New research utilizing advanced brain imaging techniques reveals that SARS-CoV-2 infection may induce lasting changes in the brain, even in individuals who feel fully recovered. The study identified specific alterations in tissue microstructure and chemical levels that distinguish people with Long COVID from those who recovered without lingering symptoms, as well as from those never infected. These findings were published in the journal Brain, Behavior, & Immunity – Health.
The global spread of COVID-19 resulted in a significant number of people experiencing persistent health issues known as Long COVID. Common symptoms include severe fatigue, cognitive dysfunction often called brain fog, and sleep disturbances.
The research team at Griffith University’s National Centre for Neuroimmunology and Emerging Diseases had previously studied Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). They noted that Long COVID symptoms frequently overlap with those observed in ME/CFS. This observation prompted the team to investigate whether similar brain mechanisms might be at play.
Medical professionals have also noted that even individuals who recover from the acute phase of COVID-19 sometimes demonstrate subtle cognitive slowing. Previous imaging studies have attempted to map these changes but have produced inconsistent results.
Many prior studies did not directly compare three distinct groups: those with Long COVID, those who recovered fully, and those who never contracted the virus. The researchers aimed to fill this knowledge gap by employing a multimodal magnetic resonance imaging (MRI) approach. This allowed them to simultaneously assess myelin content, tissue integrity, and neurochemical levels.
“When the COVID-19 pandemic emerged, many people began experiencing symptoms similar to those seen in ME/CFS. This observation motivated us to investigate long COVID and determine whether it involves brain changes similar to those found in ME/CFS,” said study author Kiran Thapaliya, a research fellow at the National Centre for Neuroimmunology and Emerging Diseases.
“Even after full recovery from COVID-19, some individuals continued to report persistent symptoms such as brain fog. This further inspired us to compare brain alterations across three groups: people with long COVID, individuals who have fully recovered from COVID-19, and those who have never had COVID-19.”
The study included 47 participants from the Gold Coast area in Queensland, Australia. The sample included 19 individuals diagnosed with Long COVID according to World Health Organization guidelines. It also included 12 individuals who had recovered from COVID-19 and reported no lasting symptoms. A third group consisted of 16 healthy controls with no history of SARS-CoV-2 infection. All participants were between the ages of 18 and 65.
The researchers excluded individuals with other significant medical conditions to ensure the results were specific to COVID-19. Participants completed detailed questionnaires regarding their symptoms. These assessments measured pain levels, physical function, fatigue severity, and cognitive impairment. The Long COVID group reported significantly higher levels of pain and fatigue compared to the other groups. They also recorded lower scores for physical and cognitive function.
The participants underwent scanning using a 3 Tesla MRI scanner. The researchers acquired three specific types of data during the scans. First, they used T1-weighted and T2-weighted images to create ratio maps. This technique provides an estimate of myelin content in the brain. Myelin is the protective sheath around nerve fibers that facilitates rapid communication between neurons.
Second, the team utilized diffusion-weighted imaging. This method tracks the movement of water molecules within brain tissue. It helps reveal the microscopic architecture of the brain and the integrity of white matter tracts. Finally, they employed magnetic resonance spectroscopy. This technique acts like a virtual biopsy, allowing scientists to measure the levels of specific chemicals in a targeted brain region. The researchers focused this chemical analysis on the posterior cingulate cortex, a hub involved in memory and emotion.
The study revealed widespread differences in the T1w/T2w ratio maps, which serve as a proxy for myelin signal intensity. When comparing Long COVID patients to healthy controls, the researchers found higher signal intensity in the precentral gyrus and the middle temporal gyrus. The precentral gyrus is essential for motor control, while the middle temporal gyrus plays a key role in memory. This increase suggests potential remyelination or inflammatory processes occurring in these regions.
Comparison between the recovered group and the Long COVID group showed even more distinct differences. The recovered individuals displayed significantly higher signal intensities in the brainstem and cerebellum compared to the Long COVID patients. The brainstem controls vital functions such as the sleep-wake cycle and pain processing. The cerebellum coordinates voluntary movement and balance. Lower signal intensity in these areas for Long COVID patients may relate to their persistent fatigue and physical limitations.
The researchers also identified changes in individuals who had reportedly recovered fully. Compared to the never-infected controls, the recovered group showed higher signal intensity in the precentral gyrus and posterior cingulate cortex. This indicates that the virus may leave a footprint on the brain even in the absence of overt symptoms. It suggests that the brain might undergo compensatory changes after infection.
Diffusion-weighted imaging provided additional evidence of structural alteration. Long COVID patients exhibited lower mean diffusivity in the dentate regions of the cerebellum compared to healthy controls. This metric relates to the density and organization of tissue. Lower diffusivity can indicate a restriction of water movement, potentially due to swelling or tissue remodeling. The recovered group also showed lower diffusivity in the caudate nucleus compared to healthy controls. The caudate nucleus is a structure involved in motor processes and learning.
The chemical analysis via magnetic resonance spectroscopy highlighted significant metabolic imbalances. The researchers observed these differences primarily between the Long COVID group and the recovered group. Long COVID patients exhibited significantly lower levels of glutamine. Glutamine is an amino acid that supports the immune system and energy production. Its depletion suggests the body may be exhausting its reserves to fight ongoing inflammation or immune dysregulation.
On the other hand, Long COVID patients showed higher levels of N-acetyl-aspartate (NAA) compared to the recovered group. NAA is a marker of neuronal health and metabolism. Typically, lower levels indicate damage. However, the researchers propose that elevated NAA in this context might represent a compensatory response. The brain may be working harder to maintain function in the face of metabolic stress. It could also result from osmotic stress related to the symptoms of the condition.
The researchers analyzed how these biological markers related to the participants’ symptoms. In the Long COVID group, they found a significant correlation between myelin signal intensity and physical function. Lower signal intensity in the middle temporal gyrus was associated with worse physical function. This aligns with the idea that reduced myelin compromises the efficiency of brain-body communication.
A similar pattern emerged regarding cognition. There was a negative correlation between signal intensity in the midbrain and cognitive scores. This suggests that alterations in the brainstem region are linked to the severity of cognitive impairment. These associations provide a biological basis for the subjective symptoms reported by patients.
“This study clearly shows that even individuals who do not experience any symptoms after recovering from COVID-19 may still have long-term effects of the virus on the brain,” Thapaliya told PsyPost.
But the study, like all research, includes some caveats. The design was cross-sectional, meaning it captured a snapshot in time rather than tracking changes over a long period. It is impossible to determine from this data alone whether the observed brain changes are permanent or if they evolve over time. The sample size was relatively small, with fewer than 50 total participants. Small sample sizes can sometimes lead to results that are not replicable in larger populations.
The researchers also noted that the statistical methods used to identify brain clusters involve thresholds that can introduce errors. They attempted to correct for this using standard statistical adjustments. Additionally, the study is exploratory in nature. It aimed to generate hypotheses for future investigation rather than provide definitive clinical diagnostic tools.
Future research is needed to validate these findings in larger, more diverse cohorts. Longitudinal studies would be particularly beneficial. Such studies could track individuals from the point of infection through recovery or the development of Long COVID. This would allow scientists to see if the brain alterations resolve as symptoms improve. It would also help clarify the timeline of remyelination and metabolic changes.
The study, “Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study,” was authored by Kiran Thapaliya, Sonya Marshall-Gradisnik, Maira Inderyas, and Leighton Barnden.
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