Respiratory‐related cortical activity in patients with COPD and aged normal individuals: towards a different vision of dyspnoea?

In this issue of The Journal of Physiology Nguyen and colleagues (2018) report that, in almost half of their patients with chronic obstructive pulmonary disease (COPD), an electroencephalogram (EEG) recorded during spontaneous breathing at rest showed cortical activation linked to respiration, in conjunction with a higher rating of ‘excessive respiratory work/effort’ dyspnoea compared to age-matched controls. Previous studies of this phenomenon have concluded that this type of activation is a sign of a cortico-subcortical co-operation whose goal is to maintain ventilation, whether compensating for a deficit in the automatic neural drive to breathe (Tremoureux et al. 2014; Dubois et al. 2016), or because of a respiratory load-capacity imbalance, caused by weakness of the muscles of respiration (Georges et al. 2016) or experimental, mechanical (Raux et al. 2007b; Hudson et al. 2016) or pathological (Launois et al. 2015) constraints. Furthermore, the presence of cortical activity associated with respiration has been associated with dyspnoea (Raux et al. 2007a; Morawiec et al. 2015; Georges et al. 2016). Such cortical activation was also observed in age-matched control subjects, and there was no significant association between it and bronchial obstruction, so Nguyen et al. do not consider this phenomenon to be a consequence of respiratory mechanical loading. The authors suggest that respiratory-related cortical activity may be the result of a reduction in the automatic neural drive to breathe, implying that a ‘compensatory’ cortical motor drive is then brought in to play. But this interpretation is debatable for a number of reasons. Firstly, it is likely that relatively mild respiratory mechanical loading can provoke respiratory-related cortical activity (Hudson et al. 2018). Such loads can be present in elderly subjects without COPD, because of, variously, expiratory flow limitation, dynamic hyperinflation, a reduction in thoracic compliance causing an increase in elastic work, a change in the ventilation-perfusion relationship that reduces ‘respiratory yield’, weakness of the muscles of respiration or a reduction in their ability to generate adequate inspiratory pressures (Janssens et al. 1999). But it does not seem possible to completely exclude the respiratory-related cortical activity identified by Nguyen et al. being an adaptive mechanism to an increase in inspiratory load, in COPD patients and controls alike. Establishing the distinction would have required a more finely calibrated characterization of respiratory mechanics than the present study provides. It would also have been highly interesting to document the effect of bronchodilators on this respiratory-related cortical activity. Secondly, Yu et al. have shown that some COPD patients show a baseline ‘hyperexcitability’ in brain regions involved in compensation for extrinsic loads, including the motor and pre-motor cortex (Yu et al. 2016). The profile of the cerebral activity described by Yu et al. based on functional imaging is entirely compatible with Nguyen et al.’s EEG data. Yu et al. also suggest that intra-cerebral connectivity within the areas of interest seems to be related to the clinical and spirometric severity of the disease. Thirdly, Nguyen et al. highlight the association between respiratory-related cortical activity and abnormal respiratory sensation, namely a heightened perception of excessive respiratory effort, during loaded breathing. This corroborates previously published studies that reported such an association in the presence of increased respiratory loads. It has never been described in experimental or pathological situations where the automatic neural drive to breathe is depressed that are characterized by cortical activation. It should also be emphasised that their hypothesis that the reduction in the automatic neural drive to breathe is linked to ageing requires more evidence. Indeed, recently published data suggest that the ventilatory response to hypoxia and hypercapnia at rest and during sub-maximal effort in elderly subjects (mean age of 66 years) is normal (Puthon et al. 2017). The automatic ventilatory drive has never been studied in older subjects. Whatever the underlying mechanisms of the respiratory-related cortical activity observed by Nguyen et al., the study is of particular interest to those studying the pathophysiology of dyspnoea. It confirms the possible involvement of the pre-motor cortex in certain clinical pictures of dyspnoea, beyond the well-described role of the insula in particular, and the limbic system more generally. This opens new avenues for reflection on the impact of dyspnoea on the brain. An in-depth study of a patient suffering from Ondine's curse syndrome has shown that respiratory-related cortical activity reduces cognitive performance, probably because of a ‘dual tasking’ phenomenon. Furthermore, recent data suggest that experimental dyspnoea can interfere with many aspects of cognition, such as the ability to perform simple motor sequences, construct body self-image, or recognize the facial expressions caused by certain emotions (Vinckier et al. 2018). Manifest in COPD patients, the latter may have a significant impact on social competence. Such patients find themselves facing a dual social handicap: from the dyspnoea itself, which limits activity and therefore tends to reduce social opportunities, and from the cognitive deficits that the dyspnoea induces. If the data presented by Nguyen et al. lead in time to the demonstration of a deleterious effect of dyspnoea on cognitive performance, certain therapeutic interventions (such as non-invasive ventilation) may have to be completely reconsidered. There is a long way to go, but Nguyen et al.’s study sets up an important milestone along that road. More directly, the link established by Nguyen et al. between respiratory-related cortical activity and ‘excessive respiratory work/effort’ dyspnoea would justify consideration of the potential therapeutic value of approaches such as transcranial magnetic stimulation. It has already been shown that this technique changes the ventilatory response to experimental increases in inspiratory load. If an effect can be shown on the corresponding respiratory-related sensation, it may prove an interesting approach to the management of clinical patterns of dyspnoea described as ‘chronic’ (Johnson et al. 2017) or ‘persistent’ (Morelot-Panzini et al. 2017), which are characterized by persistent respiratory suffering despite optimal treatment of the underlying disease. Here also Nguyen et al. have laid an important baseline for potentially significant advances in the field.