Associations between structural brain alterations and post-COVID fatigue

In a recent study published in eClinicalMedicine, researchers examined the structural brain changes in patients with post-COVID fatigue.

Study: Structural brain changes in patients with post-COVID fatigue: a prospective observational study. Image Credit: Fabio Principe/Shutterstock
Study: Structural brain changes in patients with post-COVID fatigue: a prospective observational study. Image Credit: Fabio Principe/Shutterstock


Post-COVID syndrome (PCS) is defined as symptoms that last for at least three months following acute coronavirus disease 2019 (COVID-19). Fatigue and cognitive impairment are among the main neurologic symptoms of PCS patients. In PCS, fatiguability, assessed by hand grip strength, correlates with biomarkers of hypoperfusion and inflammation.

Recently, a meta-analysis revealed that approximately 30% of patients develop post-COVID fatigue. Moreover, the study’s authors previously reported that fatigue was twice more common after COVID-19 than in matched non-COVID-19 controls. In addition, subcortical white matter lesions were identified four months after discharge for PCS patients.

Of note, even non-hospitalized patients had a greater longitudinal reduction in grey matter thickness than healthy controls. Prior research has identified associations between structural changes in the brain and fatigue severity in neuro-immunologic disorders. However, whether such lesions exist or structural brain alterations underlie the neurologic symptoms in PCS patients remains elusive.

About the study

In the present study, researchers evaluated the clinical characteristics of PCS patients and explored the structural brain alterations in PCS patients with fatigue. They recruited 50 patients from a post-COVID outpatient clinic in Germany from April 15 to November 30, 2021. Eligible participants had a confirmed history of COVID-19, with neurologic symptoms lingering for at least three months and without any neurologic disorder pre-COVID-19.

A cohort of healthy controls without neurologic/psychiatric disorders and COVID-19 was included. Further, the researchers retrospectively included multiple sclerosis (MS) patients with fatigue as a clinical control cohort. Eligible MS patients had relapsing-remitting MS and moderate-to-severe fatigue. MS patients were age- and sex-matched to PCS patients and healthy controls.

Magnetic resonance imaging (MRI) scans were performed. High-resolution structural T1-weighted and diffusion scans were obtained for PCS patients and healthy controls. For MS patients, diffusion scan, three-dimensional fluid-attenuated inversion recovery (3D-FLAIR), and three-dimensional magnetization-prepared rapid acquisition with gradient echo (3D-MPRAGE) were acquired.

Fatigue assessments were physical and cognitive sub-scales of the fatigue scale for motor and cognitive function, symptom questionnaire for chronic fatigue syndrome/myalgic encephalomyelitis, and the Bell score for fatigue-related functional impairment. The researchers also investigated sleep problems, daytime sleepiness, anxiety, and depression. Multiple linear regression was performed to identify factors associated with post-COVID fatigue.


Most patients were females; prior medical history included allergies/atopic dermatitis, asthma, hypothyroidism, breast cancer, hypertension, and coagulation disorder. Three patients had anxiety, depression, and eating disorder episodes. Reported complaints were exhaustion, stress, forgetfulness, tiredness, difficulty concentrating or finding words, headache, and poor resilience.

Systemic inflammatory or respiratory symptoms were less frequently reported. Higher levels of depression, anxiety, daytime sleepiness, and sleep problems were observed in patients with post-COVID fatigue than in healthy controls. Subjects with post-COVID fatigue had slower response times in attention tests while maintaining adequate accuracy.

Significant inward deformation of the left thalamus was observed in patients. Lower thalamic volumes were associated with poorer short-term memory performance. There was an association between aberrant thalamic diffusion parameters and physical fatigue. Reduced volumes in the left putamen were observed in those with post-COVID fatigue, accompanied by surface deformations, especially on the lateral surface of the left putamen.

Besides the structural changes in the thalamus and basal ganglia, there were no additional imaging aberrations in the caudate or accumbens nucleus in patients with moderate/severe fatigue. Moreover, there were no differences in axial, radial, or mean diffusivity and fractional anisotropy between patients with post-COVID fatigue and healthy controls.

Regression analysis revealed significant associations of sleep quality and depressiveness with post-COVID fatigue. The severity of fatigue was not associated with acute COVID-19 variables, but it correlated with the levels of daytime sleepiness and depressiveness. Long-term physical fatigue was associated with higher neurologic disability. 

The researchers observed significantly reduced volumes of bilateral thalamus, accumbens, and putamen in MS patients with fatigue. Microstructural changes were more pronounced in them, mainly affecting the basal ganglia and thalamus. Fatigue scores were associated with disability. Structural changes in the thalamus and putamen were associated with the lesion load, not fatigue.  


To summarize, the study identified associations between post-COVID fatigue and distinct structural changes in the subcortical regions of the brain, detectable by MRI. Aberrant diffusion markers and decreased volumes of the basal ganglia and thalamus correlated with fatigue severity, short-term memory problems, daytime sleepiness, and impairments in daily activities. Future work should determine if these fatigue symptoms are persistent or temporary.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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