Developing Personalized Sensorimotor Adaptability
Countermeasures for Spaceflight!
!
A.P. Mulavara1, B. Peters2, Y.E. De Dios2, N.E. Gadd2, E.E. Caldwell2, C.D. Batson3, R. Goel4, G. Kreutzberg2, V. Koppelmans5, K. Cassidy5,!
M. Ruitenberg5, R.D. Seidler5, L. Oddsson6, S. Zanello1, T.K. Clark7, C.M. Oman7, H.S. Cohen8, M. Reschke9, S. Wood10 and J.J. Bloomberg9!
1Universities
Space Research Association, Houston, TX, 2Wyle Science Technology and Engineering Group, Houston, TX; 3MEI Technologies, Houston, TX; 4University of Houston, Houston, TX; 5University of Michigan, Ann
Arbor, MI; 6University of Minnesota, Minneapolis, MN; 7Massachussets Institute of Technology, Cambridge, MA; 8Baylor College of Medicine, Houston, TX; 9NASA Johnson Space Center, Houston, TX 10Azusa Pacific
University, Azusa, CA. !
INTRODUCTION!
RESULTS!
Sensory Bias: Proprioceptive sensitivity correlates with
the ability to respond to a locomotor balance challenge!
What Factors Explain Individual Differences in Neural & Behavioral Plasticity?
Cognitive Ability?
Sensory Dependence?
0.25!
Average stride time first epoch"
(difference from baseline, s)"
Visuomotor adaptation (VMA) task!
15
5
1-­‐p 1.0!
!
0.5!
!
0.0!
0.15!
0.10!
0.05!
Fractional Anisotropy"
0.00!
-5
0!
B. Peters, et al. 2014
-15
-25
Marginal means for Reaction Time showing 95% confidence intervals. Groups
represent the 25th (less Visually Dependent, VD) and 75th (highly VD)
percentiles for visual dependency of a modeled population. Subjects with
greater VD have difficulty adapting to a sensory discordant environment. Brady
et al. 2012 Exp Brain Res!
Block!
Correlations between early rate of learning in a VMA task and card rotation
task for young and older adults. *p < .05. Anguera et al. 2010, 2011, J Cog
Neurosci!
Brain Recruitment Patterns?!
2!
4!
6!
Mediolateral shear force (Fy, N)"
1-­‐p 8!
1.0!
!
0.5!
!
0.0!
Mean Diffusivity"
Motor Learning: Adaptation rate on the adaptive
functional mobility test correlated with the ability to
respond to a locomotor balance challenge!
Genetic Single Neucleotide Polymorphisms?!
0.25!
Average stride time first epoch"
(difference from baseline, s)"
R DLPFC
Average stride time first epoch "
(difference from baseline, s) "
0.2!
0.15!
0.1!
R² = 0.30044"
0.05!
Z = 16
Best adapter!
B. Peters, et al. 2014
0!
0!
0.2!
B. Peters, et al. 2014
0.8!
Fractional Anisotropy (FA)
Peak Voxel Body of Corpus Callosum
1!
Adaptation rate by 3 genetic COMT polymorphism in young individuals. Val-val
subjects show slower adaptation and learning. Noohi F. et al. Journal of
Neurophysiology, 2014!
Resting State Functional Connectivity: Left insular
cortex connectivity significantly associated with rate of
early learning in manual adaptation task – greater
connectivity is associated with faster rate of visuomotor
adaptation during a manual control task!
This project will identify and characterize a set of predictive measures that include: 1) behavioral tests to assess sensory bias and adaptability; 2) imaging to determine
individual brain morphological and functional features; 3) genotype markers for genetic polymorphisms that play a role in the neural pathways underlying sensorimotor
adaptation. These behavioral, brain morphological/functional and genomic measures will be used to develop a set of predictive models to explain individual differences
in sensorimotor adaptability (SA) after long-duration spaceflight and an analog bed rest environment. Information from this study will help in the design of sensorimotor
adaptability training countermeasures that may be customized for each crewmember’s individual characteristics. Following is a description of a study on ‘normal’
subjects (n=16).!
Adaptive Functional Mobility Test: Subjects will negotiate a complex
obstacle course placed on medium density foam while wearing updown vision displacing goggles. This test will be performed 10 times
per trial to obtain both strategic learning (during each trial) and plasticadaptive learning (over repeated trials). !
!
Sensory Discordance Test: This paradigm provides a multisensory
assessment of adaptive performance (Peters et al. 2013). !
!
•  Locomotor Stability: Stride frequency using foot-switches.!
!
•  Multi-Tasking Capability: Subject depressed hand-held switch in
response to a series of audible tones to measure reaction time.!
•  SeqWright Genomic Services, GE Healthcare, Houston, TX - Custom quantitative PCR (QPCR)
assays by designing flanking primers and fluorogenic probes, both specific to target alleles from
sequence information or specific pre-optimized TaqMan® assays and signal detection was
carried out using an ABI PRISM® Sequence Detection System at an accuracy level of 99.6%. !
•  Gradient echo T2*-weighted echo-planar imaging (EPI),
sequence with BOLD contrast, TR = 3660 ms, TE = 39 ms, flip
angle = 90°, FOV = 240 x 240 mm, slice thickness = 4 mm, 1
mm slice gap, voxel size = 2.55 x 2.55 x 5.0 mm, 36 axial
slices, Acquisition time is ~10 min.!
Acknowledgement"
"
This work is supported by the National Space Biomedical Research Institute through NASA NCC 9-58. !
!
!
-0.1!
Early adaptation rate"
-0.08!
-0.8!
0.2!
1.2!
2.2!
R² = 0.76731!
-0.1!
Genetic Polymorphisms: The presence of the alleles - Met in COMT (rs4680),Val in BDNF (rs6265) and 6.7 kb in α2 - Adrenergic receptor
differentiated visuomotor adaptation during locomotion. 1.2!
400!
First trial time (s)"
300!
200!
100!
1!
0.8!
0.6!
0.4!
0.2!
0!
Top Ranked"
•  Single shot gradient-echo (GRE) echo planar imaging (EPI)
sequence acquire 240 T2*-weighted BOLD images, TR = 3660
ms, TE = 39 ms, flip angle = 90°, FOV = 240 x 240 mm, slice
thickness = 4.0 mm, slice gap = 1 mm, voxel size = 2.55 x 2.55
x 5.0 mm, 36 axial slices, Acquisition time is ~10 min.!
!
Functional MRI: fMRI during manual sensorimotor
adaptation task identifies brain networks supporting
visuomotor plasticity. !
-0.08!
-0.06!
!
Resting State Functional Connectivity MRI: Strength
of communications between “hubs” in the brain’s
networks.!
•  Saliva samples ORAGENE kit (DNA Genotek, Inc.) !
-0.06!
-0.04!
•  N = 16 normal subjects, MRI scanner - 3 T Siemens
Magnetom verio, T1-weighted gradient-echo pulse, sequence
with the following parameters: 3D T1 axial, overlay TR =
1900MS, TE = 2.44MS, flip angle = 9°, FOV = 270 x 270 mm,
slice thickness = 0.9 mm, 192, slices; matrix = 288 x 288, voxel
size = 0.9375 x 0.9375 x 0.9 = 0.7910 mm3 , duration=~4
minutes.!
•  N = 16 normal subjects!
R² = 0.72296!
-0.04!
-0.02!
Structural MRI scan: High-resolution anatomical
images to assess individual differences in regional brain
volumes.!
•  Single shot EPI sequence; TR = 10100 ms, TE = 95 ms, FOV =
240 x 240 mm, slice thickness = 2.0 mm, voxel size = 1.88 x
1.88 x 2.0 mm, 75 contiguous slices, Maximum b-value = 1000
s/mm2 in 30 non-collinear directions, Acquisition time is ~11
min. Tract Based Spatial Statistics (TBSS), Non-parametric
permutation based models corrected for family-wise error @
p<0.05 and threshold free cluster enhancement was applied. !
-0.02!
-1.8!
0!
Brain Structural And Functional Metrics!
!
Diffusion Tensor Imaging (DTI): Quantify large white
matter pathways in the brain and calculate their
structural integrity specifically the cortico-spinal tract
connecting motor brain regions and the spinal cord, in
addition to other pathways.!
Activity in Dorso Lateral pre frontal
cortex"
-0.6!
0.4!
1.4!
2.4!
0!
Activity in left thalamus"
•  Metabolic cost: VO2 was collected via a portable metabolic gas
analysis system. !
Genetic Polymorphisms!
Single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase
(COMT, rs4680): COMT val homozygotes exhibit slower adaptive changes in a
manual sensorimotor adaptation task!
!
SNPs in Dopamine Receptor D2 (DRD2, rs 1076560): codes for D2 dopamine
receptors in the striatum; G>T exhibit slower adaptive changes in a manual
sensorimotor adaptation task!
!
SNPs in Brain-derived neurotrophic factor (BDNF, rs6265): BDNF val/met
carriers exhibit reduced manual sensorimotor adaptation and less retention of
adaptive learning!
!
Genetic polymorphism of C10 α2 - Adrenergic receptor: associated with
individual differences in autonomic responses to stress, including susceptibility
to motion sickness!
!
Manual visuomotor adaptation
task Motor Learning Mode Metrics!
Sensory Bias Metrics!
Tests of Visual Dependency"
Treadmill Visual Dependency Test:
Subjects walk on
treadmill with incongruent visual flow while measuring torso
kinematics. !
!
Rod and Frame Test: Subjects align a rod to vertical within a
tilted frame.!
!
Tests of Vestibular Function "
Dynamic Posturography: Use tests that parse out vestibular
contribution (sway referenced, eyed closed).!
!
Vestibular Threshold: We assessed roll tilt perceptual
thresholds in the dark. These tests identify how small of a
motion can be distinguished as being left vs. right, which is
presumably limited by internal sensory noise levels.!
!
Test of Proprioceptive Dependency"
Tests of Proprioception in Balance Performance: assessed
measuring single leg balance control on “gravity bed”.!
"
Test of Working Memory"
Working memory underlies many daily cognitive operations
assessed using two tests: Thurston’s card rotation task ;
and Cube rotation task under otolith canal conflict scenario in
a Tilt Translation Sled device.!
Functional MRI: Activity in areas of the brain during the performance of this
task that correlates with early rate of motor learning – greater activation in
these areas are correlated with faster rate of visuomotor adaptation task!
Early adaptation rate"
Right dorsolateral prefrontal cortex (DLPFC) activation correlates
with early rate of adaptation in a VMA task. The fit line/Pearson
score reflects the pooled scores for both groups. **p < .01.
Anguera et al. 2011 J Cog Neurosci!
0.4!
0.6!
Rate of adaptation"
Rate of adaptation (FMT)"
Direction Error (deg)
R² = 0.58292"
0.20!
DTI: Fractional Anisotropy (FA) and Mean Diffusivity (MD) of white matter
tracts distributed widely over the brain co-varied significantly with the
average stride time during the first minute of exposure to support surface
motion – e.g. Larger FA measured in the body of corpus callosum
corresponds with better adaptability to a locomotor balance challenge. !
Average
Rank"
Top"
Half"
λ1"
Bottom
Half"
DRD2"
rs1076560"
COMT"
rs4680"
BDNF"
rs6265"
Dral, α2 Adrenergic
receptor"
7/15 (46.7%) !
GG/GT!
6/15 (40%) "
Met-Met/!
Val-Met!
8/15 (53.3%)"
Val-Val"
3/15 (20.0%) "
6.3 kb"
1/15 (6.7%) !
TT!
2/15 (13.3%)"
Val-Val!
0/15 (0%) "
Val-Met"
5/15 (33.3%) "
6.7 kb"
6/15 (40.0%) !
GG/GT!
3/15 (20.0%) "
2/15 (13.3%) "
Met-Met/!
Val-Val"
Val-Met!
1/15 (6.7%) !
TT!
4/15 (26.7%) " 5/15 (33.3%) " 6/15 (40.0%) "
Val-Val!
Val-Met"
6.7 kb"
1/15 (6.7%) "
6.3 kb"
First Trial
Rank"
Top "
Half"
Bottom "
Half"
DRD2"
rs1076560"
COMT"
rs4680"
BDNF"
rs6265"
Dral, α2 Adrenergic
receptor"
6/15 (40.0%)!
6/15 (40.0%)! 4/15 (26.7%)!
Met-Met/!
Val-Val!
6.3 kb!
Val-Met!
1/15 (6.7%) ! 2/15 (13.3%)! 2/15 (30.0%)! 4/15 (26.7%)!
TT!
Val-Val!
Val-Met!
6.7 kb!
7/15 (46.7%)!
GG/GT!
6/15 (40.0%)!
GG/GT!
0!
Bottom Ranked"
3/15 (20%)!
4/15 (26.7%)! 0/15 (0.0%)!
Met-Met/!
Val-Val!
6.3 kb!
Val-Met!
1/15 (6.7%) ! 4/15 (26.7%)! 3/15 (20.0%)! 7/15 (46.7%)!
TT!
Val-Val!
Val-Met!
6.7 kb!
Top Ranked"
Recovery Rate
Rank"
Top "
Half"
Bottom "
Half"
DRD2"
rs1076560"
Bottom Ranked"
COMT"
rs4680"
BDNF"
rs6265"
Dral, α2 Adrenergic
receptor"
4/15 (26.7%)!
6/15 (40.0%)! 2/15 (13.3%)!
Met-Met/ !
Val-Val!
6.3 kb!
Val-Met!
0/15 (0.0%)! 4/15 (26.7%)! 2/15 (13.3%)! 6/15 (40.0%)!
TT!
Val-Val!
Val-Met!
6.7 kb!
8/15 (53.3%)!
GG/GT!
5/15 (33.3%)!
GG/GT!
5/15 (33.3%)!
4/15 (26.7%)! 2/15 (13.3%)!
Met-Met/!
Val-Val!
6.3 kb!
Val-Met!
2/15 (13.3%)! 2/15 (13.3%)!
TT!
Val-Val!
3/15 (20%)!
Val-Met!
5/15 (33.3%)!
6.7 kb!
λ3"
λ2"
SUMMARY"
1.  Sensory Bias and Motor Learning - Proprioceptive sensitivity along with the rate of visuomotor adaptation on a complex locomotor task
correlates with the ability to respond to a locomotor balance challenge. !
2.  Brain Metrics – FA and MD from DTI, activity during performance of functional task, and connectivity of different regions of brain, have all
shown the ability to predict adaptability to locomotor and visuomotor adaptation challenges.!
3.  Genetic Polymorphisms - COMT (rs4680), BDNF (rs6265) and α2 - Adrenergic receptor showed presence of specific alleles that
differentiated mobility performance during a visuomotor adaptation challenge.!
4.  These data indicate that individual sensory bias, motor learning ability, brain structural and functional metrics and genetic polymorphisms
can be predictive of individual responses to sensorimotor adaptation challenges. !