A new study by researchers from the University of Toronto-Canada, Sunnybrook Research Institute-Canada, Baycrest Academy for Research and Education-Canada and McMaster University-Canada have found that majority of non-hospitalized COVID-19 infected individuals have decreased cerebral blood flow that can contribute to various clinical manifestations and Long COVID issues.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.05.04.22274208v1
In this study, we investigated whether adults who previously self-isolated at home due to COVID-19 would exhibit alterations in CBF when compared against controls who experienced flu-like symptoms but tested negative for COVID-19. COVID-19 participants exhibited significantly decreased CBF in the thalamus, orbitofrontal cortex, and regions of the basal ganglia compared to controls.
We further examined the effect of fatigue within the COVID-19 group, which revealed between-subgroup CBF differences in occipital and parietal regions. These results provide support for long-term changes in brain physiology in adults across the post-COVID-19 timeframe.
Although COVID-19 is primarily a respiratory illness, the cerebrovasculature is also susceptible to damage as endothelial cells and pericytes are prone to viral invasion.14,29 The brain’s vasculature interfaces with the complex neurovascular unit, for instance, in the regulation of CBF.49
Furthermore, the location of potential brain involvement in relation to SARS-CoV-2 is likely to vary regionally, with some evidence to suggest that relative to the rest of the brain, ACE-2 receptor expression is highest in the thalamus, the paraventricular nuclei of the thalamus, and more generally in regions proximal to the ventricles.50
Notably, we found significantly decreased CBF in the anterior thalamus, which contains the paraventricular nuclei of the thalamus, a key region of the brain’s anxiety network.51 Moreover, decreased thalamic glucose metabolism, as measured by positron emission tomography (PET), has been observed at both acute and chronic stages of recovery from COVID-19.26,27,52
Decreased CBF was also detected in regions of the basal ganglia, including the caudate, nucleus accumbens, putamen, and pallidum. In particular, the caudate has been reported in a longitudinal PET study that observed decreased glucose metabolism in seven adults recovering from COVID-19, up to 6 months post-infection.27
Multivariate methods have also revealed that glucose metabolism within the caudate is a distinguishing feature between COVID-19 patients and controls.24 We also observed decreased CBF within the orbitofrontal cortex, a region widely reported as being associated with SARS-CoV-2 infection.12,21,53–56
Together with the thalamus and regions of the basal ganglia, the orbitofrontal cortex is a key region of the cortico-basal ganglia-thalamic loop, a circuit involved in complex behaviours including affect regulation and reward-based decision-making,57 as well as in relation to neurological and psychiatric disorders.58,59 Moreover, the orbitofrontal cortex also plays an important role in olfaction and is often referred to as the secondary olfactory cortex.60
The results of the current study align with previous PET studies that find decreased glucose metabolism within the orbitofrontal cortex, and more generally within the frontal lobe. In an early case report of one healthy 27-year-old with COVID-19 experiencing persistent anosmia, Karimi-Galougahi et al. reported decreased glucose metabolism in the left orbitofrontal cortex.55 Hosp et al. reported frontoparietal hypometabolism in 10 out of 15 adults with subacute COVID-19.24
Finally, Kas et al. reported a consistent pattern of orbitofrontal, dorsolateral, and mesiofrontal hypometabolism in seven adults with acute COVID-19-related encephalopathy, despite heterogenous symptomatology, and posited that COVID-19 is related to frontal lobe impairment.27 Notably, the results from the latter study persisted until 6 months following infection.
Altogether, the result of decreased CBF within the orbitofrontal cortex, along with the thalamus and regions of the basal ganglia, may reflect COVID-19-related disturbances to brain networks, olfactory function, and emotional/cognitive concerns. Future studies extending these potentially brain network-related results through investigations of functional and structural connectivity are warranted.
It is important to note that participants in the current study were recruited over the course of several pandemic waves in Ontario, each being associated with a different distribution of variants of concern (Figure 1). Thus, it is probable that COVID-19 participants were infected with different strains of SARS-CoV-2, likely spanning from the Alpha variant to the Delta variant. We further note that these participants were recruited prior to the emergence of the Omicron variant which, despite its high transmissibility, is believed to be less severe than previous strains.61,62
Our comparison of COVID-19 participants with and without fatigue resulted in between-subgroup CBF differences, primarily in occipital and parietal regions of the brain. There have been efforts to characterize COVID-19 based on symptoms, with the hope of predicting severity and likelihood of the post-COVID-19 condition.32,33
Others have observed fatigue-related differences in brain structure and function in those recovering from COVID-19,35 such as functional connectivity alterations in parietal regions.34 Interestingly, the post-COVID-19 condition shares many common features with chronic fatigue syndrome (i.e., myalgic encephalomyelitis), a disorder that can be triggered by viral infection,63 and that is characterized by decreased CBF, such as within the lingual gyrus.64,65
Therefore, these fatigue-related CBF differences amongst COVID-19 participants could help guide therapeutic efforts in treating fatigue as a symptom of the post-COVID-19 condition. We note that while brain-behaviour investigations in the context of COVID-19 are important in understanding symptoms, this fatigue-related analysis is a “scratch of the surface”. Higher-order multivariate analyses (e.g., principal component analysis) with larger sample sizes will be better poised to answer such questions.
These results need to be interpreted in the context of several limitations. First, although well-matched, the sample sizes of the two groups were modest and unequal; furthermore, a power analysis was not performed. To our knowledge, the current study benefits from the largest ASL dataset focusing on non-hospitalized adults in the post-COVID-19 timeframe.
Moreover, recruitment for the NeuroCOVID-19 study is on-going and will address these issues in future studies. Second, our recruitment may be confounded by selection bias. For example, the current study’s cohort was comprised of 66% female and 72% Caucasian participants. We further note that participants needed internet access to be screened for eligibility. Third, our control group exhibited flu-like symptoms of unknown origin.
The recruitment of this unique control group is a relatively novel aspect of this study, as these participants are a de-novo sample of adults that experienced non-specific flu-like symptoms during the pandemic. Fourth, ASL images were acquired at a spatial resolution comparable to the average thickness of the cortex, which may be susceptible to partial volume error.45 To address this, we included partial volume correction as an additional ASL processing step in a sensitivity analysis, which did not drastically change the results.
Fifth, our fatigue-related exploratory analysis relied on self-reported symptoms. Study staff ensured that on-going fatigue was understood as being impairing to activities of daily living. Finally, the data used in this study are cross-sectional and lack a pre-infection assessment.21 Further investigation into longitudinal changes of these participants will be performed as part of the NeuroCOVID-19 study. It may also be feasible to access pre-pandemic repository data from age- and sex-matched individuals.
In conclusion, we observed decreased CBF in those recovering from COVID-19 relative to controls. These decreases were present months after acute infection and were localized to regions that have previously been highlighted as related to SARS-CoV-2 infection. We also observed CBF differences in relation to fatigue within the COVID-19 group, suggesting that CBF may aid in parsing the heterogeneous symptoms associated with the post-COVID-19 condition. In all, these results suggest that the post-COVID-19 condition may be associated with long-term effects on brain physiology and function. Future studies that replicate and further characterize such effects are warranted.