The effects of short and long interval paired-TMS operate via GABA A (the main inhibitory neurotransmitter) and glutaminergic (excitatory neurotransmitter) intracortical circuits respectively (Di Lazzaro et al., 2000, Kujirai et al., 1993, Ziemann et al., 1996a and Ziemann et al., 1996b). ERK inhibitor libraries We have previously demonstrated that in COPD the corticospinal pathway to the diaphragm is more excitable compared to age-matched healthy subjects,

with a lower motor threshold and a shorter latency (Hopkinson et al., 2004). Moreover, intracortical facilitation induced by paired-TMS at long interstimulus intervals was markedly attenuated and voluntary efforts beyond 20% of maximal inspiratory pressure did not further facilitate the diaphragm MEP whereas in healthy controls there was a stepwise increase up to 60% of maximum volitional efforts. Taken together these results suggest that the corticospinal pathway to the diaphragm is already Selinexor datasheet highly activated and cannot be further recruited in patients with severe COPD. Given that voluntary activation of the diaphragm

appears to be increased in normal subjects at increased lung volumes (McKenzie et al., 1996) and also in patients with COPD compared to controls (Similowski et al., 1991 and Topeli et al., 2001), it seems likely that this is an adaptive response to mechanical disadvantage. Consistent with this interpretation the opposite occurs when healthy subjects have their respiratory muscles unloaded by isocapnic

non-invasive ventilation (NIV) which leads to an increased diaphragm motor threshold, increased intracortical facilitation and C-X-C chemokine receptor type 7 (CXCR-7) reduced intracortical inhibition (Sharshar et al., 2004b). The present study addresses three related hypotheses. Firstly, having previously established that there are alterations in cortical excitability in COPD compared to controls (Hopkinson et al., 2004), we hypothesized that these would be related to indices of disease severity or inspiratory muscle impairment. Secondly, we hypothesized that the requirement for long term NIV might be associated with differences in the excitability of intracortical pathways and evaluated this by comparing paired TMS responses in patients who were or were not users of home NIV. Thirdly, we addressed the question of whether the adaptation in the diaphragm motor cortex that occurs in COPD can be reversed by non-invasive ventilation, by comparing responses to single and paired-TMS during spontaneous breathing and isocapnic NIV. We studied fourteen male stable outpatients with a diagnosis of COPD consistent with GOLD criteria (Pauwels et al., 2001). The Royal Brompton Hospital Research Ethics Committee approved the study and all subjects provided written, informed consent. Some data from the non-ventilated patients was contained in our previous report (Hopkinson et al., 2004).