Therapeutic acute intermittent hypoxia alters supraspinal neural control of lower limb movement in multiple sclerosis

Acute intermittent hypoxia (AIH) therapy is a promising neurorehabilitative intervention with well-documented enhancements in motor function in people with spinal cord injury. Its enhancements in lower-limb motor control in multiple sclerosis (MS), where walking impairment is a leading source of disability, remain uncharacterized, and the supraspinal effects of AIH therapy are unknown. In a sham-controlled, double-blind crossover trial ( NCT05164705 ), 23 adults with MS completed 5 sessions of AIH therapy and of sham therapy; magnetic resonance imaging (MRI) was performed before and after each therapeutic arm. At each timepoint, blood oxygenation level-dependent (BOLD) functional MRI was collected during a repeated plantar- and dorsi-flexion task. Task-evoked activation was modeled at the group level and compared across timepoint and therapeutic arm. Activation changes differed for the left- and right-foot task. AIH augmented activation in the basal ganglia, thalamus, and cortical motor regions during left-foot movement with similar but sub-threshold patterns for the right foot. Right-foot movement additionally showed enhanced deactivation in prefrontal, parietal, and temporal cortices, although these effects were primarily in white matter voxels, limiting their interpretability. These findings suggest that changes in subcortical activation may contribute to motor function improvements following AIH therapy, implicating the basal ganglia-thalamo-cortical motor loop as a target of AIH-induced neuroplasticity. These results also indicate that AIH therapy modulates supraspinal motor circuitry, supporting further investigation of the cortical and subcortical effects of this emerging therapeutic treatment.