Neurophysiological evidence for a cortical contribution to the wakefulness-related drive to breathe explaining hypocapnia-resistant ventilation in humans

Abstract

Spontaneous ventilation in mammals is driven by automatic brainstem networks that generate the respiratory rhythm and increase ventilation in the presence of increased carbon dioxide production. Hypocapnia decreases the drive to breathe and induces apnea. In humans, this occurs during sleep but not during wakefulness. We hypothesized that hypocapnic breathing would be associated with respiratory-related cortical activity similar to that observed during volitional breathing, inspiratory constraints, or in patients with defective automatic breathing (preinspiratory potentials). Nineteen healthy subjects were studied under passive (mechanical ventilation, n = 10) or active (voluntary hyperventilation, n = 9) profound hypocapnia. Ventilatory and electroencephalographic recordings were performed during voluntary sniff maneuvers, normocapnic breathing, hypocapnia, and after return to normocapnia. EEG recordings were analyzed with respect to the ventilatory flow signal to detect preinspiratory potentials in frontocentral electrodes and to construct time-frequencymaps. After passive hyperventilation, hypocapnia was associated with apnea in 3 cases and ventilation persisted in 7 cases (3 and 6 after active hyperventilation, respectively). No respiratoryrelated EEG activity was observed in subjects with hypocapnia-related apneas. In contrast, preinspiratory potentials were present at vertex recording sites in 12 of the remaining 13 subjects (p < 0.001). This was corroborated by time-frequency maps. This study provides direct evidence of a cortical substrate to hypocapnic breathing in awake humans and fuels the notion of corticosubcortical cooperation to preserve human ventilation in a variety of situations. Of note, maintaining ventilatory activity at low carbon dioxide levels is among the prerequisites to speech production insofar as speech often induces hypocapnia.