Association of structural brain changes with cognitive deficits and fatigue in patients with post COVID-19 condition, 2026

[Arfmeister]

Association of structural brain changes with cognitive deficits and fatigue in patients with post COVID-19 condition

Abstract
Cognitive impairment and fatigue are frequent symptoms in patients with post COVID-19 condition (PCC). However, cognitive issues are often only self-reported and not compared to well-matched control groups. Furthermore, structural brain changes, underlying cognitive impairment, and fatigue in post COVID-19 condition are still not fully understood. To assess cognitive deficits, fatigue, neuropsychiatric symptoms and quality of life in patients with post COVID-19 condition, determine changes in brain volumes, cortical thickness and regional shape complexity and assess correlations of imaging measures with clinical symptoms, 49 patients with post COVID-19 condition (80% female) with a confirmed SARS-CoV-2-infection at least 3 months prior to testing and new onset of cognitive complaints and 48 healthy controls matched for sex, age and education level underwent comprehensive neuropsychological testing, MRI-based volumetric analyses and fractal dimensionality analysis to evaluate structural brain complexity. Neuropsychiatric symptoms and quality of life were assessed using questionnaires. Patients with post COVID-19 condition exhibited significant deficits of attention, executive functions, phonemic and semantic fluency, verbal learning and episodic and visuospatial memory (all p(corrected)=.002 - <.001).

Cognitive impairments were not linked to the severity of the initial COVID-19 infection, but attention performance significantly impacted daily functioning. Patients had significantly lower quality of life and higher levels of anxiety, depressive symptoms and fatigue compared to controls (all p(corrected)<.001) and were severely impacted in their working ability with 45% being unable to work. Thalamic volumes were significantly reduced in patients with post COVID-19 condition (p(corrected)=.001 - <.001). Fractal dimensionality analyses showed increased complexity in the occipital lobes and hippocampal fimbriae, and reduced complexity in the thalamus bilaterally in patients. Thalamic complexity reductions correlated with increased fatigue severity in patients and controls.

Patients with post COVID-19 condition display a wide spectrum of cognitive deficits, increased levels of fatigue, anxiety and depressive symptoms and reduced quality of life. MRI analyses revealed reduced thalamic volumes and reduced thalamic complexity that was associated with fatigue severity across the whole sample. These findings identify brain structural correlates of key symptoms in post COVID-19 condition and highlight the value of fractal dimensionality analysis to detect clinically relevant structural brain alterations that remain undetected in conventional analyses.

https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcag099/8527078?login=false

Graphical Abstract

 

[SNT Gatchaman]

Adding to Arfmeister's bolding, here are a few more quotes.

In the prospective observational CAMINO (“Cognition and MRI in post-COVID”) study, 49 post-COVID19 patients were recruited between April 2021 and November 2021 from two neurological postCOVID-19 outpatient centers at Charité […] The study was exploratory and hypothesis-generating in design

Healthy control participants […] (n = 48). […] Patients were matched 1:1 to healthy controls based on age, sex, and years of education using exact matching. The median age was 44.0 years (IQR 17) for patients and 42.5 years (IQR 21) for controls; 80% of patients (39/49) and 81% of controls (39/48) were female

Besides these classical neuroimaging measures [Volumes of cortical and subcortical regions, as well as cortical thickness and surface area], we applied a new method to estimate the structural complexity of brain regions. […] yields region-wise estimates of fractal dimensionality (FD) - a geometric measure of spatial scaling that expresses the irregularity of an object’s shape.

 

[SNT Gatchaman]

Patients reported significantly lower quality of life. General health-related quality of life and emotional wellbeing were significantly associated with fatigue, depressive symptoms, and anxiety (general health x FSMC: τ=-0.292, pFDR=0.009; general health x BDI: τ=-0.272, pFDR=0.015; emotional wellbeing x FSMC: τ=-0.323, pFDR=0.004; emotional wellbeing x BAI: τ=-0.469, pFDR<0.001, emotional wellbeing x BDI: τ=-0.644, pFDR<0.001).

Cognitive performance, even though significantly impaired, did not correlate with quality of life (absolute range τ=0.004 to 0.166, all p>0.05).

Patients had lower thalamic volumes compared to control participants (left: patients, 7621.9 (±1130.0) mm³ vs. controls, 8293.9 (±836.5) mm³, b=-672.0 mm³, 95% CI [-1068.1, -275.9], pFDR=0.001; right: patients, 7363.2 (±935.3) mm³ vs. controls, 8016.7 (±769.6), b=-653.5 mm³, 95% CI [-994.5, -312.4], pFDR<0.001).

There was no significant difference in volume in other subcortical regions). Volumetry of hippocampal subfields did not indicate significant differences between patients and controls. Furthermore, there were no significant group differences in cortical thickness, cortical area size or cortical volume between patients and the control participants after Benjamini-Hochberg correction for multiple testing.

There were no significant correlations between patients’ thalamic volume and cognitive test performances. In an exploratory analysis of ROIs with significant group differences, we found that patients’ lower left thalamic volumes correlated with more pronounced daytime sleepiness (ρ=-0.32, p=0.040).

Patients with PCC showed bidirectional changes in structural brain complexity compared to the healthy control participants. The strongest decreases in complexity were observed in the thalamus, both on the left (t = -3.4, p = 0.001) and on the right (t = -3.6, p = 5*10-4 ). […] Additionally, lower structural complexity of the thalamus was related to higher fatigue scores on the FSMC, both on the left (ρ = -0.39, p = 2.3*10-4 , pFDR = 0.023) and on the right (ρ = -0.42, p = 7.5*10-5, pFDR= 0.016).

 

[SNT Gatchaman]

Our MRI analyses identified relevant structural brain changes in patients with PCC. Patients had reduced thalamic volumes in both hemispheres compared to well-matched control participants. There was a significant correlation between patients’ lower left thalamic volumes and increased daytime sleepiness. […] However, our results are to be interpreted with caution as the observed effect size was relatively small and exploratory analyses were not corrected for multiple testing.

In contrast to earlier studies that reported cortical changes in the olfactory cortex and limbic system [18-20,24,70], we found no significant differences in cortical thickness.

this is the first study applying fractal dimensionality analyses in a cohort of post-COVID-19 patients. We observed reduced structural complexity in the left and right thalamus, with lower complexity correlating with higher fatigue scores across patients and control participants.

Moreover, structural complexity analysis detected additional alterations of brain morphology (e.g., occipital lobes, hippocampal subfields) that remained undetected in standard volumetry, supporting the potential of fractal analysis as a useful tool to capture structural brain changes in neurological disorders.

In conclusion, subjective cognitive complaints of patients with PCC reflected deficits across almost all cognitive domains in standardized tests. […] Imaging analyses identified reduced volumes and reduced complexity of the thalamus correlating with higher levels of fatigue and implicating the thalamus as key brain region involved in fatigue pathophysiology.

 

[forestglip]

Thalamic volumes were significantly reduced in patients with post COVID-19 condition (p(corrected)=.001 - <.001).

See also:

Cross-disorder comparison of brain structures among 4836 individuals with mental disorders and controls utilizing danish population-based clinical MRI scans (2026, Molecular Psychiatry)

Individuals ≥18 years of age with mental disorders were included as cases using the following ICD-10 codes: any Mental Disorders (F00-F99), and specifically Dementia (F00-F03 and G30), Substance Use Disorder (F10-19), Schizophrenia Spectrum Disorder (F20-29), Depression (F32-F33), and Anxiety Disorder (F40-F48).

Mental disorder patients showed smaller volumes in the thalamus (d = −0.298), amygdala (d = −0.250), and hippocampus (d = −0.145), larger lateral ventricular volume (d = 0.272), and a general pattern of thinner cortex (d = −0.180), particularly in the insula (d = −0.177).

 

[Arfmeister]

Important to note: patients did not (necessarily) meet strict ME CFS criteria.
- self-reported cognitive impairment ≈ Brain fog

Inclusion criteria for patients with PCC were: (1) positive PCR test for SARS-CoV-2, at least 3 months prior to inclusion, (2) no pre-existing neurological or psychiatric disorders before SARS-CoV-2 infection, and (3) self-reported cognitive impairment with onset during or shortly after COVID-19.

 

[Kitty]

Important to note: patients did not (necessarily) meet strict ME CFS criteria.
- self-reported cognitive impairment ≈ Brain fog

To be fair, though, cognitive impairment is self reported even in tightly defined ME/CFS cohorts.