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. UPDATE: final published paper here.

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

The published paper is out here

Full citation: Mari Herigstad, Olivia K. Faull, Anja Hayen, Eleanor Evans, F. Maxine Hardinge, Katja Wiech, Kyle T.S.Pattinson. Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation. 

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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.

Predicting trouble: EEG, NO and stroke

We’ve recently published a paper titled “Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage” on how electroencephalography (EEG for short) can be used to figure out which patients with a certain type of stroke (subarachnoid hemorrhage) will develop a complication after the initial brain bleed and which will not.

Subarachnoid hemorrhage is a type of stroke that can happen at any age. It is a bleed on the surface of the brain, in a space between the arachnoid membrane and the pia mater surrounding the brain (see figure below).

Meninges-en

The bleed is usually caused by an aneurysm (a bulging, weak section of a blood vessel) bursting, causing blood to escape into the subarachnoid space. Here, it puts pressure on the brain tissue (causing tissue damage) which can also reduce blood flow to other parts of the brain (causing lack of oxygen and cell death). The released blood may be toxic to the brain tissue and could cause inflammation. At worst, a subarachnoid hemorrhage results in death or severe brain damage.

Some of the damage is caused directly by the bleed (e.g. the pressure on the brain), and some is caused by how the bleed disrupts the normal control of blood flow in the brain. In particular, it is bad when the nitric oxide pathway stops functioning properly. Nitric oxide helps preserve the circulation in small blood vessels in the brain, partly through enlarging the blood vessels (vasodilation) and lowering the gathering of blood-clot forming platelets. After a bleed, nitric oxide levels in the brain are often reduced. This could be because hemoglobin in the blood stops enzymes responsible for producing nitric oxide from working properly. Another contributing factor is that the nitric oxide that is already present in the brain reacts with superoxide (part of the immune response) which leads to the levels of nitric oxide being even further lowered.

Nitric oxide disruption appears to be involved in delayed cerebral ischemia, which is the most common complication after a subarachnoid hemorrhage. For example, people with genetically lower activity in an enzyme that produces nitric oxide have a higher risk of this complication. Delayed cerebral ischemia is the unpredictable lack of oxygen to the brain leading to severe, even fatal, brain damage. This typically happens 3-14 days after the initial subarachnoid hemorrhage.

Which brings us to our question:

Patients who have the same clinical severity, no measurable genetic differences in nitric oxide production, and who seem exactly the same can go on to show very different outcomes. One can develop ischemia and suffer devastating new brain injuries, and the other return to normal without complications. How can we tell who will get it and who will not?

EEG measures neuronal (electrical) activity using electrodes placed on your scalp. It picks up fluctuations in voltage from the electric currents in the neurons, and in the clinical setting it is used to measure the spontaneous electrical activity in a brain over time. Different parts of the brain generate different signals. Some parts show signal with low frequencies (long waves, delta and theta frequencies) and some with short frequencies (rapid waves, alpha frequencies). The signal is linked to blood flow. In subarachnoid hemorrhage, it can be used to see cerebral ischemia develop naturally at an early stage, because as the blood flow is reduced, short frequencies begin to fade and long frequencies steadily increase. In short, the ratio of alpha to delta (for example), will be reduced in the ischemic patients. However, it can take several days of recording to get a result with this method. It is possible, but not practical.

However, we know that nitric oxide disruption seems to be critically involved in delayed cerebral ischemia. This means that we can give patients a nitric oxide donor (sodium nitrite) to stimulate the nitric oxide pathway, and use EEG to measure how well they respond. By doing this, we can speed the process up. We can see if the patient responds well to the sodium nitrite, or not. This means, in short, that we can see which patients show nitric oxide pathway disruption.

Using this method, we showed in our paper that patients who later went on to develop delayed cerebral ischemia showed no change (or a decrease) in the EEG signal whilst infused with sodium nitrite. Those that did not develop delayed cerebral ischemia did the exact opposite, and showed a strong increase in EEG signal.

temp3EEG spectrograms from a patient that did not develop delayed cerebral ischemia, and one who did, plus a scatter plot with the group differences in spectrogram ratio (alpha delta ratio (ADR))

So we have not only shown how the nitric oxide pathway is important in the development of delayed cerebral ischemia, but this also means we now quite possibly may be able to relatively quickly determine who is at risk for this life-threatening complication, and who is not.

Reference: Garry, P.S., Rowland, M.J., Ezra, M., Herigstad, M., Hayen, A., Sleigh, J.W., Westbrook. J., Warnaby, C.E. and Pattinson, K.T.S. (2016) Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage. doi: 10.1097/CCM.0000000000001950