The outbreak of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 rapidly escalated into a global pandemic. By November 2023, the World Health Organization (WHO) reported a staggering 771,820,937 confirmed cases of COVID-19 worldwide, with 6,978,175 recorded deaths (WHO Coronavirus (COVID-19) Dashboard).
Beyond the acute infection, studies have revealed the persistence of COVID-19 symptoms, lasting more than 12 weeks post-infection, a phenomenon characterized as post-COVID-19 syndrome or long-COVID-19 syndrome [1–3].
Long-term neurological and psychiatric complications of COVID-19 have garnered intense research attention. This includes a wide range of complications such as “brain fog,” fatigue, headache, sleep disorders, cognitive impairment, impaired sense of smell and taste, depression, anxiety, sleep disturbances, post-traumatic disorder, and obsessive–compulsive symptoms [4–14]. Of these complications, depression stands out as a major public health concern, significantly affecting the quality of life and potentially leading to disability .
Survivors of the acute phase of COVID-19 have shown an increased susceptibility to mental health disorders, including major depressive disorder (MDD) . However, distinguishing post-COVID depression (PCD) from traditional MDD remains a topic of ongoing research. Some studies have reported differences in symptomatology between PCD and MDD, suggesting a potential mixed form of depression in PCD . Nonetheless, a comparative analysis of biomarkers indicates common etiopathogenic and inflammatory factors between post-COVID depression and MDD .
The etiology of MDD is multifactorial, but post-COVID depressive symptoms are largely associated with inflammation triggered by the immune-inflammatory response to the viral infection [18,20]. Additionally, neuroinflammation has been observed in post-COVID syndrome, marked by the reactivation of microglia and astrocytes, cytokine release, and disruption of the extracellular environment, particularly affecting myelinating oligodendrocytes and oligodendrocyte precursors [21–25]. This suggests that neuroinflammation and subsequent demyelination may play a significant role in the development of post-COVID depression.
Several studies have examined brain demyelination in post-COVID patients, with findings indicating white matter damage in a substantial portion of hospitalized COVID-19 patients . Additionally, COVID-19 has been linked to the onset of demyelinating diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome [27–30].
The virus’s neurotoxic effects are attributed to its binding to angiotensin-converting enzyme-2 (ACE2) receptors, inducing cytokine storms that disrupt the blood-brain barrier and trigger autoimmune-mediated demyelination in the central nervous system [31–32]. Recent MRI studies have further shown widespread alterations in white matter microstructure and increased radial diffusivity indicative of demyelination and axonal damage following COVID-19 infection [33–39].
Considering the symptomatic similarities between MDD and PCD, it’s worth noting that MDD is often considered a disorder of white matter connectivity, linked to changes in brain myelination. Several neuroimaging studies have demonstrated impaired white matter integrity and demyelination in patients with MDD [41–47].
Despite the abundance of literature on brain demyelination in post-COVID-19 patients, no systematic study has yet assessed demyelination in patients clinically diagnosed with depression . Therefore, this study aims to employ the quantitative MRI technique known as macromolecular proton fraction (MPF) mapping to evaluate the extent of brain demyelination in individuals with clinically diagnosed post-COVID depression. The central hypothesis posits a direct correlation between depression in the post-COVID-19 period and a decrease in brain myelination.
MPF mapping has gained prominence among MRI methods due to its heightened specificity to myelin and fewer physiological confounders compared to other techniques reliant on diffusion, relaxation, and susceptibility [48–50]. Studies have demonstrated that MPF values correlate strongly with myelin content assessed through histology [51–55].
Furthermore, MPF measurements are independent of magnetic field strength and can be consistently obtained across a range of human and animal MRI platforms [56,57]. Importantly, MPF mapping can be conducted without modifying standard clinical MRI scanners’ original pulse sequences, making it a valuable tool for assessing demyelination in mental disorders [58–60].
In summary, this study endeavors to shed light on the potential role of demyelination in post-COVID depression by employing MPF mapping to quantify brain myelination in patients with clinically diagnosed post-COVID depression. The research seeks to provide valuable insights into the underlying mechanisms of this condition and contribute to our understanding of the long-term effects of COVID-19 on mental health.
In this study, we embarked on an exploration of brain demyelination as a potential causative factor for post-COVID depression. Our investigation revealed that patients recently diagnosed with clinical depression following COVID-19 infection exhibited extensive brain demyelination. These changes in myelination were statistically significant when compared to two distinct control groups: those without previous COVID-19 and those with long-term complications from COVID-19 but no diagnosed depression.
The patients in the post-COVID depression (PCD) group displayed pronounced demyelination primarily in the juxtacortical white matter, with the most significant effects observed in the occipital lobe, as well as in the frontal, parietal, and temporal lobes. Moreover, the PCD group exhibited demyelination of various white matter tracts, with the most prominent effects seen in the association pathways, including the inferior fronto-occipital fasciculus (IFOF), sagittal stratum, and left external capsule.
Demyelination was also observed in projection (posterior thalamic radiation) and commissural (left tapetum) white matter pathways. Additionally, gray matter (GM) demyelination was evident, affecting structures such as the hippocampus, putamen, left globus pallidus, and amygdala. It’s noteworthy that the noPCD group also exhibited significant demyelination compared to the control group, albeit with lesser magnitude and a smaller affected area compared to the PCD group.
The results of our multiple regression analysis revealed a crucial factor in predicting post-COVID depression, which was Factor 7. This factor exhibited the highest level of significance and was included in the regression equation for both the total sample (discriminating PCD from noPCD groups) and the equation predicting depression severity measured by Hamilton score in the PCD group.
Factor 7 was primarily characterized by two structures with the highest factor loadings: the IFOF and the uncinate fasciculus of both hemispheres. Furthermore, our analysis indicated that IFOF demyelination was the most robust predictor of clinical post-COVID depression.
The regression equation for the total sample did not include any other MPF-related variables except for Factor 7. However, in the regression equation for the PCD group, Factor 12 and Factor 15 were additionally incorporated. Factor 12 was associated with left lingual white matter, although this structure did not exhibit significant differences between groups according to ANOVA results.
Factor 15, on the other hand, displayed weak but significant correlations with myelination changes in several juxtacortical white matter regions, such as the superior and middle occipital, middle frontal, angular, inferior and superior temporal white matter. Most of these regions demonstrated a significant decrease in MPF in the PCD group compared to controls.
The number of symptoms experienced during the acute and post-COVID phases emerged as another important factor for group classification. In both the total sample and the noPCD group, the regression equations included the number of post-COVID symptoms as a significant predictor, with this variable being the sole predictor for the noPCD group. In contrast, the regression equation for the PCD group incorporated the number of symptoms experienced during the acute phase.
These findings align with existing literature suggesting that depression often involves disruptions in white matter connectivity [41–47], with the IFOF playing a prominent role [45–47]. The IFOF serves as a critical link between early visual processing and various frontal lobe regions, facilitating semantic language processing, goal-oriented behavior, and visual switching tasks. Additionally, it plays a role in connecting the cingulo-opercular and frontoparietal networks associated with executive function and goal-oriented behavior.
Previous studies on major depressive disorder (MDD) have identified demyelination in structures such as the IFOF, cingulum, corona radiata, inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus, posterior thalamic radiation, sagittal stratum, internal capsule, and frontal lobe, consistent with our findings. However, the number and specific structures showing demyelination have varied across studies, reflecting potential differences in the etiology of MDD and post-COVID depression.
MDD is typically considered a multifactorial condition, influenced by biological, genetic, environmental, and psychosocial factors . In contrast, our study suggests that COVID-19 is a central factor in the development of recent depressive episodes. Multiple regression analysis indicated that the number of symptoms during both the acute and post-COVID phases significantly predicted the presence and severity of clinical depression.
Patients in the PCD group reported higher rates of specific symptoms, such as ageusia, cough, headache, anosmia, ageusia, insomnia, fatigue, and attention deficit, compared to the noPCD group. Notably, factors such as age, gender, and COVID-19 severity did not emerge as significant predictors of post-COVID depression, despite their relevance in predicting post-COVID complications in previous studies.
In addition to white matter demyelination, our study identified decreased MPF in gray matter structures, including the hippocampus, left amygdala, putamen, and left globus pallidus. This finding is particularly noteworthy, as previous research primarily focused on white matter myelination. The application of MPF mapping allowed for reliable quantification of weak gray matter myelination, an advantage compared to other MRI methods.
While several studies have examined myelination in post-COVID patients, our results closely align with previous research concerning brain structures affected by the disease, including the IFOF, cingulum, corona radiata, internal capsule, posterior thalamic radiation, sagittal stratum, external capsule, and uncinate fasciculus. Variability in results among studies can be attributed to differences in COVID-19 complications among patients.
One study by Benedetti et al.  explored the associations between post-COVID depression manifestations, brain myelination, and functional connectivity. However, their study used self-rated depression assessments and did not include a control group, making comparisons with our results challenging.
In conclusion, our study provides valuable insights into the potential role of demyelination in post-COVID depression. The IFOF, in particular, appears to be a significant contributor to this condition. Our findings underscore the importance of considering the neurological aspects of post-COVID complications and their impact on mental health. Further research is necessary to confirm and expand upon these findings, ultimately improving our understanding of the complex interplay between COVID-19, brain myelination, and depression.
reference link : https://www.preprints.org/manuscript/202312.0698/v1