This should not be uncritically accepted as a failure of Saracatinib chemical structure voluntary drive,

firstly because patients with COPD have been shown to be able fully to activate their diaphragm (Topeli et al., 2001) and secondly because we also found a strong correlation between intracortical facilitation and a non-volitional test of diaphragm strength, the TwPdi. Interestingly, although volitional measures of inspiratory muscle strength have tended to improve, at least in patients with restrictive pulmonary disease, following the initiation of NIV, TwPdi does not (Nickol et al., 2005). It is certainly the case that cortical areas, to which vagal afferents including peripheral chemoreceptors and pulmonary stretch receptors project, are involved in the response to respiratory loading and the sensation of breathlessness (Banzett et al., 2000 and Isaev et al., 2002). The neural pathways involved in the control of breathing have the capacity for considerable functional plasticity both in adapting throughout life and in response to stress (Mitchell and Johnson, 2003). In experimental models, hypercapnia is associated in the long term with a depression in phrenic output (Baker et al., 2001). Our finding of a correlation between intracortical inhibition and PaCO2 is consistent with this and may represent a novel mechanism involving

cortical as well as brainstem responses to explain the phenomenon. It is not clear whether the increased intracortical inhibition observed in COPD patients with increasing hypercapnia is specific for the respiratory muscles or a non-specific response. In favor Selleck FDA-approved Drug Library of a specific process is our previous finding that the corticospinal pathways to the diaphragm and abdominal muscles were more excitable in patients with COPD whereas those to the quadriceps were not, implying that these changes were specific to muscles involved in breathing Thymidylate synthase (Hopkinson et al., 2004). Moreover in another study in healthy subjects, hypercapnia

increased diaphragm MEP amplitude and decreased central conduction time but had no effect on the response of a small hand muscle (Straus et al., 2004). In favor of a more generalized process is the fact that a prolonged cortical silent period, a measure of inhibitory tone, has been demonstrated in non-respiratory muscles of a population of patients with obesity hypoventilation and obstructive sleep apnea who were hypercapnic and hypoxic (Civardi et al., 2004). In another study, patients with COPD had reduced intracortical inhibition for the first dorsal interosseous muscle during acute exacerbations which returned to normal when they had been established on long term oxygen therapy and were studied several months later (Oliviero et al., 2002). To our knowledge the effect of hypoxemia and hypercapnia on the diaphragm response to paired TMS has not previously been assessed.