There is evidence from animal models that ventilatory failure is associated with a failure of voluntary motor drive (Ferguson, 1994 and Sassoon

et al., 1996), and recent human data suggest that maximal central neural output cannot be achieved during exercise either in COPD (Qin et al., 2010) or other pulmonary conditions (Reilly et al., 2011). We hypothesized that the abnormalities in corticospinal transmission that we had previously observed in patients with COPD would be more pronounced in patients who required NIV but this was not confirmed, with no significant difference observed in any TMS parameter assessed. Because the NIV patients had been successfully established on ventilation for several months (and had therefore much improved arterial blood gas parameters) Ulixertinib research buy we cannot exclude the possibility that predisposing cortical factors present at the initiation of therapy had been reversed by ventilator use. The issue is further complicated by the fact that nocturnal NIV itself alters daytime blood gas parameters that might themselves alter the response to TMS. Further studies LY2109761 nmr undertaken before and after the initiation of therapy would be required to clarify this. During the part of the study where the acute effect

of NIV was assessed we maintained PetCO2 at its baseline value as we wanted to assess the neuromechanical effect of mechanical ventilation alone rather than in combination with any possible chemical effect. This of course differs from conventional ventilator use which by increasing minute ventilation

and recruiting alveoli should produce a reduction in PaCO2 as well as an increase in PaO2. A related issue is the problem of distinguishing cortical from brainstem and spinal influences on the response NADPH-cytochrome-c2 reductase to TMS. The observation that the diaphragm response to TMS is the same in normocapnic as in hypocapnic conditions, when the respiratory oscillator is assumed to be silent and also that the response is similar during volitional and hypercapnia driven hyperventilation has been taken as evidence that the corticospinal pathways ‘bypass’ the brainstem (Corfield et al., 1998 and Murphy et al., 1990). However, phrenic spinal motor neurons are distinctive in having an ‘automatic’ bulbospinal input as well as a volitional, ‘higher’ corticospinal one, so that their output is dependent both on the amplitude of the corticospinal volley and the output from brainstem respiratory centers. Thus it has been argued that the increase in diaphragm MEP observed during hypercapnia driven hyperventilation is a consequence of an increased brainstem output pre-activating spinal motor neurons rather than an increased cortical response (Straus et al., 2004).