Exploring the Structural Network Involved in Brain-Immune Interactions through Neuroimaging in long-COVID

Background: About 5% of survivors of acute Corona Virus Disease-19 (COVID-19) experience long-lasting symptoms known as Post-Acute Sequelae of Covid 19 Syndrome (PASC), or long-COVID. Symptoms contributing to long-COVID are heterogenous and include fatigue, post-exertional malaise, ‘brain fog’, cognitive impairment, memory loss, disordered sleep, anosmia, shortness of breath, and many other symptoms (Thaweethai et al., 2023)(Davis et al., 2023) suggesting that the presence of several subtypes of long-COVID.

The neuropsychiatric subtype of PASC is mainly characterized by deficits in executive function (cognition), ongoing fatigue (autonomic system symptoms), and the presence of proinflammatory markers in the blood (Pallanti et al., 2023). It is not known yet how the peripheral proinflammatory markers and the nervous system interact.

Recent theories propose that the brainstem serves as a key site where the immune system interacts with the central nervous system, impacting autonomic processes, limbic behaviors, and cognitive function. This occurs through brain white matter tracts linking the brainstem with cognitive regions in the forebrain. Disruptions in these connecting tracts may occur in neuroimmune disorders such as acute COVID and long-COVID. Key components of this neuroimmune circuitry include brainstem nuclei such as the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMNV), along with their white matter connections with forebrain areas. However, the nuclei in the brainstem are small and difficult to accurately segment on MRI images, posing a challenge to delineating the white matter tracts of the brain neuroimmune circuit.

Methods: To tackle this challenge, we acquired brain images using diffusion MRI (dMRI) and structural MRI (sMRI) from seven patients with the neuropsychiatric subtype of long-COVID. We created an innovative morphometric segmentation method for the brainstem’s medulla. This approach uses sMRI brain imaging where we divided the rostral medulla into distinct subregions. Inter-rater reliability assessments were conducted for these subregions, yielding high values ranging from 0.97 to 0.99, demonstrating the protocol’s strong reliability. Subsequently, the subdivision of the medulla containing the nucleus of the solitary tract and the dorsal motor nucleus of the vagus was employed as a region of interest (ROI) for diffusion tractography from dMRI data in the long-COVID patient (Kikinis et al., 2024).

Results: The fiber tracts delineated from the dMRI and sMRI data using the protocol above aligned with the medial forebrain bundle (MFB) and the dorsal longitudinal fascicle of Schutz (DLF). These pathways are significant components of the neuroimmune circuitry that connects brainstem and forebrain regions.

Conclusion: This method marks the initial phase in advancing our comprehension and assessment of the brain’s role in neuroimmune interactions. This is particularly important in conditions such as long-COVID, and also in other fatigue syndromesmyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

References:

Davis, H. E., McCorkell, L., Vogel, J. M., & Topol, E. J. (2023). Long COVID: Major findings, mechanisms and recommendations. Nature Reviews Microbiology. https://doi.org/10.1038/s41579-022-00846-2
Kikinis, Z., Castañeyra-Perdomo, A., González-Mora, J. L., Rushmore, R. J., Toppa, P. H., Haggerty, K., Papadimitriou, G., Rathi, Y., Kubicki, M., Kikinis, R., Heller, C., Yeterian, E., Besteher, B., Pallanti, S., & Makris, N. (2024). Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: A critical review for its relevance in acute and long COVID-19. Frontiers in Psychiatry, 15, 1337888. https://doi.org/10.3389/fpsyt.2024.1337888
Pallanti, S., Di Ponzio, M., Gavazzi, G., Gasic, G., Besteher, B., Heller, C., Kikinis, R., Makris, N., & Kikinis, Z. (2023). From ‘mental fog’ to post-acute COVID-19 syndrome’s executive function alteration: Implications for clinical approach. Journal of Psychiatric Research, 167, 10–15. https://doi.org/10.1016/j.jpsychires.2023.09.017
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