Structural brain changes in patients with persistent headache after COVID-19 resolution

Abstract

Headache is among the most frequently reported symptoms after resolution of COVID-19. We assessed structural brain changes using T1- and diffusion-weighted MRI processed data from 167 subjects: 40 patients who recovered from COVID-19 but suffered from persistent headache without prior history of headache (COV), 41 healthy controls, 43 patients with episodic migraine and 43 patients with chronic migraine. To evaluate gray matter and white matter changes, morphometry parameters and diffusion tensor imaging-based measures were employed, respectively. COV patients showed significant lower cortical gray matter volume and cortical thickness than healthy subjects (p < 0.05, false discovery rate corrected) in the inferior frontal and the fusiform cortex. Lower fractional anisotropy and higher radial diffusivity (p < 0.05, family-wise error corrected) were observed in COV patients compared to controls, mainly in the corpus callosum and left hemisphere. COV patients showed higher cortical volume and thickness than migraine patients in the cingulate and frontal gyri, paracentral lobule and superior temporal sulcus, lower volume in subcortical regions and lower curvature in the precuneus and cuneus. Lower diffusion metric values in COV patients compared to migraine were identified prominently in the right hemisphere. COV patients present diverse changes in the white matter and gray matter structure. White matter changes seem to be associated with impairment of fiber bundles. Besides, the gray matter changes and other white matter modifications such as axonal integrity loss seemed subtle and less pronounced than those detected in migraine, showing that persistent headache after COVID-19 resolution could be an intermediate state between normality and migraine.

Multivariate prediction of long COVID headache in adolescents using gray matter structural MRI features

“…It can be interpreted as the gray matter decrease in the orbitofrontal and medial temporal lobes will make SVM classifier move toward (or classifies) CH. Interestingly, the regions with negative weights resembled the results from previous mass-univariate results, that is, involving the orbitofrontal and medial temporal lobes ( Díez-Cirarda et al, 2022 ; Planchuelo-Gómez et al, 2022 ). For example, Planchuelo-Gómez et al (2022) reported decreases in gray matter in anterior areas, including the pars orbitalis, the fusiform gyrus and the frontal pole, in patients with persistent headache after COVID-19 resolution.…”

“…For example, one of the pioneering study using the UK biobank observed gray matter reduction in patients with COVID-19, specifically in orbitofrontal cortex and parahippocampal gyrus ( Douaud et al, 2022 ). These findings are reported not only in comparison to healthy controls but also against migraineurs ( Planchuelo-Gómez et al, 2022 ).…”

“…To date, long COVID headache does not have a specific clinical presentation, therefore the diagnosis is mainly a diagnosis of exclusion ( Tana et al, 2022 ). We used the inclusion criteria for the long COVID headache (CH) patients adapted from previous studies ( Planchuelo-Gómez et al, 2022 ; Tana et al, 2022 ), as follows: (1) microbiologically confirmed COVID-19 diagnosis based on a real-time reverse transcriptase-polymerase-chain-reaction (RT–PCR) assay using respiratory tract samples or by the presence of anti-SARS-CoV-2 IgM + IgA antibodies, following World Health Organization protocols; (2) new-onset headache presenting during the acute phase of COVID-19, fulfilling criteria for acute headache attributed to systemic viral infection according to International Classification of Headache Disorders, 3rd edition (ICHD-3) ( Arnold, 2018 ); and (3) persistence of headache for at least 3 months after the acute phase of COVID-19. Because we assumed that sufficient long-term deterioration from long COVID is needed to cause a brain morphological change ( Rezaeyan et al, 2022 ), persistence for a 3-month period was selected as a criterion ( National Institute for Health and Care Excellence [NICE], 2020 ).…”

“…The 2020–2022 period was marked by a severe pandemic due to a novel coronavirus, namely, COVID-19. In addition to respiratory symptoms, headache is one of the most frequent features accompanying COVID-19 and is described by approximately a quarter of patients ( Planchuelo-Gómez et al, 2022 ). Moreover, some people who recover from acute COVID-19 still exhibit a spectrum of symptoms persisting for weeks and even months, so-called long COVID ( Tana et al, 2022 ).…”

“…Overall, knowledge of long COVID headache is limited; however, interestingly, specific patterns of neuroimaging findings using a mass-univariate approach are continuously being reported in COVID patients. These changes include structural and functional brain changes as well as connectivity alterations ( Douaud et al, 2022 ; Planchuelo-Gómez et al, 2022 ; Voruz et al, 2022 ). For example, one of the pioneering study using the UK biobank observed gray matter reduction in patients with COVID-19, specifically in orbitofrontal cortex and parahippocampal gyrus ( Douaud et al, 2022 ).…”