Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease

Abstract

We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.

Keywords: ALS; Amyotrophic lateral sclerosis; Arm; Barriers; Breathing; Combinatorial treatment; Hand; Intermittent hypoxia; MS; Multiple sclerosis; Plasticity; Road map; SCI; Spinal cord injury; Task-specific training; Therapeutic; Translation; Walking.

Figure 1:. Overview of key steps towards tAIH translation.

Step 1: Formulate hypothesis driven questions leading to discovery and mechanisms of AIH-induced plasticity. Step 2: Validate tAIH protocols across patients and populations, ensuring reproducibility by identifying those most likely to benefit from tAIH therapy. Step 3: Verify safety and efficacy of tAIH in health and injury or disease. Step 4: Determine optimal tAIH dose and delivery and refine outcome measures to assure safety and detect tAIH effects (and develop adequate device to deliver refined protocols). Step 5: Establish standards for tAIH delivery and practice for randomized control trials (RCT) seeking to track long-term outcomes. Only when all 5 steps have been taken will we be ready to apply tAIH in routine clinical practice.

Figure 2:. Schematic representations of tAIH-Induced motor plasticity.

In panel a: Neural network model of tAIH-induced plasticity, including hypoglossal (XII), phrenic and limb motor neurons (MN). In panel b: Working model of cellular mechanisms giving rise to tAIH-induced motor plasticity. Moderate acute intermittent hypoxia (Po₂ >40 mmHg) activates carotid body chemo-afferent neurons that then activate raphe serotonergic neurons and trigger serotonin release in widespread motor nuclei. Serotonin activates Gq coupled 5-HT receptors, initiating phrenic motor facilitation via the Q pathway (serotonin-induced, BDNF protein synthesis). Spinal tissue hypoxia also stimulates glia to release of ATP/adenosine into the extracellular space; subsequent binding to Gs coupled adenosine 2A receptors on motor neurons elicits a distinct intracellular signaling cascade that either: 1) elicits a distinct form of phrenic motor plasticity (but only at severe levels of tissue hypoxia), and/or 2) inhibits the Q pathway via cross-talk inhibition. In panel c: tAIH effects are widespread among motor neuron pools, leading to plasticity of many motor systems, including: tongue/upper airway (XII), breathing (C3-C5), grasping (C6-T1) and locomotion (L4-S4). Thus, tAIH elicits global effects on motor neurons that elicit outcomes depending on the target muscle. The impact of AIH is enhanced by combination with task specific training, amplifying BDNF/TrkB effects within the targeted (task specific) motor system.

Figure 3:. Synergy between Acute Intermittent Hypoxia and Task-Specific Training.

Combinatorial treatments (eg. intermittent hypoxia and task-specific training) elicit greater motor plasticity versus intermittent hypoxia or task specific training alone, largely due to unique effects on motor neurons that are only elicited when both AIH and task specific training are combined. In specific, we hypothesize that greater BDNF accumulation in motor neurons exposed to AIH and then activated during task-specific training elicits greater dose-dependent plasticity (ie. motor behavior vs. motor neuron BDNF expression; Welch et al., 2020). In this scheme, task specific training alone (teal) elicits minimal plasticity; in contrast, intermittent hypoxia alone (darker green) elicits some plasticity. However, only when AIH is paired with task specific training is synergy revealed (light green).