Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization

Abstract

Following long-duration spaceflight, some astronauts exhibit ophthalmic structural changes referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). Optic disc edema is a common sign of SANS. The origin and effects of SANS are not understood as signs of SANS have not manifested in previous spaceflight analog studies. In the current spaceflight analog study, 11 subjects underwent 30 days of strict head down-tilt bed rest in elevated ambient carbon dioxide (HDBR+CO2 ). Using functional magnetic resonance imaging (fMRI), we acquired resting-state fMRI data at 6 time points: before (2), during (2), and after (2) the HDBR+CO2 intervention. Five participants developed optic disc edema during the intervention (SANS subgroup) and 6 did not (NoSANS group). This occurrence allowed us to explore whether development of signs of SANS during the spaceflight analog impacted resting-state functional connectivity during HDBR+CO2 . In light of previous work identifying genetic and biochemical predictors of SANS, we further assessed whether the SANS and NoSANS subgroups exhibited differential patterns of resting-state functional connectivity prior to the HDBR+CO2 intervention. We found that the SANS and NoSANS subgroups exhibited distinct patterns of resting-state functional connectivity changes during HDBR+CO2 within visual and vestibular-related brain networks. The SANS and NoSANS subgroups also exhibited different resting-state functional connectivity prior to HDBR+CO2 within a visual cortical network and within a large-scale network of brain areas involved in multisensory integration. We further present associations between functional connectivity within the identified networks and previously identified genetic and biochemical predictors of SANS. Subgroup differences in resting-state functional connectivity changes may reflect differential patterns of visual and vestibular reweighting as optic disc edema develops during the spaceflight analog. This finding suggests that SANS impacts not only neuro-ocular structures, but also functional brain organization. Future prospective investigations incorporating sensory assessments are required to determine the functional significance of the observed connectivity differences.

Keywords: CO2; SANS; bed rest; functional connectivity; optic disc edema; resting-state fMRI; spaceflight.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Figures

FIGURE 1

Baseline data collection (BDC) was carried out during a 14‐day ambulatory phase in standard ambient air. Participants then underwent 30 days of strict 6° head down‐tilt bed rest with 0.5% ambient carbon dioxide (HDBR+CO2). The bed rest intervention was followed by a 14‐day ambulatory recovery (R) phase in standard ambient air. Resting‐state fMRI scans were acquired on sessions BDC‐13, BDC‐7, HDT7, HDT29, R5, R12

FIGURE 2

Contrast models used to longitudinal FC changes. The gray shaded region indicates the HDBR+CO2 phase. The model shown in orange was used to identify brain networks showing stable FC across the baseline phase followed by a gradual FC increase during HDBR+CO2, then a gradual return to baseline following bed rest. The model shown in purple was used to identify brain networks showing stable FC across the baseline phase followed by a gradual FC decrease during HDBR+CO2, then a gradual return to baseline following bed rest. BDC, baseline data collection; HDBR+CO2, head down‐tilt bed rest with elevated carbon dioxide; R, recovery; FC, functional connectivity

FIGURE 3

Differential longitudinal FC changes between the SANS and NoSANS subgroups. (a) The NoSANS subgroup (gray squares) showed a FC decrease between the ROI in right posterior parietal cortex (PPC) and clusters in bilateral insular cortices during HDBR+CO2 followed by a post‐bed rest reversal. The SANS subgroup (triangles) exhibited FC increases between these regions during HDBR+CO2 followed by a post‐bed rest decrease. (b) The NoSANS subgroup (gray squares) showed a FC increase between the ROI in left posterior cingulate cortex (PCC) and right primary visual cortex (V1) during HDBR+CO2 followed by a post‐bed rest reversal. The SANS subgroup (triangles) exhibited a FC decrease between these regions during HDBR+CO2 followed by a post‐bed rest increase. The dashed line on each graph represents the hypothesized longitudinal model. Error bars represent standard error. L, left; R, right; ROI, region of interest; FC, functional connectivity; SANS, spaceflight associated neuro‐ocular syndrome; HDBR+CO2, head down‐tilt bed rest with elevated CO2

FIGURE 4

Pre‐bed rest FC differences between the SANS and NoSANS subgroups. (a) During the baseline phase, the NoSANS subgroup (gray squares) exhibited FC between the ROI in right primary visual cortex (V1) and visual areas V3 and V4 within the left hemisphere. The SANS subgroup exhibited an anti‐correlation or lower FC between visual brain areas prior to bed rest (colored triangles) prior to the HDBR+CO2 intervention. (b) During the baseline phase, the NoSANS subgroup (gray squares) exhibited anti‐correlations between the ROI in left insular cortex and left primary motor cortex (M1), lateral occipital cortex (LOC), inferior and middle temporal gyri (ITG/MTG), parahippocampal gyrus (PHG), precuneus/posterior cingulate cortex (PCC), and right cerebellar lobule 7b. The SANS subgroup (colored triangles) exhibited greater FC than the NoSANS subgroup during the baseline phase. FC, functional connectivity; L, left; ROI, region of interest; SANS, spaceflight associated neuro‐ocular syndrome

FIGURE 5

Baseline FC values. Within each panel, we present session‐wise FC values between the indicated target cluster and the ROI in right primary visual cortex (a) or the ROI in left insular cortex (b–g). Each marker represents data from one participant. Triangle markers indicate participants who developed signs of SANS during the HDBR+CO2 intervention (SANS). Square markers indicated participants who did not develop signs of SANS (NoSANS). At the bottom of each scatterplot, we present subject‐wise FC values from the BDC‐13 session. To the left, we present subject‐wise FC values estimated during the BDC‐7 session. The scatterplot shows BDC‐13 FC values plotted against BDC‐7 FC values for each participant. The identity line is represented by the dashed line. FC, functional connectivity; BDC, baseline data collection; PCC, posterior cingulate cortex; M1, primary motor cortex; PHG, parahippocampal gyrus; ITG/MTG, inferior and middle temporal gyri; LOC, lateral occipital cortex; SANS, spaceflight associated neuro‐ocular syndrome

FIGURE 6

Associations between pre‐ to post‐HDBR+CO2 FC values and SANS biomarkers. Scatterplots show relationships between the number of risk alleles, Vitamin B6 and B12 concentration, and homocysteine with participants' change in FC from pre‐ to post‐HDBR+CO2 (i.e., BDC‐7 to HDT29). Triangle markers indicate participants who developed signs of SANS during the HDBR+CO2 intervention (SANS). Square markers indicated participants who did not develop signs of SANS (NoSANS). Dashed lines indicate the linear trendline across all 11 participants. (a) In the upper panel, the y axes of plots indicate FC changes between the ROI in right posterior parietal cortex and target clusters in bilateral insular cortices. (b) In the lower panel, the y axes of plots indicate FC changes between the ROI in left posterior cingulate cortex and target clusters in right primary visual cortex (V1). FC, functional connectivity; L, left; ROI, region of interest; SANS, spaceflight associated neuro‐ocular syndrome

FIGURE 7

Associations between baseline FC values and SANS biomarkers. Scatterplots show relationships between the number of risk alleles, Vitamin B6 and B12 concentration, and homocysteine with participants' pre‐bed rest FC (i.e., averaged across BDC‐13 and BDC‐7). Triangle markers indicate participants who developed signs of SANS during the HDBR+CO2 intervention (SANS). Square markers indicated participants who did not develop signs of SANS (NoSANS). Dashed lines indicate the linear trendline across all 11 participants. (a) In the upper panel, y axes indicate baseline FC values between the ROI in right primary visual cortex and target clusters spanning left V3 and V4. (b) In the lower panel, y axes indicate baseline FC values between the ROI in left insular cortex and A target cluster in left precuneus/posterior cingulate cortex. FC, functional connectivity; L, left; ROI, region of interest; SANS, spaceflight associated neuro‐ocular syndrome