Caffeine Enhances Intermittent Hypoxia-Induced Gains in Walking Function for People with Chronic Spinal Cord Injury

Incomplete spinal cord injury (iSCI) often results in lifelong walking impairments that limit functional independence. Thus, treatments that trigger enduring improvement in walking after iSCI are in high demand. Breathing brief episodes of low oxygen (i.e., acute intermittent hypoxia, AIH) enhances breathing and walking function in rodents and humans with chronic iSCI. Pre-clinical studies found that AIH also causes the accumulation of extracellular adenosine that undermines AIH-induced functional plasticity. Pharmacologically blocking adenosine A2a receptors (A2aR) prior to AIH resulted in a dramatic improvement in motor facilitation in rodents with iSCI; however, a similar beneficial effect in humans is unclear. Thus, we conducted a double-blind, placebo-controlled, crossover randomized study to test the hypothesis that a non-selective A2aR antagonist (i.e., caffeine) enhances AIH-induced effects on walking function in people with chronic (≥1yr) iSCI. We enrolled 12 participants to receive daily (5 days) caffeine or placebo (4 mg/kg) 30 min before breathing 15, 1.5-min low oxygen (AIH; F_IO₂ = 0.10) or SHAM (F_IO₂ = 0.21) episodes with 1-min intervals. We quantified walking function as the change in the 10-meter walk test (speed) and 6-min walk test (endurance) relative to baseline, on Day 5 post-intervention, and on follow-up Days 12 and 19. Participants walked faster (Day 19; p < 0.001) and farther (Day 19; p = 0.012) after caffeine+AIH and the boost in speed persisted more than after placebo+AIH or caffeine+SHAM (Day 19; p < 0.05). These results support our hypothesis that a caffeine pre-treatment to AIH training shows promise as a strategy to augment walking speed in persons with chronic iSCI.