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

本研究的目的是确定急性间歇性缺氧（AIH）是否安全 医学上稳定的慢性创伤性脑损伤（TBI）患者。有证据表明，AIH促进 中枢神经系统（CNS）神经可塑性。AIH刺激大脑皮层中的氧敏感性多巴胺能神经元 脑干的中缝核导致5-羟色胺释放到中枢神经系统的不同区域。这一释放导致 激活皮质神经元上或附近的5-羟色胺受体，并增加多种营养因子的合成 包括脑源性神经营养因子、血管内皮生长因子和促红细胞生成素。这些行动 也影响神经递质如GABA的功能。生长因子的表达增加， 大脑通过增加突触强度、皮质神经元和中间神经元兴奋性来促进神经可塑性， 脑内和脑间区域连接。值得注意的是，缺氧诱导的神经可塑性仅发生在急性缺氧时。 间歇性暴露，但不诱发相同持续时间的连续缺氧。AIH安全吗 创伤性脑损伤患者？先前动物和人类证据的优势表明，轻度AIH的每日发作 不会对重要的安全性参数产生负面影响，如静息血压、动脉压、心脏 心率、心率变异性、心输出量或认知功能。迄今为止，诱导有益的AIH方案 不引发病理后遗症的神经可塑性仅限于短暂的适度缺氧 低循环数，例如10%吸入氧气的15 × 90秒发作。最近的人类研究 慢性脊髓损伤和中风表明，这些适度的AIH发作重复五年， 可以安全地耐受连续几天而没有病理后果。最近的另一项研究表明， 即使是4周的每日中度AIH方案（每1.5分钟循环9%/21%氧气，每天15个循环， 4周）不会引起不良的医学后果或认知障碍。因此，累积 有证据表明，重复性AIH可以安全地用于研究它是否可以增强神经行为功能。 在TBI患者中发挥作用而没有有害影响。在这项研究中，我们将对16名轻度AIH患者进行治疗， 在两周内的四个不同天数，从正常氧浓度（目标SpO 2为98%）开始， 然后在接下来的三个疗程中逐渐降低氧气浓度（至93%，87%和82%）。我们 主要目的是确定对慢性TBI患者进行轻度AIH治疗是否安全， 功能障碍但临床表现稳定作为本研究的次要目标，我们将评估 轻度AIH给药是否对记忆和认知有任何治疗后或累积效应， 使用成对脉冲抑制的皮层激活，或者是否预先研究大脑结构或功能连接 通过结构和静息态功能磁共振成像检测，可预测对AIH的反应。如果 在这项研究中，轻度AIH没有不良反应，单独使用轻度AIH或与 神经行为治疗可以评估AIH是否有助于TBI后改善功能表现。

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.