EXPERIMENT RECORD N° 9483
BRAIN-DTI - Spaceflight induced neuroplasticity studied with advanced magnetic resonance imaging methods
  1. 2014 • ISS Increments 39-40
  2. 2014 • ISS Increments 41-42
  3. 2015 • ISS Increments 43-44
  4. 2015 • ISS 44S (Soyuz TMA-18M) "IrISS" - short-duration mission
  5. 2015 • ISS Increments 45-46
  6. 2016 • ISS Increments 47-48
  7. 2016 • ISS Increments 49-50
  8. 2017 • ISS Increments 51-52
  9. 2017 • ISS Increments 53-54
  10. 2018 • ISS "Horizons" - long-duration mission
  11. 2018 • ISS Increments 55-56
  12. 2018 • ISS Increments 57-58
  13. 2019 • ISS 61S (Soyuz MS-15) SpaceFlight Participant mission
  14. 2019 • ISS Increments 59-60
  15. 2019 • ISS Increments 61-62
Life Sciences:
  • Human Physiology
  • Neuroscience
Jennifer Ngo-Anh
jennifer.ngo-anh@esa.int
F. Wuyts (1), A. Van Ombergen (1), J. Sijbers (2), B. Jeurissen (2), W. Van Hecke (3), D. Loeckx (3), P. Parizel (4), A. Van der Linden (5), P. Van de Heyning (6), S. Laureys (7), A. Demertzi (7), L. Heine (7), S. Sunaert (8), G. Cheron (9), I. Kozlovskaya (10), E. Tomilovskaya (10), G. Clement (11), V. Sinitsin (12), E. Mershina (12), E. Pechenkova (12)
(1)  
Antwerp University Research Center for Equilibrium and Aerospace
University of Antwerp
Groenenborgerlaan 171
2020 Antwerp
BELGIUM
Tel:  
+32(0)3265.34.29
Fax:  
+32(0)3.825.0536
e-mail:  
floris.wuyts@uantwerpen.be
Angelique.Vanombergen@uantwerpen.be
(2)  
Vision Lab
University of Antwerp
Universiteitsplein 1, Building N
2610 Wilrijk
BELGIUM
Tel:  
+32(0)3265.34.05
e-mail:  
jan.sijbers@uantwerpen.be
ben.jeurissen@uantwerpen.be
(3)  
IcoMetrix
Tervuursesteenweg 244
3001 Leuven
BELGIUM
Tel:  
+32(0)16849697
e-mail:  
wim.vanhecke@icometrix.com
dirk.loeckx@icometrix.com
(4)  
Department of Radiology
University Hospital Belgium
Wilrijkstraat 10
2650 Edegem
BELGIUM
Tel:  
+32(0)3.821.3000
e-mail:  
paul.parizel@uantwerpen.be
(5)  
Bio-Imaging Lab
University of Antwerp
Universiteitsplein 1
2610 Wilrijk
BELGIUM
Tel:  
+32(0)3265.27.75
e-mail:  
annemie.vanderlinden@uantwerpen.be
(6)  
Department of ENT
University Hospital Belgium
Wilrijkstraat 10
2650 Edegem
BELGIUM
Tel:  
+32(0)3.821.3000
e-mail:  
paul.van.de.heyning@telenet.be
(7)  
University of Liège
Cyclotron Research Center, Coma Science Group
Allée du 6 août
Liege
BELGIUM
Tel:  
+32(0)43662304
e-mail:  
steven.laureys@ulg.ac.be
a.demertzi@ulg.ac.be
lheine@ulg.ac.be
(8)  
University of Leuven (KU Leuven)
Department of Imaging & Pathology, Translation MRI
Herestraat 49
3000 Leuven
BELGIUM
Tel:  
+32(0)16343770
e-mail:  
stefan.sunaert@uzleuven.be
(9)  
Laboratory of Neurophysiology and Movement
Biomechanics Faculty of Movement Science
Université Libre de Bruxelles
808, Route de Lennik
1070 Brussels
BELGIUM
e-mail:  
gcheron@ulb.a.c.be
(10)  
IBMP - Institute of Biomedical Problems
Laboratory of gravitation physiology and sensory motor system
76A Khoroshevskoye Shosse
123007 Moscow
RUSSIA
Tel:  
+7(0)499.1951573
e-mail:  
ikozlovs@mail.ru
finegold@yandex.ru
(11)  
International Space University
Parc d´Innovation
1, rue Jean-Dominique Cassini
67400 Illkirch-Graffenstaden
FRANCE
Tel:  
+33(0)388655444
e-mail:  
clement@isunet.edu
(12)  
Federal Center of Medicine and Rehabilitation
Radiology Department
Ivankovskoye sh., 3
125367 Moscow
RUSSIA
Tel:  
+7.4954901705
e-mail:  
vsini@mail.ru
elena_mershina@mail.ru
evpech@gmail.com
BACKGROUND
Spaceflight constitutes several physiological changes in the human body. Astronauts adapt fairly appropriately to these changes, depending on the site of action and the applied counter measures. Still, despite several decades of human spaceflight, counter measures are not entirely successful, since e.g. space motion sickness is still present among several astronauts when arriving in the ISS. Upon return to Earth, orthostatic intolerance often occurs as well as spatial disorientation. Also osteoporosis and muscle atrophy and cardiovascular deconditioning are serious side effects of microgravity. Some astronauts adapt easier to the relatively hostile environment of space than others, and 2nd time fliers certainly experience fewer problems. But in general, after a given period, the human central nervous system seems to be capable of adaptation to microgravity, a process called "neuroplasticity".

A recently developed MR technique called Diffusion Tensor Imaging (DTI) allows investigating brain tissue microstructure and connectivity, particularly in white matter (WM) (Assaf & Pasternak, 2008) (Basser, Mattiello, & LeBihan, 1994). This non-invasive imaging method probes the diffusion characteristics of water molecules in biological tissue, for example the human brain. This allows determining the neuro-anatomy of the brain since water molecules are subject to random thermal motion (´Brownian motion´). This process causes these molecules to move in a translational matter and thus ´to diffuse´ (Zhang et al., 2006). In an infinite homogeneous fluid, diffusion may be truly random. This is called isotropic diffusion and means diffusion is equal in all directions. However, in biological tissue, such as the human brain, free motion of the water molecules is restricted due to natural barriers such as cytosol, cell membranes and other macromolecules (Hajnal et al., 1991). In this case, water will move more easily in one direction than the other, corresponding with the underlying organisation of the tissue. Movement will be easier along the axonal bundle than perpendicular to these bundles. This is due to the fact that there are fewer obstacles to prevent movement along the fibres (EO Stejskal, 1965). In contrast to isotropic diffusion where diffusion is equal in all directions, diffusion with a strong directional preference is called anisotropic diffusion (Figure 1).

It is this anisotropy that is used in DTI to make an estimation of the underlying axonal organisation of the brain. It is proven that in white matter, water molecules diffuse more freely along the direction of the axons than perpendicular with this direction and thus white matter tracts will show a high degree of anisotropy. Grey matter such as nuclei and the cortex of the brain only shows a small degree of anisotropy (JS Shimony, 1999), whereas diffusion in the cerebrospinal fluid (CSF) can be considered more or less isotropic (Pierpaoli, Jezzard, Basser, Barnett, & Di Chiro, 1996). DTI has greatly been applied in neuroscientific research to elucidate the underlying microstructural characteristics of healthy brains and to obtain diagnostic information regarding various neurological diseases. However, with conventional DTI a Gaussian distribution of diffusion displacement is assumed and this is not the case for biological tissues due to restrictions by cellular microstructures (Susumu, 2007). Diffusion Kurtosis Imaging (DKI), an extension of the DTI model, can overcome this limitation of DTI by using kurtosis to estimate the non-Gaussian distribution and thus providing insights into the underlying microstructure (Chen et al., 2012). Recent studies have shown that DKI has an improved sensitivity compared to conventional DTI when it comes to detecting complex developmental and pathological changes in neuronal structures (Blockx et al., 2012; Fieremans, Jensen, & Helpern, 2011) and in addition elucidate directionally specific information (Cheung et al., 2009; Hui, Cheung, Qi, & Wu, 2008; Wu & Cheung, 2010). Another approach to address the limitations of the DTI model is high-angular resolution diffusion imaging (HARDI) (Tournier, Mori, & Leemans, 2011). In essence, HARDI measures the diffusion-weighted (DW) signal by using a much larger number of uniformly distributed DW gradient directions than are used with conventional DTI. In this way, the DW signal, along with its higher angular frequency features, gets measured and thus improved sensitivity over standard DTI analysis is established (Emsell et al., 2013).

Additionally, other advanced methods in Magnetic Resonance Imaging (MRI), such as resting state functional MRI (rfMRI), will be used to study the effect of microgravity on the adaptive processes in the brain.

Based on neuro-anatomical data and previous work from PET and fMRI studies, we expect to find biomarkers of neuroplasticity in the following ROIs (Region Of Interest):
1. for the vestibular system: retroinsular cortex, parietal operculum 2, posterior and anterior insula, amygdala, cerebral peduncle, posterolateral thalamus and cerebellum.
2. for orientation and navigation capabilities: MT/V5+ and MSTd homologue.
3. for vestibulo-autonomic regulation: locus coeruleus, nucleus tractus solitarius, parabrachial nucleus, anterior and posterior insula.
4. for the motor control system in the following fiber tracts: superior and posterior thalamic radiation, corticospinal and corticobulbar tracts.
Elucidating the changes in structural and functional brain wiring in microgravity will help to better understand common problems encountered in space flights such as space motion sickness, and autonomic deconditioning. Thus, better insight in these processes will enable to define more efficient counter measures.

Justification for Need of Space Experiment
Space flight is a model where a ´controlled´ and reversal stimulus is given to the human body. Almost no other ethically approvable situation provides such a clear but also immense stimulus to the human body as several months of microgravity. It is crucial to understand the adaptation and plasticity of the brain to tackle the countermeasure problems that currently still exist in human spaceflight. Next, it opens a huge domain of research that benefits the general public. Indeed, it is not possible, due to ethical reasons, to study the effect of vestibular disorders pre and post disease for example. Indeed, we can´t impose in healthy subjects such a dramatic effect on the vestibular system as obtained by microgravity. The advantage of this project is that no in-flight data are needed to obtain the relevant answers in the context of neuroplasticity and MRI methods.

It is expected that when these advanced in vivo MRI techniques are used to investigate astronauts before and after long duration spaceflight, evidence for neuroplasticity will be found at different sites and regions of interest. A non-flying healthy subject group will serve as control group. Additionally, a specific group of patients with vestibular disorders such as ´visual vestibular mismatch syndrome´ will be investigated with the same methods.
Comparison between the three groups of subjects will allow obtaining the desired insight in brain plasticity.

Experiment Specific Goals and Detailed OBJECTIVES
The overall objective of this research is to determine whether biomarkers of neuroplasticity in vestibular signal processing can be found using the model of microgravity.

More specific the following OBJECTIVES are set:
a) to obtain knowledge on how astronauts adapt to microgravity at the level of the brain.
b) to use the model of microgravity to gain insight in which specific regions of interest are involved in space motion sickness (SMS), spatial disorientation, vertigo, and convergence of otolith and semicircular canal signals.
c) to link biomarkers of brain plasticity with clinical outcome, obtained by motion sickness questionnaires.
d) to use the obtained knowledge on this adaptation of the astronaut brain to microgravity as a starting point to optimize countermeasures against space motion sickness, spatial disorientation, vertigo and convergence of otolith and semicircular canal signals.
e) to use this knowledge as a starting point in the treatment of specific groups of vertigo patients (e.g. visual vertigo syndrome, mal de debarquement, uncompensated peripheral lesions).
Space flight serves as a unique model to gain fundamental insight in neuroplasticity.
Fundamental knowledge of how and where microgravity-induced neuroplasticity takes place may provide key solutions towards countermeasures against the deleterious effects of microgravity. In the past decades of human space travel, numerous countermeasures have been invoked. Several are still under development with the aim for manned missions to the Moon and Mars since countermeasures are of crucial importance. Gravity transitions induce physiological effects that can jeopardize the astronauts’ ability to function appropriately, and can be lethal. Previous space missions have shown that most astronauts adapt relatively efficiently to the environmental changes that are imposed upon them. However, knowledge on these adaptation processes is very scarce, especially those concerning the neuroplasticity.

PILOT STUDY in vestibular patients
In a pilot study, performed May-July 2013 at the University of Antwerp, we examined patients and hypothesized that structural connectivity changes may be related to functional disability, possibly indicating vestibular decompensation. To gain insight in these biomarkers of neuroplasticity, we used the same advanced MRI techniques (DTI/DKI/HARDI) as proposed here. HARDI outcome data such as fractional anisotropy (FA) were correlated with functional outcome measures from vestibular testing.

For this pilot study, five patients (two men, three women; mean age = 49.9 years (SD = 13.7 years); age range 36.2 years to 69.5 years) suffering from vestibular ‘decompensation’ and five healthy controls (two men, three women; mean age = 52.2 years (SD = 12.8 years); age range 38.1 years to 72.4 years) were recruited

Fiber orientations were estimated by using validated constrained spherical deconvolution (CSD) methods, coupled with a probabilistic streamlines tracking algorithm. Hereto, the MRtrix 0.2.11 (http://www.brain.org.au/software/mrtrix/) software package was used (Tournier J.D., 2012). The colour of each tract represents its direction; red for left - right or vice versa, green for anterior - posterior or vice versa and blue for a superior - inferior direction or vice versa (Figure 2).

For this study, we selected fiber tracts that were previously proven or suggested to be involved in vestibulo-autonomic processes, as summed up above. A single rater (AVO) performed all ROI placements. Figures 3a and 3b give an impression of this method.

The following diffusion parameters were calculated for each tract and region:
- mean diffusivity (MD) and
- fractional anisotropy (FA).
MD describes the average amount of diffusion within a voxel and is given in 10-3 mm2/s. The FA is a dimensionless normalized measure of the degree of anisotropy within a voxel. This can be related to the orientation of the axons crossing through the voxel.

The results of this pilot study showed significant group differences (p = 0.009) reflecting greater FA values in control subjects compared with patients in the right OP2 region (Figure 4).

Not only are these findings really promising for knowledge on how neuroplasticity works (or not works) in these vestibular patients, but it also proves that large cohorts are not needed to find significant results which is inevitable when working with astronauts.

HYPOTHESIS

The general hypothesis of this study is that long duration microgravity induces neuroplasticity in different regions of interest (ROI) that are involved in the integration of neuro-sensory information, provided by the vestibular organs, vision and proprioception.
By means of advanced MRI methods (DTI, DKI, HARDI and rfMRI), we hypothesize that biomarkers for space flight induced neuroplasticity can be identified when images of the same astronaut, acquired before and after 6 months of space flight, are compared with each other. Consequently this will allow for the identification and verification of specific regions of interest (ROI) and fiber tracts that are expected to be involved in neuro-vestibular and vestibulo-autonomic processes. The objective is to study 12 astronauts before and after long duration space flight.

EXPECTED RESULTS
We expect to find biomarkers of neuroplasticity when looking for changes in the ROIs specified above.


RELATED RESEARCH
Parabolic flight induced neuroplasticity studied with advanced magnetic resonance imaging methods
62nd ESA Parabolic Flight Campaign - 2015
1st Cooperative Parabolic Flight Campaign - 2015

BRAIN-DTI - Microgravity induced neuroplasticity after parabolic flight studied with advanced MRI techniques
61st ESA Parabolic Flight Campaign - 2014
60th ESA Parabolic Flight Campaign - 2014

SPIN - Validation of Centrifugation as a Countermeasure for Otolith Deconditioning During Spaceflight
ISS Increment 16 to 30 - 2007 to 2011

SPIN-D - validation of a specific drug against g-level transition induced spatial disorientation and orthostatic intolerance (D)

GAZE-SPIN - Validation of centrifugation as a countermeasure for otolith deconditioning during spaceflight and study of gaze holding mechanisms during optokinetic stimulation and centrifugation after long-term exposure to weightlessness
BRAIN-DTI is a entirely ground based experiment.

Pre-flight: Two sessions in the period L-180 to L-30.
Post-flight: as early as feasible R+1 (± 5), R+10 (±3), R+45 (±7), R+180 (±14).

Data collection will be performed at the Radiology Department of the Moscow Federal Institute for Rehabilitation Medicine in Moscow on the 3T MRI before and after space flight in a group of 12 astronauts. In the period before the launch to the ISS, 2 moments will be allocated to take MRI images (between L-180 and L-30) while after landing, MRI images will be taken during 4 moments: R+5, R+10, R+45, R+180.
High angular resolution diffusion imaging data will be acquired using a single-shot echo-planar imaging (EPI) sequence. The examination will be performed with the subject in the head first - supine position.

The following diffusion parameters will be calculated for each tract or region:
- Mean diffusivity (MD): MD describes the average amount of diffusion within a voxel and is given in 10-3 mm2/s.
- Fractional anisotropy (FA): FA is a dimensionless normalized measure of the degree of anisotropy within a voxel. This can be related to the orientation of the axons crossing through the voxel.
- Axial diffusivity (AD): AD is a parameter that relates to the degree of diffusion perpendicular to the principal direction of diffusion and this parameter is known to be more specific to underlying biological processes, such as the degree of myelination and axonal changes (Song et al., 2002).
- Radial diffusivity (RD): RD relates to the degree of diffusion along the principal direction of diffusion. Just as AD, RD can reflect myelination and axonal properties.
- Voxel volume of studied tracts and regions: by including this parameter as a covariate in the statistical analysis, we can exclude partial volume effects (PVE), which have been proven to have a nefast impact on the analysis of diffusionweighted images (Vos et al., 2011).
Test Subjects
Number of subjects desired: minimum 16 crew members
Number of subjects required: 12 crew members (if data are sufficiently noise free)
Subject exclusions: provide rationale if some crewmembers cannot participate in the study (e.g. gender limitations, or physical limitations). No exclusions. However, by preference first time flyers. If possible, half of the subjects should be first time flyers.

Mission Duration

Minimum Mission Duration: approximately 6 months is the target mission duration, but in case shorter flights are done, these crew members are also very valuable to be investigated and invited to participate in the project.
Maximum Mission Duration: no maximum duration.

Ground Reference Experiments:
Using exactly the same protocol, 16 healthy subjects will be tested on 2 moments, with 6 months time interval between the tests, to see the effect of 6 months time on the brain. These trials are control experiments. In 2014/2015, parabolic flight campaigns were used for testing the same protocol on subjects participating in parabolic flights. In parallel, patients with specific vestibular problems are investigated in the Antwerp University Hospital with an identical protocol (except the foot stepping device and associated protocol) and analysed with the same methodology.
HYPOTHESIS
The general hypothesis of this study is that long duration microgravity induces neuroplasticity in different regions of interest (ROI) that are involved in the integration of neuro-sensory information, provided by the vestibular organs, vision and proprioception.
By means of advanced MRI methods (DTI, DKI, HARDI and rfMRI), we hypothesize that biomarkers for space flight induced neuroplasticity can be identified when images of the same astronaut, acquired before and after 6 months of space flight, are compared with each other. Consequently this will allow for the identification and verification of specific regions of interest (ROI) and fiber tracts that are expected to be involved in neuro-vestibular and vestibulo-autonomic processes. The objective is to study 12 astronauts before and after long duration space flight.

EXPECTED RESULTS
We expect to find biomarkers of neuroplasticity when looking for changes in the ROIs specified above.

FIRST RESULTS
First results of the BRAIN-DTI experiment were obtained during ISS Increment 39-40. Please, consult Reference Document #11 for more details:

A. Demertzi, A. Van Ombergen, E. Tomilovskaya, B. Jeurissen, E. Pechenkova, C. Di Perri, L. Litvinova, E. Amico, A. Rumshiskaya, I. Rukavishnikov, J. Sijbers, V. Sinitsyn, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, P.H. Van de Heyning, S.S.L. Laureys, F.L. Wuyts, (2015), "Cortical reorganization in an astronaut´s brain after long-duration spaceflight", Brain Structure and Function, DOI 10.1007/s00429-015-1054-3, pp. 1-4.
or look for the PDF of that document in the "Attachments" section. 

RESULTS as of 2018
We prospectively studied data from T1-weighted magnetic resonance imaging (MRI) that was performed in 10 male cosmonauts (mean age, 44 years; average space-mission duration, 189 days) at three time points: preflight (in 10 cosmonauts), short-term postflight (average, 9 days postflight; in 10), and long-term postflight follow-up (average, 209 days postflight; in 7). The volumes of gray matter, white matter, and cerebrospinal fluid (CSF) were analyzed with the use of voxel-based morphometry. (The complete methods and additional analyses are provided in the Supplementary Appendix, which is available with the full text of Reference Document no 14 at NEJM.org or as PDF in the "Attachments" section) Aging effects that may occur over the interval between preflight and postflight were accounted for by longitudinal data from matched controls.

The gray-matter volume postflight as compared with preflight showed a widespread decrease in the orbitofrontal and temporal cortexes; the maximal decrease was 3.3% in the right middle temporal gyrus. At long-term postflight follow-up, most reductions in gray-matter volume had recovered toward preflight levels (e.g., a 1.2% reduction in gray-matter volume persisted in the right temporal gyrus). The white-matter volume postflight as compared with preflight was reduced along a longitudinal tract of the left temporal lobe, but there was a global reduction of cerebral white-matter volume at long-term follow-up as compared with postflight. The ventral CSF spaces of the cerebral hemispheres and the ventricles had increased in volume postflight as compared with preflight (maximal increase, 12.9% in the third ventricle), while CSF volume below the vertex decreased. At long-term follow-up, the CSF volume in the ventricles had returned toward preflight values, while the CSF volume in the entire subarachnoid space around the brain had increased. Changes in the volumes of gray matter and CSF are shown in Figure 5.

The findings from an average of 7 months after a return to Earth can be summarized as showing that most of the loss in the gray-matter volume that was seen immediately postflight had recovered to preflight levels, while CSF volume continued to increase in the subarachnoid compartment. The expansion of CSF spaces in light of postflight decreases in the gray-matter volume and a reduction in the white-matter volume at follow-up suggests a persistent disturbance in CSF circulation even many months after a return to Earth. These brain-volume changes may relate to clinical findings, such as ocular and visual abnormalities after long-duration spaceflight. Future investigation is required in order to determine the overall clinical significance of the findings and to mitigate risks in long space missions.

RESULTS as of 2019
from Reference Document [15]  (also see PDF in "Attachment" section below) 
A. Van Ombergen, S. Jillings, B. Jeurissen, E. Tomilovskaya, A. Rumshiskaya, L. Litvinova, I. Nosikova, E. Pechenkova, I. Rukavishnikov, O. Manko, S. Danylichev, R.M. Rühl, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, V. Sinitsyn, S. Laureys, S.J. Sijbers, P. zu Eulenburg, F.L. Wuyts, (2019), "Brain ventricular volume changes induced by long-duration spaceflight", PNAS - Proceedings of the National Academy of Sciences on the United States of America, 116, 21, DOI: https://doi.org/10.1073/pnas.1820354116, pp. 10531-10536.

Linear mixed model analysis revealed a significant effect of time on the ventricular volume measurements in the cosmonauts for the lateral ventricle, third ventricle, and total ventricular volume (all P < 0.0001). There was no significant effect of time on the volume of the fourth ventricle for the cosmonauts.

Post hoc analyses in the cosmonaut group revealed a significant difference between preflight and postflight values in the lateral ventricle (mean % change ± SE = 13.3 ± 1.9; P < 0.0001), third ventricle (mean % change ± SE = 10.4 ± 1.1; P < 0.0001), and total ventricular volume (mean % change ± SE = 11.6 ± 1.5; P < 0.0001), with higher volumes at postflight. Comparison between postflight and follow-up showed a significant difference for the third ventricle (mean % change ± SE = −5.7 ± 0.4; P = 0.0002) and total ventricular volume (mean % change ± SE = −3.9 ± 1.0; P = 0.0104). Finally, comparison between preflight and follow-up revealed significant differences for the lateral ventricle (mean % change ± SE = 7.7 ± 1.6; P = 0.0009), the third ventricle (mean % change ± SE = 4.7 ± 1.3; P = 0.0063), and total ventricular volume (mean % change ± SE = 6.4 ± 1.3; P = 0.0008). These results are summarized in Figure 6, which shows the percentage volume difference for each ventricular compartment. In addition, the interaction effect of group and time was significant for the lateral ventricle (cosmonauts mean % change ± SE = 13.3 ± 1.9; controls mean % change ± SE = −1.2 ± 1.3; P = 0.0001), third ventricle (cosmonauts mean % change ± SE = 10.4 ± 1.1; controls mean % change ± SE = −0.6 ± 0.9; P < 0.0001), fourth ventricle (cosmonauts mean % change ± SE = 2.3 ± 1.2; controls mean % change ± SE = −2.0 ± 1.0; P = 0.0102), and total ventricular volume (cosmonauts mean % change ± SE = 11.6 ± 1.5; controls mean % change ± SE = −1.2 ± 1.2; P < 0.0001). Post hoc analyses revealed that the significant interaction effect was driven by the volume change between preflight and postflight measurements in cosmonauts for third, lateral, and total ventricular volume (P < 0.0001). For the fourth ventricle, none of the post hoc tests revealed significance.

The correlation analyses showed no significant relationship between the percentage of total ventricular volume change and mission duration, age at launch, previous space experience, total intracranial volume (Figure 7), and change in visual acuity scores (Figure 8). However, the lateral ventricular volume change was significantly correlated with visual acuity change in the left eye only (r = −0.517; P = 0.035), showing greater ventricular volume increases for greater visual acuity loss (Figure 8). Veiled original data (except for total intracranial volume) for each potential correlation analysis are shown in Figure 7 to depict the distribution pattern.

Statistical comparison of postflight versus preflight visual acuity scores revealed a significant decrease postflight for both the left eye [median difference (median absolute deviation, MAD) = −0.3 (0.3); P = 0.023] and the right eye [median difference (MAD) = −0.1 (0.1); P = 0.016]. However, the visual acuity scores postflight did not fall below the clinical norm of 1.0.

No significant differences in ventricular volume were found in any of the ROIs for the control group over time or between cosmonauts and controls at any time point.
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A. Demertzi, A. Van Ombergen, E. Tomilovskaya, B. Jeurissen, E. Pechenkova, C. Di Perri, L. Litvinova, E. Amico, A. Rumshiskaya, I. Rukavishnikov, J. Sijbers, V. Sinitsyn, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, P.H. Van de Heyning, S.S.L. Laureys, F.L. Wuyts, (2015), "Cortical reorganization in an astronaut’s brain after long-duration spaceflight", Brain Structure and Function, DOI 10.1007/s00429-015-1054-3, pp. 1-4.
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A. van Ombergen, S. Laureys, S. Sunaert, E. Tomilovskaya, P.M. Parizel, F.L. Wuyts, (2017), "Spaceflight-induced neuroplasticity in humans as measured by MRI: what do we know so far?", Nature Partner Journals: Microgravity, 3(2).
[13]  
A. van Ombergen, A. Demertzi, E. Tomilovskaya, B. Jeurissen, J. Sijbers, I.E. Kozlovskaya, P. Parizel, P. Van de Heyning, S. Sunaert, S. Laureys, F.L. Wuyts, (2017), "The effect of spaceflight and microgravity on the human brain", J Neurol, 264 (Suppl 1), S18-S22 DOI: 10.1007/s00415-017-8427-x.
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A. Van Ombergen, S. Jillings, B. Jeurissen, E. Tomilovskaya, R.M. Rühl, A. Rumshiskaya, I. Nosikova, L. Litvinova, J. Annen, E.V. Pechenkova, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, V. Sinitsyn, S. Laureys, J. Sijbers, P. Zu Eulenburg, F.L. Wuyts, (2018), "Brain Tissue-Volume Changes in Cosmonauts", New England Journal of Medicine, 379, 17, DOI: 10.1056/NEJMc1809011, pp. 1678-1680.
[15]  
A. Van Ombergen, S. Jillings, B. Jeurissen, E. Tomilovskaya, A. Rumshiskaya, L. Litvinova, I. Nosikova, E. Pechenkova, I. Rukavishnikov, O. Manko, S. Danylichev, R.M. Rühl, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, V. Sinitsyn, S. Laureys, S.J. Sijbers, P. zu Eulenburg, F.L. Wuyts, (2019), "Brain ventricular volume changes induced by long-duration spaceflight", PNAS - Proceedings of the National Academy of Sciences on the United States of America, 116, 21, DOI: https://doi.org/10.1073/pnas.1820354116, pp. 10531-10536.
[16]  
E. Pechenkova, I. Nosikova, A. Rumshiskaya, L. Litvinova, I. Rukavishnikov, E. Mershina, V. Sinitsyn, A. Van Ombergen, B. Jeurissen, S. Jillings, S. Laureys, J. Sijbers, A. Grishin, L. Chernikova, I. Naumov, L. Kornilova, F.L. Wuyts, E. Tomilovskaya, I. Kozlovskaya, (2019), "Alterations of Functional Brain Connectivity After Long-Duration Spaceflight as Revealed by fMRI", Frontiers in Physiology - Environmental, Aviation and Space Physiology, 10, DOI: 10.3389/fphys.2019.00761, pp. article no. 761.
click on items to display

Figure 1: Graphical display of the range of isotropic towards anisotropic diffusion as can be observed in the various regions of the brain. Adapted from (Huisman, 2010) and redrawn by P. Rombaut.

Figure 2: Slab visualization of whole brain CSD tractography. Courtesy of B. Jeurissen.

Figure 3.a and 3.b: Visualisation of the left corticobulbar tract of a patient in the sagittal plane. 3.a, above: Left corticobulbar tract. Each colour represents the direction of the tracts: green = anterior <-> posterior, blue = inferior <-> superior, red = left <-> right. Combinations of the above are also possible. 3.b, under: The same left corticobulbar tract positioned on the anatomical 3D MP-RAGE image of the patient.

Figure 4: Boxplot shows statistically significant differences (p = 0.009) in FA (dimensionless) for the right operculum parietal 2 region between control subjects and patients.

Figure 5: Brain-Volume Changes in Cosmonauts at Three Time Points. Shown are topologic patterns of volume change in gray matter and cerebrospinal fluid (CSF) spaces in cosmonauts. Data are from MRI scans that were obtained preflight (in 10 cosmonauts), at short-term postflight (average, 9 days; in 10), and at long-term postflight follow-up (average, 209 days; in 7). White-matter changes are not shown. Panel A shows decreased gray-matter volume (dark blue) in the orbitofrontal and temporopolar regions postflight as compared with preflight. CSF volume for the same comparison is decreased under the vertex (light blue), while CSF volume is increased in the cerebral ventricles and basal cisterns (yellow-red). Panel B shows volume changes at long-term follow-up as compared with preflight. There is a persistent reduction in the gray-matter volume in the ventral cortical regions (dark blue) but less so than immediately postflight. Panel C shows increases in the gray-matter volume (pink) for these same regions at long-term follow-up as compared with short-term postflight. The CSF volume in the ventricles almost returned to preflight levels, but there was residual enlargement of the subarachnoid CSF space (yellow-red) surrounding the brain. This enlargement occurred after the return to Earth. Results were corrected for multiple comparisons after threshold-free cluster enhancement (TFCE) with the false discovery rate (P<0.05). Details of the methods of constructing these maps are provided in the Supplementary Appendix (see "Attachment" section). L and R denote left and right, and A and P anterior and posterior.

Figure 6: Percentage volume change for each ventricular CSF compartment, as well as total ventricular volume change given for comparisons postflight vs. preflight (dark colored bar) and follow-up vs. preflight (light colored bar). The percentage volume difference between the two time points for the controls is also given (diagonal stripes). The bar colors represent each ventricular ROI, as also indicated on the sagittal slice. A positive value indicates an increase in ventricular volume at postflight compared with preflight or at follow-up compared with preflight. A negative value indicates a decrease in ventricular volume at postflight compared with preflight or at follow-up compared with preflight. ***P < 0.0001 (Bonferroni-corrected) and *P < 0.017 (Bonferroni-corrected), from post hoc tests of the linear mixed model. Bars indicate SE. credit: Ref. Doc. no 15 - Brain ventricular volume changes induced by long-duration spaceflight, Van Ombergen et. al. (2019)

Figure 7: Scatter plots showing the relationship between total relative brain ventricular volume change for preflight and postflight (in 11 cosmonauts) with respect to (A) mission duration (in days), (B) age at launch (in years), (C) previous space experience (in days), and (D) total intracranial volume (in milliliters). No significant correlations were found. Results in A, B, and C are blurred to guarantee anonymity of the cosmonauts, given the fact that most of the information is publicly available. The masking cloud follows the actual data distribution pattern, but is modified to disguise individual data points. credit: Ref. Doc. no 15 - Brain ventricular volume changes induced by long-duration spaceflight, Van Ombergen et. al. (2019)

Figure 8: Scatter plots showing the relationship between (A) total and (B) lateral relative brain ventricular volume change for preflight and postflight (in 11 cosmonauts) with respect to visual acuity difference. No significant correlation was found for total ventricular volume difference and visual acuity difference, while a marginally significant correlation was found for lateral ventricular volume change and visual acuity difference for the left eye only. credit: Ref. Doc. no 15 - Brain ventricular volume changes induced by long-duration spaceflight, Van Ombergen et. al. (2019)

Figure 9: Overview of the changes occurring in the subarachnoid and intracerebral CSF spaces [including the superior sagittal sinus (area 1) and the ventricles (area 2) of the cosmonauts across the different time points. (A−C) Schematic coronal visualization, taking together the current findings as well as an overview of previously described changes in previous studies of long-duration space travelers (Roberts DR, et al. (2017) Effects of spaceflight on astronaut brain structure as indicated on MRI. N Engl J Med 377:1746-1753. / Van Ombergen A, et al. (2018) Brain tissue-volume changes in cosmonauts. N Engl J Med 379:1678-1680.). (D−F) Exemplary individual raw data on similar coronal slices, from which, especially, the ventricular enlargement is visible to the untrained, naked eye. (A and D) Baseline status, i.e., the preflight situation. (B and E) Postflight situation (on average, 9 d after returning to Earth). Cerebral ventricular enlargement, widening of the subarachnoid CSF space around the temporal and parietal lobes (Van Ombergen A, et al. (2018) Brain tissue-volume changes in cosmonauts. N Engl J Med 379:1678-1680.), and a compression of the superior sagittal sinus (Roberts DR, et al. (2017) Effects of spaceflight on astronaut brain structure as indicated on MRI. N Engl J Med 377:1746-1753. / Van Ombergen A, et al. (2018) Brain tissue-volume changes in cosmonauts. N Engl J Med 379:1678-1680.) and a narrower longitudinal fissure can be noted. (C and F) Illustrations of the situation at follow-up (on average, 7 mo after returning to Earth). They show a partial normalization of ventricular CSF volumes and rewidening of the superior sagittal sinus. credit: Ref. Doc. no 15 - Brain ventricular volume changes induced by long-duration spaceflight, Van Ombergen et. al. (2019)
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ESA web story on BRAIN-DTI: "Astronaut Brains as Beacons for Researchers"

First results of the BRAIN-DTI experiment, obtained during ISS Increment 39-40, are described in this article: "Cortical reorganization in an astronaut’s brain after long-duration spaceflight", Brain Structure and Function, DOI 10.1007/s00429-015-1054-3

Supplementary Appendix to Reference Document no 12: Van Ombergen A, Jillings S, Jeurissen B, et al. Brain tissue-volume changes in cosmonauts. New England Journal of Medicine 2018; 379:1678-80. DOI: 10.1056/NEJMc1809011
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A. Van Ombergen, S. Jillings, B. Jeurissen, E. Tomilovskaya, A. Rumshiskaya, L. Litvinova, I. Nosikova, E. Pechenkova, I. Rukavishnikov, O. Manko, S. Danylichev, R.M. Rühl, I.B. Kozlovskaya, S. Sunaert, P.M. Parizel, V. Sinitsyn, S. Laureys, S.J. Sijbers, P. zu Eulenburg, F.L. Wuyts, (2019), "Brain ventricular volume changes induced by long-duration spaceflight", PNAS - Proceedings of the National Academy of Sciences on the United States of America, 116, 21, DOI: https://doi.org/10.1073/pnas.1820354116, pp. 10531-10536.

Pechenkova, E., Nosikova, I., Rumshiskaya, A., Litvinova, L., Rukavishnikov, I., Mershina, E., Sinitsyn, V., Van Ombergen, A., Jeurissen, B., Jillings, S., Laureys, S., Sijbers, J., Grishin, A., Chernikova, L., Naumov, I., Kornilova, L., Wuyts, F.L., Tomilovskaya, E., Kozlovskaya, I., (2019), "Alterations of Functional Brain Connectivity After Long-Duration Spaceflight as Revealed by fMRI", Frontiers in Physiology - Environmental, Aviation and Space Physiology, 10, DOI: 10.3389/fphys.2019.00761, pp. article no. 761.
 
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