Respiratory Central Neural Drive Deficits in Down Syndrome

Purpose: Respiratory complications are the leading cause for ER visits in down syndrome (DS), with respiratory infection and aspiration pneumonia accounting for ~30% of mortality. Studies in humans with DSs are limited to identifying structural problems in upper airways, respiratory muscles weakness and immune compromise, whereas deficits in respiratory neural drive were never explored. Our objective was to determine if individual with DS have reduced central neural drive for breathing, compared to age-sex matched controls. We hypothesize that undiagnosed neural drive deficits in volitional (cortico-spinal) and automatic (bulbo-spinal) respiratory circuits impair breathing in individuals with DS. We also hypothesize that tests of automatic breathing impairments will be feasible and easier than conventional volitional measures commonly used in the clinic. Subjects: Five individuals with DS (ages 10–30 years) without prior neurological conditions or seizures, and five age-matched neurotypical controls with no history of developmental, neurological, or psychiatric disorders. Materials and Methods: In this cross-sectional study, participants underwent testing for volitional respiratory pressures–maximum inspiratory (MIP), expiratory (MEP) pressure generation, as well as forced vital capacity (FVC); and automatic respiratory measures–airway occlusion pressure at 0.1 sec (P0.1) & chemosensitivity (change in minute ventilation per drop in oxygen saturation) following a 1.5-minute exposure to a hypercapnic-hypoxic gas mixture (9% O 2 , 4% CO 2 , balance N 2 ). Respiratory neural drive was further assessed using single-pulse transcranial magnetic stimulation (TMS) for central (cortico-phrenic) pathways and cervical magnetic stimulation (CMS) for peripheral (spinal) integrity. Results: Compared to controls, DS participants had reduced volitional respiratory pressures (mean difference ± SD): MIP (55.9 ± 13.7 cmH 2 O, p < 0.01) and MEP (33.4 ± 13.4 cmH 2 O, p < 0.05). FVC was not significantly different from controls (0.84 ± 0.73 L, p = 0.28). Automatic respiratory drive (P0.1) was reduced in 4 of 5 DS participants (0.56 ± 0.26 cm H 2 O, p = 0.06). In response to hypercapnic-hypoxic chemosensitivity challenge to 88% desaturation, a greater minute ventilation response was observed in 3 of 5 DS participants as compared to controls. TMS and CMS-evoked diaphragm responses in DS showed higher activation thresholds compared to controls, indicating reduced central and peripheral respiratory neural drive. Conclusions: While the volitional measures (MIP and MEP) showed significant difference between DS and controls, these results should be interpreted with caution due to difficulty in performing these tests in individuals with DS due to cognitive demands and limited compliance. In contrast, automatic measures, which are independent of participant effort, revealed a specific deficit in bulbospinal respiratory drive. This is the first study to demonstrate reduced P0.1 and elevated chemosensitivity to hypoxemia in DS, suggesting impaired automatic respiratory neural control. Clinical Relevance: This is the first study to presents evidence for respiratory neural drive deficit in DS. Recognizing these deficits opens new avenues for non-invasive interventions—such as breathing exercises, transcutaneous spinal cord stimulation, acute intermittent hypoxia and neural excitability-enhancing pharmacologics like ampakines to stimulate respiratory drive, reduce symptom severity, and potentially shorten hospital stays. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.