Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in Traumatic Brain Injury
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in Vitals at Visit 2
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
AIH group
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.).
干预措施: Acute Intermittent Hypoxia (Procedure)
结局指标
主要结局
Change in Vitals at Visit 2
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- California Verbal Learning Test (CVLT-II) Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- D-KEFS (Delis-Kaplan Executive Function System) Verbal Fluency Test Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- Serial Reaction Time Task (SRTT) Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- Trail Making Test (TMT) Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- 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))
- 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))
- 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))
- Beck Depression Inventory (BDI-II) Scores(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
- 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))
- 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))
- MRI(Visit 1 (baseline) and Visit 6 (i.e., 9-17 days after baseline))
研究者
Jordan Grafman, Ph.D
Principle Investigator
Shirley Ryan AbilityLab