Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation

Key findings

Pulmonary rehabilitation was associated with improvements in breathlessness, exercise capacity and quality of life, in line with previously published research [4, 6, 18, 19]. Changes in ratings of VAS breathlessness (wB) positively correlated with changes in activity in the brain's stimulus valuation network, whereas changes in ratings of VAS breathlessness-anxiety (wA) negatively correlated with activity in attention-regulating networks. At baseline, activity in the stimulus valuation network correlated with change in wB and wA scores following pulmonary rehabilitation.

Effect of pulmonary rehabilitation on brain and behaviour

Group improvements were observed in a range of affective domains (table 2) that occurred independently of any changes in spirometry [5]. However, not all participants showed clinically important improvements, emphasising the need to understand the brain processes that are associated with pulmonary rehabilitation.

In chronic diseases such as COPD, prior experiences of symptoms can vastly alter outcomes and symptom perception [37]. Learned associations between environmental cues and symptoms can influence this symptom expectation and subsequent perception. We therefore used a word-cue task to probe these associations. The changes in ratings of breathlessness-anxiety (wA) positively correlated with the changes in the clinical measure of breathlessness (D12) across the course of rehabilitation (figure 4). This supports previous work demonstrating that pulmonary rehabilitation has greater effects upon the affective components of breathlessness [18, 19].

We then examined the changes in brain activity associated with word-cue presentation across pulmonary rehabilitation. Changes in the ratings of breathlessness (wB) were positively correlated with changes in brain activity in the anterior insular cortex, anterior cingulate cortex, prefrontal cortex and posterior insular cortex. Taken together, these form key components of the stimulus valuation network, which is responsible for the conscious awareness of the internal state of the body, or interoception [9]. These observations may represent re-evaluated associations relating to breathlessness expectations.

The posterior insula plays a role in sensory-discriminative processing, with connectivity both to somatosensory cortices and to the anterior insula to integrate sensory inputs with the stimulus valuation network [9]. The positive correlation between changes in wB ratings and changes in BOLD activity seen in this structure over the course of pulmonary rehabilitation suggests that the reappraisal of learned associations may also influence lower-order sensory processing.

fMRI activity was negatively correlated with ratings of breathlessness-anxiety (wA) in the angular gyrus, supramarginal gyrus and posterior cingulate cortex. These changes in brain activity could represent a shift in expectancy towards that seen in healthy controls [14, 21]. The angular gyrus and supramarginal gyrus form a multimodal complex that integrates somatosensory inputs to the brain and is associated with attention processing. The posterior cingulate cortex is thought to mediate interactions between emotions and memory, controlling attentional focus [38]. All these functions are impaired by anxiety [39, 40]. Additionally, the increase in activity in the granular primary and pre-motor cortices may reflect a shift towards more objective perceptual processing less dominated by learned associations [9, 14, 41].

Baseline fMRI correlates with changes in VAS scores following pulmonary rehabilitation

Change in VAS responses over pulmonary rehabilitation was positively correlated with baseline BOLD activity in the ventromedial prefrontal cortex and anterior cingulate cortex in response to wA ratings (figure 5), and in the anterior insula (bilateral), orbitofrontal cortex and motor cortex in response to wB ratings. These areas comprise much of the stimulus valuation network. Our findings suggest that people with greater brain activity during word-cue presentation are more likely to benefit from pulmonary rehabilitation, particularly with regard to the wA contrast, as this correlates with the clinically validated D12 score. Although tempting to dissect the specific brain areas relating to wA and wB in more detail, this is best reserved for future studies where connectivity profiles might better explain the components of this network function more comprehensively.

It is possible that the repeated episodes of breathlessness experienced in a “safe” setting during pulmonary rehabilitation help to re-shape associations. These findings and interpretations are supported by a recent behavioural study [42], which showed that higher breathlessness-fear before pulmonary rehabilitation was associated with greater reductions in breathlessness during exercise following pulmonary rehabilitation.

Driving forces behind changes in behaviour

We also interrogated how the relationship between VAS scales and associated brain activity may be related to other clinical and behavioural measures of breathlessness. The full correlation matrix (figure 3) demonstrates that many of the behavioural measures are at least partially explained by each other. A notable exception is spirometry, which is poorly explained by all of the other measures. This distinction between lung function and the various measures of breathlessness perception adds to the weight of evidence that the impact of COPD is poorly reflected by spirometry [3].

When investigating the VAS scores associated with the breathlessness expectancy task, the strongest correlation with wA was the D12 questionnaire; a well-validated clinical measure of breathlessness [27]. In addition, strong correlations exist between wA and breathlessness catastrophising and depression. Conversely, the wB measure did not correlate significantly with any of the measures. Mediation analysis [32] revealed that the relationship between wA and the D12 scale appears to be mediated by changes in depression, and when this component is removed there is no remaining relationship between D12 and wA (figure 4f). Although the direction of the relationship between anxiety, depression and breathlessness remains unknown, many consider it to be bidirectional [17]. Some even speculate that aberrant predictions mediated by the stimulus valuation network may drive depression, anxiety and fatigue [9].

Thus, based upon predictive models of sensory perception, we speculate that pulmonary rehabilitation exerts its benefit by two broad mechanisms in the brain: 1) by updating of the brain's set of breathlessness-related priors (through associative learning), and 2) by acting upon measures of negative affect that act as moderators of priors and influence gain of sensory information processing. Improvements in muscle function with fitness would additionally adjust afferent inputs [4]. These factors are likely to work together to contribute to the well-documented improvements in well-being with pulmonary rehabilitation [4, 19, 42].

Further considerations

Although some of the brain regions identified in the present study overlap with brain regions activated by induced breathlessness, it is important to note that this does not necessarily implicate activity in identical neuronal populations or networks. A single MRI voxel may contain over half a million neurons, not all of which would activate simultaneously. Future work could also explore connectivity profiles, or functional communication between different areas of the brain, which may differ across perceptions even with similar task activation patterns.

Although it is possible that changes in ratings of breathlessness (wB) and breathlessness-anxiety (wA) may be influenced by a generalised changes in negative valence, arousal or attention, the fact that we observed no changes in brain activity correlated with wB and wA during the random-letter-string control task suggests that this unlikely to be a major confound.

The current study used a parametric design, investigating changes in brain activity that correlated with individual subject's VAS scores of wA and wB. With the range of responses to pulmonary rehabilitation, future work could look to more formally compare responders with nonresponders, but this would require considerably larger sample sizes.

We did not include a control group of COPD subjects who either did not undertake pulmonary rehabilitation treatment or received a sham treatment. Without a control group, potential contributing factors (such as placebo effects and natural fluctuations in disease severity) cannot be disentangled from the effects of pulmonary rehabilitation. However, our primary question was to understand the brain mechanisms underlying subject-specific changes in breathlessness perception. Future work may wish to include a control group, to better understand group-wide effects of rehabilitation compared with control or sham-treated subjects. Importantly, the clinical changes we have observed are very much in line with clinical reports of pulmonary rehabilitation (e.g. the UK National Pulmonary Rehabilitation Audit [6]), suggesting we have studied a representative sample of individuals.

Clinical relevance

This study examined brain mechanisms underlying the variable changes in breathlessness over a course of pulmonary rehabilitation. We have shown that changes in breathlessness ratings are positively correlated with changes in activity in the stimulus valuation network, and changes in ratings of breathlessness-anxiety are negatively correlated with activity in attention processing and motor control areas of the brain. We have also demonstrated that changes in ratings of breathlessness-anxiety correspond with a clinically meaningful measure of breathlessness, the D12 questionnaire. Therefore, specifically targeting associative learning might be a way to further improve efficacy of pulmonary rehabilitation. This might arise from combining pulmonary rehabilitation with drugs that target relevant neurotransmitter systems [43]. As many patients decline the invitation to pulmonary rehabilitation, alternative behavioural therapies could be developed to focus on re-evaluating the interpretation of respiratory sensations, such as through breathing exercises or mindfulness [44].

Our findings also demonstrate the first steps towards using fMRI as a tool for patient stratification. We speculate that this is most likely to be achieved in real life by using a detailed understanding of neural mechanisms to guide the development of appropriate behavioural tests (questionnaires, computerised tasks) that can be used at the bedside. These tests could be incorporated with appropriate clinical measures to personalise the treatment of COPD, targeting treatment options where they are needed in each individual.

Conclusions

In conclusion, we have demonstrated that changes in ratings of breathlessness and breathlessness-anxiety over the course of pulmonary rehabilitation likely reflect changes in associative learning. Our findings suggest that changes in the brain responses to breathlessness-related word cues over the course of pulmonary rehabilitation become less dependent upon learned associations, thus reducing “over-perception” of symptoms. Understanding the neural processing of breathlessness in a clinical population is crucial for advances to be made in its treatment, such as the development of patient stratification, leading to individualised treatments that may target breathlessness independently of disease mechanisms.