Prolonged microgravity induces reversible and persistent changes on human cerebral connectivity

The human brain exhibits remarkable neuroplasticity, adapting to various internal and external changes. While neuroplasticity has been extensively studied in development, brain damage, and skill learning, its response to extreme environmental factors like altered gravity remains less understood. Long-duration space missions present a unique opportunity to study this, as astronauts experience prolonged microgravity. Previous research using structural MRI has revealed changes in cerebrospinal fluid distribution, ventricular enlargement, and gray matter modifications in astronauts after spaceflight, largely attributed to fluid shifts. Functional MRI (fMRI) studies have shown altered connectivity in vestibular, motor, and multisensory brain regions after spaceflight or simulated microgravity (e.g., parabolic flight or head-down bedrest). These changes are interpreted as adaptive processes to altered sensorimotor demands. However, longitudinal studies examining both sustained and reversible changes in functional connectivity are limited. This study aimed to characterize longitudinal functional connectivity adaptations in cosmonauts using repeated resting-state fMRI scans before, immediately after, and eight months post spaceflight to the International Space Station (ISS). The study employed a whole-brain exploratory approach to identify regions modulated by long-duration spaceflight, irrespective of behavioral performance data, which was unavailable.

Prior research on the effects of spaceflight and simulated microgravity on the brain has yielded mixed results. Structural MRI studies consistently report changes in cerebrospinal fluid distribution, ventricular enlargement, and gray matter volume. These structural changes are often attributed to fluid shifts caused by the altered gravitational environment. Studies using fMRI have shown changes in functional connectivity, particularly in regions associated with vestibular processing, motor control, and multisensory integration. For example, studies have reported reduced connectivity in vestibular and motor regions after spaceflight. Some studies have also observed changes in connectivity within multisensory integration areas after spaceflight or parabolic flights. However, there has been a lack of comprehensive, longitudinal studies investigating the long-term effects of prolonged microgravity on functional brain connectivity, including both persistent and reversible alterations. This gap in knowledge motivated the current study.

This study involved 13 male Russian cosmonauts who participated in long-duration space missions to the ISS. Resting-state fMRI data were acquired at three time points: preflight, postflight (shortly after return to Earth), and approximately eight months postflight (follow-up). A control group of 14 age- and gender-matched healthy participants underwent two fMRI scans with a similar time interval as the cosmonauts' pre- and postflight scans. fMRI data were preprocessed using SPM12, including motion correction, slice-time correction, spatial normalization, and smoothing. aCompCor was used for noise reduction. Functional connectivity analysis was performed using CONN, employing intrinsic connectivity contrast (ICC) as a voxel-wise measure of global connectivity. Statistical analyses included paired t-tests (comparing pre- and postflight data in both groups) and repeated measures analyses (comparing preflight, postflight, and follow-up data in cosmonauts to identify sustained and normalized effects). Bayesian statistics were used to assess the strength of evidence for each finding. Seed-to-voxel analyses were conducted to investigate specific region-to-region connectivity changes contributing to the global connectivity alterations. Network associations of the identified regions were investigated using seed-based correlation analysis. Finally, correlation analyses were conducted to investigate potential confounding effects of age, mission duration, and structural brain changes on the observed functional connectivity changes.

The study revealed significant alterations in functional brain connectivity after prolonged exposure to microgravity. Firstly, a decrease in global connectivity was observed in the left precuneus/posterior cingulate cortex (PCC) postflight, which persisted at follow-up. This region is a key hub in the default mode network (DMN). Secondly, the left thalamus also showed a sustained decrease in global connectivity. Specifically, the decreased ICC that sustained over time was mostly due to a sustained decrease in postflight connectivity with the right middle frontal gyrus and the left superior frontal gyrus. Thirdly, the right angular gyrus demonstrated a sustained increase in global connectivity postflight. Finally, a decrease in global connectivity in the bilateral insular cortex was observed postflight, which normalized at follow-up. This normalization was related to a decreased connectivity with the middle cingulate cortex and an increase in connectivity with other brain regions. Bayesian analyses provided strong evidence for these findings in the cosmonaut group, while showing no significant changes in the control group. Seed-to-voxel analyses further revealed specific region-to-region connectivity changes contributing to the global changes. No significant correlations were found between functional connectivity changes and structural changes (gray matter volume or CSF) or demographic variables.

The findings indicate that prolonged microgravity induces both persistent and reversible changes in functional brain connectivity. The sustained decreases in PCC/precuneus and thalamus connectivity, both key hubs for integrating various brain functions, suggest a long-term adaptation to the microgravity environment. The sustained increase in right angular gyrus connectivity possibly reflects adaptation to spatial disorientation and altered action-outcome monitoring. The reversible changes in insular cortex connectivity suggest that salience network processing adapts to the gravitational conditions; suppressed in microgravity and enhanced on Earth. These adaptations may represent strategies to cope with unfamiliar and conflicting sensory input in microgravity. This interpretation is supported by previous research on space motion sickness, which involves salience network regions. The findings are also supported by parallel observations in studies using simulated microgravity (head-down bed rest).

This study demonstrates that prolonged microgravity induces both persistent and reversible changes in functional brain connectivity, impacting key brain networks including the default mode network, and salience network. These changes likely represent adaptation mechanisms to the unique sensory environment of spaceflight. Future research should investigate the long-term consequences of these changes and explore the potential for interventions to mitigate adverse effects of spaceflight on the brain.

The study had several limitations. The relatively small sample size of cosmonauts might have limited the statistical power, potentially missing more subtle effects. The postflight fMRI scans were acquired on average nine days after return, which might not fully capture the immediate post-flight adaptations. The study lacked behavioral data, limiting the understanding of the functional implications of the observed connectivity changes. Future research with larger samples and behavioral measures is needed to further investigate these findings.