Brain Injuries, Traumatic
Conditions
Keywords
Hypoxia
Brief summary
This study is designed to answer questions related to safety and preliminary efficacy of Acute Intermittent Hypoxia (AIH) in Traumatic Brain Injury (TBI) survivors. First, we aim to establish whether brief reductions in inhaled oxygen concentration can be safely tolerated in TBI survivors. Second, we aim to establish whether there are any effects of AIH on memory, cognition, and motor control. Participants 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.
Detailed description
The purpose of this study is to determine whether Acute Intermittent Hypoxia (AIH) is safe to administer to medically stable chronic traumatic brain injury (TBI) patients. There is evidence indicating that AIH promotes central nervous system (CNS) neuroplasticity. AIH stimulates oxygen-sensitive serotonergic neurons in the brainstem's raphe nucleus leading to serotonin release into different regions of the CNS. This release leads to activation of serotonin receptors on or near cortical neurons and increased synthesis of multiple trophic factors including brain-derived neurotrophic factor, vascular endothelial growth factor, and erythropoietin. These actions also influence the functioning of neurotransmitters such as GABA. Greater expression of growth factors in the brain facilitates neuroplasticity by increasing synaptic strength, cortical neuron and interneuron excitability, and intra- and inter-brain region connectivity. Of note is that hypoxia-induced neuroplasticity only occurs with acute intermittent exposure, but is not evoked by continuous hypoxia of the same duration. Is AIH safe to administer to TBI patients? The preponderance of prior animal and human evidence suggests that daily episodes of mild AIH do not negatively impact important safety parameters such as resting blood pressure, arterial pressure, heart rate, heart rate variability, cardiac output, or cognitive function. To date, AIH protocols that induce beneficial neuroplasticity without triggering pathological sequelae have been restricted to brief episodes of modest hypoxia with a low cycle number, such as 15 x 90-second episodes of 10% inspired oxygen. Recent studies in humans with chronic spinal cord injury and stroke demonstrated that these modest AIH episodes repeated for five consecutive days can be safely tolerated without pathological consequences. Another recent study showed that even a 4-week protocol of moderate daily AIH (cycling 9%/21% oxygen every 1.5 minutes, 15 cycles per day, for 4 weeks) does not elicit adverse medical consequences or cognitive impairment. Thus, the cumulative evidence suggests that repetitive AIH may be safely used to study whether it can enhance neurobehavioral functioning in TBI patients without deleterious effects. In this study, we will administer mild AIH to 16 patients on four different days spread over the course of two to four weeks, starting with normal oxygen concentration (target SpO2 of 98%) and then progressively reducing the oxygen concentrations over the next three sessions (to 93%, 87%, and 82%). Our primary objective is to determine whether it is safe to administer mild AIH to chronic TBI patients with persistent functional impairments, but who are clinically stable. As a secondary objective in this study, we will assess whether mild AIH administration has any post-session or cumulative effects post-study on memory and cognition, cortical activation as assessed by single-pulse Transcranial Magnetic Stimulation, or whether pre-study brain architecture or functional connectivity as detected by structural and resting-state functional magnetic resonance imaging predicts response to AIH. If no adverse effects to mild AIH are observed in this study, clinical trials using mild AIH alone or in conjunction with neurobehavioral therapies could evaluate whether AIH facilitates the improvement of functional performance after TBI.
Interventions
PROCEDUREAcute Intermittent Hypoxia
Four hypoxia sessions, consisting of 15 cycles of hypoxia (21%, 17%, 13% or 9% O2), each of which lasts up to 60 seconds, interspersed with up to 90-second normoxic episodes.
Sponsors
Shirley Ryan AbilityLab
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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 * Not 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 a participant from understanding the protocol and consent form * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Vitals at Visit 2 | Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 | Number of Participants With Treatment-Related Adverse Events as assessed by concerning change in blood pressure, SpO2, and heart rate from baseline, as reviewed and determined by the medical monitor. |
| Change in Vitals at Visit 3 | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by concerning change in blood pressure, SpO2, and heart rate from baseline, as reviewed and determined by the medical monitor. |
| Change in Vitals at Visit 4 | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by concerning change in blood pressure, SpO2, and heart rate from baseline, as reviewed and determined by the medical monitor. |
| Change in Vitals at Visit 5 | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by concerning change in blood pressure, SpO2, and heart rate from baseline, as reviewed and determined by the medical monitor. |
| Change in Symptoms at Visit 2 | Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 | Number of Participants With Treatment-Related Adverse Events as assessed by the presence of "Yes" responses on a verbally-administered 9-item "Yes/No" subjective symptom checklist, as reviewed and determined by the medical monitor. The nine symptoms on this checklist are as follows: 1) chest pain, 2) shortness of breath, 3) lightheadedness, 4) neck pain, 5) dizziness, 6) arm pain (left side for cardiac symptoms), 7) sweatiness/feeling warm, 8) sensory changes (new signs of numbness), 9) increased weakness. Participants will be asked if they are experiencing any of the above symptoms at the 2-minute, 6-minute, 14-minute, 24-minute, and 30-minute timepoints throughout an AIH session. |
| Change in Symptoms at Visit 3 | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by the presence of "Yes" responses on a verbally-administered 9-item "Yes/No" subjective symptom checklist, as reviewed and determined by the medical monitor. The nine symptoms on this checklist are as follows: 1) chest pain, 2) shortness of breath, 3) lightheadedness, 4) neck pain, 5) dizziness, 6) arm pain (left side for cardiac symptoms), 7) sweatiness/feeling warm, 8) sensory changes (new signs of numbness), 9) increased weakness. Participants will be asked if they are experiencing any of the above symptoms at the 2-minute, 6-minute, 14-minute, 24-minute, and 30-minute timepoints throughout an AIH session. |
| Change in Symptoms at Visit 4 | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by the presence of "Yes" responses on a verbally-administered 9-item "Yes/No" subjective symptom checklist, as reviewed and determined by the medical monitor. The nine symptoms on this checklist are as follows: 1) chest pain, 2) shortness of breath, 3) lightheadedness, 4) neck pain, 5) dizziness, 6) arm pain (left side for cardiac symptoms), 7) sweatiness/feeling warm, 8) sensory changes (new signs of numbness), 9) increased weakness. Participants will be asked if they are experiencing any of the above symptoms at the 2-minute, 6-minute, 14-minute, 24-minute, and 30-minute timepoints throughout an AIH session. |
| Change in Symptoms at Visit 5 | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) | Number of Participants With Treatment-Related Adverse Events as assessed by the presence of "Yes" responses on a verbally-administered 9-item "Yes/No" subjective symptom checklist, as reviewed and determined by the medical monitor. The nine symptoms on this checklist are as follows: 1) chest pain, 2) shortness of breath, 3) lightheadedness, 4) neck pain, 5) dizziness, 6) arm pain (left side for cardiac symptoms), 7) sweatiness/feeling warm, 8) sensory changes (new signs of numbness), 9) increased weakness. Participants will be asked if they are experiencing any of the above symptoms at the 2-minute, 6-minute, 14-minute, 24-minute, and 30-minute timepoints throughout an AIH session. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Update consists of twelve subtests that are used to compute Index scores on five cognitive domains, including Immediate Memory, Delayed Memory, Visuospatial/Constructional Abilities, Language, and Attention. Index scores on each domain range between 40 and 160. Lower scores correspond to greater cognitive deficits. |
| California Verbal Learning Test (CVLT-II) Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The California Verbal Learning Test (CVLT-II) is a multi-trial word learning test that evaluates verbal memory performance. The test measures Immediate Free Recall (possible score range: 0-80), Short-Delay Free Recall (0-16), Short-Delay Cued Recall (0-16), Long-Delay Free Recall (0-16), Long-Delay Cued Recall (0-16), and Long-Delay Recognition (0-16). The score on each subscale represents the number of correct responses. Higher scores indicate better memory. |
| D-KEFS (Delis-Kaplan Executive Function System) Verbal Fluency Test Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The D-KEFS (Delis-Kaplan Executive Function System) Verbal Fluency Test measures one's ability to retrieve words from memory. The task is to produce as many words as possible that (1) begin with a specific letter (e.g., F,A,S), (2) belong to a certain semantic category (e.g., animal names), or (3) belong to two alternating categories (e.g., fruits and furniture). The scores (range: 0-unlimited) represent the number of correct responses produced in each condition. Higher scores mean better performance on the test. |
| Serial Reaction Time Task (SRTT) Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The Serial Reaction Time Task (SRTT) measures implicit motor learning. Participants press four keyboard keys in sequence in response to cues on the screen. At first, the same ten-key pattern is repeated without participants' awareness. Next, key presses follow a random sequence. The outcome measure is the difference in average reaction time between the random and learned sequences. An increase in reaction time during the random sequence reflects the cognitive effort required to inhibit the previously learned pattern. Therefore, larger differences indicate stronger implicit motor learning. |
| Trail Making Test (TMT) Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The Trail Making Test (TMT) is a measure of motor and executive function. This test has two parts, Part A and Part B. 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 draw a line, alternating between ascending numbers and letters (e.g., 1-A-2-B…etc.). The outcome measures are the reaction times in seconds required to complete Part A and Part B. Faster reaction times indicate better test performance. |
| Finger Tapping Test Scores | baseline (Visit 1) and follow-up (Visit 6, 9-17 days after baseline), as well as one hour after AIH in Visit 2 (1-6 days after baseline), Visit 3 (2-7 days after baseline), Visit 4 (6-12 days after baseline) and Visit 5 (8-14 days after baseline) | The Finger Tapping Test measures the rate of finger presses in order to assess simple motor coordination. In this task, participants are asked to tap the lever on a wooden board with their index finger as fast as possible for ten seconds. Five trials with each hand are administered. The first two trials are discarded as practice. The average number of taps on the subsequent three trials are recorded as the test score. Higher scores reflect better motor function. |
| Grooved Pegboard Test Scores | baseline (Visit 1) and follow-up (Visit 6, 9-17 days after baseline), as well as one hour after AIH in Visit 2 (1-6 days after baseline), Visit 3 (2-7 days after baseline), Visit 4 (6-12 days after baseline) and Visit 5 (8-14 days after baseline) | The Grooved Pegboard Test measures manual dexterity and eye-hand coordination. It consists in inserting grooved pegs into a 5×5 board as quickly as possible, without skipping any slots, starting from the top row. One hand is tested at a time, starting with the dominant one. When using the right hand, participants are asked to fill the board from left to right. When using the left hand, they complete the board from right to left. The outcome measure is the amount of time in seconds required to complete the board. Faster reaction times reflect better motor function. |
| Rey Auditory Verbal Learning Test (RAVLT) Scores | approximately one hour after AIH in Visit 2 (1-6 days after baseline), Visit 3 (2-7 days after baseline), Visit 4 (6-12 days after baseline) and Visit 5 (8-14 days after baseline) | The Rey Auditory Verbal Learning Test (RAVLT) is a standardized assessment of verbal learning and memory that measures Immediate Free Recall (score range: 0-75), Short-Delay Free Recall (0-15), Long-Delay Free Recall (0-15), and Long-Delay Forced-Choice Recognition (0-15). The scores on each subscale represent the total number of correct responses. Higher scores mean better test performance. |
| Beck Depression Inventory (BDI-II) Scores | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | The Beck Depression Inventory (BDI-II) is a 21-item self-report questionnaire assessing the severity of depressive symptoms. Each question has four response options, scored from 0 to 3. The outcome measure is the total score (range: 0-63). Higher scores reflect greater severity of depression symptoms. |
| Visual Analogue Mood Scale (VAM-S) Scores | approximately one hour after AIH in Visit 2 (1-6 days after baseline), Visit 3 (2-7 days after baseline), Visit 4 (6-12 days after baseline) and Visit 5 (8-14 days after baseline) | The Visual Analogue Mood Scale (VAM-S) consists of a single 100-mm horizontal line representing a scale ranging from "very bad mood" (score: 0) to "very good mood" (score:100). Participants are asked to place a mark on the line corresponding to their current mood. The outcome measure is the length of the segment between the leftmost part of the scale and the mark made by the participant in mm. Higher scores mean better mood. |
| Motor Evoked Potentials (MEPs) | approximately 45 min after AIH in Visit 2 (1-6 days after baseline) and Visit 5 (8-14 days after baseline) | Transcranial magnetic stimulation (TMS) is delivered to the scalp in order to elicit MEPs in the first dorsal interroseous muscle of the dominant hand. The optimal stimulation site is determined by moving the coil over the scalp in small steps along the hand representation of the primary motor cortex to find the region where the largest MEPs can be evoked in the target muscle with the minimum intensity. Change in MEP amplitudes is used to assess improvement in motor function. |
| MRI | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) | MRI was used to determine whether there are changes in brain structure or function from baseline, as assessed by a physician and a neuroimaging data analyst. The outcome measure is the number of participants with observable changes in structural or functional images of the brain following the AIH intervention. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJordan Grafman, PhD
Shirley Ryan AbilityLab
Participant flow
Recruitment details
Participants were recruited through physician referrals, outreach via research registries, flyers and online ads distributed within the Shirley Ryan AbilityLab and other Northwestern-affiliated hospitals. Twelve participants were enrolled into the study between March 2022 and January 2024.
Pre-assignment details
All participants underwent the same treatment protocol.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Months since injury | 41.4 months STANDARD_DEVIATION 27.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 5 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
None listed