In a recent study published in 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 frequently present with fatigue, a symptom that affects the performance of routine activities. Fatigue seems to involve multiple systems, resulting in immunological, hormonal, and metabolic abnormalities, especially affecting neurocognitive functions and leading to a feeling of weakness. However, the pathophysiology of long COVID fatigue is not well-characterized and warrants further investigation.

About the study

In the present cross-sectional study, researchers investigated the pathophysiology of fatigue in 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, among 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 analysis.

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

In addition, the muscles were electrically stimulated to evaluate 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 evaluate muscle motor units’ activity, from which the neuromodulatory system metrics were derived.

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

Results

Among the study participants, 73% (n=27) and 71% (n=37) of the pCF and control group individuals were female. Compared to sex- and age-matched controls, long COVID patients experiencing fatigue demonstrated under-activity in particular cortical circuits, dysregulated autonomic functions, and myopathic changes in the skeletal muscles. However, 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 distinct entity with individual-level variations instead of a combination of different syndromes.

The mean FIS score among pCF patients was 83, indicating that fatigue moderately impacted daily 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 since the SARS-CoV-2 infection.

Based on the previously published relative SARS-CoV-2 variants of concern (VOC) incidence rates in the United Kingdom (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 among 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 reaction 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 result in lowered force output. Post-COVID fatigue patients had normal grip strength, without any evidence of fatiguing transmission at the neuromuscular junction (NMJ), and normal intrinsic excitability of motoneurons.

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

The findings indicated reduced vagal (relative to sympathetic) tone among pCF patients, indicating that at least a few pCF group individuals suffered from dysautonomia.

In addition, pCF patients had lower HR variability, indicating increased sympathetic nervous system activity. Habituation of galvanic skin responses to loud (startling) sounds was also lower among 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. The most frequently reported pCF symptoms include exhaustion following slight cognitive or physical activity, depending on neural circuits.

Post-COVID fatigue does not 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 rather than symptoms only.

In addition, objective assessments can identify high-risk individuals for whom more prompt management of otherwise mild COVID-19 may be required.

However, further research should be conducted, including longitudinal evaluations of post-COVID fatigue patients, to determine whether the changes occurred before the onset of fatigue or alongside fatigue.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.