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| ID | Type | Description | Link |
|---|---|---|---|
| 1R21NS114815-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AIH group | Experimental | Hypoxia will be administered via a specialized face mask attached to a gas mixing device (HYP123, Hypoxico Inc.), which controls oxygen content in inhaled air. The hypoxia administering unit will be manually adjusted to supply O2 at the target level for a given session (approximately 21%-normal room air, 17%, 13%, and 9% respectively). Each session will include 15 cycles of hypoxia, each lasting up to 60 seconds, interspersed with up to 90-second normoxic episodes. An oxygen monitor will continuously measure and record the fraction of inspired oxygen delivered (MAX-250E, Maxtec Inc.). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acute Intermittent Hypoxia | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Vitals at Visit 2 | 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. | Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 |
| Change in Vitals at Visit 3 | 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. | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) |
| Change in Vitals at Visit 4 | 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. | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) |
| Change in Vitals at Visit 5 | 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. | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) |
| Change in Symptoms at Visit 2 | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Scores | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jordan Grafman, PhD | Shirley Ryan AbilityLab | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shirley Ryan AbilityLab | Chicago | Illinois | 60611 | United States |
IPD will be made available to other researchers when published.
IDP will become available when published, starting 6 months after publication.
Requests to access IPD can be emailed to the P.I., who will review requests on a case-by-case basis.
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All participants underwent the same treatment protocol.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | AIH Group | All participants completed six research visits to the Shirley Ryan AbilityLab, including four AIH treatment sessions (Visits 2-5), as well as the pre- and post-treatment assessments of motor, cognitive and affective function (Visits 1 and 6 respectively). During each of the four AIH interventions administered in Visits 2 through 5, the participants received brief bouts of reduced oxygen (O2), that they inhaled through a non-rebreathing face mask. The gas mixture was delivered using a customized Hyp-123 device (Hypoxico, Gardiner, NY), and O2 concentrations were monitored using a Maxtec Handi+ oxygen analyzer (Maxtec, Salt Lake City, UT). Participants' peripheral oxygen saturation levels (SpO2) and heart rate (HR) were monitored in real time with a Nonin 7500 pulse oximeter (Nonin Medical Inc., Plymouth, MN). To assess the potential changes in corticospinal excitability associated with the AIH intervention, transcranial magnetic stimulation (TMS) was applied to the left primary motor cortex 45 min after completing the AIH intervention in Visit 2 and Visit 5, and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the right hand. In addition to an extensive behavioral testing battery administered in Visit 1 and Visit 6, a brief assessment of motor, cognitive and affective function was administered 60 min after the completion of each AIH intervention in Visits 2 through 5. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | AIH Group | All participants completed six research visits to the Shirley Ryan AbilityLab, including four AIH treatment sessions (Visits 2-5), as well as the pre- and post-treatment assessments of motor, cognitive and affective function (Visits 1 and 6 respectively). During each of the four AIH interventions administered in Visits 2 through 5, the participants received brief bouts of reduced oxygen (O2), that they inhaled through a non-rebreathing face mask. The gas mixture was delivered using a customized Hyp-123 device (Hypoxico, Gardiner, NY), and O2 concentrations were monitored using a Maxtec Handi+ oxygen analyzer (Maxtec, Salt Lake City, UT). Participants' peripheral oxygen saturation levels (SpO2) and heart rate (HR) were monitored in real time with a Nonin 7500 pulse oximeter (Nonin Medical Inc., Plymouth, MN). To assess the potential changes in corticospinal excitability associated with the AIH intervention, transcranial magnetic stimulation (TMS) was applied to the left primary motor cortex 45 min after completing the AIH intervention in Visit 2 and Visit 5, and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the right hand. In addition to an extensive behavioral testing battery administered in Visit 1 and Visit 6, a brief assessment of motor, cognitive and affective function was administered 60 min after the completion of each AIH intervention in Visits 2 through 5. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Vitals at Visit 2 | 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. | Posted | Count of Participants | Participants | Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 |
|
from the first AIH session (Visit 2) until the end of follow-up (Visit 6), up to three weeks
Task-related Adverse Events (AEs) were assessed during each of the four AIH sessions using a 9-item symptom checklist (Systematic Assessment) and have been reported in detail as Primary Outcome Measures. Additionally, all new symptoms self-reported by participants throughout the course of the study were logged (Non-Systematic Assessment). All such self-reported symptoms were determined to be unrelated to the intervention by the physician monitor.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AIH Group | All participants completed six research visits to the Shirley Ryan AbilityLab, including four AIH treatment sessions (Visits 2-5), as well as the pre- and post-treatment assessments of motor, cognitive and affective function (Visits 1 and 6 respectively). During each of the four AIH interventions administered in Visits 2 through 5, the participants received brief bouts of reduced oxygen (O2), that they inhaled through a non-rebreathing face mask. The gas mixture was delivered using a customized Hyp-123 device (Hypoxico, Gardiner, NY), and O2 concentrations were monitored using a Maxtec Handi+ oxygen analyzer (Maxtec, Salt Lake City, UT). Participants' peripheral oxygen saturation levels (SpO2) and heart rate (HR) were monitored in real time with a Nonin 7500 pulse oximeter (Nonin Medical Inc., Plymouth, MN). To assess the potential changes in corticospinal excitability associated with the AIH intervention, transcranial magnetic stimulation (TMS) was applied to the left primary motor cortex 45 min after completing the AIH intervention in Visit 2 and Visit 5, and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the right hand. In addition to an extensive behavioral testing battery administered in Visit 1 and Visit 6, a brief assessment of motor, cognitive and affective function was administered 60 min after the completion of each AIH intervention in Visits 2 through 5. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lightheadedness | Nervous system disorders | Systematic Assessment | Transient lightheadedness reported by participants during an AIH session, as assessed by the 9-item Symptom Monitoring checklist (see the Primary Outcome Measure "Change in Symptoms" for details). |
Data from the Rey Auditory Verbal Learning Test administered in Visits 2 through 5 were excluded from the analysis due to significant ceiling effects - the same word list was used across all four sessions, leading to substantial long-term memory contamination, precluding reliable estimation of within-session learning trajectories.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ekaterina Delikishkina, Ph.D. | Shirley Ryan AbilityLab | 312-238-4579 | kdelikishk@sralab.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Oct 21, 2025 | Jan 26, 2026 | Prot_SAP_ICF_000.pdf |
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| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D000860 | Hypoxia |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 |
| Change in Symptoms at Visit 3 | 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. | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) |
| Change in Symptoms at Visit 4 | 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. | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) |
| Change in Symptoms at Visit 5 | 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. | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) |
| Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| California Verbal Learning Test (CVLT-II) Scores | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| D-KEFS (Delis-Kaplan Executive Function System) Verbal Fluency Test Scores | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| Serial Reaction Time Task (SRTT) Scores | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| Trail Making Test (TMT) Scores | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| Finger Tapping Test Scores | 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. | 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) |
| Grooved Pegboard Test Scores | 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. | 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) |
| Rey Auditory Verbal Learning Test (RAVLT) Scores | 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. | 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) |
| Beck Depression Inventory (BDI-II) Scores | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| Visual Analogue Mood Scale (VAM-S) Scores | 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. | 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) |
| Motor Evoked Potentials (MEPs) | 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. | approximately 45 min after AIH in Visit 2 (1-6 days after baseline) and Visit 5 (8-14 days after baseline) |
| MRI | 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. | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
| years |
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| Sex: Female, Male | 12 | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Months since injury | months since injury at the time of enrollment | Mean | Standard Deviation | months |
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| Primary | Change in Vitals at Visit 3 | 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. | Posted | Count of Participants | Participants | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) |
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| Primary | Change in Vitals at Visit 4 | 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. | Posted | Count of Participants | Participants | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) |
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| Primary | Change in Vitals at Visit 5 | 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. | Posted | Count of Participants | Participants | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) |
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| Primary | Change in Symptoms at Visit 2 | 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. | Posted | Count of Participants | Participants | Visit 2 (AIH session #1, 21% O2, sham), conducted 1-6 days after baseline assessment in Visit 1 |
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| Primary | Change in Symptoms at Visit 3 | 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. | Posted | Count of Participants | Participants | Visit 3 (AIH session #2, 17% O2), conducted 1-5 days after Visit 2 (i.e., 2-7 days after baseline) |
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| Primary | Change in Symptoms at Visit 4 | 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. | Posted | Count of Participants | Participants | Visit 4 (AIH session #3, 13% O2), conducted 1-5 days after Visit 3 (i.e., 6-12 days after baseline) |
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| Primary | Change in Symptoms at Visit 5 | 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. | Posted | Count of Participants | Participants | Visit 5 (AIH session #4, 9% O2), conducted 2-6 days after Visit 4 (i.e., 8-14 days after baseline) |
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| Secondary | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Scores | 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. | One participant was excluded from the Coding Task that requires writing digits on a piece of paper in Visit 6 due to a right (dominant) arm fracture sustained three days prior. Since the Coding Task score is accounted for in the Attention Cognitive Domain score, it was computed only for the eleven remaining subjects. | Posted | Mean | Standard Deviation | scores on a scale | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | California Verbal Learning Test (CVLT-II) Scores | 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. | Posted | Mean | Standard Deviation | scores on a scale | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | D-KEFS (Delis-Kaplan Executive Function System) Verbal Fluency Test Scores | 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. | Posted | Mean | Standard Deviation | scores on a scale | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | Serial Reaction Time Task (SRTT) Scores | 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. | Visit 1 data from two subjects were not recorded due to a technical error. One participant could not complete the task in Visit 6 due to a right (dominant) arm fracture sustained three days prior. The data from nine remaining participants were submitted to the analysis. | Posted | Mean | Standard Deviation | seconds | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | Trail Making Test (TMT) Scores | 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. | One participant was excluded from the TMT in Visit 6 due to a right (dominant) arm fracture sustained three days prior. The data from eleven remaining participants were submitted to the analysis. | Posted | Mean | Standard Deviation | seconds | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | Finger Tapping Test Scores | 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. | One participant was excluded from the Finger Tapping Test in Visit 6 due to a right (dominant) arm fracture sustained three days prior. The data from eleven remaining participants were submitted to the analysis. | Posted | Mean | Standard Deviation | average number of taps | 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) |
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| Secondary | Grooved Pegboard Test Scores | 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. | One participant was excluded from the Grooved Pegboard Test in Visit 6 due to a right (dominant) arm fracture sustained three days prior. Another participant was excluded from the Grooved Pegboard Test in Visit 6 due to a bruised left thumb. The data from ten remaining participants were submitted to the analysis. | Posted | Mean | Standard Deviation | seconds | 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) |
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| Secondary | Rey Auditory Verbal Learning Test (RAVLT) Scores | 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. | Posted | Mean | Standard Deviation | scores on a scale | 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) |
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| Secondary | Beck Depression Inventory (BDI-II) Scores | 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. | Posted | Mean | Standard Deviation | scores on a scale | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| Secondary | Visual Analogue Mood Scale (VAM-S) Scores | 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. | Posted | Mean | Standard Deviation | millimeters | 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) |
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| Secondary | Motor Evoked Potentials (MEPs) | 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. | Three participants were excluded from TMS: one could not complete the required brain MRI scan due to claustrophobia, and two were unable to undergo TMS due to scheduling issues. The data from nine remaining participants were submitted to the analysis. | Posted | Mean | Standard Deviation | μV (microvolt) | approximately 45 min after AIH in Visit 2 (1-6 days after baseline) and Visit 5 (8-14 days after baseline) |
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| Secondary | MRI | 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. | One participant was excluded from MRI due to claustrophobia. The Visit 1 dataset from another participant was lost due to a failed export from the scanner. The MRI data for the remaining ten subjects were reviewed for the presence of observable changes in structural and functional brain images. | Posted | Count of Participants | Participants | Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline) |
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| 0 |
| 12 |
| 0 |
| 12 |
| 5 |
| 12 |
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| Claustrophobia | Psychiatric disorders | Non-systematic Assessment | One participant reported feeling claustrophobic during MRI scanning in the baseline assessment (Visit 1), after which they were immediately removed from the scanner. Their repeat MRI scan and neuronavigated TMS in subsequent visits were canceled. |
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| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment | One participant reported a red rash on their left leg in the follow-up assessment (Visit 6), which they noticed after the first non-sham AIH intervention (Visit 3). |
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| Fracture | Injury, poisoning and procedural complications | Non-systematic Assessment | One participant broke their right wrist as a result of a rollerblading accident three days prior to the follow-up assessment (Visit 6) and had their right arm in a cast during the visit. |
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| Contusion | Injury, poisoning and procedural complications | Non-systematic Assessment | One participant bruised their left thumb by jamming it in the door on the day preceding the last AIH session (Visit 5). |
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Not provided
Not provided
| D006259 |
| Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Title | Measurements |
|---|---|
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| Neck pain |
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| Dizziness |
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| Arm pain |
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| Sweatiness/feeling warm |
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| New numbness |
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| Increased weakness |
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| Title | Measurements |
|---|---|
|
| Neck pain |
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| Dizziness |
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| Arm pain |
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| Sweatiness/feeling warm |
|
| New numbness |
|
| Increased weakness |
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| Title | Measurements |
|---|---|
|
| Neck pain |
|
| Dizziness |
|
| Arm pain |
|
| Sweatiness/feeling warm |
|
| New numbness |
|
| Increased weakness |
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| Title | Measurements |
|---|---|
|
| Neck pain |
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| Dizziness |
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| Arm pain |
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| Sweatiness/feeling warm |
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| New numbness |
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| Increased weakness |
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| Visuospatial/Constructional Abilities, Visit 1 |
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| Visuospatial/Constructional Abilities, Visit 6 |
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| Language, Visit 1 |
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| Language, Visit 6 |
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| Attention, Visit 1 |
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| Attention, Visit 6 |
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| Delayed Memory, Visit 1 |
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| Delayed Memory, Visit 6 |
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| Short-Delay Free Recall, Visit 6 |
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| Short-Delay Cued Recall, Visit 1 |
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| Short-Delay Cued Recall, Visit 6 |
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| Long-Delay Free Recall, Visit 1 |
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| Long-Delay Free Recall, Visit 6 |
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| Long-Delay Cued Recall, Visit 1 |
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| Long-Delay Cued Recall, Visit 6 |
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| Long-Delay Recognition, Visit 1 |
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| Long-Delay Recognition, Visit 6 |
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| Title | Measurements |
|---|---|
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| Category Fluency, Visit 6 |
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| Category Switching, Visit 1 |
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| Category Switching, Visit 6 |
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| Title | Measurements |
|---|---|
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| TMT Part B, Visit 6 |
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| Title | Measurements |
|---|---|
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| Right hand, Visit 4 |
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| Right hand, Visit 5 |
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| Right hand, Visit 6 |
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| Left hand, Visit 1 |
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| Left hand, Visit 2 |
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| Left hand, Visit 3 |
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| Left hand, Visit 4 |
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| Left hand, Visit 5 |
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| Left hand, Visit 6 |
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| Title | Measurements |
|---|---|
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| Right hand, Visit 4 |
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| Right hand, Visit 5 |
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| Right hand, Visit 6 |
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| Left hand, Visit 1 |
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| Left hand, Visit 2 |
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| Left hand, Visit 3 |
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| Left hand, Visit 4 |
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| Left hand, Visit 5 |
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| Left hand, Visit 6 |
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| Title | Measurements |
|---|---|
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| Immediate Recall, Visit 5 |
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| Short-Delay Free Recall, Visit 2 |
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| Short-Delay Free Recall, Visit 3 |
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| Short-Delay Free Recall, Visit 4 |
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| Short-Delay Free Recall, Visit 5 |
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| Long-Delay Free Recall, Visit 2 |
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| Long-Delay Free Recall, Visit 3 |
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| Long-Delay Free Recall, Visit 4 |
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| Long-Delay Free Recall, Visit 5 |
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| Long-Delay Forced-Choice Recognition, Visit 2 |
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| Long-Delay Forced-Choice Recognition, Visit 3 |
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| Long-Delay Forced-Choice Recognition, Visit 4 |
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| Long-Delay Forced-Choice Recognition, Visit 5 |
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| Title | Measurements |
|---|---|
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| VAM-S, Visit 5 |
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