Scientists observe altered brain metabolism and connectivity in COVID-19 patients

A new study published in the journal Neuroscience finds that individuals recovering from COVID-19 exhibit signs of a potential brain repair and recovery process. The research reveals that survivors have higher levels of specific brain chemicals associated with neuron health and plasticity, which are in turn linked to better brain structure and fewer cognitive complaints.

The persistence of neurological and psychiatric symptoms after a COVID-19 infection, often called long COVID, has become a significant public health concern. Many individuals report experiencing issues like brain fog, fatigue, and memory problems for months or even years. To understand the biological basis for these symptoms, scientists have been examining how the virus affects the brain. Previous imaging studies have identified changes in the brain’s white matter, the network of nerve fibers that connects different brain regions, but the underlying chemical and functional changes have been less clear.

A team of researchers led by Beatrice Bravi sought to explore the relationship between brain chemistry, brain structure, and cognitive function in people who had recovered from COVID-19. They were particularly interested in two brain chemicals, or metabolites: glutamate and N-acetyl-aspartate. Glutamate is the brain’s primary excitatory messenger, playing a key role in learning, memory, and brain plasticity. N-acetyl-aspartate is widely considered a marker of the health and integrity of nerve cells and is also involved in the production of myelin, the protective sheath that insulates nerve fibers. The researchers theorized that these metabolites might be linked to both the brain alterations and the cognitive symptoms reported by survivors.

The investigation involved 64 participants who had recovered from a COVID-19 infection and a comparison group of 33 healthy individuals. The COVID-19 survivors were recruited from a long-term study at the San Raffaele Hospital in Milan, Italy. Researchers conducted clinical interviews with the survivors to determine if they were experiencing subjective cognitive complaints, such as new difficulties with forgetfulness in daily life or problems with concentration. Based on their answers, participants were categorized as either having cognitive complaints or not.

All participants underwent a series of brain scans using a powerful 3.0 Tesla magnetic resonance imaging machine. The researchers used several specialized imaging techniques. One technique, magnetic resonance spectroscopy, allowed them to measure the concentration of glutamate and N-acetyl-aspartate in a specific brain region encompassing parts of the prefrontal and anterior cingulate cortex, areas involved in higher-order thinking and emotional regulation.

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Another technique, known as diffusion tensor imaging, was used to examine the microstructure of the brain’s white matter. This method tracks the movement of water molecules through brain tissue. In well-organized, healthy white matter, water tends to flow in a single direction along the nerve fibers. Measures like fractional anisotropy reflect this directionality, while measures like radial and mean diffusivity reflect the degree of water movement in other directions. Finally, the researchers used resting-state functional magnetic resonance imaging to assess how different brain regions coordinate their activity when a person is not engaged in a specific task, providing a map of the brain’s functional networks.

The first major finding was a significant difference in brain chemistry between the groups. The COVID-19 survivors had notably higher levels of both glutamate and N-acetyl-aspartate in the scanned brain region compared to the healthy control group. This result was consistent even when the analysis was restricted to a smaller subgroup of participants who were matched for age and sex, strengthening the reliability of the finding.

Next, the researchers examined how these brain chemicals related to the participants’ experiences. They found that among the COVID-19 survivors, higher levels of glutamate and N-acetyl-aspartate were associated with a lower likelihood of reporting cognitive complaints. In addition, the level of N-acetyl-aspartate was positively associated with the amount of time that had passed since the initial infection. This suggests a progressive process, where this marker of neuronal health may increase over time during recovery.

The analysis of white matter structure yielded further interesting results. The COVID-19 survivors, as a group, showed signs of more organized white matter compared to the healthy controls. They exhibited higher fractional anisotropy and lower radial and mean diffusivity. These patterns can indicate more compact and well-insulated nerve fibers, possibly as a result of remyelination, the process of repairing the protective myelin sheath.

Connecting these observations, the researchers found a direct link between brain chemistry and white matter structure specifically in the COVID-19 survivor group. Higher concentrations of both glutamate and N-acetyl-aspartate were associated with healthier white matter metrics, including higher fractional anisotropy and lower diffusivity. This association was absent in the healthy control group, suggesting that this relationship is a unique feature of the post-infection brain environment.

The study also uncovered a more complex interaction. The positive relationship between higher glutamate levels and a lower probability of cognitive deficits was most pronounced in individuals who also had highly organized white matter, as measured by high fractional anisotropy. This finding suggests that the brain’s structural integrity may moderate the beneficial effects of its chemical environment. In other words, the neuroprotective processes associated with glutamate may be most effective when the underlying “wiring” of the brain is also in good condition.

The functional connectivity analysis provided additional insights. In the COVID-19 survivors, higher levels of N-acetyl-aspartate were associated with stronger synchronized activity, or functional connectivity, between the scanned brain region and the posterior cingulate gyrus. The posterior cingulate is a central hub in the brain involved in regulating attention and internal thought. The researchers propose that this enhanced connectivity could be another manifestation of a restorative process, facilitated by improved neuronal health.

The study does have some limitations. The number of participants was relatively modest, and the cross-sectional design of the study means it captured only a single moment in time. This makes it impossible to determine cause and effect; for example, whether the chemical changes lead to structural repair or vice versa. The assessment of cognitive problems was also based on self-report rather than objective neuropsychological testing. Future research could address these points by following a larger group of individuals over time and incorporating standardized cognitive tests.

Despite these limitations, the study offers a new perspective on the neurological consequences of COVID-19. Instead of solely documenting damage, the findings suggest the brain may engage in active repair and neuroplasticity following the infection. The elevated levels of key metabolites, combined with signs of enhanced white matter integrity and functional connectivity, point to a potential compensatory or recovery mechanism that may help protect against cognitive symptoms. This research paves the way for future studies to further investigate these repair processes and explore potential interventions to support brain recovery in individuals with long COVID.

The study, “Long term effect of COVID-19 on brain metabolism and connectivity,” was was authored by Beatrice Bravi, Marco Paolini, Federica Colombo, Mariagrazia Palladini, Valentina Bettonagli, Mario Gennaro Mazza, Rebecca De Lorenzo, Patrizia Rovere-Querini, Francesco Benedetti, and Sara Poletti.