Neural mechanisms that cause COVID-19 long-term fatigue

In a recent study published in brain communication Journal, researchers investigated the neural mechanisms underlying post-coronavirus disease (COVID) fatigue (pCF).

study: Neuronal dysregulation in post-COVID fatigue. Image Credit: VitaliiVodolazskyi/Shutterstock.com

Background

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

Such patients frequently exhibit fatigue, a symptom that affects their performance in daily activities. Fatigue appears to involve multiple systems, causing immunological, hormonal, and metabolic abnormalities that particularly affect neurocognitive function and lead to weakness. The pathophysiology of fatigue is not well characterized and requires further investigation.

About research

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

The study consisted of 37 adults aged 65.0 years or younger who reported fatigue 6 to 26 weeks after mild SARS-CoV-2 infection and had no history of neurological disease.

For comparison, 52 gender- and age-matched individuals without fatigue (controls) were included, 6 of whom suffered mild COVID-19 and recovered without pCF.

Several noninvasive neurophysiological and behavioral tests assessing the autonomic nervous system (ANS), central nervous system (CNS), and peripheral nervous system (PNS) were performed, followed by K-mean clusters K and A gap analysis was done.

We performed transcranial magnetic stimulation (TMS) to assess primary motor cortical function and stimulated sensory nerves to assess dysfunction of sensory circuit feedback to the CNS.

In addition, muscles were electrically stimulated to assess peripheral and central fatigue levels, and heart rate (HR) and galvanic skin responses were recorded to assess ANS function.

In addition, high-density surface electromyography was performed to assess muscle motor unit activity, from which indices of neuroregulatory systems were derived.

In addition, participants completed an online Fatigue Impact Scale (FIS) questionnaire and machine learning-based classifiers were used to classify individuals as pCF patients and controls using multivariate data.

result

Of study participants, 73% (n=27) and 71% (n=37) of pCF and control individuals were female. Compared with sex- and age-matched controls, long-term COVID patients experiencing fatigue showed hypoactivity of specific cortical circuits, dysregulation of autonomic function, and altered skeletal muscle myopathy . However, abnormal sensory function and descending neuromodulatory drives are unlikely to contribute to pCF.

Additionally, no subgroups were found. This indicates that long-term fatigue in COVID is a distinct entity with individual-level variability, rather than a combination of different syndromes.

Patients with pCF had an average FIS score of 83, indicating that fatigue has a moderate impact on their daily activities. The time from diagnosis of COVID-19 to laboratory testing for SARS-CoV-2 was 121 days. No correlation was observed between the severity of fatigue and the number of days since SARS-CoV-2 infection.

Based on previously published relative incidence of SARS-CoV-2 related variants (VOCs) in the United Kingdom (UK), the team found that 83.0% of the pCF group were infected with SARS-CoV-2 alpha VOC. We assumed that

TMS findings showed that intracortical facilitation (ICF), a measure of intracortical glutamatergic function, was significantly lower in patients with pCF than in controls (conditioned motor evoked potentials vs. unconditioned motor evoked potentials). potential 171% vs 258%), indicating decreased cortical excitability.

Patients with pCF showed increased peripheral fatigue levels and increased visual reaction time. Maximal twitches evoked by direct electrical stimulation of the muscle following sustained muscle contraction were 49% and 67% in pCF and controls, respectively.

Patients with pCF have been shown to undergo metabolic changes in muscle fibers after prolonged activity resulting in reduced force output. had normal grip strength without evidence of normal endogenous excitability of motor neurons.

Mean resting heart rate was significantly higher in pCF patients than in controls (75 vs. 68 beats/min, respectively).On the contrary, patients with post-COVID fatigue had significantly lower blood levels oxygen saturation (SaO2) values ​​were higher than controls (95% vs. 97%, respectively), probably due to persistent lung injury and/or vascular injury.

The findings show reduced vagal (compared to sympathetic) tone in pCF patients, indicating that at least a few individuals in the pCF group suffered from dysautonomia.

Furthermore, patients with pCF had lower HR variability, indicating increased sympathetic nervous system activity. Galvanic cutaneous response habituation to loud (surprising) sounds was also low among pCF subjects, further corroborating sympathetic overpowering.

Moreover, patients with pCF have elevated core body temperature, indicating the long-term effects of acute COVID-19 on immunological activation and lung function and/or the generalized sympathetic drive of pCF. The average accuracy of the ML classifier was 70.0%.

Conclusion

Overall, the study results highlighted the neurological aspects of pCF pathogenesis. The most frequently reported symptoms of pCF include fatigue following minimal cognitive or physical activity, depending on neural circuitry.

Post-COVID fatigue results from specific alterations in specific neural circuits rather than a general disorder. The findings may aid in more accurate pCF diagnosis based on signs rather than symptoms alone.

In addition, objective assessment can identify at-risk individuals who require more immediate management of mild COVID-19.

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