Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in Traumatic Brain Injury
Phase: NA
Conditions: Brain Injuries, Traumatic
Sponsor: Shirley Ryan AbilityLab

 
 
PROTOCOL TITLE: 
Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in 
Traumatic Brain Injury 
 
NCT number: NCT04890639 
 
Document date: October 21, 2025 
 
Principal Investigator: 
Jordan Grafman, Ph.D. 
Director, Brain Injury Research 
Chief, Cognitive Neuroscience Lab 
Think + Speak Lab 
Shirley Ryan AbilityLab 
 
Professor, Department of Physical Medicine & Rehabilitation, Neurology, Cognitive 
Neurology and Alzheimer’s Center, Department of Psychiatry, Feinberg School of 
Medicine & Department of Psychology, Weinberg College of Arts and Sciences 
Northwestern University 
 
 
 
Supported by: 
Exploratory Neuroscience Research Grant from the National Institute of Neurological 
Disorders and Stroke (National Institutes of Health) 
 
Grant number: 
R21 NS1148150-01A1 
 
 
 

 
2
TABLE OF CONTENTS 
 
Institutional Review Board Protocol………………………………………………………….3 
Statistical Analysis Plan Update…………………………………………………………….23 
Informed Consent Form……………………………………………………………………...25 
 

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Institutional Review Board Protocol 
 
PROTOCOL TITLE: 
Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in 
Traumatic Brain Injury 
 
PRINCIPAL INVESTIGATOR: 
Name: Jordan Grafman, Ph.D.  
Director, Brain Injury Research 
Chief, Cognitive Neuroscience Lab 
Think + Speak Lab 
Shirley Ryan AbilityLab 
  
Professor, Department of Physical Medicine & Rehabilitation, Neurology, Cognitive 
Neurology and Alzheimer’s Center, Department of Psychiatry, Feinberg School of 
Medicine & Department of Psychology, Weinberg College of Arts and Sciences 
Northwestern University 
 
Telephone Number: 312-238-1495 
Email Address: jgrafman@northwestern.edu 
E-Mail Address: jgrafman@sralab.org 
 
 
VERSION DATE: 
October 3, 2022 
 
  
STUDY SUMMARY: 
 
Investigational Agent(s)  
(Drugs or Devices) 
N/A 
IND / IDE / HDE #   
Indicate 
Special Population(s) 
Children  
 Children who are wards of the state  
 Adults Unable to Consent   
 Cognitively Impaired Adults  
 Neonates of Uncertain Viability  
 Pregnant Women  
 Prisoners (or other detained/paroled individuals)  
 Students/Employees  
Sample Size 16 
Funding Source NIH grant 1 R21 NS114815-01A1 
Indicate the type of consent to 
be obtained 
Written  
Verbal/Waiver of Documentation of Informed Consent 
Waiver of HIPAA Authorization  
Waiver/Alteration of Consent Process   
Site 
 Lead Site (For A Multiple Site Research Study) 
 Data Coordinating Center (DCC) 
 
 

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Research Related Radiation 
Exposure 
Yes  
 No  
DSMB / DMC / IDMC 
Yes  
No 
 
OBJECTIVES: 
Aim 1: To establish safety boundaries for administering acute intermittent 
hypoxia therapy in subjects with traumatic brain injury (TBI), in order to provide 
guidance for future therapeutic hypoxia interventions. 
This is a Phase I safety study that has as a primary goal to determine whether there are 
any negative effects of administering acute intermittent hypoxia (AIH) to patients who 
suffered a mild to moderate traumatic brain injury. We will administer hypoxia dose-
escalation exposures with continual assessment of the effects of these modest hypoxia 
exposures in individuals with traumatic brain injury. We hypothesize that we will not see 
any adverse events related to the hypoxia exposures consistent with the reports of 
ongoing studies with spinal cord injured (SCI) and stroke patients. 
Aim 2: To collect preliminary data about the potential efficacy of this approach in 
improving cognitive processing, as a prelude to a more extensive clinical trial. 
We plan to measure memory/cognitive processing and motor control at baseline and 
post-treatment along with a brief exam following each AIH exposure sequence. We 
hypothesize that similar to motor improvements reported in ongoing stroke and SCI 
studies using AIH, we will see stable or improved cognitive learning and motor control 
after AIH sessions.  
 
BACKGROUND: 
Of the 1,000,000+ people who experience a TBI every year in the US, only a small 
percentage of those with moderate to severe TBI will achieve full recovery. While 
current rehabilitation therapies promote a variety of sensory, motor and cognitive skills, 
none directly address the unique potential of the brain to reorganize following injury. 
The goal of this project is to explore the effects of a novel therapy, acute intermittent 
hypoxia (AIH). During this therapy, individuals receive brief bouts of reduced oxygen 
levels by inhalation through a face mask. (This is akin to climbing to the top of a tall 
mountain). In brief exposures, AIH is known to trigger the release of specific proteins 
that help the brain adapt to oxygen reductions and thereby facilitate neuroplasticity. 
Published results in people with incomplete spinal cord injury have shown that AIH 
enhances muscle strength and coordination rather quickly. We now aim to study the 
effects of AIH in TBI survivors. 
 
AIH has most often been studied in patients with spinal cord injury. In the past five 
years, the main findings relevant to the use of AIH in persons with incomplete spinal 
cord injury (SCI) are:  
1. The neuroplasticity mechanisms linked to AIH described initially in animal models 
appear to be present and active in humans.  
2. In persons with incomplete SCI, the use of AIH alone (15 60-second episodes of 9% 
oxygen) can augment muscle strength and joint torque at the ankle. The effects of AIH 
are often dramatic, increasing voluntary strength in ankle muscles by 30-40% within 90- 
120 minutes.  

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3. Repeated (daily) acute intermittent hypoxia (dAIH) exposure combined with 
conventional rehabilitation therapy such as over ground walking can greatly improve 
walking speed and endurance beyond that achieved with either intervention applied 
separately.  
 
Recent work has also demonstrated the effectiveness of dAIH to enhance spinal motor 
plasticity related to respiration in SCI patients. (Tester, Fuller et al. 2011, Yokhana, 
Gerst et al. 2012) A randomized, triple-blind, two-arm parallel clinical trial was recently 
done in Chile (Navarrete-Opazo, Alcayaga et al. 2016) This study compared the effects 
of a 4-week protocol of dAIH combined with body weight-supported treadmill training on 
walking in persons with incomplete SCI. Subjects received dAIH or sham dAIH 
combined with 45 minutes of training for 5 consecutive days, followed by dAIH or sham 
dAIH 3 times per week for 3 additional weeks. They found that walking recovery was 
significantly better after dAIH + training, compared to training alone. Moreover, 
additional 3 times per week dAIH prolonged or enhanced daily IH-induced walking 
speed and endurance improvements up to 5 weeks post dAIH. In addition, this protocol 
of dAIH does not elicit any visual or verbal memory impairment (Navarrete-Opazo, 
Alcayaga et al. 2016). 
  
TBI is a leading cause of long-term disability worldwide. Despite the spontaneous 
recovery that occurs following mild TBI, young and older people experiencing complex 
mild-to-severe TBI show substantial residual impairments, imposing difficulties in 
everyday life including challenges in returning to the same level of work or schooling. 
These burdens are likely to increase in coming decades, due to a rapidly aging 
population at risk for TBI along with the stable risk of experiencing a TBI in younger 
people. Accordingly, new interventions to alleviate impairment in TBI survivors are 
urgently needed. The development and testing of one such novel intervention, 
termed Acute Intermittent Hypoxia (AIH), is the primary focus of this NINDS 
funded R21 study.  
 
Our aim is to answer questions related to safety and preliminary efficacy of AIH in TBI 
survivors.  
 
• First, we will establish whether brief reductions in inhaled oxygen concentration 
can be safely tolerated in TBI survivors. A research associate will closely monitor 
subjects for any adverse events and immediately report any such events to the 
resident on-call (ROC) and the independent study physician monitor and then to 
the IRB.  
 
• The second aim is to establish whether there are any effects of AIH on memory, 
cognition, and motor control.  
 
Subjects will be monitored closely for any adverse events during these experiments. 
Data will be analyzed to determine if there is an improvement in key outcomes at any 
dose level.  
 

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STUDY ENDPOINTS: 
Primary study endpoint: Safety will be assessed through the continuing review of the 
clinical/neurological status over the duration of the study including post-session 
assessment of mood, episodic memory, and motor coordination. This study is intended 
to determine if AIH can be safely tolerated in patients with TBI as it has been in patients 
with spinal cord injury and stroke. Therefore, all adverse events will be reviewed for 
safety and study continuation by the medical monitor. It will be determined if a specific 
subject should continue the experimental hypoxia protocol or if the study should be 
terminated.  
 
Secondary outcome: Each subject will also serve as his/her control; imaging and 
neurobehavioral data collected at baseline will be compared to the imaging and 
neurobehavioral data collected post-treatment. Clinical outcomes evaluated at baseline 
and post-treatment include The Repeatable Battery for the Assessment of 
Neuropsychological Status, Finger Tapping Test, Grooved Pegboard Test, California 
Verbal Learning Test, Serial Reaction Time Test, Word Fluency, Trail Making Test, the 
Effort Expenditure for Rewards Task, and Beck Depression Inventory. These tests 
evaluate a broad range of cognitive abilities, memory, response times, language 
production, executive functions, and mood.  
 
Imaging outcomes: The 3T-MRI protocol duration will be one hour and will be done prior 
to initiating our tests at baseline, and at the follow-up visit. The MRI will be a structural 
/resting state MRI looking at a change in structure or brain network function from pre- to 
post-treatment. The sequence of the MRI will be the type typically used in the standard 
of care for a TBI evaluation and measuring resting state and is described in more detail 
below under Procedures.  
 
STUDY INTERVENTION(S)/INVESTIGATIONAL AGENT(S):  
Hypoxic Experimental Therapy: The hypoxic stimulus will be implemented through a 
facemask. Hypoxia sessions will consist of a baseline breathing normoxic (containing 
normal concentration of oxygen), ambient air, followed by 15 cycles of hypoxia for up to 
60 seconds, interspersed with up to 90-second normoxic episodes.  
 
All conditioning sessions will be supervised by a research associate, who will be:  
1. Assisting the lab techs to complete a pregnancy test (in females) and a resting EKG 
prior to the hypoxia session.  
2. Monitoring the SpO2, blood pressure and pulse rate throughout the hypoxia session. 
If there are concerns, the medical monitor will review.  
 
PROCEDURES INVOLVED: 
 
Each of the Hypoxia sessions consist of a baseline during which participants breathe 
normoxic, ambient air, followed by 15 cycles of hypoxia for up to 60 seconds, 
interspersed with up to 90-second normoxic episodes. 
 

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Outcome and Monitoring Assessments are listed below followed by details 
describing the intervention and outcome measures.  
 
Visit 1: Prescreening and Baseline; Length of Visit: estimated 6 hours 
• MRI (no task) 
• Medical history 
• Demographic data  
• Current medications/comorbidities 
• TMS screening and neuronavigated motor mapping (to locate the hand motor 
area of the brain that will be stimulated by TMS in Visits 2 and 5) 
• Pregnancy test for women of child-bearing potential (WOCBP) 
• Resting 12-lead EKG 
• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),  
• State-Trait Anxiety Inventory (STAI), 
• Ohio State University TBI (OSU TBI) Identification Method interview, 
• Finger Tapping Test,  
• Grooved Pegboard Test,  
• California Verbal Learning Test (CVLT-II),  
• Serial Reaction Time Task (SRTT),  
• Word Fluency Test,  
• Trail Making Test (TMT) – Parts A & B,  
• Effort Expenditure for Rewards Task (EEfRT), and  
• Beck Depression Inventory (BDI-II).  
 
Visit 2: 21% “normal oxygen”; Intervention Day 1; Length of visit: estimated 2 hours  
• Hypoxia session: 30 mins 
• Outcome assessments plus transcranial magnetic stimulation (TMS) and 
electromyographic (EMG) measurement 
• Monitoring assessments 
 
Visit 3: 17% oxygen; Intervention Day 4; Length of visit: estimated 2 hours 
• Hypoxia session: 30 mins 
• Outcome assessments 
• Monitoring assessments 
 
Visit 4: 13% oxygen; Intervention Day 8; Length of visit: estimated 2 hours 
• Hypoxia session: 30 mins 
• Outcome assessments 
• Monitoring assessments 
 
Visit 5: 9% oxygen; Intervention Day 12; Length of visit: estimated 2 hours  
• Hypoxia session: 30 mins 
• Outcome assessments plus transcranial magnetic stimulation (TMS) and 
electromyographic (EMG) measurement 

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• Monitoring assessments 
 
Visit 6: Post-Treatment Evaluation; Post-intervention Day 16; Length of visit: estimated 
4 hours  
• MRI (no task) 
• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),  
• Finger Tapping Test,  
• Grooved Pegboard Test,  
• California Verbal Learning Test (CVLT-II),  
• Serial Reaction Time Task (SRTT),  
• Word Fluency,  
• Trail Making Test (TMT) – Parts A & B,  
• the Effort Expenditure for Rewards Task (EEfRT), and  
• Beck Depression Inventory (BDI-II).  
 
Note: The time interval between interventions is subject to modification, depending on 
the staff and equipment availability, as well as the patient’s scheduling preferences. The 
above visit lengths are our best time estimations given the procedures involved in each. 
The actual amount of time for each visit will vary from participant to participant, to 
account for variations including waiting room time, transport time from one procedure to 
another, and other timing aspects of the study that cannot, by nature, be set.  
 
Intervention procedures: During each of the four AIH sessions, study participants will 
undergo a single session of AIH, consisting of 15 periods of hypoxia, lasting up to 60 
seconds, alternating with up to 90 seconds of normoxia (21% O2), for a total of up to 35 
minutes. AIH will be applied by directing gas flow to a reservoir bag connected via 
plastic tubing to a non-re-breathing facemask/respiratory valve system while the 
participants are in a seated upright position. Defined gas mixtures will be delivered by 
manual adjustment of one-way valves attached to a hypoxia generator (HYP123, 
Hypoxico Inc.). An oxygen monitor will continuously measure and record the fraction of 
inspired oxygen delivered to the subject (MAX-250E, Maxtec Inc.).  
 
Inspired fraction of oxygen (FiO2) of the gas mixture will be individually adjusted using 
the valve settings to reach the target SpO2. The gas mixtures administered during the 
four sessions will be 21% O2 (target SpO2 = 95%), 17% O2 (target SpO2 = 92%), 13% 
O2 (target SpO2 = 87%) and 9% O2 (target SpO2 = 82%).  
 
The Shirley Ryan AbilityLab and study co-investigators have extensive experience with 
this protocol and have administered it to both healthy, spinal cord injury, and stroke 
individuals. As the individuals get hypoxic gas for only a brief period, i.e., up to 60 
seconds, the risks associated are minimal. To put into perspective, SpO2 of 82% is akin 
to oxygen levels at the top of a tall mountain. 
 
All conditioning sessions will be supervised by a research associate, who will be: 1) 
assisting in administering the EKG and the pregnancy test prior to the first hypoxia 

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session (if applicable), 2) monitoring SpO2 levels, blood pressure and pulse rate 
throughout the session. If there are concerns, the medical monitor will be notified and 
will review the concerns. If there is an unforeseen alteration in the cardiopulmonary 
parameters being assessed, the experiment will be stopped and appropriate care will be 
provided by the ROC and the medical monitor, and the emergency medical team at the 
Shirley Ryan AbilityLab will be promptly notified. We will resume normoxia immediately 
should the participant develop complaints, while awaiting the arrival of the ROC, via the 
“ROC Stat” procedure at the Shirley Ryan AbilityLab, in conjunction with the hospital 
Security department and announced immediately via the emergency loudspeaker 
system at the hospital.  
 
Any and all adverse events will be documented and appropriately reported, as required 
by the Institutional Review Board.  
 
Outcome assessments: 
 
• MRI – evaluates brain structure and examines correlations between brain 
regions’ functional activity at rest. Magnetic resonance imaging (MRI) will be 
used to determine whether there are alterations in the brain structure or resting 
state functional connectivity pre- to post-treatment. Subjects will have a total of 
two MRIs in the Shirley Ryan AbilityLab Siemens 3T machine. The structural MRI 
will be reviewed by a physician to confirm  the extent of brain damage due to TBI 
at baseline, to certify the results were collected and reviewed correctly, and to 
compare the post-treatment scan to the baseline one.  
• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) – 
The brief test battery evaluates various aspects of cognition and memory and 
has two psychometrically equated versions.  
• State-Trait Anxiety Inventory (STAI) – This self-report scale measures  the 
intensity of anxiety.   
• Ohio State University TBI (OSU TBI) Identification Method interview – OSU TBI 
is a standardized procedure for eliciting a person's lifetime history of TBI through 
a 3-5-minute structured interview.  
• Finger Tapping Test – This test measures the rate of finger presses  in order to 
assess simple motor coordination. Five to ten ten-second trials per hand are 
administered. 
• Grooved Pegboard Test – this task measures motor coordination requiring the 
participant to rotate a peg with a groove in it to fit in a grooved hole. There are 25 
pegs and holes and each hand is tested once. 
• California Verbal Learning Test (CVLT-II) – this is a multi-trial word learning test 
that includes recall and recognition measures, as well as recording recall 
improvement across 12 trials. 
• Serial Reaction Time Task (SRTT) – this is a procedural learning task.  
Participants are asked to press a key that is below a marker (filled circle) 
appearing on a monitor. They are generally unaware that there is a repeated 
sequence. Implicit learning is measured as the difference between the average 

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time required to respond to repeated sequences vs random presentations of the 
markers on the screen. 
• Word Fluency – participants are asked to produce as many words as possible 
that begin with a specific letter (F,A,S) or a category (e.g., animal names). This is 
a simple measure of the ability to retrieve words from semantic memory. 
• Trail Making Test (TMT) – Parts A & B – Trail Making Part A requires participants 
to draw a line between circles containing numbers in ascending order (e.g., 1-2-
3…etc.).  Part B requires participants to alternate drawing a line between 
ascending letters and numbers (e.g., 1-A-2-B…etc.). The key measures are the 
time required to complete and the number of errors done in Part A and Part B. 
This test measures various aspects of cognition including attention, visual 
search, motor coordination, reasoning, and task-switching (executive function).  
• Effort Expenditure for Rewards Task (EEfRT) – the EEfRT measures the trade-
off between the likelihood of the reward and the amount of effort required to 
procure the reward. This trade-off is considered a measure of motivation.  
• Beck Depression Inventory (BDI-II) – this self-report scale measures the amount 
of depressive symptoms. The total score across the items contained in the 
Inventory is indicative of depression severity. A score of 14 and above indicates 
the participant is experiencing depression. 
• Rey Auditory Verbal Learning Test (RAVLT) – Five presentations of a 15-word 
list (list A) are given, each followed by attempted recall. This is followed by a 15-
word interference list (list B), followed by recall of list A. Delayed recall and 
recognition are tested. 
• VAM-S – a visual analogue mood scale 
• TMS: Transcranial magnetic stimulation with targeted neuronavigation (based on 
individual MRI scans) will be delivered using one of the two available set-ups: (1) 
MagPro X100 with MagOption stimulator and a C-B60 figure-of-eight coil 
(MagVenture, Farum, Denmark), Localite neuronavigation system (St Augustin, 
Germany); (2) Nexstim eXimia NBS stimulator, coil and neuronavigation system 
(Helsinki, Finland). TMS will be delivered to the optimal scalp position for 
activation of the target muscle in TBI patients. The optimal scalp position will be 
determined by moving the coil in small steps along the hand representation of the 
primary motor cortex to find the region where the largest MEP can be evoked 
with the minimum intensity in the targeted muscle. The muscle to be activated 
will be the first dorsal interosseous of the dominant hand. We will measure the 
resting motor threshold (minimum intensity required to induce MEPs greater than 
50 μV in 5/10 consecutive trials at rest). We will collect 20 MEPs at an intensity 
20% above the resting motor threshold.  
 
Monitoring assessments (carried out throughout the hypoxia administration): 
 

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• Vitals: Blood pressure guidelines for participation include systolic blood pressure 
between 90-160mmHg, diastolic blood pressure between 60-100mmHg before 
and during each hypoxia session; SpO2 and pulse rate 
• Symptom checklist: A simple yes/no subjective checklist will be asked and 
repeated to the participant at each time point: 2, 6, 14, 24 and 30 mins from the 
beginning of the hypoxia session. 
 
Subjective Symptom checklist:  
Symptom  
Yes  
No  
Chest pain  
 
 
Shortness of breath  
 
 
Lightheadedness  
 
 
Neck pain  
 
 
Dizziness  
 
 
Arm pain (left side) for cardiac symptoms   
 
Sweaty/feeling warm  
 
 
Sensory changes: new signs of numbness  
 
Increased weakness  
 
 
 
 
Other outcome assessments immediately following the hypoxia administration include: 
• Motor coordination (Finger Tapping Test, Grooved Pegboard Test), mood 
assessment (VAM-S), and word-list learning (RAVLT) 
Other outcome assessment before and after hypoxia sessions #1 (Visit 2) and #4 (Visit 
5): 
• Single-pulse assessment for motor cortical functioning using transcranial 
magnetic stimulation and electromyographic recording 
 
Transcranial Magnetic Stimulation (TMS) and electromyography (EMG): TMS 
sends a magnetic pulse to the brain and stimulates brain activity. A wire TMS coil will be 
placed over the participant’s head. The TMS coil will be held to the head with a custom 
coil holder. To limit head movement, the head will be secured to the headrest with a soft 
Velcro strap. When the TMS is activated, this coil will generate a magnetic pulse over a 
specified area of the brain that is responsible for hand movement. When the pulse 
occurs, the participant will hear a click or a snapping sound, and may feel a pulling 
sensation on their skin underneath the area where the coil is placed. They may also feel 
a light twitch of the muscles in their arm, face or leg. During Visit 1, we will do motor 
mapping, that is, we will use neuronavigation to find the area of the brain that activates 
the target hand muscle. During Visits 2 and 5 we will apply a series of TMS pulses to 
this brain area to evoke EMG responses from the target muscle. During the EMG 
recording, the participant will be comfortably positioned so that their arms are supported 
by a testing device. Recording electrodes will be attached to the surface of the skin over 
the target hand muscle to record its activity. 
 
Exclusion criteria to TMS participation for TBI patients:  

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• Uncontrolled medical problems including pulmonary, cardiovascular or 
orthopedic disease  
• Premorbid, ongoing major depression or psychosis, altered cognitive status  
• History of stroke 
• Metal in head (e.g., surgical clips, shrapnel) 
• History of seizures or epilepsy diagnosis 
• Receiving drugs acting primarily on the central nervous system, which lower the 
seizure threshold such as antipsychotic drugs (chlorpromazine, clozapine) or 
tricyclic antidepressants  
• Surgery to the head  
• Any non-TBIrelated neurological diseases 
• Illnesses that may have caused brain injury 
• Unexplained frequent or severe headaches 
• Pregnancy in females  
• Implanted devices (e.g., pacemakers, medical pumps, brain stimulators) 
 
Patients will not be eligible to participate in the study if they are not eligible to undergo 
MRI or TMS. 
 
Blood draw. A blood draw from WOCBP will be carried out once, as part of health 
screening routines during Visit 1. A serum pregnancy test requires a sterile needle to be 
inserted into a vein to collect a 1-5 ml (0.2-1 tsp) blood sample. 
 
 
DATA AND SPECIMEN BANKING 
Data from the study (e.g., assessment and outcome variables) will be stored in a 
password-protected database, REDCap, which is managed by Northwestern University. 
If needed, an Excel or SPSS file will be managed with password protection; located on 
the secure network at the Shirley Ryan AbilityLab. Upon enrollment, each subject will be 
assigned an identifier number such that the data do not contain identifiable private 
information; the data will only be coded with the identifier number. Thus, there is no 
identifiable data. The data will be uploaded into REDCap or an Excel/SPSS file. Only 
authorized personnel of this study (IRB-approved) will have direct access. Once all 
patient data has been collected and uploaded, the study investigators and statisticians 
will analyze the data and provide reports, which will be used to publish relevant findings. 
Names of participants will not be used in study reports. We will retain study 
documentation including all case report forms, data correction forms or queries, source 
documents, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms) for at 
least three years after the completion and final study report of this investigational study.  
 
SHARING RESULTS WITH PARTICIPANTS 
This is not a blinded study; all subjects will each be given the same treatment. 
 
Subjects will be provided with a phone number to call if they have any questions about 
the study treatment they received or the results of the clinical trial. It is not anticipated 

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that any information, unless an adverse event occurs, will need to be shared with 
primary care or other physicians.  
 
 
STUDY TIMELINES 
Participants will be initially screened over the phone or in person to ensure eligibility 
based on the established inclusion and exclusion criteria. We anticipate that each 
participant will take about 2-4 weeks to complete the study procedures/testing 
(depending on scheduling and study staff availability). We anticipate a total of 2 years to 
enroll, complete data collection and complete the primary analyses.  
 
 
INCLUSION AND EXCLUSION CRITERIA 
Inclusion criteria:  
• 
Aged 18-65 years  
• 
A first time, mild to moderate traumatic brain injury (TBI) confirmed by medical 
records  
• 
When available, a Glasgow Coma Scale score between 9-15  
• 
Able to use a keyboard  
• 
Able to understand and communicate in English 
• 
Able to consent independently  
• 
Able to leave a research visit with a companion/group transportation  
• 
Women of child-bearing age must be comfortable confirming a negative 
pregnancy prior to participating in the study  
• 
Must not be involved in any other research intervention study testing 
neurobehavioral functioning  
Exclusion criteria:  
• Other neurological diagnoses or a diagnosis of severe psychiatric disorder (e.g., 
psychosis) or a reported childhood learning disability 
• 
Severe aphasia, preventing subject from understanding the protocol and giving 
written consent  
• 
Pre-existing hypoxic pulmonary disease  
• 
Severe hypertension (>160/100)  
• 
Medically documented history of obstructive lung diseases [e.g., Chronic 
obstructive pulmonary disease (COPD) or significant asthma] 
• 
Ischemic cardiac disease  
• 
Ineligible to undergo MRI or TMS  
 
 
VULNERABLE POPULATIONS 
N/A 
The participants will be post-traumatic brain injury patients living in the community and 
be independent without significant cognitive impairment.  
 
PARTICIPANT POPULATION(S) 
The total recruitment goal is 16 subjects.  

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RECRUITMENT METHODS 
Potential participants will be identified through a variety of means, including: medical 
records, physician contacts, recruitment flyers within the Shirley Ryan AbilityLab and 
other Northwestern-affiliated hospital and websites (e.g., 
https://www.feinberg.northwestern.edu/research/clinical-research/trials/, text of the 
recruitment ad attached), surrounding community hospitals, the Clinical Research 
Registry (NU IRB # STU00212893; see Authorization Letter in Supporting Documents), 
the Center for Rehabilitation Outcomes Research (CROR) research registry (NU IRB # 
STU00012894; see Letter of Support uploaded in Supporting Documents), 
ClinicalTrials.gov (Identifier: NCT04890639) and community outreach presentations.  
 
Shirley Ryan AbilityLab Research Registries: Subjects will be recruited through the 
Clinical Neuroscience Research Registry. The database is maintained through 
combined efforts of the Shirley Ryan AbilityLab and Northwestern University 
Department of Physical Therapy. It includes up to 1000 individuals with various 
neurologic conditions, including traumatic brain injury. Researchers are able to modify 
their search criteria based on level of injury, severity of injury, and primary means of 
mobility. Patients will also be recruited through the Shirley Ryan AbilityLab’s electronic 
medical records and through the PM&R clinic physicians.  
 
Flyers: These will be primarily distributed through the Shirley Ryan AbilityLab hospital 
and websites, surrounding community hospitals, and at the surrounding Chicagoland 
support groups for individuals having suffered a TBI.  
 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES 
• 
Payment will be provided through ClinCard.  
• 
Each participant will be compensated $20 per hour for participation in the study. 
Partial hours completed will be compensated at a prorated rate of $5 per 15 
minutes. 
  
 
During the Covid-19 pandemic, we will reimburse round-trip private transportation cost 
within the Chicago metropolitan area, including driver tip (e.g., accessible Uber, Lyft, 
taxi, parking fees etc.), for visits to and from the Shirley Ryan AbilityLab. A receipt is 
required for full reimbursement of transportation cost.  
 
WITHDRAWAL OF PARTICIPANTS 
Subjects may withdraw from participation in the study at any time. Any data collected up 
to the time of withdrawal will be retained for study purposes.  
 
Participants may withdraw from the study at any time at their own request or they may 
be removed at the discretion of the investigator for safety, behavioral or administrative 
reasons.  
The reason(s) for discontinuation will be documented and may include:  

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• Participant voluntarily withdraws from treatment;  
• Participant withdraws consent;  
• Participant is unable to comply with protocol requirements;  
• Researcher staff decides that continuation with the study would not be in the best 
interest of the participant.  
 
Subjects will be considered as not evaluable if they choose to drop out voluntarily and 
will be replaced. However, if an adverse event is experienced and it is deemed that the 
subject must be removed from the research study for safety, that subject with not be 
replaced. This determination will be made by the medical monitor and will be reflected in 
subjects’ research record in the data file used.  
 
Subject accrual will stop at any point in the study if two or more subjects (out of the 16) 
experience an adverse effect (AE) at any of the dose levels following baseline.  
 
RISKS TO PARTICIPANTS 
Potential risks related to acute intermittent hypoxia, although rare, may include 
headaches, lightheadedness, dizziness, altered vision, respiratory distress, cyanosis, 
increase in breathing rate, sweating, muscle spasms and fainting. There can be 
alterations in the field of vision, a sensation of numbness or tingling and feelings of 
euphoria. An additional risk to wearing a mask in severely claustrophobic individuals is 
discomfort, anxiety or panic. 
 
In case of a sudden emergency, the ROC (Resident on Call) will be summoned via the 
hospital’s loudspeaker to attend to the participant. We will resume normoxia 
immediately should the participant develop complaints, while awaiting the arrival of the 
ROC, via the “ROC Stat” procedure at the Shirley Ryan AbilityLab, in conjunction with 
the hospital Security department and announced immediately via the emergency 
loudspeaker system at the hospital. 
 
There are two major risk groups that could be determined, 1. cerebral or 2. cardiac, 
described in more detail below.  
 
(1) A non-silent cardiac event will require the ROC to be called to the 
clinic room for immediate and urgent attention for the chest pain 
experienced. The medical monitor will determine the next steps for 
the safety of the subject, which may include a visit to the 
emergency room located at Northwestern Memorial Hospital.  
 
(2) A cerebral adverse event is experienced through a change in vision 
and/or changes in the neurological assessment. The medical 
monitor will be informed of this outcome and will provide advice 
accordingly.  
 
 

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In terms of research-related risks, participants may become frustrated, tired, or bored 
during the testing. While undergoing the MRI, the participant may experience mild 
stress from lying still in a noisy machine in an enclosed space. Our study team is trained 
to respond to indications of unease with support and comfort. If the participant is unable 
to lie still or if they seem distressed by the scanning, the study will be stopped 
immediately. We will immediately stop all of the testing, including neuropsychological 
tests and MRI scanning, at the request of the participant. 
 
The following items may interfere with the MRI scan and can be potentially hazardous: 
cardiac pacemaker, aneurysm clip(s), implanted insulin/drug pump, neurostimulator 
(TENS unit), biostimulator/bone growth stimulator, hearing aid/cochlear implant, 
Gianturco coil (embolus coil), vascular clip(s), surgical clip or staple(s), heart valve 
prosthesis, Greenfield vena cava filter, middle ear implant, shrapnel or bullet, wire 
sutures, tattooed eyeliner, dental items held in place by a magnet, other implanted items 
not mentioned, intraventricular shunt, wire mesh, artificial limb or joint, orthopedic items 
(i.e., pins, rods, screws, nails, clips, plates, wire, etc.), certain tattoos, dentures, dental 
braces, or any type of removable dental items. The SRALab Safety Questionnaire (see 
“MRI_Screening_Form”) submitted as a Supporting Document with this protocol is a 
screen for the presence of the above-listed items. If the SRALab radiology staff deems 
any of the items checked by the participant to be hazardous, they will not be allowed to 
have an MRI. 
 
MRIs are considered to be safe and have been used for many years. It is a completely 
non-invasive procedure. No needles, chemicals, or radiation are used. Instead, a 
powerful magnet and radio waves are used to create images of the participant’s brain. 
There is no evidence that the magnetic field used by the scanner has any harmful 
effects. MRI scanning has been performed for over 20 years, but nonetheless, there 
could be unknown risks. In our MRI work performed so far, there have been no 
significant adverse events reported. These procedures have also been safely used in 
participants in previous studies and are commonplace at major medical centers 
worldwide.  
 
TMS may cause temporary discomfort to some individuals due to the sensations of 
tingling or twitching in the scalp, jaw or face, as well as twitches in the stimulated 
muscles. Seizures are a possible, but an extremely rare risk associated with undergoing 
TMS. 
 
The possible risks associated with blood drawing are pain, bleeding, a rare risk of 
fainting, bruising, infection and/or hematoma (blood clot under the skin) at the injection 
site. 
 
All adverse events occurring to participants enrolled in this protocol will be reported 
according to the Northwestern University IRB standard procedure. 
 
 
POTENTIAL BENEFITS TO PARTICIPANTS 

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There may be no direct benefit for participants enrolled in this study.  
 
DATA MANAGEMENT AND CONFIDENTIALITY 
All case report forms will be kept in study binders for each subject. Each subject will 
only be identified by subject number (subject ID). Study binders will be kept in a locked 
cabinet on the 16th or 25th floors of the Shirley Ryan AbilityLab. The 16th floor is not a 
public access floor. The 25th floor is where our research lab and offices are located and 
are secured when unoccupied.  
 
 
Statistical Considerations for AE detection 
Trial Design. Participants enrolled in this study will undergo within-subject dose 
escalation of hypoxia. The planned dose levels are standard O2 content (21%, dose 
level d0), 17% (dose level d1), 13% (dose level d2) and 9% (dose level d3) O2 content. 
Each participant will initially be tested at dose level d0 (baseline). At the second study 
visit, the participant will be treated at the next dose level (d1), and, if no qualifying 
adverse events (AEs) occur, dose level will be further escalated to d2 at the third visit. 
Similarly, if no qualifying AEs occur at visit 3, the participant will be treated at dose level 
d3 at the last visit. Participants who experience adverse events or cannot tolerate 
treatment at dose level d0 will be excluded from the study. Participant accrual will stop if 
at any point in the study 2 or more participants experience an AE at any of the dose 
levels d1, d2 or d3. AIH will be considered unsafe if 2 or more participants experience 
an AE at any dose level. 
Sample Size Considerations: We used simulation studies to determine operating 
characteristics for detecting excessive AEs for this trial. Under the null hypothesis, we 
assume that the AE rate is extremely low, 𝐻𝐻0 :𝑝𝑝1 =𝑝𝑝2 = 𝑝𝑝3 = 0.01, where 𝑝𝑝𝑗𝑗 
corresponds to the probability of AE at dose level 𝑑𝑑𝑗𝑗. We further assume that 𝑝𝑝𝑗𝑗 are 
uncorrelated under 𝐻𝐻0. Under the alternative hypothesis, we consider three types of 
dose-toxicity curves: (I) 𝑝𝑝2 = 𝑝𝑝1 +0.025, 𝑝𝑝3 = 𝑝𝑝1 + 0.025, (II) 𝑝𝑝2 = 𝑝𝑝1 +0.025,𝑝𝑝3 
= 𝑝𝑝1 +0.050, and (III) 𝑝𝑝2 = 𝑝𝑝1 +0.050, 𝑝𝑝3 = 𝑝𝑝1 + 0.050. We considered 𝑝𝑝1 
ranging between 0.05 and 0.125. Under the alternative hypothesis, subjects’ outcomes 
(AE, yes or no) at the three dose levels were simulated as correlated binary data, 
assuming within-subject correlation between AE occurrence at the various dose levels 
is 𝜌𝜌 = 0.3. R=10,000 trials were simulated under each scenario using the “bindata” 
package in R. For each simulated trial, we calculated the number of AEs occurring 
among all participants at any dose level, and hypoxia treatment was declared unsafe 
if ≥ 2 participants in a given trial experienced an AE at any dose level. Type I error rate 
(𝛼𝛼-level) was calculated as the proportion of all R=10,000 trials simulated under 𝐻𝐻0 
that were declared unsafe. Power was calculated as the proportion of all trials under a 
particular alternative hypothesis scenario that were declared unsafe. We considered 
sample size n=14 or 16. Under 𝐻𝐻0, the probability of declaring hypoxia unsafe (Type I 
error) was 0.063 when n=14 and 0.081 when n=16. Power curves for the three types of 
dose-toxicity curves are presented in the Figure below. For example, for a dose-toxicity 
curve of type III when {𝑝𝑝1 = 0.08,𝑝𝑝2 = 0.13,𝑝𝑝3 = 0.13} under the alternative 
hypothesis, we will have 87.6% power with n=14 and 91.6% power when n=16. More 
generally, when n=14, we will have >80% power under all dose-toxicity scenarios with 

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𝑝𝑝1 ≥ 0.08. When n=16, we will have >80% power to under all dose-toxicity scenarios 
when 𝑝𝑝1 ≥ 0.07. 
Aim 2: To collect preliminary data about the potential efficacy of this approach in 
improving neurobehavioral functions, as a prelude to a more extensive clinical trial. We 
plan to use a standard set of memory and cognitive tasks and neuroimaging at baseline 
and after completion of the AIH trial as well as an abbreviated evaluation immediately 
after each session for finger tapping, motor coordination, mood, and word-list recall 
along with single-pulse evaluations before and after AIH sessions 1 and 4 respectively. 
Statistical Analysis of Efficacy: AIH efficacy will be assessed at each O2 dose level for 
all subjects, as continuous outcomes (e.g., finger tapping speed). Data will be analyzed 
using generalized linear mixed models with repeated measures, with the outcome 
measure as the response variable, and dose level as a categorical predictor to allow for 
a nonlinear dose-response relationship. Baseline measurements will be adjusted for in 
the model. Within-subject correlation between multiple doses will be accounted for with 
an appropriate variance-covariance structure (e.g. compound symmetry or 
autoregressive of order 1, AR(1)). Model fit and assumptions will be checked using 
model diagnostic techniques for mixed models, and the outcome variable may be 
transformed to satisfy the normality assumption. Mixed models with repeated measures 
have been shown to be robust when data are normally distributed even with small 
sample sizes. Post-hoc tests will be used to determine whether there is an improvement 
in outcome relative to baseline at any dose level, and whether there is a difference 
between dose levels. Because of the small sample size, these analyses will be 
exploratory. Analysis will be done using PROC MIXED in SAS, R, MATLAB, SPSS or 
other available statistical software package. 
 
Research material will include questionnaires assessing inclusionary/exclusionary 
criteria, neurobehavioral tasks, orientation questions during the acute intermittent 
hypoxia sessions, outcome questionnaires, electromyographic recordings, and 
neuroimaging scans and datasets. All data will be used solely for the purposes of the 
research proposed herein. Personal medical records, results of previous laboratory, 
neuroimaging, neuropsychological testing, and information from attending physicians 
that are obtained will be held in secure files. Identifying information will not be included 
in any report or publication. All data will be labeled with a participant code only and will 
be kept on a password-protected server. Participants will be identified by a code 
number, and access to their names will only be available to the PI, the Co-Investigators, 
post-doctoral fellows, and the research assistants approved by the Northwestern 
University Institutional Review Board. A master list connecting the participant names 
with their participant ID number will be stored in an Excel file kept on an SRALab IT-
supported, secure, password-protected server. All collected data will be used for 
research purposes only. The Principal Investigator (PI) will manage access to the 
project data, including identifiable private information. Only approved research team 
members will have access to the data. All paper files will be kept in a locked and secured 
file cabinet in the Cognitive Neuroscience Laboratory at the Shirley Ryan AbilityLab. All 
electronic data will be de-identified and kept on an SRALab, IT-supported, secure, 
password-protected server, with the exception of the original MRI scans. These scans will 
be stored on the SRALab, IT supported, secure, password-protected server, but by nature 

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could contain facial features, names, and birthdates in the metadata (this is standard for these 
types of files). Original MRI scans will additionally be stored on DVDs that will be locked in a 
drawer on the 25th floor, and accessible only to study team members. 
 
Electronic data, including survey data, will be backed up in REDCap. While REDCap can be 
used to collect data in many environments (including compliance with 21 CFR Part 11, FISMA, 
HIPAA, and GDPR) and is specifically designed to support online and offline data capture for 
research studies and operations. (For further details, https://www.project-redcap.org) 
 
Apart from the original scans and master list, identifying information will be stored separately 
from the de-identified experimental data. Only the PI and approved study members, who 
are listed on the IRB protocol, will have access to the data. Neuroimaging data will be 
uploaded to the Northwestern University Research Image Processing System 
(NURIPS), an online collaborative research environment for securely storing, managing, 
analyzing and sharing de-identified medical imaging, associated data (e.g. behavioral), 
and results from advanced customizable processing pipelines. NURIPS is supported by 
both NUIT and FSM-IT and takes advantage of the NU high performance computing 
cluster, Quest. NURIPS is a secure environment that supports the latest NU policy and 
procedures for encryption of data during transit and rest, provides granular project level 
access controls with varying permissions based on user groups, and allows non-NU 
collaborators access once they obtain an affiliate NetId. All data are backed up and 
have restore points that go back for 30 days. Users have access to common data 
analysis pipelines and the opportunity to create and share their own pipelines. 
 
An encrypted SRALab IT-approved USB stick will be used to carry the anatomical MRI 
scan from the MRI lab to the TMS lab on the same floor of the SRALab hospital. Once a 
scan has been transported to the TMS lab computer for cortical reconstruction and 
properly stored on the SRALab server, it will be deleted from the USB stick. (The USB 
stick is intended as a temporary transport device only). 
 
We are not collecting any urine or tissue specimens.  
 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
PARTICIPANTS 
The PI has the ultimate responsibility for this study. Dr. Grafman will oversee the entire 
project with respect to study design, recruitment processes, study progress, participant 
safety, data interpretation and data reporting. An independent Medical Safety Monitor 
will review all adverse events and make recommendations to the participant and the PI.  
 
Medical Monitor: 
The medical monitor on this study is Dr. Elliot Roth, MD (Physical Medicine and 
Rehabilitation, Shirley Ryan AbilityLab). Responsibilities will include:  
 
1. Observing recruitment and enrollment procedures and the consent process for 
individuals 

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2. Overseeing study interventions and interactions. 
3. Reviewing monitoring plans. 
4. Overseeing data matching, data collection, and analysis. 
5. Placing the MRI order to determine the presence of a brain damage due to a TBI 
before the subject can be scheduled for intervention visits. A detailed analysis of the 
size and location of the damage will be done by a radiologist during data 
collection/analysis after all subject data has been collected. 
6. Reviewing any report of an adverse event. 
 
Additionally: 
1. May discuss the research protocol with the investigators, interview human subjects, 
and consult with others outside of the study about the research; 
2. Shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report; 
3. Shall have the responsibility to promptly report their observations and findings to the 
IRB.  
 
The medical monitor will be placing the order for the research MRI. Once results of the 
MRI have been generated, the medical monitor will review and sign off on the images to 
confirm the results and for safety of the subject receiving hypoxia. If results generate 
safety concerns, then a radiologist on subscription with  the Shirley Ryan AbilityLab will 
be contacted for assistance.  
 
 
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS 
An ongoing dialogue will take place during the subject's introduction to the study and the 
informed consent process to ensure that the candidate fully understands the study, what 
is required, the risks and the benefits, and their rights as a participant. Only participants 
that are able to independently consent in English will be approached. 
 
All information provided by participants will be de-identified. 
 
Documentation will be stored within a locked cabinet within a specified specialty lab 
within the Shirley Ryan AbilityLab. Furthermore, all data stored electronically will be 
password-protected. Only authorized individuals will have access to files and data, as 
entered within the Northwestern IRB site.  
 
COMPENSATION FOR RESEARCH-RELATED INJURY 
N/A  
 
ECONOMIC BURDEN TO PARTICIPANTS 
There are no costs to participants for participating in this study. 
 
CONSENT PROCESS 

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After potential subjects are identified, they will be invited to return to the Shirley Ryan 
AbilityLab for a research appointment to complete screening and consent. This 
appointment will be arranged and coordinated by the designated research associate for 
the study. The informed consent documentation will be reviewed with the participant 
and authorized research personnel during Visit 1, prior to any testing or interventions. 
The principal investigator/medical monitor will be available for any questions regarding 
the consent of the participant.  
 
This process will be completed in a private space within the Shirley Ryan AbilityLab.  
 
Participants will be encouraged to ask questions related to study purpose or 
procedures, or have family present. They will be provided a copy of the signed informed 
consent. Participants will be told that they are volunteers who can stop participation at 
any time without penalty. The consent process should take approximately 30 minutes. 
Individuals who are not yet adults, are not cognitively intact, unable to understand 
English or unable to consent will not be recruited for this study. 
 
 
NON-ENGLISH SPEAKING PARTICIPANTS 
Non-English speaking participants will not be recruited because the tests are 
standardized in English and all other study materials and study instructions will be given 
in English.  
 
 
WAIVER OR ALTERATION OF CONSENT PROCESS  
N/A 
 
 
PROTECTED HEALTH INFORMATION (PHI AND HIPAA) 
Protected health information will remain for the most part in the Cerner Research 
Medical Record database, which is used to maintain clinical medical records, and is 
accessible only by authorized personnel with electronic ID and password. Any other PHI 
will be in paper records (e.g. CRFs), which will include only the subject’s study ID and 
not their names. Paper records will be stored on the 25th floor of the Shirley Ryan 
AbilityLab in the research offices which are secured when unoccupied. These records 
are kept in locked cabinets. All paper records will be kept for three years after the end of 
the study and then will be destroyed in accordance with the Shirley Ryan AbilityLab 
policies. We will have in the research database from this study information that 
characterizes participants including age, education level, sex of subject, but not any of 
the following information: name, geographic subdivision, telephone number, fax 
number, social security number, medical records numbers, health plan numbers, other 
account numbers, vehicle identifiers, photographs, biometrics or related identifiers, and 
the information generated from their research participation will not be put in any of their 
medical records. 
 
SETTING  

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This single-site study will have all research procedures and visits take place at the 
Shirley Ryan AbilityLab, located at 355 E. Erie St, Chicago, IL 60611.  
 

 
 
23
Statistical Analysis Plan Update 
 
Date: February 12, 2025 
 
 
Sample Size: While the initial target was to recruit 16 participants, we encountered 
challenges finding eligible volunteers who would be able to participate in six in-person 
research visits and were only able to enroll 12 participants, all of whom completed all six 
visits and whose data will be included in the analyses. 
 
 
Statistical Analysis: To evaluate the efficacy of the AIH protocol and its effects on vital 
signs, motor function, cognition and mood we will implement the following analyses. 
 
Vital signs data (HR, SpO2) will be preprocessed in MATLAB R2020a (MathWorks, 
Natick, MA). For each cycle in an AIH session, the highest HR and the lowest SpO2 
readings will be identified; then, the average highest HR (max HR) and lowest SpO2 (min 
SpO2) across all cycles will be computed per session. 
 
Across-session comparisons of behavioral performance on the motor and cognitive 
tests, vital signs (min HR, max SpO2) and motor evoked potentials (MEPs) will be 
conducted using IBM SPSS Statistics v. 29.0, with the significance level set at α = .05. 
Normality of data will be assessed using the Shapiro-Wilk test (α = .05). For normally 
distributed variables, means (M) and standard deviations (SD) will be calculated, and 
groups will be compared using a two-tailed paired-samples t-test or a repeated 
measures (RM) ANOVA. Mauchly’s test will be used to check the RM ANOVA’s 
assumption of sphericity; when violated (p < .05), the Greenhouse-Geisser correction 
will be applied. For non-normally distributed data, medians (Mdn) and interquartile 
ranges (IQR) will be calculated, and group comparisons will be performed using the 
Wilcoxon signed-rank test or the Friedman test. Effect sizes will be calculated as 
follows: Cohen’s d for t-tests, r for Wilcoxon tests, partial eta squared (ηp2) for RM 
ANOVA, and Kendall’s W for Friedman tests. Post hoc tests for RM ANOVA and 
Friedman tests will be conducted using paired-samples t-tests and Wilcoxon signed-
rank tests respectively, with multiple comparisons corrected using the false discovery 
rate (FDR) method (Benjamini & Hochberg, 1995), as implemented in the R function 
p.adjust. Data visualizations will be created using the ggplot2 package (Wickham, 2016) 
in R v. 3.6.3 (R Core Team, 2020). 
 
 
References: 
 
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical 
and powerful approach to multiple testing. Journal of the Royal Statistical Society: 
Series B (Methodological), 57(1), 289–300. https://doi.org/10.1111/J.2517-
6161.1995.TB02031.X 

 
 
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Wickham, H. (2016). ggplot2: Elegant graphics for data analysis. Cham: Springer 
International Publishing. https://doi.org/10.1007/978-3-319-24277-4 
 

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Informed Consent Form 
 
Title of Research Study: Safety and Cognitive Effects of Acute Intermittent 
Hypoxia-Induced Neuroplasticity in Traumatic Brain Injury. 
 
 
Principal Investigator: Jordan Grafman, Ph.D 
 
Supported By: This research is supported by the National Institute of Neurological 
Disorders and Stroke. 
 
 
 
 
Why am I being asked to take part in this research study? 
We are asking you to take part in this research study because you are over the age of 
18, have experienced a first-time traumatic brain injury, which was confirmed by a 
medical report. Additionally you speak and understand English with the ability to 
independently consent and are able to travel without a companion/group transportation.  
 
What should I know about a research study? 
• Someone will explain this research study to you. 
• Whether or not you take part is up to you. 
• You can choose not to take part. 
• You can agree to take part and later change your mind. 
• Your decision will not be held against you. 
• You can ask all the questions you want before you decide. 
 
Why is this research being done? 
The aim of this study is to answer questions related to the safety and effectiveness in 
improving cognition of a new intervention, acute intermittent hypoxia (AIH), in traumatic 
brain injury survivors. For the purposes of this study, hypoxia means reducing the 
amount of oxygen you will be breathing, using a specialized face mask which controls 
oxygen content in inhaled air. 
 
In order to deliver the air with the different concentrations of oxygen, we will use the 
Hypoxico gas-mixing generator. It is considered an investigational medical device as 
used in this study, and is not approved by the US Food and Drug Administration (FDA). 
Key Information:  
The first few pages of this document include a summary of this study to help you 
decide whether or not to participate. Detailed information is provided after the 
summary. 

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First, we will establish whether brief and moderate reductions of oxygen in breathing air 
can be safely tolerated by people participating in this study. A clinician will closely 
monitor you for any negative medical occurrences also known as adverse events.  
 
The second aim is to establish what effects AIH may have on cognitive processing. You 
will be closely monitored for any adverse events during these experiments. Data will be 
analyzed to determine if there is a change in cognitive performance at any of the 
oxygen dose levels.  
 
How long will the research last and what will I need to do? 
We expect that you will be in this research study for two to four weeks.  
You will be asked to come in for six visits total (one screening visit, four treatment visits 
and one post-treatment follow-up appointment).  
 
More detailed information about the study procedures can be found under the section 
What happens if I say “Yes, I want to be in this research”? 
 
Is there any way being in this study could be bad for me? 
There are two major risk outcomes that could be experienced; in the brain (cerebral) or 
in the heart (cardiac). These two risks are described in more detail below in the section, 
“Detailed Risks: Is there any way being in this study could be bad for me?”. These 
risks are based on using the similar procedure in patients with spinal cord injury or 
stroke, which are conditions that include risk factors related to change in oxygen and 
normal brain blood flow, among others. There are no known risks related directly to AIH 
sessions used in mild-to-moderate patients with brain injury, although risks have been 
documented when AIH is used in patients with spinal cord injury and stroke, as 
mentioned previously and described further in Detailed Risks. While we do not 
anticipate the same degree of risk in patients with mild-to-moderate brain injury, we 
simply do not know the full range of risks at this time, when AIH is used specifically in 
patients with mild-to-moderate brain injury. This study will help us document any such 
risks in patients with mild-to-moderate brain injury. You will be screened before your 
participation to make sure that these types of events are unlikely, but a small possibility 
remains that either a cardiac or cerebral event might occur.  
 
The research associate who is responsible for administering the acute intermittent 
hypoxia sessions will be frequently evaluating your medical and cognitive status during 
all sessions (including the baseline session) and in the event of an emergency will be 
trained to seek emergency medical staff. Prior studies at the Shirley Ryan AbilityLab 
with spinal cord injury and stroke patients receiving acute intermittent hypoxia sessions 
similar to our study reported no adverse events during their studies. 
More detailed information about the risks of this study can be found under “Is there any 
way being in this study could be bad for me? (Detailed Risks)” 

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Will being in this study help me in any way? 
There are no direct benefits to you from taking part in this research. We cannot promise 
any benefits to others from taking part in this research.  
 
What happens if I do not want to be in this research? 
Participation in research is completely voluntary. You decide whether or not to 
participate. If you choose not to participate, there will be no penalty to you or loss of 
benefit to which you are entitled. 
 
 
Your alternative to participating in this research study is not to participate. 
 
 
 
 
 
Who can I talk to? 
If you have questions, concerns, or complaints, or think the research has hurt you, talk 
to the Principal Investigator, Dr. Jordan Grafman at (312) 238-1495. 
 
This research has been reviewed and approved by an Institutional Review Board (IRB). 
You may talk to them at (312) 503-9338 or irb@northwestern.edu if: 
• Your questions, concerns, or complaints are not being answered by the research 
team. 
• You cannot reach the research team. 
• You want to talk to someone besides the research team. 
• You have questions about your rights as a research participant. 
• You want to get information or provide input about this research. 
 
How many people will be studied? 
We expect that 16 people will complete this research study.   
 
What happens if I say “Yes, I want to be in this research”? 
You will be asked to come to the Shirley Ryan AbilityLab for a total of 6 visits. The first 
visit is a baseline evaluation, that will include a health screening, MRI scans of your 
brain, TMS motor mapping, along with neuropsychological testing and questionnaires. 
The following four visits will include the acute intermittent hypoxia delivery, monitoring 
Detailed Information: 
The rest of this document includes detailed information about this study (in addition to the 
information listed above). 

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assessments, and a series of brief outcome assessments; two of these four visits will 
also include TMS. The final visit is a post-treatment evaluation that will include another 
MRI scan along with neuropsychological testing and questionnaires.  
 
Each visit is broken down with the exact tasks that will occur just below. A detailed 
explanation of the assessments is listed at the end of the consent. 
 
Experimental Hypoxia Sessions: 
Hypoxia will be administered via a specialized face mask, which controls oxygen 
content in inhaled air while breathing into a gas mixing device, called Hypoxico.The 
hypoxia administering unit will be manually adjusted to reach the target oxygen level 
(approximately 21%-normal oxygen, 17%, 13%, and 9%) for each of the four sessions. 
The acute intermittent hypoxia sessions consist of 15 cycles of hypoxia lasting for up to 
60 seconds alternated with up to 90-second cycles of breathing ambient air. All 
sessions will be supervised by a trained research associate, with a resident-on-call 
(“ROC”) physician present at the Shirley Ryan AbilityLab during the hypoxia 
administration, who will be reachable via the hospital’s “ROC Stat” procedure. 
 
PROCEDURES: research visits will all take place at the Shirley Ryan AbilityLab 
Visit 1: Prescreening and Baseline. Length of visit: estimated 6 hours 
• Discuss the research project, complete the informed consent process and 
confirm eligibility 
• Magnetic resonance imaging (MRI). This study uses magnetic resonance 
imaging (MRI) to allow investigators to look at the brain structure and function. 
Magnetic resonance imaging is a technique that uses magnetic fields and radio 
waves to make images of the brain. The scanning session will include no-task 
MRI scans looking at brain structure and activity while you are at rest. During the 
session, you simply have to lie still in the scanner while we image your brain. 
• Medical history 
• Demographic data 
• Current medications/comorbidities 
• TMS screening and neuronavigated motor mapping (to locate the area of the 
brain that will be stimulated by TMS in Visits 2 and 5) 
• Pregnancy test for women of childbearing potential via a blood draw 
• Resting 12-lead EKG 
Neurobehavioral assessments - Clinical outcomes measured at the baseline and post-
treatment sessions:  
 
The neurobehavioral assessment will include the following: 
 
• Repeatable Battery for the Neuropsychological Assessment of Status (RBANS) 
o This brief assessment evaluates various aspects of cognition, including 
visuospatial perception, attention, memory, and language. 
• State-Trait Anxiety Inventory (STAI) 

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o This self-report scale measures  the intensity of anxiety. 
• Ohio State University TBI (OSU TBI) Identification Method interview 
o OSU TBI is a standardized procedure for getting a person’s lifetime history 
of TBI through a 3-5-minute structured interview. 
• Finger Tapping Test  
o This test measures the rate of  finger presses. It is a measure of simple 
motor coordination. Five to ten ten-second trials per hand are 
administered. 
• Grooved Pegboard Test 
o This task is to rotate a peg with a groove to fit in a grooved hole. It 
measures motor coordination. There are 25 pegs and holes. Each hand is 
tested once. 
• California Verbal Learning Test (CVLT-II)  
o This is a word learning test including word recall and recognition 
measures. 
• Serial Reaction Time Task (SRTT) 
o This task is to press a key that is below a marker appearing on a monitor. 
It measures attention and learning. 
• Word Fluency 
o This task is to produce as many words as possible that begin with a 
specific letter or a category. It is a measure of the ability to retrieve words 
from semantic memory. 
• Trail Making Test (TMT) – Parts A & B  
o This task is to draw a line between circles containing numbers and/or 
letters in ascending order. It measures various aspects of cognition 
including attention, visual search, motor coordination, reasoning, and task-
switching. 
• Effort Expenditure for Rewards Task (EEfRT) 
o This task is to make a series of choices between an easier, low‐reward 
option and a harder, high‐reward option. It is a measure of motivation.   
• Beck Depression Inventory (BDI-II) 
o This scale measures the amount of self-reported depressive symptoms.  
  
These tests provide a brief general evaluation of cognitive functions (RBANS), memory 
(CVLT-II, SRTT, Word Fluency), executive functions (TMT, EEfRT), and emotional 
wellbeing (BDI-II, STAI).  
 
We will also administer two motor tasks (Finger Tapping Test and Grooved Pegboard 
Test) for comparison purposes with ongoing AIH studies in patients with spinal cord 
injury and stroke after each session along with a visual analogue scale so you can tell 
us how your mood is at the moment, and a brief word recall test using items from the 
Rey Auditory Verbal Learning Test. 
 

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Visit 2: 21% oxygen, that is, the same exposure as normal room air. Intervention Day 1, 
Length of visit: estimated 2 hours 
• Hypoxia session with 21% oxygen: 30 minutes 
• Outcome assessments – as above plus the measurement of motor evoked 
potentials (TMS) 
• Monitoring assessments – taking your vital signs - We will measure your blood 
pressure, SpO2 (the amount of oxygen in your blood), and pulse rate during the 
hypoxia session.  
Visit 3: 17% oxygen. Intervention Day 4, Length of visit: estimated 2 hours 
• Hypoxia session with 17% oxygen: 30 minutes 
• Outcome assessments – as above 
• Monitoring assessments – as above 
Visit 4: 13% oxygen. Intervention Day 8, Length of visit: estimated 2 hours  
• Hypoxia session with 13% oxygen: 30 minutes 
• Outcome assessments – as above 
• Monitoring assessments – as above 
Visit 5: 9% oxygen. Invervention Day 12, Length of visit: estimated 2 hours 
• Hypoxia session with 9% oxygen: 30 minutes 
• Outcome assessments – as above plus the measurement of motor evoked 
potentials (TMS) 
• Monitoring assessments – as above 
Visit 6: Post-Treatment Evaluation Day 16, Length of visit: estimated 4 hours 
• Discuss the research project 
• Magnetic resonance imaging (MRI), same as in Visit 1. 
• Medical history – update baseline evaluation 
• Current medications/comorbidities – update baseline evaluation 
• Neurobehavioral assessments – see baseline evaluation (minus the STAI and 
OSU TBI assessments). 
 
(Note: The time interval between interventions is subject to modification, depending on 
the staff and equipment availability, as well as your scheduling preferences. The above 
visit lengths are our best time estimations given the procedures involved in each. The 
actual amount of time for each visit will vary from participant to participant, to account 
for variations including waiting room time, transport time from one procedure to another, 
and other timing aspects of the study that cannot, by nature, be set.)  
 
We would like to audio or video record the neurobehavioral assessment sessions during 
Visits 1 and 6. The recording is optional. If you agree to it, you will be asked to indicate 
so at the end of this consent form. 
 
Outcome assessments: 

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Monitoring assessments (carried out throughout the hypoxia administration):  
• Vitals: We will measure your blood pressure, SpO2 (the amount of oxygen in 
your blood), and pulse rate.  
• Symptom checklist: A simple yes/no subjective checklist of physical 
symtpoms, such as chest pain, lightheadedness, etc., will be administered to 
you at 2, 6, 14, 24 and 30 minutes from the beginning of the hypoxia session.  
 
Other outcome assessments before and afterAIH session #1 (Visit 2) and #4 (Visit 5): 
• Single-pulse assessment of motor cortical functioning using transcranial 
magnetic stimulation and electromyographic recording 
Transcranial Magnetic Stimulation (TMS) and electromyography (EMG): TMS 
sends a magnetic pulse into your brain and stimulates brain activity. A wire TMS coil will 
be placed over your head. The TMS coil will be held to your head with a custom coil 
holder. To limit head movement, your head will be secured to the headrest with a soft 
Velcro strap. When the TMS is activated, this coil will generate a magnetic pulse over a 
specified area of your brain that is responsible for hand movement. When the pulse 
occurs, you will hear a click or a snapping sound, and you may feel a pulling sensation 
on your skin underneath the area where the coil is placed. You may also feel a light 
twitch of the muscles in your arm, face or your leg. During Visit 1, we will do motor 
mapping, that is, we will use neuronavigation to find the area of your brain that activates 
the target muscle of your hand. During Visits 2 and 5 we will apply a series of TMS 
pulses to this brain area to evoke EMG responses from the target muscle. During the 
EMG recording, you will be comfortably positioned so that your arms are supported by a 
testing device. Recording electrodes will be attached to the surface of your skin over the 
target hand muscle to record its activity. 
 
Exclusion criteria for TBI patients for TMS and EMG: 
• Uncontrolled medical problems affecting the lungs (pulmonary diseases), the heart 
(cardiovascular diseases) or the muscuskeletal system (orthopedic diseases)  
• Pre-injury, ongoing major depression or psychosis, altered cognitive status  
• History of stroke 
• Metal in head (e.g., surgical clips, shrapnel) 
• History of seizures or epilepsy diagnosis  
• Receiving drugs acting primarily on the central nervous system, which lower the 
seizure threshold such as antipsychotic drugs (chlorpromazine, clozapine) or 
tricyclic antidepressant  
•  
• Surgery to your head  
• Any non-TBI-related neurological diseases 
• Illnesses that may have caused brain injury 
• Unexplained frequent or severe headaches 
• Pregnancy in females  
• Implanted devices (e.g., pacemakers, medical pumps, brain stimulators) 
 

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You will not be eligible to participate in the study if you are not eligible to undergo MRI or 
TMS.  
 
 
What are my responsibilities if I take part in this research? 
If you take part in this research, you will be responsible to arrive at the Shirley Ryan 
AbilityLab for all the scheduled visits and complete the research procedures with the 
staff.  
 
What happens if I say “Yes”, but I change my mind later? 
You can leave the research at any time; it will not be held against you. If you decide to 
leave the research, contact the investigator.  
 
Choosing not to be in this study or to stop being in this study will not result in any 
penalty to you or loss of benefit to which you are entitled. Specifically, your choice not to 
be in this study will not negatively affect your right to any present or future medical 
treatment.   
 
Detailed Risks: Is there any way being in this study could be bad for me? 
 
Cardiac adverse events could be silent (non-symptomatic) or non-silent (symptomatic). 
 
In the event of a silent event subjects will be given a referral to a cardiologist at 
Northwestern Memorial Hospital to undergo more comprehensive assessments to 
confirm the severity of the adverse event.  
 
A non-silent event will require the ROC (resident on-call) to be called to the clinic room 
for immediate and urgent attention for the chest pain experienced. The medical 
professional will decide the best care plan for you, which could include a trip to the 
emergency room. 
 
A cerebral adverse event is experienced through a change in the neurological 
assessment, such as blurred vision or slurred speech. The Medical monitor will be 
informed of this outcome and will provide advice accordingly, which may result in being 
withdrawn from this research study for your own safety.  
 
Breathing low levels of oxygen causes low levels of oxygen in the blood. Some of the 
side effects could include lightheaded sensation, dizziness, reduced vision, feeling short 
of breath, abnormally elevated heart rate, euphoria, and fainting. An additional risk to 
wearing a mask in individuals afraid of enclosed spaces (claustrophobic) is discomfort, 
anxiety or panic. We will monitor for these side effects, as well as monitor  your vital 
signs to assure your safety during the session. In the event of an emergency, you will 
be withdrawn from the breathing apparatus, and the resident physician on-call will be 
notified for further management. There may also be other side effects that we cannot 
predict, or there may be risks that may hurt you in ways that are unknown. These may 
be a minor inconvenience or so severe as to cause death.  

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Some people cannot have an MRI because they have certain type of metal in their 
body. For instance, if you have a heart pacemaker, artificial heart valves, metal implants 
such as metal ear implants, bullet pieces, chemotherapy or insulin pumps or other metal 
such as metal clips or rings, you may not be allowed to have an MRI. If you are 
claustrophobic, lying in a small closed area inside a large magnetic tube during this test 
may feel uncomfortable. The MRI scanner makes loud banging noises while taking a 
measurement, so either ear plugs or specially designed headphones will be used to 
reduce the noise. 
 
Some people experience temporary discomfort from undergoing TMS including mild 
headaches and/or tingling or twitching sensation in the scalp, jaw, or face. Seizures are 
a rare, but possible risk from undergoing TMS. 
 
The primary risks associated with participation in neurobehavioral assessments are 
boredom, tiredness, and/or frustration. These risks are more likely to occur if you feel 
that you are not performing well on certain tasks. We will try to minimize these risks by 
offering you frequent rest breaks and providing positive feedback and encouragement.  
 
A feeling of suffocation or breathlessness during Acute Intermittent Hypoxia is a rare but 
possible adverse event. 
 
An additional research-related risk involves the use of your identifiable, personal 
information, and there is a chance that a loss of confidentiality could occur. The 
researchers have procedures in place to reduce the possibility of this happening. (See 
the section below titled: “What happens to the information collected for the 
research?”). 
 
For any additional concerns, the number of the researcher is listed in the section “Who 
can I talk to?”  
 
There may be some unknown or unanticipated risks or discomforts, because some of 
the procedures are relatively new and are attempts to advance medical knowledge. 
Every known precaution will be taken to ensure your personal safety and to minimize 
discomfort.  
 
The possible risks associated with blood drawing are pain, bleeding, a rare risk of 
fainting, bruising, infection and/or hematoma (blood clot under the skin) at the injection 
site. If you develop bruising, this will go away after a couple of days and can be treated 
with warm compresses and/or medication. 
 
 
What do I need to know about reproductive health and/or sexual activity if I am in 
this study? 
The effect of this study’s breathing intervention on human sperm and eggs has not been 
studied. The effects on the developing fetus during breathing low oxygen levels during 

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pregnancy and the risk of birth defects are also unknown. Therefore, both men and 
women should not attempt pregnancy and women should not be pregnant or breast-
feeding while taking part in this study.  
 
If you are sexually active, both men and women should use at least one effective means 
of birth control while participating in this research study. According to the World Health 
Organization and the United States Center for Disease Control and Prevention, the 
most effective forms of birth control include complete abstinence, surgical sterilization 
(both male and female), intrauterine devices (IUDs), and the contraceptive implant. The 
next most effective forms of birth control include injectable, oral contraceptive pills, the 
contraceptive ring, or the contraceptive patch. Acceptable but least effective methods of 
birth control include male condoms (with or without spermicide) and female condoms.  
If you or your partner become pregnant while participating in this research study or for a 
week after you complete the study, it is important that you tell the study doctor or other 
research team member immediately. You may be required to stop participation in this 
study; however, other treatment options will be discussed with you at that time if 
necessary.  
 
If you or your partner [are/is] considered to be postmenopausal, you are not required to 
use contraception while participating in this research study. Postmenopausal women 
rarely become pregnant. 
 
Will it cost me anything to participate in this research study? 
Taking part in this research study will be of no cost to you. All visits are entirely 
research-related and will not result in a cost to you or your insurance.  
 
What happens to the information collected for the research? 
Efforts will be made to limit the use and disclosure of your personal information, 
including research study and medical records, to people who have a need to review this 
information. We cannot promise complete secrecy. Organizations that may inspect and 
copy your information include the following:  
• IRB and other representatives of this institution  
• The study sponsor, monitors, auditors 
• The Northwestern University Office for Research Integrity  
• The US Office of Research Integrity (ORI)  
• The US Office for the Protection of Human Research Protections (OHRP) 
• The US Food and Drug Administration (FDA)  
 
Any of these entities may be granted direct access to your medical records to conduct 
and oversee the research. By signing this document, you are authorizing this access. 
We may publish the results of this research. However, we will keep your name and 
other identifying information confidential.  
 

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If we learn about current or ongoing child [or elder] abuse or neglect, we may be 
required or permitted by law or policy to report this information to authorities. 
 
 
Data Sharing  
De-identified data from this study may be shared with the research community at large 
to advance science and health. We will remove or code any personal information that 
could identify you before files are shared with other researchers to ensure that, by 
current scientific standards and known methods, no one will be able to identify you from 
the information we share. Despite these measures, we cannot guarantee anonymity of 
your personal data. 
 
Can I be removed from the research without my OK? 
The person in charge of the research study, Jordan Grafman, Ph.D., can remove you 
from the research study without your approval. Possible reasons for removal include 
inability to comply with study requirements and/or appointments.  
 
We will tell you about any new information that may affect your health, welfare, or 
choice to stay in the research.  
 
What else do I need to know? 
If you become ill or are injured as a result of this study (medications, devices or 
procedures), you should seek medical treatment through your doctor or treatment 
center of choice. You should promptly tell the study doctor about any illness or injury.   
 
The hospital [university, researchers] will not pay for medical care required because of a 
bad outcome resulting from your participation in this research study. This does not keep 
you from seeking to be paid back for care required because of a bad outcome.  
 
You will receive $20 per hour, that includes compensation for the treatment sessions, 
the baseline and the post-treatment evaluations. Any partial hours completed will be 
compensated at a prorated rate of $5 per 15 minutes. The Shirley Ryan AbilityLab will 
issue you a ClinCard, which is a specially designed debit card for clinical research. 
Once a visit that qualifies for compensation is completed, funds will be approved and 
loaded onto your card. The funds will be available within 1 day after being loaded and 
can be used at your discretion. You will be issued one card for the duration of your 
participation. If your card is lost or stolen, please call (866) 952-3795 or ask a 
coordinator for a replacement ClinCard.   
 
Fees are incurred if used at an ATM (fees vary by location). However, if the card is used 
for in-store or online purchases via credit or debit, there are no associated fees and no 
expiration date.  
 

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Please be advised: Inactivity on the card for more than 3 months will incur a monthly 
fee. However, as long as there is activity on the card within 3 months (funds are added 
or a transaction is completed), the month period will reset and no monthly fee will be 
applied. 
 
If you do incur a monthly fee, please contact Greenphire Support at the number on the 
back of your card and they will reverse the fee. See “Tips for Using the Attached 
ClinCard” for more information. 
 
The Finance Department at the Shirley Ryan AbilityLab will be provided with your 
information, including your Social Security Number, in order to issue payment for your 
study participation. Study payments are considered taxable income and reportable to 
the Internal Revenue Service (IRS). An IRS Form 1099 will be sent to you if your total 
payments are $600 or more in a calendar year. 
 
You may be given access to new inventions that are being developed by the 
investigator, the study sponsor, or other people involved in the study. Certain laws can 
make it harder to obtain legal protection for a new invention shared with a study 
participant, unless the study participant agrees to keep information about the invention 
confidential. You agree to keep confidential information you may receive about new 
inventions, such as new drugs, new devices, or new methods. 
 
A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health (NIH). The researchers can use this Certificate to 
legally refuse to disclose information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings; for example, if there is a 
court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you. You should understand that a Certificate of 
Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research. If an insurer, 
medical care provider, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 

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HIPAA Authorization 
We are committed to respect your privacy and to keep your personal information 
confidential. When choosing to take part in this study, you are giving us the permission 
to use your personal health information that includes health information in your medical 
records and information that can identify you. For example, personal health information 
may include your name, address, phone number or social security number. Your health 
information we may collect and use for this research includes: 
 
• Results of physical and other medical examinations related to your TBI 
• Medical history from self-report and medical records 
• Lab tests, or certain health information indicating or relating to a particular 
condition, as well as diaries and questionnaires 
• Records about study medication or drugs  
• Certain demographic information like age, sex, education level 
 
 
The following clinical providers may give the researchers information about you: all 
current and previous health care providers, including but not limited to the Shirley Ryan 
AbilityLab (SRALAB), Northwestern Medical Group (NMG), Northwestern Memorial 
Hospital (NMH), and Northwestern Lake Forest Hospital (NLFH). 
 
Once we have the health information listed above, we may share some of this 
information with the following offices or entities outside of Northwestern University and 
its clinical partners (or affiliates): the Northwestern University Institutional Review Board 
Office and Office for Research Integrity; the US Office of Research Integrity; the US 
Office for Human Research Protections; the US Food and Drug Administration.   
 
Any research information shared with outside entities will not contain your name, 
address, telephone or social security number or any other personal identifier unless 
disclosure of the identifier is necessary for review by such parties or is required by law 
or University policy [except that such information may be viewed by the Study sponsor 
and its partners or contractors at the Principal Investigator’s office]. 
 
The following entities may receive your health information: 
 
• Authorized members of the Northwestern University and the Shirley Ryan 
AbilityLab workforce, who may need to see your information, such as 
administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board. 
• Clinical affiliates, including but not limited to the Shirley Ryan AbilityLab 
(SRALAB), Northwestern Medical Group (NMG), Northwestern Memorial 
Hospital (NMH), Northwestern Lake Forest Hospital (NLFH), and the Ann & 
Robert H. Lurie Children’s Hospital of Chicago (Lurie Children’s). Your 
participation in this clinical trial may be tracked in an electronic database and 

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may be seen by investigators running other trials that you are enrolled in and 
by your healthcare providers.  
• Clinical affiliates, including but not limited to Northwestern Medical Group 
(NMG), Northwestern Memorial Hospital (NMH), and Northwestern Lake 
Forest Hospital (NLFH), for purposes including, but not limited to, the 
affiliate’s provision of care to you and/or the affiliate’s scheduling of 
appointments and/or billing activities. 
• Other University research centers and University contractors who are also 
working on the study. 
• Government agencies and public health authorities, such as the Food and 
Drug Administration (FDA) and the Department of Health and Human 
Services (DHHS). 
 
Those persons who get your health information may not be required by Federal privacy 
laws (such as the Privacy Rule) to protect it. Some of those persons may be able to 
share your information with others without your separate permission. 
 
The results of this study may also be used for teaching, publications, or for presentation 
at scientific meetings.   
 
Unless you revoke your consent, it will expire on January 1st, 2024. 
 
Although you may revoke consent to participation in this research at any time and in any 
format, you must revoke authorization for use or disclosure of your health information in 
writing. To revoke your authorization, write to: 
 
 
 
PI’s Name:  Jordan Grafman, Ph.D.  
Address:   
Cognitive Neuroscience Lab 
Think and Speak Lab, 25th Floor 
Shirley Ryan AbilityLab 
355 E. Erie Street 
Chicago, Illinois 60611-5146 
 
 
You do not have to authorize the use or disclosure of your health information; however, 
you will not be allowed to take part in this research study unless you do so. If you do not 
authorize the use or disclosure of your health information, it will not affect your 
treatment by health care providers, or the payment or enrollment in any healthcare 
plans, or affect your eligibility for benefits. 
 
 

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Optional Elements: 
The following research activities are optional, meaning that you do not have to agree to 
them in order to participate in the research study. Please indicate your willingness to 
participate in these optional activities by placing your initials next to each activity. 
I  agree 
 
disagree 
 
_______ 
 
 
_______ 
The researcher may audio or video record me to aid with 
data analysis. The researcher will not share these 
recordings with anyone outside of the immediate study team. 
_______ 
 
 
 
 
 
_______ 
The researcher may audio or video record me for use in 
scholarly presentations or publications. These recordings will 
be permanently available in print or electronic format (i.e., 
the internet). My identity may be shared as part of this 
activity, although the researcher will attempt to limit such 
identification. 
_______ 
 
 
_______ 
The researcher may contact me in the future to see whether 
I am interested in participating in other research studies by 
the Principal Investigator of this study. 
 
 
 
Signature Block for Capable Adult: 
 
Your signature documents your permission to take part in this research.  You will be 
provided a copy of this signed document. 
 
_______________________________________________      __________________ 
Signature of Participant                                                               Date 
 
_______________________________________________ 
Printed Name of Participant 
 
 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                     Date 
 
______________________________________________________ 
Printed Name of Person Obtaining Consent