Does the motor cortical control of the diaphragm 'bypass' the brain stem respiratory centres in man?

In humans, cortico-motor excitation of the diaphragm may act directly on the phrenic motor nucleus via the cortico-spinal tract 'bypassing' brain stem respiratory centres (RC); alternatively, or in addition, this control may be indirect via the RC and bulbo-spinal paths. To investigate this, we stimulated the motor cortex using transcranial magnetic stimulation (TMS) in six subjects at end-expiration (diaphragm relaxed) and during voluntary inspiration. The sizes of the evoked compound action potentials in the diaphragm and also, as a control, in the thumb were no different whether TMS was delivered during normocapnia or during hypocapnia (PET(CO2) = 25 mmHg) when, presumably, the respiratory 'oscillator' was silent. In a further six subjects, TMS was performed during relaxed spontaneous breathing at three different points in the respiratory cycle. No perturbations in respiratory pattern (either tidal volume or respiratory timing) were seen. Thus we have been unable to demonstrate that the cortico-motor excitation of the diaphragm acts via the brain stem RC.