Temporal Nature of Cognitive and Visuospatial Brain Domain Changes During Long-Duration Low-Earth Orbit Missions (Spatial Cognition)
Phase: NA
Conditions: Brain Structure, Cognitive Performance
Sponsor: University of Pennsylvania

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Protocol for the Study 
 
Temporal Nature of Cognitive and Visuospatial Brain Domain Changes 
During Long-Duration Low-Earth Orbit Missions (Spatial Cognition) 
 
NASA Grant 80NSSC19K1046 
NASA Johnson Space Center IRB Protocol STUDY00000175 
 
 
Date: 7/31/2020 
 
 

Page 2 of 35 
1.1 
Study Identification Information   
a) 
Study Name:  
Temporal Nature of Cognitive and Visuospatial Brain Domain Changes During 
Long-Duration Low-Earth Orbit Missions (Spatial Cognition) 
 
b) 
Brief Synopsis / Abstract:  
This is an international proposal consisting of two projects with synergistic aims 
that will be carried out in a joint effort by NASA and DLR/ESA. It addresses the 
HRP Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric 
Disorders, HRP's requirement to demonstrate the presence or absence of 
unacceptable deleterious neurocognitive effects beyond the experience base of 
six-month expeditions, and to permit extrapolation to early interplanetary 
expeditions. It also addresses several other critical HRP risks and gaps (e.g., 
BMed1, BMed2, BMed3, BMed5, CNS-1, SM26). More specifically, we will target 
NASA's particular interest in studying the 'Cognitive-perceptual-visuospatial 
brain domain changes due to isolation and confinement' as part of the 
integrated One-Year Mission Project (i1YMP) on the International Space Station 
(ISS). The data we propose to collect will - for the first time - reliably 
demonstrate whether prolonging mission duration to one year will have 
detrimental effects on general cognitive performance (measured with the 
Cognition test battery), spatial cognition, structural and functional brain changes 
in general, and hippocampal plasticity more specifically relative to the shorter 6-
month and 2-month missions. Using state-of-the-art neuroimaging techniques, 
we will determine the biological basis for any changes in cognitive performance, 
with a focus on hippocampal plasticity. Similar data already gathered on the ISS 
and in several short- and long-duration space analog environments will be used 
to generate a normative data base for long-duration missions. Finally, we will 
derive dose-response relationships between cognitive-visuospatial brain domain 
changes and mission duration that will allow predicting vulnerability to adverse 
cognitive or behavioral impairment and psychiatric disorders on interplanetary 
expeditions such as a mission to Mars. The two 7-yr projects will deliver a highly 
unique and comprehensive set of integrated neuroimaging and neurocognitive 
tools for the evaluation and ultimately prevention of adverse effects on brain 
structure and function that lead to behavioral effects associated with 
exploration-type missions. 
 
 
c)      
Is this a Ground-Based or Space Flight study? 
  
 
 
__X__Ground-Based Study: Control subjects 
 
 
__X__Space Flight Study: ISS 
  
 
d) 
What type of data does the research study require? 
  

Page 3 of 35 
 
 
_____Prospective: Collecting new data  
 
 
_____Retrospective: Use of archived data 
 
 
__X__Both: Combination of new and archived data 
 
If “Retrospective” is selected above, PI must submit a data request through the NASA’s 
LSDA/LSAH Data Request Portal at the following link (https://lsda.jsc.nasa.gov/ ) to 
obtain the LSAH-AB feasibility letter that MUST accompany your eIRB protocol 
submittal. 
 
If “Both” is selected above, please ensure both the prospective and retrospective 
components are clearly covered in the Informed Consent Form. 
 
Investigators requesting NASA subject(s) archived data, agree that ALL publications 
resulting from this project will be submitted to LSAH for privacy review before 
submission for publication, including presentations, abstracts, and manuscripts. 
 
 
e) 
Name of Co-Principal Investigators 
Mathias Basner, MD, PhD, MSc 
Alexander C. Stahn, PhD 
1.2 
External Review and Approval 
 
 
Has the protocol been reviewed by another institution? ____Yes  __X__ No 
If “yes”, what was the disposition or determination of the external review? Please list 
 
the institution, board and contact information where this protocol was or will be 
 
reviewed. 
 
1.3 
Conflict of Interest 
Do any of the participating study investigators or other research personnel (or   
 
their immediate family/significant other) have a financial and/or intellectual  
 
 
property interest in the sponsor or products used with this project? 
 ____Yes  __X__No 
 
If “yes”, Conflicts of interest statements must be submitted by all key personnel on 
dated, signed, institutional letterhead with the study title identified. The letter must 
answer affirmatively and disclose the relationship with the company or entity 
arrangements. A related financial interest does NOT automatically mean that the 
investigator cannot participate in the research. The IRB will determine if the financial 
and or other conflict of interest can be reduced, eliminated or managed in order to allow 
participation in the research project. 
 

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If “no”, Conflicts of interest statements must be submitted by all key personnel on dated, 
signed, institutional letterhead with the study title identified.  The letter must include 
the following statement: 
 
 
“I do not receive any research support from non-public sponsors of research. I do 
 
not perform any validation research of a drug or device. I do not receive any gifts 
 
or income from individuals associated with my research studies. I do not use my 
 
position with_____(fill in the blank with name of employer, i.e. NASA, 
 
KBRWyle etc) or proprietary or confidential information obtained in performing 
 
my duties, in any marketing, investing, or commercial ventures. 
 
1.4  
Study Funding Information  
 
Has funding been awarded for this study? Yes __X__    No ____ 
 
If “yes”, please list all sources of funding: 
NASA grant 80NSSC19K1046 (Definition Phase) 
DLR grant (number not yet assigned) 
 
Please list the funded study title if different from the Study Name listed in this 
 
protocol submission: 
N/A 
 
 
1.5  
Scientific Merit Assessment 
Has this study received a scientific merit assessment? Yes__X__   No ____ 
 
If “yes”, what organization, review body and or individual conducted the review?  
NASA 
 
 
If “no”, has there been a technical assessment? 
 
 
Has this study been modified since the last merit review?   
Yes 
 
If so please describe all modifications to the study: 
The project is funded for a definition phase first. Any changes identified during the 
definition phase will be addressed in an amendment to this protocol. 
 
1.6  
Human Genetic Testing 
 
Does the NASA Policy Directive 7170, Use of Human Research Genetic Testing, apply to 
 
this study?  
Yes____ No__X__    
 

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If “yes”, please mark the study as greater than minimal risk in the protocol document 
(Section 2.1.a)) and answer the following questions. 
 
 
Human Genetic Testing Procedures 
 
a) What is the purpose of the human research genetic testing? 
 
 
b) Will the human research genetic data be extracted from biospecimens?  
Yes___ No_____ 
 
c) Please describe the process for human research genetic data extraction from the 
subject and then from the subsequent sample. 
 
 
d) Please provide a plan to protect human research genetic test data. The following 
are required to be included or addressed in the plan: 
 
i) Please state that attributable or identifiable human research genetic data will 
not be publicly released without the prior approval of the individual research 
subject and other subjects whose anonymity might be affected by the release, as 
well as the NASA IRB or the Lifetime Surveillance of Astronaut Health Advisory 
Board. 
ii) Outline the procedures to protect the privacy of genetic information. (Including 
after death of the subject, to avoid unwarranted invasion of personal privacy of 
surviving family members.)  
iii) Please state that no whole genomic sequence data will be published or made 
public without written consent from the subject or their direct family members 
who may be  impacted by the release of the data.  
iv) Please state that all human research genetic testing data will be considered 
protected data for the purposes of safeguards. 
v) Please state that results from human research genetic testing will not be data-
mined or cross-referenced with other databases of any kind unless approved by 
the NASA IRB. 
vi) Please state that investigators will not attempt to identify or contact individual 
participants from whom data was collected without approval from the NASA IRB. 
vii) Because it may be possible to reidentify deidentified genomic data, please 
describe how this research data will be controlled. 
viii) Any human research genetic data will be stored in a database separately from 
data containing personally identifiable information (e.g., sex, age, name, 
address, phone number, social security number), unless it has been included in 
the research subject’s Electronic Medical Record (EMR). 
N/A 

Page 6 of 35 
 
e) Please describe the plan to provide genetic counseling. In the plan, please name 
the genetic counselor(s). 
 
 
f) Please provide the plan to adhere to IT security and privacy policy practices. 
 
 
g) Please describe the reporting plan for any inadvertent data release, breach of data 
security, or other data management incidents. 
 
h) Please provide a plan describing the process to archive at NASA (or elsewhere), 
return original study data, and destroy all copies of the original study data after 
the study is complete.  
 
 
 
2.0  
Background and Significance 
 
a) Background and Significance: Successful human space exploration depends on the 
integrity of a range of cognitive abilities. In addition to the physiological effects of 
microgravity, spaceflight involves exposure to multiple environmental (e.g., radiation) 
and psychological stressors related to living in an isolated, confined, and extreme (ICE) 
environment that have the potential to degrade astronaut cognitive performance and 
jeopardize mission success. On the first human mission to Mars, astronauts will spend 
unprecedented times in space beyond low earth orbit. Our knowledge on how humans 
will cope with living for prolonged periods of time in an ICE environment is extremely 
limited (only 4 humans have spent consecutively more than 1 year in space). Studies 
investigating the neurocognitive effects of living in ICE environments beyond the 
standard 6-month ISS mission are therefore critically needed to (1) understand the 
effects on brain plasticity and cognitive performance, (2) demonstrate and verify the 
techniques needed to monitor, diagnose, and prevent such effects, (3) establish a 
baseline for proposed Deep Space Gateway expeditions of up to 7 months and up to 400 
days in the Deep Space Transport, and (4) allow for the confident prediction of adverse 
neurocognitive trends out to two to three years of typical Mars conjunction-class 
missions. 
This proposal addresses the HRP Risk of Adverse Cognitive or Behavioral Conditions and 
Psychiatric Disorders and HRP’s requirement to demonstrate the presence or absence of 
unacceptable deleterious neurocognitive effects beyond the experience base of six-
month expeditions and to permit extrapolation to early interplanetary expeditions. It 
also addresses several other critical HRP risks and gaps (e.g., BMed1, BMed2, BMed3, 
BMed5, CNS-1, SM26). More specifically, we will target NASA’s particular interest in 
studying the ‘cognitive-perceptual-visuospatial brain domain changes due to isolation 
and confinement’ and in ‘operationally-relevant behavioral health and performance 

Page 7 of 35 
tools’ as part of the integrated One-Year Mission Project (i1YMP) on the International 
Space Station (ISS). The data we propose to collect will - for the first time - reliably 
demonstrate whether prolonging mission duration to one year will have detrimental 
effects on general cognitive performance, spatial cognition and hippocampal plasticity 
relative to the shorter 6-month and 2-month missions. Using state-of-the-art 
neuroimaging techniques, we will determine the biological basis for any changes in 
cognitive performance, with a focus on hippocampal plasticity. Similar data already 
gathered on the ISS, in several space analog environments, and in astronaut and 
astronaut-surrogate control groups will be used to generate a normative data base for 
long-duration missions. Finally, we will derive dose-response relationships between 
cognitive-visuospatial brain domain changes and mission duration that will allow 
predicting vulnerability to adverse cognitive or behavioral impairment and psychiatric 
disorders on interplanetary expeditions such as a mission to Mars. The two 7-yr projects 
will deliver a highly unique and comprehensive set of integrated neuroimaging and 
neurocognitive tools for the evaluation and ultimately prevention of adverse effects on 
brain structure and function that lead to behavioral effects associated with exploration-
type missions. To meet these objectives, we propose an international collaboration 
combining two projects that will address synergistic objectives and specific aims. 

Page 8 of 35 
b) Preliminary Studies:  
 
Figure 1: Panel A: This panel shows standardized differences of Cognition performance 
of Scott Kelly (SK) pre-flight, early in-flight (months 1-6), late in-flight (months 7-12), and 
post-flight relative to his twin brother Mark (MK) and to 5 astronauts on standard 6-
month ISS missions (ISS) (published in the journal Science in April 2019). SK showed a 
slight decline in cognitive speed and accuracy across a range of cognitive domains late 
in-flight compared to the 6-monthh ISS crew, and a more pronounced decline in 
performance post-flight compared to both his brother and the 6-monthh ISS crew. This 
suggests minor effects of prolonging mission duration from 6 to 12 months, but more 
major effects for the post-flight period. This study will increase our knowledge base 
from N=1 to N=11. (MP: Motor Praxis; VOLT: Visual Ob-ject Learning; F2B: Fractal 2-
Back; AM: Abstract Matching; LOT: Line Orientation; ERT: Emotion Recognition; MRT: 
Matrix Reasoning; DSST: Digit Symbol Substitution; PVT: Psychomotor Vigilance; BART: 
Balloon Analog Risk; ALL: average scores across cognitive domains)   Panel B: This panel 
shows that the post-flight decline in cognitive performance of SK was not transient. It 
persisted until the last post-flight measurement at R+180 (blue arrows).   Panel C: This 
panel provides an overview of the number of subjects and the number of Cognition 
batteries that will contribute to the normative data-base for standard- (≤6 months) and 
long-duration (>6 months) missions. 
 
Mark
ISS
Mark 1-6
ISS 1-6
Mark 7-12
ISS 1-6
Mark
ISS
MP
VOLT
F2B
AM
LOT
ERT
MRT
DSST
PVT
> 2.5 SD
BART
> 1.5 SD
ALL
> 0.5 SD
± 0.5 SD
MP
< -0.5 SD
VOLT
< -1.5 SD
F2B
< -2.5 SD
AM
LOT
ERT
MRT
DSST
PVT
ALL
BART
Speed
Accuracy
Pre-
Flight
In
1-6
In
 7-12
Post-
Flight
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
-150
-50
50
150
250
350
450
550
Standard Deviations
Flight Day
Accuracy
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
-150
-50
50
150
250
350
450
550
Standard Deviations
Flight Day
Speed
A
B
Scott 
relative 
to Mark 
and ISS
C
Analog Environment
# Subjects
# Batteries
# Subjects
# Batteries
ISS i1YM
20
90
10
110
Existing ISS Data
5
53
1
11
HI-SEAS
5
35
12
270
Neumayer Station
51
465
Halley Station
25
215
Concordia Station
25
150
HERA
64
788
ESA Bedrest Studies
43
175
Total
137
1,141
124
1,221
Standard (≤ 6 months)
Long (> 6 months)

Page 9 of 35 
 
Figure 2: Panel A: Whole brain analyses using voxel-based morphometry showing the 
effects of 30 days of isolation in the NASA HERA habitat (blue, N=16, 7 women) and 60 
days of head-down tilt bed rest (N=23 men). Both space analogs reveal a significant 
(P<0.001) decrease around the hippocampal head (anterior hippocampus) and the 
border of the amygdala. These data were confirmed by high-resolution imaging (see bar 
plot). Panel B: Individual and mean (±SE) age- and gender-adjusted in dentate gyrus 
volumes before and after long-duration overwintering (circles and triangle show women 
and men respectively). *P=0.023 for paired t-test. Mixed models including subject as 
random intercept confirmed a significant interaction (P=0.042) between time (pre vs. 
post) and group (Antarctic overwintering crew vs. control group). N=17 (8 winter-overs, 
9 controls). 
 
 
Figure 3: Panel A: Association between rate of change in visuospatial ability (mental 
rotation) and change in dentate gyrus volume. The rate of change in cognitive change 
was computed by regressing the monthly performance data (total of 10 time points per 
subject) during an Antarctic winter-over against time for each individual participant, 
respectively (N=8). Panel B, left: Example of a probe trial of the wayfinding task 
(cognitive mapping). After a route learning phase until 100% criterion, subjects were 
positioned in front of an object that they passed during the learning. They were then 
asked to point to another specific object that they encountered during their route 
learning. In the example shown here, the subject faces the front of the church, and 

Page 10 of 35 
asked to turn himself toward the Chinese restaurant by virtually turning his position 
using the arrow keys of the computer. Panel B, right: Pointing error (difference between 
correct vector and subjective pointing) of wayfinding task after 56 days of bed rest com-
pared to performance in a group of bed rest subjects after a recovery phase of 180 days 
and a group of gender- and age-matched controls (N=34, 11 bed rest subjects after 180 
days, 11 bed rest subjects after 56 days of bed rest, 12 control subjects). *P=0.018 and 
P=0.019 compared to CTRL and R+180, respectively. Panel A, left: Example of spatial 
updating probe trial. During the encoding phase two objects are briefly shown on the 
screen. Once the objects disappear the participants experiences either a virtual 
translation (dynamic condition) or remains in his position (static condition), after which 
one of the two objects is shown again in the middle of the screen. Using a 3D-arrow the 
participant now has to move the arrow towards the original position of that object. 
Panel A, right: Effect of weightlessness on spatial updating performance. During each 
parabola, subjects performed two trials in 1g and 0g, respectively, for a total of 15 
parabolas N=10 (4 women, 6 men), aged 33 to 50 years. The experiment was performed 
as part of the 66th ESA parabolic flight campaign. Data are mean (±SE) changes between 
0g and 1g. Green refers to spatial updating trials, i.e. trials involving virtual forward 
movement. Red shows control trial, i.e. no translation. *P=0.028. 
 
 
2.1   
Level of Risk and Medical Monitor 
 
 
a)  What is this study's level of risk? 
__X__Minimal 
 _____Greater Than Minimal  
 
If different parts of the study have different levels of risk, please briefly outline the 
risks associated with each part in this protocol and consent form. Please note that 
the use of human research genetic testing is considered greater than minimal risk. 
 
b)   What is this study's Medical Monitor level?  
 
 
 
_____Level 1    
 
 
_____Level 2 
 
 
_____Level 3 
__X__Level 4 
_____Not Required 
 
If not required, please explain. 
 
 
 
 

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2.2  
Study Summary 
a) 
Expected Start Date: 
7/1/2019 (Definition Phase) 
1/1/2020 (Project Phase) 
b) 
Expected End Date: 
 
 
12/31/2019 (Definition Phase) 
 
12/31/2026 (Project Phase) 
c) 
Type of Subjects (please mark all that apply): 
__X__Astronaut (US) 
__X__Astronaut (CSA) 
__X__Astronaut (ESA) 
__X__Astronaut (JAXA) 
_____Cosmonaut 
__X__Non-Astronaut 
 
2.3 
Study Location(s):  Identify the NASA location(s) where research procedures, including 
 
data collection and storage, will be performed. 
Johnson Space Center, Clear Lake, TX 
UTMB Victory Lakes, League City, TX 
 
2.4  
Other Sites/Institution(s):  Please list any non-NASA sites or institutions where research 
 
procedures, including data collection and storage, will be performed.  
University of Pennsylvania, Philadelphia, PA (data analysis and storage) 
Charité Berlin, Germany (data analysis and storage) 
 
3.0   
Specific Aims and Hypothesis 
 
a) Specific Aims:  
This study consists of two projects: 
Project A: Neurostructural and Cognitive Changes During Long Duration Low-Earth 
Orbit Missions: Cognition (PI Basner) 
Project B: Spatial Cognition and Hippocampal Plasticity During Long-Duration Low-
Earth Orbit Missions: HypoCampus in i1YMP (PI Stahn) 
This study has the following specific aims: 
 Specific Aim A1: Effects of Long-Duration Low-Earth Orbit Missions on 
Cognition performance 
 Specific Aim A2: Normative Cognitive Performance Data as a Baseline for 
Future Long-Duration Missions 
 Specific Aim A3: Brain Structural, Functional and Connectivity Substrates of 
Changes in Cognitive Performance Induced by Long-Duration Low-Earth Orbit 
Missions 

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 Specific Aim B1: Visuospatial Brain Domain Changes Induced by Low-Earth 
Orbit Missions 
 Specific Aim B2: Effects of Long-Duration Low-Earth Orbit Missions on Visuo-
Spatial Cognition 
 Specific Aim B3: Biological Basis of Neurocognitive Changes During Low-Earth 
Or-bit Missions 
 
b) Hypothesis(es): In line with the solicitation, the study is considered a non-inferiority 
trial. Accordingly, our aim is to show that the effects of the 1-year mission are not 
worse, i.e. non-inferior to the standard space missions of 6-month duration (applies 
to Specific Aims A1, A3, B1, B2, and B3 above). For Specific Aim A2, we will generate 
a normative database that can serve as a baseline for future long-duration missions. 
The 10 year-long astronauts will be the basis for this data-base, which will be 
augmented with existing data from 5 astronauts on 6-month missions and with Scott 
Kelly’s data from his one-year mission. Importantly, we already collected Cognition 
data in N=86 astronaut surrogate subjects spending >6 months in space analog 
environments (3 Antarctic research stations and HI-SEAS). These data will be 
contrasted to the in-flight data and, if comparable, used to augment the normative 
database for LDM. We continue to collect data at Neumayer station in two NASA-
funded projects, and will have up to 27 more subjects available for potential 
inclusion in the database by the end of this project. 
 
c) Primary Outcome Measure: (Dependent Variables) 
Specific Aim A1: Cognitive efficiency across domains as determined with the 
Cognition test battery 
Specific Aim A3: fMRI local task activation while performing the MRI version of 
Cognition in the scanner 
Specific Aim B1: Accuracy and reaction times for each cognitive task as determined 
with the Spatial Cognition test batteries 
Specific Aim B2: Structural brain changes and local task activation while performing 
visuospatial tasks in the scanner  
Specific Aim B3: BDNF, IGF-1, VEGF, Oxytocin (IL-1, IL-1ra, IL-10, TNFa) 
 
d) Statistical Analysis:  To assess the effect of spaceflight we will employ mixed-model 
analyses with time and group (control vs. spaceflight) and mission length as fixed 
factors and subjects as random factors. Significant main effects for variables will be 
followed-up using sequentially rejective multiple contrasts. To assess the 
relationships between several predictors and the primary outcomes, regression 
analyses such as ridge, lasso, and elastic net regression will be considered to 
minimize any problems associated with overfitting. To identify the relationship 
between changes, within-subject correlations, accounting for non-independence 
among observations using analysis of co-variance (ANCOVA) and statistically adjust 
for inter-individual variability will be used. 
 
 

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3.1   
Study Design Characteristics 
 
Sample Size: This study will include N=10 astronauts on 12-month missions, N=10 
astronauts on 6-month missions, and N=10 astronauts on 2-month missions. These 
sample sizes were set by NASA. In line with the solicitation, the study is considered a 
non-inferiority trial. Accordingly, our aim is to show that the effects of the 1-year 
mission are not worse, i.e. non-inferior to the standard space missions of 6-month 
duration. For Project A, existing Cognition data from 6 astronauts on 6-month or 12-
month ISS missions were used to determine the statistical power to demonstrate non-
inferiority of cognitive efficiency across domains in the 12-month crew (expected N=11, 
including data from 1 existing astronaut) relative to the 6-month crew (expected N=15) 
for non-inferiority margins (NIM) of 0.2, 0.25, and 0.3 SD, when, in-fact, there is no 
performance difference. By sampling repeatedly in-flight, we increase precision for 
individual astronauts, which stabilizes variance across astronauts and thus increases 
statistical power. The analyses show that we expect to have >80% power (at α=0.05) to 
demonstrate non-inferiority with an a priori defined NIM of 0.25 standard deviations for 
≥2 in-flight tests (we plan to acquire 6 and 5 tests in-flight during months 1-6 and 7-12, 
respectively). Should the performance of the 12-month crew be 0.05 SD (20% of 0.25 SD 
NIM) lower compared to the 6-month crew, we still expect to have >70% power to 
determine non-inferiority at a NIM of 0.25 SD. For Project B, the primary endpoint will 
be hippocampal subfield volume measured using a high-resolution brain MRI scan. The 
standard deviation is anticipated to be 50 mm3. Assuming N=10 for each group (i.e. 6-
month missions and 1-year missions), a type I error rate of 5% and that the true mean 
difference between missions is thought to be zero, we expect to achieve >80% for 
showing non-inferiority with a margin of >55mm3. Considering a true difference of 5 
mm3 between 6-months and 1-year missions, corresponding to 10% of the non-
inferiority limit, will still have >70% power to determine non-inferiority of 1-year 
missions. 
 
 
 

Page 14 of 35 
4.0    
Study Procedures, Tests, Evaluation 
a) Study Procedures, Tests, and Evaluations: Please list, in sequence, all study 
procedures, tests, and evaluations required for the study.  
 
(1) Brain-MRI 
In order to examine both structural and functional brain changes associated with 
spaceflight, the MRI scanning of the brain shall include the following scanning 
sequences (depending on the scanner, software, and timing, the protocol can be slightly 
adapted accordingly): 
 
Structural MRI measures will provide detailed information about anatomical features of 
the brain and allow us to monitor changes in an individual’s brain structure. Functional 
MRI will provide information about brain function and allow for the measurement of 
individual differences in brain performance during challenging cognitive tasks.  
 
Structural MRI: 
- 
Field Map (Projects A&B) 
- 
Whole brain T1-weighted MPRAGE anatomical sequence (Projects A&B) 
- 
Whole brain T2-weighted SPACE anatomical sequence (Project A) 
- 
Proton density weighted sequence for a high-resolution image of the 
hippocampus (Project B) 
- 
T1-weighted fast spin echo locus coeruleus sequence (Project B) 
Functional MRI: 
- 
Whole brain resting BOLD MRI sequence (Projects A&B) 
- 
Whole brain perfusion sequence (Project A) 
- 
Whole brain task BOLD sequence - fCognition (Project A) 
- 
Whole brain visuo-spatial task BOLD sequences (Project B) 
 
 
During all MRI scans, subjects shall lie in a supine position with their eyes opened or 
closed based on task demands. Functional MRI scans may require subject responses to 
visual stimuli (tasks) using an MRI safe response box while lying in the scanner. 
 
Prior to imaging, subjects will be required to complete specific surveys assessing subject 
eligibility to perform MRI scanning, and a questionnaire assessing their handedness. 
 
 
 

Page 15 of 35 
(2) Cognitive Performance 
 
Project A: 
Cognition 
Astronauts with perform NASA’s Cognition test battery (10 neuropsychological tests 
always performed in the same sequence) according to the schedule below (see 4.0 d). 
Some of the tests are shared with NASA’s Standard Measures project. A detailed 
description of the Cognition test battery can be found in Basner, M., et al. (2015). 
"Development and validation of the Cognition test battery " Aerospace Medicine and 
Human Performance 86(11): 942-952. 
 
 
Project B: 
Spatial Cognition 
Astronauts will perform a set of cognitive tests specifically targeting spatial learning and 
memory and navigation. The test batteries will be divided into:  
- 
Spatial Cognition Test Battery 1: includes the computerized tests and surveys to be 
applied both during ground and inflight sessions.  
- 
Spatial Cognition Test Battery 2: includes the computerized tests and surveys to be 
applied during ground sessions only.  
 
Outside of the test batteries, a survey assessing the level of computer experience will 
also be requested on-ground. It shall take place only once and it can be filled out any 
time during the pre-flight period. 
 
When performing the tests or filling out the surveys, the subject shall not interrupt the 
test or survey but can stop for short periods in between tests and surveys. 
 
For ground sessions: The test batteries shall be performed with the computer in seated 
position, at room temperature, preferably in a quiet room. Headphones may be used 
not only for noise cancelling purposes, but also in case specific instructions need to be 
provided during test batteries. On-ground, one of the tasks – Navigation Search – will 
not only be performed in seated position with the computer, but also in standing 
position with a head-mounted display with controllers (see Table 1). During this task, 
subjects will move freely within a circular area (about 4 m diameter).  
 
For inflight sessions: In order to keep cognitive testing standardized between the ground 
and in-flight sessions, the Test Battery shall be performed with the computer in a fixed 
position. There is no special requirement on how the subject shall be fixed, providing 
that the subject is comfortable, not free floating and, preferably, in a quiet 
environment. Headphones may be used not only for noise cancelling purposes, but also 
in case specific instructions need to be provided during test batteries. 
 
Table 1 provides an overview of the Test Batteries 1 and 2 compositions and in which 
sessions they shall be applied. 
 

Page 16 of 35 
Table 1: Test Batteries 1 and 2 composition and definition. It does not include the level of computer 
experience survey, as this will be filled in only once, outside the test batteries. 
 
 
Test Battery 1 & 2 
Visual Analogue Scales (VAS) 
Purpose:  To assess mood, fatigue and sleep 
Description: To assess mood, fatigue and sleep, affective 
states, visual analogue scales (VAS) will be used. 
Test Battery 1 
Spatial Updating 
Purpose:  To assess spatial updating 
Description: Subjects initially have to encode the position of an 
object presented at unpredictable positions in a virtual 
environment. The object then gradually disappears, followed 
by a static or dynamic delay phase. In the dynamic delay phase 
subjects experience a virtual forward translation and rotation, 
after which subjects have to point toward the remembered 
location of the object. In contrast, in the static delay phase 
they remain stationary instead of moving forward, thus 
requiring them to point toward the original location of the 
target object at retrieval.  
Publication: Nat Neurosci 11, 1223-1230 (2008) 
Four Mountains Task 
Purpose:  To assess topographical memory 
Description: To specifically target topographical memory, a 
version of the Four Mountains Task will be performed. 
Subjects will be asked to briefly study a landscape scene. 
Subsequently, they will be shown several variations of the 
previously displayed scene from a novel viewpoint and under 
altered non-spatial conditions and they have to identify, which 
of these scenes is identical to the one that was initially 
presented.  
Publication: Front Hum Neurosci 6, 338 (2012). 
Point to Origin Task  
Purpose:  To assess path integration 
Description:  A sparse visual flow is presented on a screen to 
the subjects, and supported by auditory information. At the 
end of each path, subjects will be asked to point back to the 
origin by rotating an arrow. In addition, they will also have to 
estimate the distance of the homing vector (linear distance to 
the point of origin). After each trial, subjects will be asked to 
rate the level of difficulty of the trial.  
Publication: J Exp Psyc: Human Perception and Performance 
31, 1199 (2005); Sci Rep 5, 11426 (2015). 
Navigation Search 
Purpose: To assess spatial memory and spatial updating  
Description: Subjects will be shown a virtual environment that 
contains a number of boxes. Some of the boxes contain a 
target, which can only be seen when the box is approached 
from the front to a close distance.  The task is to locate and 
collect all targets as quickly as possible. Each session the task 
will be performed in two different conditions, differing in their 
background (night vs. day). On-ground the task will also be 
administered with a head mounted display and controllers, 
while moving in a small circular area (radius: 4 m). 

Page 17 of 35 
 
Test Battery 2 
Perspective Taking 
Purpose:  To assess spatial orientation ability, i.e. the ability to occupy new 
imaginary positions within a configuration of objects  
Description: A picture with several objects is displayed on a screen. On each item, 
the subject is asked to imagine being at the position of one object in the display 
(the station point) facing another object (defining their imagined heading or 
perspective within the array) and is asked to indicate the direction to a third 
(target) object.   
Publication: Intelligence 32, 175-191 (2004) 
Virtual Mazes 
Purpose: To assess spatial navigation 
Description: This test comprises several tasks. During each task a 3D environment 
is presented to the subject from a first-person perspective. The subject is then 
asked to move to a target using different cues, starting from different positions 
as quickly as possible. Subjects may perform variations of this task during 
preflight- and postflight testing, including different environments and set ups, 
and complete questions about their strategies. 
Publication: Hum Brain Mapp 36, 1265-1277 (2015); Frontiers in aging 
neuroscience 4, (2012); Neurobiol Learn Mem 117, 42-50 (2015) 
Cognitive Mapping 
Task 
Purpose:  To assess spatial memory formation 
Description: Subjects will be asked to first learn a route through a novel virtual 
large realistic environment, consisting of a network of paths, non-specific 
buildings, and distinctive landmarks. They are instructed that they are required to 
learn a long, indirect route through the environment and will be asked to provide 
directions during a subsequent probe trial. Following the completion of the 
learning phase, subjects will be asked to perform a cognitive map test by 
indicating spatial relationships between two specific landmarks encountered 
along the route during the learning phase. Importantly, the target landmark is 
never visible from the respective trial location. The pointing error between the 
correct direction and estimated direction between the current location and the 
target landmark will be used to quantify spatial memory. After completion of the 
task subjects will perform a debriefing questionnaire about their sense of 
direction and a survey about their response strategies. Subjects may perform 
variations of this task pre- and postflight. 
Publication: Hippocampus 26, 185-193 (2016) 
 
 
(3) Biospecimen 
 
Project B: 
Venous Blood Collection 
 
A total of 7.5 ml of blood shall be collected in fasting state (water is allowed) following 
standard procedures. After blood collection the blood samples shall be centrifuged and 
moved to on-orbit cold stowage. 
 
Scheduling and session constraints 
- 
No EVA, EVA training or physical exercise 12 hours prior to start of blood collection, 
cognitive testing and MRI 

Page 18 of 35 
- 
In-flight, no sleep shifting of more than 2 hours three days prior to data collections, 
and no time shifting of 6 or more hours one week prior to data collections (for each 
hour of sleep shifting, one day should pass between the actual time shift and the 
start of cognitive testing and neuroimaging). For ground sessions, the sleep shift 
requirements can be relaxed as needed to fit the crew’s schedule constraints, but 
the deviation should be kept to the minimum possible. 
- 
Blood collection in fasting state (water is allowed).  
- 
It is recommended that subjects void immediately prior to cognitive testing and 
neuroimaging to avoid interruption of these activities due to visit to the toilet. 
- 
No caffeine consumption 4 hrs prior to blood collection, cognitive testing and MRI. 
- 
No alcohol consumption 12 hrs prior to blood collection, cognitive testing and MRI. 
- 
Ideally, no other cognitive testing (i.e., tests not related to this experiment) should 
be scheduled on the day of cognitive testing or neuroimaging sessions. If this is not 
possible, deviations to the above requirement shall be coordinated with the project 
PIs on a case by case basis. 
- 
fMRI, MRI & Spatial Cognition must be at least 24 hours after Gadolinium and/or 
Dotarem contrast application 
- 
No Nitroglycerin, Aminophylline or Proparacaine use within 8 hours prior to 
Cognition or Spatial Cognition. 
- 
fMRI, MRI & Spatial Cognition either before or at least 24 hours after administration 
of Fluorescein, Definity, LexiScan or Omnipaque. No Fluorescein, Definity, LexiScan 
or Omnipaque use within 8 hours prior to Cognition or Spatial Cognition. 
- 
fMRI, MRI, Spatial Cognition, and Cognition must be done before dilation of the eye 
with Tropicamide, Phenylephrine or other dilating eye drops if on same day. 
 
b) Will subjects or their health care provider be given the results of any experimental 
tests that are performed for the study? Yes____ No __ X___ 
 
If “yes”, please describe the tests, provide a rationale for providing subjects with the 
experimental test results and explain what, how and by whom subjects and their health 
care provider will be told about the meaning, reliability, and applicability of the test 
results for health care decisions. 
 
c) Will subjects undergo any study procedures or tests off-site? Yes __X__ No____ 
fMRI scans will be performed at UTMB’s Victory Lakes scanning facility.  
 
d) Time commitment: Indicate how much time will be required of the subjects, both per 
visit and in total, for the study. Do not include time spent passively, such as periods 
when a monitoring device is worn, but no special activity is required.

Page 19 of 35 
Project A time commitment: 
 
Preflight 
Test/Activity  
Schedule 
Crew Time 
(min)  
Post-flight 
Test/Activity 
Schedule 
Crew Time 
(min)  
per 
session 
total 
per 
session 
total 
Cognition 
familiarization 
L-180* 
60 
60 
Cognition debrief 
R+95 
30 
30 
Cognition 
L-180, L-120* 
30 
60 
Cognition 
R+6*, R+30*, R+90, 
R+180, R+360 
30 
150 
Cognition with fMRI 
Cognition 
familiarization 
L-60 
45 
45 
 
 
 
 
Combined fMRI with 
Cognition (Project A) 
and MRI Spatial 
Cognition (Project B) 
L-59 
90+ 
90+ 
Combined fMRI with 
Cognition (Project A) 
and MRI Spatial 
Cognition (Project B) 
R+1-7, R+30 
90+ 
180 
*shared with ISS Crew Standard Measures project +shared with Project B, total scan time 180 min 
 
 
TOTAL PREFLIGHT BDC (per subject) 
255 
TOTAL POSTFLIGHT BDC (per subject) 
360 
 
Test/Activity 
Schedule 
Crew time (min) 
per 
session 
total 
Cognition (1 month crew) 
R-14* 
30 
30 
Cognition (2 month crew) 
FD 15-30*, R-14* 
30 
60 
Cognition (6 months crew) 
FD 15-30*, 60, 120, R-14* 
(reserve sessions @ FD 90 and FD 150) 
30 
120 (to 
180) 
Cognition (12 months crew) 
FD 15-30*, 60, 120, 180*, 240, 300, R-14* 
(reserve sessions @ FD 90, 150, 210, 270, 330) 
30 
210 (to 
360) 
TOTAL IN-FLIGHT CREW TIME (per subject): 1-month crew 
30 
TOTAL IN-FLIGHT CREW TIME (per subject): 2-months crew 
60 
TOTAL IN-FLIGHT CREW TIME (per subject): 6-months crew 
120 (to 
180) 

Page 20 of 35 
 
 
 
 
 
TOTAL IN-FLIGHT CREW TIME (per subject): 12-months crew 
210 (to 
360) 
*shared with ISS Crew Standard Measures project 
 

Page 21 of 35 
Project B time commitment: 
 
Preflight 
Test/Activity  
Schedule 
Crew Time 
(min)  
Post-flight 
Test/Activity 
Schedule 
Crew Time 
(min)  
per 
session 
total 
 
 
per 
session 
total 
Spatial Cognition 
Familiarization 
L-180 
90 
90 
 
 
 
 
Spatial Cognition Test 
Battery I 
L-180, L-60 
60 
120 
Spatial Cognition Test 
Battery I 
R+6, R+30, R+180, 
R+360 
60 
240 
Spatial Cognition Test 
Battery II 
L-179, L-59 
90 
180 
Spatial Cognition Test 
Battery II 
R+6, R+31, R+181, 
R+361 
90 
360 
MRI Spatial Cognition 
(Project B) 
L-179 
130 
130 
MRI Spatial Cognition 
(Project B) 
R+181, R+361 
130 
260 
Combined fMRI with 
Cognition (Project A) 
and MRI Spatial 
Cognition (Project B) 
L-59 
90+ 
90+ 
Combined fMRI with 
Cognition (Project A) 
and MRI Spatial 
Cognition (Project B) 
R+1-7, R+30 
90+ 
(95 on 
R+1-7) 
185 
Blood draw 
L-180, L-60 
15 
30 
Blood draw 
R+5, R+30, R+180, 
R+360 
15 
60 
+shared with Project A, total scan time 180 min; R+1-7 includes additional 5 min for re-familiarization with the MRI protocol (total of 
185 min) 
TOTAL PREFLIGHT BDC (per subject) 
640 
TOTAL POSTFLIGHT BDC (per subject) 
1105 
 
Test/Activity 
Schedule 
Crew time 
(min) 
per 
session 
total 
Spatial Cognition (1 month crew) 
R-14 
60 
60 
Blood Draw (1 month crew) 
R-14 
(time covered by other experiments) 
85 
85 
Spatial Cognition (2 months crew) 
FD 15-30, R-14 
60 
120 
Blood Draw (2 months crew) 
FD 15-30, R-14 
(time covered by other experiments) 
85 
170 
Spatial Cognition (6 months crew) 
FD 15-30, 60, 120, R-14 
60 
240 

Page 22 of 35 
 
  
 
 
Blood Draw (6 months crew) 
FD 15-30, 60, 120, R-14 
(time covered by other experiments) 
85 
340 
Spatial Cognition (12 months crew) 
FD 15-30, 60, 120, 180, 240, 300, R-14 
60 
420 
Blood Draw (12 months crew) 
FD 15-30, 60, 120, 180, 240, 300, R-14 
(time covered by other experiments) 
85 
595 
TOTAL IN-FLIGHT CREW TIME (per subject): 1-month crew 
145 
TOTAL IN-FLIGHT CREW TIME (per subject): 2-months crew 
290 
TOTAL IN-FLIGHT CREW TIME (per subject): 6-months crew 
580 
TOTAL IN-FLIGHT CREW TIME (per subject): 12-months crew 
1015 

Page 23 of 35 
 
e) Facilities: Please provide a description of the facilities used in this research. 
Pre/Post-flight:  
 NASA Johnson Space Center, 2101 E NASA Pkwy, Houston, TX 77058, USA  
 UTMB Health League City, 2240 Gulf Fwy S, League City, TX 77573, USA  
 
f) Adequacy of Resources: Principal investigators must have the necessary resources 
required to conduct the proposed research in a way that assumes the rights and 
welfare of participants are adequately protected. Describe the resources you have in 
place to conduct this study. Examples may include personnel, funding, and equipment 
required to perform the study. 
 
The principal investigators and their teams have all necessary resources to conduct 
the proposed research in a way that assumes the rights and welfare of participants 
are adequately protected. Adequate office space for data analysis is available at the 
University of Pennsylvania and Charité Berlin. Specific funding including personnel, 
hardware and traveling costs will be provided by NASA and the German Aerospace 
Agency (DLR). 
 
g) Please provide/describe the test termination or withdrawal criteria guidelines and 
associated rationale. 
 The subject experiences discomfort or pain that cannot be alleviated  
 The subject voluntarily withdraws from the study 
 The researcher believes that it is not in the best interest of the test subject to 
stay in the study  
 There is any problem with following study related instructions 
 There is any serious complication during the study  
 There is inappropriate behavior 
 The study is suspended or canceled 
 The subject’s information is or becomes unusable for any reason 
 Events beyond NASA’s control occur, for example: fire, explosion, disease, 
weather, floods, terrorism, wars, insurrection, civil strife, riots, government 
action, or failure of utilities 
 
4.1   
Equipment Used During Research 
 
Unmodified, commercially available devices that are being used in accordance with 
 
their intended use and that are already FDA certified or CE marked as being MDD 
 
93/42/EEC compliant do not require additional assessment. An exception to this is any 
 
device whose primary function is to radiate or store electrical, thermal, or mechanical 
 
energy during their operation. In this case, a safety assessment will be performed to 
 
determine the “suitability of intended use” and you could be contacted with a request 
 
for specific data. 
 

Page 24 of 35 
 
Any device that is modified from the commercially available version, that will not be 
 
used in accordance with the manufacturers recommendations, or that has been 
 
designed and built for research purposes will require an additional assessment. 
 
 
Computers and other equipment used to collect and process your data do not need to 
 
be listed however software used to control potentially hazardous test operations should 
 
be identified and is subject to review. 
 
 
Any device that will be in electrical contact with the research subject must show 
 
compliance with ANSI/AAMI ES1-1993, Safe Current Limits for Electromedical Apparatus. 
 
a)  Having read the above statements, will any equipment be used during research 
(i.e., for retrospective studies answer "No")?   Yes ____ No__X__ 
  
If “no”, then continue to the next numbered section. If “yes”, then answering (b) and 
(d) are required. 
 
b) Are all of the devices that you are using in this research: 
 
1. Unmodified and commercially available 
2. Used in accordance with manufacturers recommendations 
3. FDA certified or CE marked as being MDD 93/42/EEC 
Has been previously reviewed by the NASA JSC Test Safety Office 
 
Yes ____No____ 
 
If “yes”, skip to (d).  If “no”, provide the common name for each device and 
 
include the manufacturer and the model number of your specific device(s). 
 
c) For each of the devices listed in 4.1 (b) attach the following additional information 
so that a safety assessment may be performed. Please attach supporting 
documentation to the Local Site Documents section. 
 
1. A description of any hardware modifications that have been made to 
commercially available equipment. Explain how these modifications have not 
modified the safety of the hardware. Attach design data as required to 
support these statements. 
2. A description of how operations that are not in accordance with the 
manufacturers recommendations will not affect the research subject safety. 
3. Hardware that is not commercially available or that has been built only to 
support research requires additional information. 
 
For electronic equipment include a: 

Page 25 of 35 
 
block diagram 
 
detailed schematic 
 
description of circuit operations 
 
description and test data for software that controls critical functions For 
mechanical devices include: 
 
detailed design data 
 
structural or loads analysis showing factors of safety 
 
Research Device Information Documents 
Research Device Document Description 
 
Date Created  
Date Modified  
There are no items to display 
 
d) Is the primary function of any of the devices used in your protocol to radiate or 
store electrical, thermal, or mechanical energy that could come into contact with 
the research subject during their operation?  Include devices even if they are FDA 
certified or MDD 93/42/EEC complaint and CE marked. Do not include radiographic 
imaging or ultrasound hardware.    
 
Yes____ No__ X__ 
 
If “yes”, provide the common name for each device and include the manufacturer 
and the model number of your specific device(s). You will be contacted with a 
request for specific data if required. 
 
5.0    
Remuneration Payment to Participants 
Will any subjects receive remuneration for study participation? Yes__X__ No____ 
 
If “yes”, please describe the remunerations subjects will receive and in what form. 
Control subjects will be numerated according to standard policies for participation 
suggested by FAP/BHP and/or ESA/DLR Standard policies, if applicable. 
 
5.1    
Costs Related to Participation 
a) Select all categories indicating costs which participants or their insurance 
companies will be responsible for: 
__X__Participants will have no costs associated with this study 
____Study Related procedures 
____Study Drugs or Devices 
____Other 
b) If study participants or insurance companies will assume any costs for this study, 
describe the procedures, drugs, or devices for which the participants or their 
insurance companies must assume costs: 
N/A 
5.2  
Study Population 

Page 26 of 35 
a) General description of the study population: 
Astronauts participating in ~1 to 2 month, 6-month, and 12-month duration space 
missions. Subjects participating in the ground control experiment will be matched 
for age, sex, and educational background, but must not necessarily be astronauts. 
 
b) Target number of non-astronaut participants: 
30 
c) Target number of astronaut participants: 
30 
d) Does this investigation have an open ended study population? Yes____ No__X__ 
If “yes”, please describe the rationale for an open ended population. 
 
e) Please list the inclusion and exclusion criteria for enrollment of normal, healthy 
volunteers (Non-Astronauts) and, if applicable, astronauts : 
 
 
1. 
Subjects who do not comply with the mission duration (Refer to 3.2 b)) 
2. 
Subjects that do not comply with the MRI testing requirements. The following 
conditions may exclude the subject from MRI scanning or require additional 
examination to assess specific contraindications: 
- 
Tinnitus;  
- 
Sensori-neural hearing loss > 30 dB;  
- 
Pace-maker or internal defibrillator;  
- 
metallic implants (e.g. orthopedic plates after bone fractures, joint replacements, 
surgical staples or clips, artificial heart valves, stents, cava filters);  
- 
Metallic splinters (e.g. after an accident or due to war injury);  
- 
Non-removable dental brace;  
- 
Intrauterine contraceptive device;  
- 
Cochlear implant (implanted hearing device);  
- 
Medication pump;  
- 
Acupuncture needle;  
- 
Other foreign bodies/objects which are non-removable;  
- 
Pregnancy (or its possibility);  
- 
Previous brain and/or heart surgery. 
- 
Tattoos and/or permanent make-up in the body (some inks contain metallic 
particles). 
 
f) If pregnant women are excluded from participation please provide a justification: 
 
Female subjects in this study are either astronauts or will model those in the 
astronaut population for whom participation in space missions is not allowed during 
pregnancy. 
 

Page 27 of 35 
g) If there are any age, ethnic, language, or gender-based exclusion criteria, please 
provide justification. Additionally, if women of child-bearing potential are to be 
excluded please provide a scientific or medical justification for their exclusion:  
 
Female subjects in this study are either astronauts or will model those in the 
astronaut population for whom participation in space missions is not allowed during 
pregnancy. 
 
5.3  
Risk Assessment 
a) Please describe the risks associated with this study : 
 (Women of child-bearing potential or pregnant women: If your study includes pregnant 
 subjects and/or women of child-bearing potential please include the risks to pregnant 
 females and fetuses. If there are currently no known risks please add the following 
 statement “Currently there are no known risks to a pregnant female and a fetus for 
 this protocol. However, unknown adverse fetal events may occur, even in the absence 
 of maternal symptoms.”) 
 
(1) Risk associated with exposure to strong magnetic field.  
 
(2) Risk of a metallic object flying through the air toward the MRI magnet and hitting a 
person. 
 
(3) Risk of an unexpected abnormality being observed in a specific subject's MRI even 
though scans are not intended for diagnostic purposes. These abnormalities are 
termed “incidental findings.”  
 
(4) Risk associated with feeling uncomfortable or claustrophobic while inside the MRI 
magnet. 
 
(5) Loud noise while in MRI scanner. 
 
(6) There is the potential that subjects may develop a headache or motion sickness 
and/or experience stress during cognitive testing due to the amount of computer 
work and/or moving in 3D environments. 
 
(7) There may be some discomfort associated with the collection of the blood samples, 
including possible bruising of the arm, redness, swelling around the site, bleeding at 
the site, dizziness, fainting, sweating, coldness of skin, numbness and tingling of 
hands and feet, nausea, vomiting, possible visual disturbance, syncope and injury 
fall from fainting. In some cases, more than one venipuncture may be necessary. 
Rare adverse effects include thrombosis of the vein due to trauma and infection 
which results in thrombophlebitis. 

Page 28 of 35 
b) Please describe how you are going to minimize the risks: 
(1) The levels of energy used to perform magnetic resonance measurements are far 
less than are used in a X ray, and many patients have been safely studied using 
magnetic resonance techniques. Subjects will also undergo a checklist before 
entering the MRI room to verify that they do not have anything harmful in or on their 
body. 
(2) We require that all people involved with the study remove all metal from their 
clothing and all metal objects from their pockets. No metal objects are allowed to 
be brought into the magnet room at any time. In addition, once subjects are in the 
magnet, the door to the room will be closed so that no one inadvertently walks into 
the magnet room. 
(3) Most incidental findings have no significant health consequences, but in a small 
percentage of cases further evaluation or treatment may be indicated. If an 
incidental finding is noted in a subject's MRI data, the subject will be notified and 
given a written report describing it. It will then be up to the subject to pursue it with 
his/her physician. Although study personnel may be able to provide some advice, 
the decision of whether and how to pursue an incidental finding can only be made 
by the subject's physician who has  knowledge of the subject's medical  history. 
(4) If a subject becomes uncomfortable inside the magnet, the subject may withdraw 
immediately from the study. They will be able to talk to the operator throughout 
the study via intercom,  and will be able to let us know right away if they want to 
stop the study and get out of the scanner. 
(5) Participants will wear foam earplugs and / or headphones to reduce the loud noises 
made by the scanner. 
(6) If subjects feel upset and emotional discomfort while participating in the study, 
subjects may contact the PI. Should they feel that they are unable to complete the 
task during the course of the study, they are free to withdraw their consent to 
participate in this experiment. 
(7) Sterile disposable hardware will be used for all blood drawing procedures.  In the 
event of fainting during the blood draw, a  medical evaluation will be performed. 
Food and drink will be available. 
 
c) Has a hazard analysis been done? Yes__X__ No_____ 
If “yes”, please attach the documentation of the analysis. 
 
5.4  
Potential Benefits and Alternatives 
a) Are there potential direct benefits to study subjects? Yes_____ No__X___ 
If “yes”, please describe any potential for direct benefits to participants in this study 
 
b) Please describe any potential benefits to Society or Space Flight: 
There is no direct benefit to subjects. However, given the neurocognitive functions 
required for effective performance in space, our knowledge on how humans will 
cope with living for prolonged periods of time in an ICE environment is extremely 
limited (only 4 humans have spent consecutively more than 1 year in space). The 

Page 29 of 35 
data we propose to collect will, for the first time, reliably demonstrate whether 
prolonging mission duration to one year will have detrimental effects on general 
cognitive performance, spatial cognition and hippocampal plasticity relative to the 
shorter 6-month and 2-month missions. 
 
c) Please describe any alternatives to study participation available to prospective 
subjects: 
Choose not to participate 
 
6.0 
Privacy & Data Confidentiality 
 
Subject privacy and data confidentiality must be maintained in accordance with 1) NASA 
 
Policy Directive (NPD) 7100.8, “Protection of Human Research Subjects”; 2) NASA 
 
Procedural Requirements (NPR) 7100.1A, “Protection of Human Research Subjects”; and 
 
3) to the extent allowed by Federal law. 
 
a)     Please select all data types that will be collected: (check all that apply) 
 
___X___Name 
___X___Age  
___X___Gender 
___X___Race  
_______Full Face Photographic Image   
_______Full or partial Social Security Number 
___X___Telephone number 
___X___Email Address 
___X___Mission 
___X___Relative Day 
___X___Space Flight Duration 
___X___Crew Position 
___X___Other, please specify: Neurobehavioral / psychological data, 
biochemical data, neuroimaging data. 
 
This study is part of a complement of interrelated studies that will be 
implemented as one study. 
 
This specific investigation is requesting data from the following other 
investigations in this complement or from other experiments collecting as 
defined in the crew’s individual Data Sharing Plans:  
 
Standard Measures (Pro2231, PI: Clement): 
 Cognition 
 Blood (Insulin-like growth factor 1, Vascular endothelial growth factor) 
 Cellular profile 

Page 30 of 35 
 Actigraphy 
 Biochemical Markers 
 Microbiome 
 Sleep 
 Sensorimotor 
 
NINSCAN (STUDY00000247, PI: Zhang): 
 Blood (Brain-derived neurotrophic factor) 
 
This specific investigation is also requesting the following from Medical 
Operations (MEDB): 
 
 T1 and T2 weighted structural scans, DTI Sequence (Med Ops MRI, MEDB 
1.10) 
 WinSCAT (Med Ops, MEDB 7.4) 
 Radiation - Personal Dosimetry (Med Ops, MEDB 3.1) 
 Exercise Logs (Med Ops, ASCR Exercise, MEDB5.2) 
 Medication Logs (Med Ops, MEDB 1.1/1.3) 
 Clinical Lab Assessment (Med Ops, MEDB 2.1) 
 Physical Fitness Evaluation: Functional Fitness (Med Ops, MEDB 5.1) 
 Cycle Ergometer/Aerobic Functional Capacity (Med Ops, MEDBN 3.07) 
 
This specific investigation is also requesting the following Environmental/ECLSS 
variables: 
 
 CO2 Levels 
 Radiation - Station Level 
 Ambient Temperature 
 Humidity 
 Air Pressure 
 O2 Levels 
 
This specific investigation is also requesting the blood draw spreadsheet and the 
timeline from day before until end of each session from ROI. 
 
b) How will the data and/or biospecimens for this study be collected, recorded, and 
by whom? 
Specific Aims A3 and B1: Neuroimaging will be performed using a 3T Siemens 
scanner equipped with a head coil and a projection system. A laptop, running 
Presentation® (Neurobehavioral Systems, Inc., Berkeley, CA, USA) and in-house 
developed software and an MRI-compatible response box (Lumina, Cedrus 
Corporation, San Pedro, CA, USA/Current Designs Inc., Philadelphia, PA, USA). 

Page 31 of 35 
 
Specific Aims A1, A2, and B2: Cognitive Performance. The Cognition battery will be 
administered with calibrated laptops at JSC and on the ISS. Cognitive tests and VAS 
will be administered using laptops and/or iPads, running executable files provided by 
the science team. Responses shall be logged using the keyboard and/or a standard 
joystick. During on-ground testing, some tests will not only be executed using a 
laptop, but it will also be administered via head mounted display with controllers 
(e.g., HTC Vive). 
 
Specific Aims B3: Blood draws are obtained via venipuncture using standard blood 
collection equipment will be employed. After collection samples will be immediately 
centrifuged for 10 min and then aliquoted in up to 10 tubes of 250 microL each. All 
samples will be stored at –80°C (–68°C to –100°C). 
 
The data will be collected by the Co-PIs Dr. Basner (Specific Aims A1-3) and Dr. Stahn 
(Specific Aims B1-3) with the help of Dr. Stahn’s team and the Behavioral Health and 
Performance Lab at JSC (Co-I Dr. Roma). 
 
c) Select how data and/or biospecimens will be identified: 
_____No identifiers will be obtained by the investigators. 
__X__Identifiers are obtained. However, data is coded and an investigator has the 
code key.  
 
d) Select how data and/or biospecimens will be stored (select all that apply): 
___X__Data are kept in locked file cabinet 
___X__Data are kept in locked office or suite 
___X__Electronic data is encrypted and protected with a password 
___X__Data are stored on a secure network 
______Biological samples are kept in a locked freezer  
___X__Other, please specify: 
Any paper records generated for this investigation will be coded using non-
attributable codes. Such records will be stored in locked filing cabinets and in 
locked rooms. Electronic records for this investigation also will be coded using 
the non-attributable codes. Any electronic records will be stored on computers 
located in locked rooms in the offices. These computers are password protected 
and meet the information technology security requirements. If Internet 
connection is available, encrypted data will be transmitted to secure servers.  
 
e) Please describe the encryption method employed to protect the data. 
All cognitive test and neuroimaging data will be encrypted. The Cognition database 
is maintained and operated by Penn Medicine Academic Computing Services 
(PMACS) on their secure servers. User authentication to the central database is 
implemented using the password hashing algorithm described in RFC 2898, 

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recommended for use by federal agencies. The encryption method we use to protect 
the data while "in-motion" to the server is a 256-bit AES (Advanced Encryption 
Standard) encryption algorithm. Any identifiable information will be stripped from 
all data sets and will only be accessible by the Co-PIs or their designee. The 
electronic data is de-identified and encrypted automatically at the time of collection. 
Only the Principle Investigator or his designee will be able to access the data. 
 
f) Please describe the authentication methods use to ensure the security of the 
database. 
To validate the identity of data users and prevent unauthorized access, all hard 
drives and each file will be protected using password-based authentication and the 
following requirements: The password must (i) not contain significant parts of the 
user name, first name and/or last name of the user, (ii) have at least 8 characters 
and (iii) contain three out of the following four categories: capital letters, small 
letters, numbers, and symbols. 
 
g) Who, other than the specified study team, will have access to the study records or 
data? Specify their name, role, and affiliation. 
None. 
 
h) How will the investigator maintain data privacy in the test setting(s)? 
Testing is restricted to the subject and the test operators only, unless a subject gives 
permission for an observer to attend. Subjects will be pseudonymized. The coding 
sheet will be kept in a locked office. All data, including electronically stored data and 
hard copies will be labeled with the designated subject code. The coding sheet will 
be retained by the investigator team only and will not be released without his or her 
consent unless specifically required by law. Information extracted from medical 
records (if applicable) will be treated in the same fashion as data gathered during 
experimentation. 
 
i) What are the consequences to participants of a loss of privacy (e.g., risks to 
reputation, insurability, and other social risks)?  
The researchers of this study will do everything in their power to ensure the 
participant does not experience a loss of privacy from their participation in this 
study. This study collects data on current behavioral/psychological states, and brain 
structure and function. It includes a survey consisting of visual analog scales that ask 
the subjects to indicate when they went to bed and when they got up, and whether 
they a conflict within the past 3 days and if so if it was solved. In addition, it asks 
subjects to provide a rating between 0 and 100 on their sleep quality, fatigue, 
tiredness, exhaustion, stress, workload, happiness, sickness, motion sickness, 
depression and loneliness. Due to the small sample size, and especially for astronaut 
subjects in which other factors make it difficult to ensure non-attributability of the 
data, the loss of privacy could generally pose a risk to their reputation. However, 
given that these scales are not considered valid tools to diagnose any 

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neuropsychiatric disorders and/or any other diseases, and also assess states, but not 
traits, this risk is suggested to be minimal. 
 
j) If coded or identified data will be released, specify the persons/agencies to whom 
the information will be released. Please also indicate the provisions that will be 
taken to assure that the transmission of the data will be maintained confidential: 
Data will not be released to any persons other than those on the study team. In case 
any data needs to be transmitted, we use Transport Layer Security (TLS), Secure 
Socket Layers (SSL), or secure transfer protocol (sFTP) for sending and receiving files 
over the network. 
 
k) When the study is completed and the data is submitted and accepted by NASA, 
please indicate your plans for the destruction of the local dataset. 
De-identified data will be kept with the Co-PIs at the University of Pennsylvania and 
at Charité University Medicine Berlin, Germany. 
 
l) Is this study collecting or using health information? Yes __X__No____ 
 
m) Describe any additional steps taken to assure that identities of subjects and any of 
their health information, which is protected under the law, is kept confidential. If 
photography, video or audio recordings will be made as part of the study, 
disposition of these recordings should be addressed here and in the consent form. 
Any photo or video recordings taken will be treated as any other data from subjects 
and will be kept separately. 
 
n) Please describe how data and biospecimens will be handled if a participant 
withdraws their consent. 
The data will contribute to the specified analyses unless the participant explicitly 
asks that their data shall not be used this way. 
 
7.0    
Process of Consent 
a) Describe when, where, and how potential participants will be recruited. 
The consent process will be initiated at the JSC with an informed consent 
presentation to prospective study participants by the science team. 
 
b) Describe how, when, and where the consent process and documentation will be 
completed. 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make informed decisions about their 
participation in this study. In addition, the investigators will discuss all the study 
procedures with the subjects, and will make sure that all their questions are 
answered. The formal consent of a subject, using the IRB-approved consent form, 
will be obtained before that subject is submitted to any study procedure. All aspects 

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of the protocol and procedures are disclosed to the subjects. Subjects' participation 
in this study is completely voluntary, and subjects may withdraw at any time without 
prejudice. 
 
c) Who will obtain informed consent from participants for this protocol? 
The Co-PIs or their designee will obtain consent. 
 
d) Describe the consent withdrawal procedures 
 
Study participants can contact the Co-PIs or their designees listed on the consent 
form at any time to withdraw from the study. 
 
7.1 
Drugs, Devices, Biologics, foods and dietary supplements 
 
 If no drugs, devices, biologics, foods or dietary supplements are being used please skip 
 
this section 
a) Does the study specify the use of an approved drug or biologic, use an unapproved 
drug or biologic, or use a food or dietary supplement to diagnose, cure, treat, or 
mitigate a disease or condition? 
 Yes____ No__X__ 
 
If “yes”, please list name(s) here and complete the drug section of the eIRB 
smartform. 
 
 
 
b) Does the study evaluate the safety or effectiveness of a device? Yes _____No__X__ 
 
 
 
If “yes”, please list name(s) and complete the device section of the eIRB smartform. 
 
7.2      Data and Safety Monitoring Plan 
 
a) Please provide a plan for data and safety monitoring for this study. 
The study will be monitored only by the study investigators and/or sponsor, and 
without a formal Data Safety Monitoring Plan. 
 
b) Describe the clinical criteria for withdrawing an individual subject from the study 
due to safety or toxicity concerns. 
A subject will be withdrawn from the study if any contraindications for performing 
MRI scans should apply. Subjects will also be withdrawn from the study if any of the 
neurobehavioral measures should cause considerable discomfort (e.g. develop a 

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headache or motion sickness and/or feeling highly stressed), and potentially impair 
their well-being and performance. 
 
c) Summarize any pre-specified criteria for stopping or changing the study protocol 
due to safety concerns. 
Personal discomfort such as headaches, motion sickness and/or highly increased 
stress levels observed during cognitive testing, that lead to mood disturbances and 
performance impairments.