Pulmonary rehab: changing the signal

Pulmonary rehabilitation is one of the most effective treatments for breathlessness in chronic obstructive pulmonary disease (COPD), yet its effect is variable. While up to 60% of patients who complete a course of treatment see an improvement, that leaves 40% that do not. Understanding why it works for some and not for others can help personalise and improve treatment for COPD. This is what we’ve focused on in our most recent paper (preprint here) that will be published in the European Respiratory Journal.

A bit of background on how sensations are perceived. When we feel a sensation, our brains often both register and modulate the sensory information from the body. In fact, our sensory perception is probably quite dependent on how the brain processes incoming sensory information. This is influenced by what the brain thinks will happen and why. It is thought that previous experiences (called priors) create expectations in the brain about sensations, and that these are updated whenever the brain receives actual sensory information.

Below is a quote from a paper on how priors influence pain perception by Geuter et al. [1], explaining the concept so clearly I decided to reproduce it in its entirety:

All over the human body, there are receptors that help to alert the brain to potential harm. For example, intense heat on the skin elicits a signal that travels to the brain and activates many parts of the brain. Some of the same brain regions that are switched on by signals of potential bodily harm also help the brain to form expectations about events. A person’s expectations may have a strong influence on how they experience pain. For example, if a person expects that taking a pill will reduce their pain, they may feel less pain even if the pill is a fake.

Exactly how the brain processes pain signals and expectations remains unclear. Does the brain activity simply reflect how intense the heat is? Some scientists think there may be two separate processes going on: one that predicts what will happen and another that calculates the difference between the prediction and what the receptors actually detect. This difference is called a prediction error. If every unpredicted sensory signal elicits a calculation of the prediction error that would help improve the brain’s future predictions.

This system is open to manipulation. There are many factors that can adjust these priors or weight the incoming sensory information, causing the person to over- or under-perceive sensations. For example, anxiety and attentional bias may cause over-perception of sensations.

But how? How does this relate to COPD? In COPD, a prior may be formed linking shortness of breath to physical activity, for example climbing stairs. This prior, if bolstered by for example anxiety and attentional bias, may begin to dominate and cause over-perception of breathlessness. This means that breathlessness perception would be governed more by the prior and the anxiety/fear than by the input from the body. In this example, a simple flight of stairs become a cue for the brain to access its priors, which means generating an expectation of breathlessness and anxiety, all because that is what previous experiences have demonstrated will happen.

Pulmonary rehabilitation, however, challenges these priors. Rehabilitation makes the patient face their breathlessness, but in a safe healthcare setting. This may change the patient’s priors and how they process breathlessness-related cues. If this is the case, we may expect that patients with different priors show different treatment outcome, and we may expect that patients show a different response to cues after treatment than before.

But where? We know that predictions about bodily state and emotion (i.e. priors) are typically generated in a stimulus valuation network. This network consists of many brain regions, including the anterior insula, anterior cingulate cortex (ACC), orbitofrontal cortex and ventromedial prefrontal cortex. There are also more ‘downstream’ regions associated with breathing, including the posterior insula, which process incoming respiratory sensory information. These are responsible for sending sensory information from the body to other parts of the brain (both those dealing with the physical sensation and those processing the emotional impact such as the stimulus valuation network). The posterior insula, along with regions such as the angular gyrus and the supramarginal gyrus, are involved with how much attention a physical sensation gets. All of these regions might be likely places where pulmonary rehabilitation would change activation patterns.

What we did. We recruited 31 people with COPD and studied them before and after pulmonary rehabilitation. On each visit, we did the same tests: we collected a set of behavioural questionnaires (of which we used one, the Dyspnoea-12 [2], as our main measure of breathlessness); we did a lung function and an exercise test; and we did a functional brain scan (FMRI) to test their brain activity while they were looking at (and rating) breathlessness-related cues for anxiety (How anxious would this make you feel?”) and breathlessness (“How breathless would this make you feel?”). *

Behavioural changes. The ratings of the patients were overall much lower for anxiety after rehabilitation, and this correlated with the main measure of breathlessness (Dyspnoea-12). The correlation was influenced by changes in depression in our patients, although we don’t know whether it is the depression that influences anxiety and breathlessness, the anxiety that influences depression and breathlessness, or the breathlessness that influences anxiety and depression. It may easily be that all of these factors influence each other. We do, however, know that they are linked. The figure below (Fig 1) shows how all the behavioural and physiological measures are correlated.

prepost1bFig 1. Correlation matrices of the measured behavioural variables. Abbreviations: wA, cue ratings of anxiety; wB, cue rating of breathlessness; StG, St Georges Respiratory score; Cat, Catastrophising score; Vig, Vigilance/Awareness score; Dep, Depression score; T Anx, Trait anxiety; S Anx, State Anxiety; Fat, Fatigue; BisBas, inhibition/activation scale; Spir, lung function (FEV1/FVC); ISWT, exercise ability (incremental shuttle walk test).**

While rehabilitation worked for the group as a whole, we saw that there was variability in the treatment response between patients. There was also no improvement in breathlessness ratings, nor was there any change in lung function in the group. Lung function was not linked to any of the behavioural measures, meaning that it isn’t a good measure of the impact of breathlessness in COPD.

Brain changes. Then we looked at how variation in brain activity explained the variation in our patients’ ratings of the cues over the course of their treatment. By looking at how variation in brain activity follows variation in ratings, we could make sure that even the patients that didn’t respond normally to treatment were included in the analysis. In other words, if a patient didn’t respond it is likely that their brain activation would not change either, and if a patient got worse we might see that their brain activation went in a different direction from those that got better. This gives us a much stronger idea of which areas get upregulated and downregulated (or stays the same) with successful treatment.

Looking at this variation, we saw that reduced breathlessness was linked with less activation in some brain regions (the anterior insula, ACC, posterior insula and supramarginal gyrus). This is a dampening in activity in brain areas handling expectations of breathlessness, and it could mean that successful treatment works by making patients re-evaluate their priors. Reduced anxiety was linked with greater activation in a slightly different set of brain regions (the posterior cingulate cortex, angular gyrus, primary motor cortex and supramarginal gyrus). As a set, these are involved with how much attention a physical sensation gets, and may be dampened by anxiety. In other words, if you are anxious, it is difficult to regulate how much attention you give a thing (i.e. if you are scared of spiders, you can’t just ignore one if you see one). So when we see an increase in these regions, this may mean that the patients are less anxious and more able to regulate attention. Taken together, this suggests that our patients had a more objective processing of breathlessness cues and were less dominated by their priors after rehabilitation.

prepost1.jpgFig 2. Change in brain activity that fits with rehabilitation-induced changes in response to breathlessness cues (both for anxiety and for breathlessness). Blue colours mean lower brain activity, and red/yellow colours mean higher brain activity. **

Predicting treatment outcome. We also looked at whether brain activation before the treatment could predict who would benefit from the treatment and who would not. Several regions showed higher activation in those patients who went on to improve with treatment. These included the stimulus valuation network plus the primary motor cortex. Improvements in anxiety ratings were predicted by high activation in the ACC and ventromedial prefrontal cortex, which overlaps with one of our previous studies looking at breathlessness and anxiety in COPD patients versus healthy controls [3]. These findings are also supported by a study that showed how higher fear levels before pulmonary rehabilitation tends to mean a greater response to treatment [4].

prepost3Fig 3. Brain activity before treatment that is linked with treatment outcome, both in terms of breathlessness (top) and anxiety (bottom). **

To conclude. Pulmonary rehabilitation seems to lead to reduced activity in the brain’s stimulus valuation network and increased activity in attention regulating networks. Those with strong responses in the stimulus valuation network before pulmonary rehabilitation typically see a bigger reduction in their responses to breathlessness cues after treatment. It may be that pulmonary rehabilitation works both by updating breathlessness-related priors and by reducing feelings of depression and anxiety that typically influence sensory processing. *** If this is the case, then we could improve treatment by focusing on re-learning priors, either by using drugs or alternative behavioural therapies. We could also use MRI as a way of developing behavioural tests (questionnaires, computerised tasks) that can be used to figure out who will benefit the most and in which way from the treatment.

References:
[1] Geuter, S. et al. eLife 2017; 6:e24770
[2] Yorke, J. et al. Thorax 2010; 65: 21-26
[3] Herigstad, M. et al. Chest 2015; 148(4): 953-961
[4] Janssens, T. et al. Chest 2011; 140: 618-625

Footnotes:
*The FMRI analysis used standard significant thresholds (cluster Z = 2.3, corrected cluster p = 0.05 corrected for multiple comparisons across the whole brain).
**Adapted from Herigstad et al, 2017, biorxiv: https://doi.org/10.1101/117390. The copyright holder for this preprint is the author/funder. It is made available under a CC-BY 4.0 International license
***In addition to potential improvements in fitness. We did see an increase in exercise capacity, even if none of the measured baseline physiological variables were changed, and it is possible that the rehabilitation causes the patients to become healthier and stronger.

Link: 
The paper is available from here: http://biorxiv.org/content/early/2017/03/23/117390
DOI: https://doi.org/10.1101/117390

Breathlessness and opioids

We’ve recently published a paper on how opioids can modulate breathlessness. (The whole manuscript is open access here). Low-dose opioids can be used for treating chronic breathlessness, but we don’t know exactly how they work.

Opioid receptors exist across the brain. These are part of the internal opioid system (endogenous opioid system) for natural pain relief. When opioids are used in the clinical setting to treat negative stimuli, such as pain, they influence the unpleasantness and the intensity of the stimulus in different ways(1). In terms of breathing, opioids lower breathing by influencing brainstem respiratory centres(2), causing breathing to stop completely in high doses, and they can also affect higher brain centres(3).

Opioids also have behavioural effects, and may, amongst other things, influence associative learning. Associative learning is when an association between two stimuli is learnt by pairing these together. For example, in chronic breathlessness this could be previously neutral stimuli (e.g. a flight of stairs) and breathlessness. This could create an anticipatory threat response, which means that simply seeing a flight of stairs is enough to bring about breathlessness or the fear associated with breathlessness. This can worsen the breathlessness for the patient in the long run.

In this study, we hypothesized that opioids improve breathlessness in part through changing the anticipatory response to breathlessness. We focused on two brain regions in particular: the amygdala and hippocampus. Both are strongly involved in associative learning(4) and are rich in opioid receptors(5,6).

What did we do? First, we asked healthy volunteers to do a breathing test where we paired three different degrees of breathlessness and three symbols. The symbols were presented immediately before the volunteer was made breathless and were matched to the level of breathlessness that they signified. We invited those volunteers who learnt to associate each different symbol and its corresponding breathlessness to undertake two MRI scans in random order. Before one scan they received a low-level opioid (remifentanil) infusion, and before the other they received a control (saline) infusion. During the scans, the volunteers repeated the breathlessness/symbol task. Below is a schematic of the breathing circuit used for the study, showing how different levels of breathlessness was induced.

breathingsystemFigure 1. Breathing circuit for inducing breathlessness

What did we find? We were able to show that breathlessness anticipation in the control condition was processed in the right anterior insula and operculum, and that the breathlessness itself was processed in the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex, primary sensory cortices and motor cortices. These regions have been identified in other studies on breathlessness (as discussed in a previous blogpost).

However, in the opioid condition, we saw the following:
1. Opioids reduced breathlessness unpleasantness (Figure 2)
2. This reduction correlated with reduced activity in the amygdala and hippocampus during anticipation of breathlessness (Figure 3)
3. This reduction also correlated with increased activity in the anterior cingulate cortex and nucleus accumbens during the actual breathlessness (Figure 3)
4. During the actual breathlessness, the opioid infusion directly reduced activity in the anterior insula, anterior cingulate cortex and sensory motor cortices (Figure 4).

opioid_res1Figure 2. Ratings of breathlessness and intensity. Abbreviation: Remi=remifentanil

Reduction in unpleasantness. The reduction in unpleasantness with opioids was expected – the different effect of opioids on intensity and unpleasantness has been shown in many other negative conditions, including pain(1). Interestingly, we could confirm that this lowered unpleasantness correlated with reduced activity in brain regions linked with associative learning and memory (amygdala and hippocampus) before the breathlessness began (Figure 3, bottom). This reduced activation in the amygdala and hippocampus, regions that are needed for formation of unpleasant memories, may explain how low-dose opioids gradually become more efficient as a therapy over the first week of administration. The reduction in amygdala/hippocampus activation may mean that fewer new negative memories and reaction patterns are formed.

opioid_res2.jpgFigure 3. Brain activity linked to lowered unpleasantness, relating to breathlessness (top) and anticipation of breathlessness (bottom). NA=nucleus accumbens, paraCC=paracingulate cortex, ACC=anterior cingulate cortex, PC=precuneus, ant hipp=anterior hippocampus, amyg=amygdala. 

We also see that the reduced unpleasantness correlates with activation during the actual breathlessness in the anterior cingulate cortex and nucleus accumbens (Figure 3, top). These are parts of the endogenous opioid system which reduces the perception of negative stimuli. This means that the reduced unpleasantness our volunteers felt is linked with these regions being more active. In other words, they may act to further dampen the negative sensation. Less unpleasantness during the breathlessness means that even less negative memories are likely to be formed.

Reduction in breathlessness activation. Finally, opioids directly reduced activity in the anterior insula, anterior cingulate cortex, sensory motor cortices and brainstem (Figure 4). The activation during control (saline) in the figure below is typical of breathlessness, and has been found in several other studies using breathing challenges.

opioid_res3.jpg

Figure 4. Brain activity during breathlessness in the control (saline) condition (top) and where it is reduced by the opioid (remifentanil, bottom). Increased activation is shown in red-yellow, and decreased in blue. M1/S1=primary motor & sensory cortices, OP=operculum, dlPFC=dorsolateral prefrontal cortex, Thal=thalamus, ACC=anterior cingulate cortex, vmPFC=ventromedial prefrontal cortex, PAG=periaqueductal grey, SMG=supramarginal gyrus.

The areas that are reduced in activation with opioids are commonly activated in breathlessness and central to respiratory sensation. For example, the anterior insula, the most commonly activated brain region during breathlessness, is believed to assess the quality of the stimulus and help control interpretation. The anterior cingulate cortex, which is also commonly activated in breathlessness, is similarly involved in control of negative emotions. These regions may be part of an interpretation process that is shaped by expectation and learning(7) similar to other control systems in the body (e.g.(8)).

Summary: Opioids manipulate brain regions associated with learning, negative memory formation and negative stimulus control. We have shown that the opioid remifentanil may alter breathlessness perception and the brain regions associated both with anticipation of and actual breathlessness. This suggests that opioids work to reduce breathlessness in part through direct effects on respiratory control mechanisms in the brainstem, insula and anterior cingulate cortex, and in part through changes in how breathlessness is anticipated, by changing associative learning processes in the amygdala/hippocampus.

References:
1. Pain, 22 (1985), pp. 261–269
2. Br J Anaesth, 100 (2008), pp. 747–758
3. J Neurosci, 29 (2009), pp. 8177–8186
4. Curr Opin Neurobiol, 14 (2004), pp. 198–202
5. Life Sci, 83 (2008), pp. 644–650
6. Pain, 96 (2002), pp. 153–162
7. Nat Rev Neurosci, 16 (2015), pp. 419-429
8. Exp Physiol, 92 (2007), pp. 695-704

DOI: http://dx.doi.org/10.1016/j.neuroimage.2017.01.005
Link: https://www.ncbi.nlm.nih.gov/pubmed?term=10.1016%2Fj.neuroimage.2017.01.005
All images presented with permission, creative commons licence.

Breathlessness & the Brain

Breathlessness can be many things. For example, it can be the shortness of breath after exercise – short-lived and laced with endorphins – or it can be the frightening gasping for breath experienced by patients with a range of diseases from cardiac failure and cancer to respiratory disease. From a physiological point of view, these may look quite similar, but they are not really the same thing. Breathlessness is the sensation produced by sensory input evaluated within the context of psychological and environmental factors. In short, the quality of breathlessness depends on why, who and where it is experienced – it’s situational and subjective. This means it cannot be approached, from a medical point of view, with a one size fits all solution. It’s important to understand its nuances.

So, which parts of the brain are involved in processing breathlessness? The answer is quite simple: we don’t know yet. To date, studies are few and far between, with the majority being on breathlessness in healthy controls which may or may not translate to various patient groups. While we don’t know anything for certain, particularly for patients, we do however have a few likely suspects.

usual

The usual suspects. The first is the insular cortex. This is a region of the brain that has been identified in the majority of neuroimaging studies on breathlessness. It plays a role in the conscious awareness of body state and is involved in the perception of other unpleasant sensations, such as pain. The role of the insula is two-fold, with the posterior (towards the back) part processing the physical aspects and the anterior (towards the front) part processing the affective (relating to moods and feelings) aspects of the sensation 1. This anterior-posterior division may also be present in breathlessness, as the anterior insula appears to be more associated with the unpleasantness of breathlessness.

The next on the list of likely suspects are somatosensory and motor regions (e.g. 2), which are also activated in a number of breathlessness studies. This is not surprising, given the added work of breathing harder than normal when you’re breathless. In addition to cortical somatosensory/motor regions, we also see activation in the brainstem (particularly in the brainstem respiratory centres) and in the cerebellum (a region associated with motor function). Some of these areas may be mostly involved with breathing itself and not with breathlessness specifically, as they appear frequently in studies looking at simple breathing responses without any breathlessness.

Then there are regions that sometimes appear and sometimes don’t: the prefrontal cortex, the periaqueductal grey (PAG), the amygdala and the anterior cingulate cortex (ACC). In the case of the PAG, which is a structure in the midbrain involved in pain processing and fight-or-flight responses, this may simply be because it is small and hard to image. Recent studies using high resolution imaging have found that the PAG is involved with unpleasant respiratory sensations, and that parts of the PAG have different roles in processing respiratory threat (see Figure 1 below) 3. Looking further into its sub-divisions, the lateral PAG is downregulated during restricted breathing, and the ventrolateral PAG is upregulated. This is interesting as the lateral PAG has been associated with active coping strategies for stressful situations that can be escaped, and the ventrolateral PAG with passive coping strategies for stressful situations that cannot be escaped. In short, it seems as if different parts of the PAG are involved in different aspects of breathlessness.

elife-12047-fig2-v3-480wFig 1. 7T FMRI of respiratory threat in the PAG. Faull et al. 2016.

The prefrontal cortex has been implicated in the processing of breathlessness cues (i.e. a non-physical stimulus) in COPD patients (medial prefrontal cortex, mPFC), as has the ACC (see Figure 2 below) 4. The latter has also been identified in many studies on breathlessness in healthy volunteers, and the former is an area of the prefrontal cortex involved in emotion processing, and particularly associated with responses to fear and threat. In the above study, both patients and controls showed activation in the insula (labelled ‘Conjunction’). Opioids, which can cause make breathlessness less unpleasant, dampens brain responses to breath holding in the prefrontal and anterior cingulate cortices as well as in the insula 5. So, it’s a good guess that the prefrontal cortex and ACC are involved in the modulation of breathlessness.

chestpaperFig 2. COPD patients and control. Response to breathlessness cues. From Herigstad et al. 2015.

Similarly, the amygdala, which is frequently identified in a whole range of studies relating to emotion, threat appraisal and fight-or-flight responses, is also activated in some studies of breathlessness. The amygdala is strongly connected to the anterior insula, and breathlessness studies that have seen activation in the amygdala also show large activation in the insula.

There are also another few regions that are occasionally found and we don’t quite know how they fit in. These include the before-mentioned cerebellum, the dorsolateral prefrontal cortex and the precuneus.

The cerebellum is probably mostly involved in the motoric response to breathlessness, as it is a centre for coordination of motor function, but as the cerebellum has also been associated with cognitive function, we can’t yet determine its role in breathlessness. The dorsolateral prefrontal cortex may be part of the cognitive evaluation of breathlessness, as this is a structure that is associated with attention and working memory. The precuneus could be involved in both sensory and cognitive aspects of breathlessness, depending on which part of the precuneus is active. It is a poorly mapped structure, but in general it has a sensorimotor anterior region which links to sensory/motor areas of the brain and the insula, and a cognitive central region which links to prefrontal regions, including the dorsolateral prefrontal cortex. It also links to the thalamus, which is a subcortical structure that relays a vast range of information between the brainstem and the higher brain areas.

Linking it all together. We don’t know how this all ties together. However, one could speculate ways in which breathlessness is processed in the brain:

Brainstem breathing control. We know that respiratory centres in the brainstem receive peripheral input (input from the rest of the body) and adjust the breathing pattern in response to this. The brainstem is crucial for breathing – without it, no breathing occurs – and it almost certainly plays a part in the actual breathing response to breathlessness. The cerebellum, which is probably involved in the motor response to breathlessness, connects to the higher brain areas through the brainstem. So far so good.

PAG as a gateway. Peripheral input is also believed to be received in the PAG, which could act as a gateway of sorts. The lateral PAG relays signal directly to primary motor/sensory cortices and the (posterior?) insula, and this path may be processing breathlessness intensity. The ventrolateral PAG relays signal directly to the prefrontal cortex, (anterior?) insula and also to motor regions of the brain, and this path may be processing the threat and/or possible responses to the breathlessness. The PAG probably also connects with the thalamus, which in turn acts as a hub (see below).

Thalamus as a hub. Finally, signal could also be relayed via the PAG (or directly) to the thalamus, which has been identified in a range of breathlessness studies and is a common hub for cortical communication. From the thalamus, signal is transmitted to a range of cortical areas (including prefrontal regions and the amygdala via the medial/frontal thalamus, and somatosensory and motor regions via the ventroposterior thalamus). Breathlessness is likely modulated by several of these cortical areas and how they interact.

The complexity of the interactions may be best explained by an example:

Anxiety relating to threat is modulated by activation in both the medial prefrontal cortex (mPFC) and the amygdala. The mPFC possibly influences threat by dampening activation in the amygdala. So far, so good. The prefrontal cortex receives signal from the PAG, and may also receive input from the ACC. Both the ACC and PAG are in turn linked to the anterior insula. The anterior insula also receives input from the thalamus, which relays signal to the amygdala. The thalamus also receives input from the PAG. So now we have a network of interconnected regions which may all influence each other and work to fine-tune the anxiety response. Furthermore, the anterior insula may also receive and integrate information on the physical sensation from the posterior insula, which is linked to the ventroposterior thalamus. This part of the thalamus is connected with somatosensory and motor cortices. These are also influenced by the PAG. The thalamus and somatosensory/motor cortices also relay signal to the precuneus, which in turn could connect to the dorsolateral prefrontal cortex, thus incorporating cognitive processing. And so on. It can get a bit complex.

A suggested network is presented in the figure below.

brain3 Fig 3. Possible breathlessness network. Purple=connected cortical regions, black= signal to/from periphery, blue=signal from PAG. ‘Hubs’ are shown in green. PFC = prefrontal cortex (encompasses both medial (emotional/threat processing) and dorsolateral (cognitive processing) PFC)

In short, various studies have shown that a range of brain regions are activated during breathlessness, but we don’t yet know exactly how they are involved in processing the sensation. We may still only guess at the full picture, based on breathlessness work as well as studies on other unpleasant sensations (pain, mostly), threat or emotional processing. Much of the same processing mechanisms are likely to be found in these similar sensations. While the above figure outlines some possible networks for the processing of breathlessness, based on our current understanding of breathlessness and related conditions, (much) more information is needed.

References:
1. Oertel, B., Preibisch, C., et al. Clin Pharmacol Ther 2008; 83:577–588.
2. Hayen, A., Herigstad, M., et al. NeuroImage 2012; 66: 479-488.
3. Faull, O., Jenkinson, M., et al. eLife 2016; 5: e12047
4. Herigstad, M., Hayen, A., et al. Chest 2015; 148(4): 953-61
5. Harvey, A., Pattinson, K., et al. J Magn Reson Imaging 2008; 28:1337–1344.