Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in TBI

TBI 中急性间歇性缺氧引起的神经可塑性的安全性和认知影响

基本信息

批准号：
10322176
负责人：
Jordan Henry Grafman
金额：
$ 24.91万
依托单位：
REHABILITATION INSTITUTE OF CHICAGO D/B/A SHIRLEY RYAN ABILITYLAB
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322176
关键词：
Acute Adverse effects Affect Air Animals Architecture Blood Pressure Brain Brain Stem Brain region Brain scan Brain-Derived Neurotrophic Factor Cardiac Output Chronic Clinical Clinical Trials Cognition Cognitive Data Dose Erythropoietin Evaluation Functional Magnetic Resonance Imaging Future Growth Factor Heart Rate Human Hypoxia Impaired cognition Individual Interneurons Intervention Link Medical Memory Molecular Moods Motor Neuraxis Neuronal Plasticity Neurons Neuropsychology Neurotransmitters Oxygen Pathologic Patients Performance Physiologic pulse Physiological Protocols documentation Rattus Recovery Recovery of Function Reporting Research Rest Risk Safety Serotonin Signal Transduction Site Spinal Cord Spinal cord injury Spinal cord injury patients Stroke Synapses TBI Patients Thalamencephalon Therapeutic Therapeutic Intervention Time Training Traumatic Brain Injury Traumatic Brain Injury recovery Vascular Endothelial Growth Factors Work base brain magnetic resonance imaging cognitive function conditioning dosage early phase clinical trial emotional functioning functional disability gamma-Aminobutyric Acid heart rate variability improved improved functioning neglect neurobehavioral neuroimaging predicting response pressure raphe nuclei serotonin receptor stroke patient tool

项目摘要

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 sequelaehave 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 demonstrates 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 two 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%, & 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 had any post-session or cumulative effects post-studyon memory and cognition, cortical activation using paired-pulse inhibition, 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 there are no adverse effects of mild AIH in this study, clinical trials using mild AIH alone or in conjunction with neurobehavioral therapies could evaluate whether AIH facilitates improved functional performance after TBI.

这项研究的目的是确定急性间歇性缺氧（AIH）是否安全地进行为了医学稳定的慢性脑损伤（TBI）患者。中枢神经系统（CNS）神经塑料。脑干的raphe核导致5-羟色胺释放到中枢神经系统的不同。羟色胺受体在皮质神经元或附近的激活发育不形成合成的营养因子包括脑衍生的神经营养因子，血管造型的研究因子和红细胞生成素还会影响神经递质（例如GABA）的功能。大脑通过提高突触强度，皮质神经元和静脉内兴奋性来促进神经塑料，并且脑内和脑间区域连接。可以安全管理是否可以安全管理。 TBI患者每天发作的先前动物和人类的优势请勿负面影响重要的重要安全参数，例如静止血压，心脏速率，心率变异性，心脏输出或认知功能。神经塑料带有触发病理性后遗性的神经塑料仅限于短暂发作。具有可爱的循环数字，例如10％的氧气中的15 x 90秒发作。慢性脊髓损伤和中风表明，重复的五次AIH发作。连续几天可以安全地耐受性耐受性。即使是每日中度AIH的4周方案（每1.5分钟循环9％/21％氧气，每天15个循环，在4周内）不会引起不良的医疗通讯或认知障碍有证据表明，可以安全地使用thah来研究它是否可以增强神经行为在本研究中没有有害影响的TBI患者四个不同的日子在两个星期中蔓延然后逐渐降低三个会议上的氧气浓度（达到93％，87％和82％）主要目的是确定对持续的慢性TBI患者进行轻度AIH安全功能障碍，但在临床上是稳定的。温和的AIH管理是否具有会话后或累积效应后苏联记忆和认知，使用配对脉冲吸入的皮质激活，或者是研究前脑结构还是功能连接随着检测器和静止状态功能磁共振成像预测对AIH的响应。在这项研究中，轻度AIH没有不利影响 Neurobehaviolal疗法可以评估AIH是否促进了TBI后的功能性能。