[Simon presents an overview of the Robert Dantzer’s Lecture on the Neuroimmune Basis of Fatigue at the UK CFS/ME Research Collaborative (CMRC) Conference in September of this year. Thanks for Simon’s and Action for ME for allowing us to post his summary. You can find more of their summaries here.
First I present an introduction to the UK effort –then we’re on to Simon’s blog. I added many images as well as comments (in brackets [ ]). Please note that my interpretations may reflect neither Simon’s or Dr. Dantzers.
The UK CFS/ME Research Collaborative (CMRC) Conference
“By coming together in this way, the application of state-of-the-art research methodology… will greatly increase the chance of identifying pathways linked to disease causation and novel therapeutic targets”
The efforts attempt to bring all aspects of the field together, from pathophysiology to psychology, naturally engendered some controversy . Yes, Julia Newton, was there but so was Esther Crawley, who while acknowledging some biological findings in ME/CFS is also overseeing the ME/CFS Lightning Process study.
While the effort aimed to increase the use of cutting-edge technology in ME/CFS (proteomics, metabolomics, pathway analysis, systems biology) and building infrastructure (BioBanks), statements such “important maintaining factors include comorbid mood disorders, beliefs about causation, and either pervasive inactivity or swinging from inactivity to over-activity (boom and bust pattern of behaviour).” made some patients wary and patient opinions were decidedly mixed about the effort.
“Firstly, the collaborative is bringing EVERYONE together who is involved in ME/CFS research – that includes ALL specialties, new and potential researchers, research funding (or supporting) charities, respresentatives of the pharmaceutical companies (in due course) and government (MRC, NIHR, DoH). So the membership will be right across the spectrum from neurology and immunology to psychiatry and psychology…..It is, as I keep saying, a very big tent and the ME/CFS charities that are signing up to join (I think the number is now 7) accept that this is the case.Secondly, it is quite likely that the UKRC is going to play a major role in stimulating new research funding, new research infrastructure (bricks and mortar) and academic acceptance of ME/CFS in hospitals and universities (something that is very sadly lacking at present). We believe it is is better to be inside the tent putting your point of view than complaining about what is happening from outside the tent and (in some cases) trying to drown this initiative before it has even started to swim.”He went so far as to make it explicit that ” It will NOT be promoting psychiatric research in preference to biomedical research. If this was the intention we would not have joined. If this were to ever to be the case we would not want to be a member.” See the rest of his remarks here.
- Check out Simon’s blog on the launch here
Robert Dantzer Lecture
“My research group focuses on the behavioral and psychopathological consequences of the effects of inflammatory mediators on the brain”
The goal to bring outside researchers into the field was already paying off with Dr. Robert Dantzer, a seminal figure in the understanding of how inflammatory factors effect brain functioning and behavior, presenting. Dantzer has co-authored hundreds of studies on the effects of inflammation on fatigue, depression and pain. (See his review paper “From inflammation to sickness and depression: when the immune system subjugates the brain” for the immune systems effects on depression)
Coming up we’ll have an account of one person with chronic fatigue syndrome who benefited greatly from prescription anti-inflammatories.]
Robert Dantzer Lecture on the Neuroimmune Basis of Fatigue – University of Texas Anderson Cancer Centre – by Simon McGrath
In his presentation, Professor Robert Dantzer explained how sickness behaviour, which includes fatigue, is part of the normal, ‘healthy’, response to infection and usually subsides after the infection. It is triggered by cytokines released by immune cells when they detect a pathogen. Chronic fatigue may be linked to long-term activation of sickness behaviour. Professor Dantzer finishes by describing the ‘orexin’ system in the brain, which may play a critical role in fatigue and could be a target for drug therapies.
“Remember that last time we had the flu — the sleepiness, depressed mood, decreased activity, fatigue, reduced appetite, etcetera? All of this is triggered by cytokines released by white blood cells”. Professor Robert Dantzer is describing ‘sickness behaviour’, the characteristic response of all mammals to an infection. It is a biological process that exists to promote recovery and healing.
Professor Dantzer’s pioneering research helped reveal the biology of sickness behaviour He now works on cancer-related fatigue, which he believes could be a result of sickness behaviour gone wrong — and which might be related to chronic fatigue syndrome, both in symptoms and underlying mechanisms.
In his model, cancer-related fatigue is driven by white blood cells releasing tiny molecules called cytokines that act on the brain. This process is modified by risk factors, including the version of immune genes you have, neuroendocrine factors and psychosocial factors.
“Previous work on communication pathways between the immune system and the brain needs to guide us”, said Professor Dantzer, as he reviewed the long-running saga of how researchers discovered the relationship between sickness, fatigue and inflammation.
The Brain’s “Immunostat”
Researchers began to realise that, just like any other organ, the immune system is regulated by the brain. There must be what Professor Dantzer calls an ‘immunostat’ in the brain, and much like a thermostat in a central heating system, senses and regulates the temperature, the immunostat senses the state of the immune system and regulates it accordingly. But this requires communication between the immune system and the brain.
Work in the 1980’s found evidence of two-way communication between the brain and the immune system. When they detect infection, immune cells produce molecules called cytokines (Interleukin 1, IL-1, is a key cytokine here). These molecules signal to the brain, alerting it to inflammation in the body. Back then, it was a radical idea that the immune system could produce molecules that affect the brain and physiology. It took a bit longer to discover that these same molecules also lead to changes in behaviour.
More research showed that the communication is a two-way street: the brain controls the release of molecules that regulate the immune cells, including glucocorticoids via the Hypothalamus-Pituitary-Adrenal (HPA) axis. (Glucocorticoids are widely used in medicine to damp down inflammation.)
These and other discoveries on the immune mechanisms of fever were brought together in 1988 by Benjamin Hart with his proposal that sickness behaviour is a normal and important process, part of the animals’ deliberate response to infection driven by biology. A key part of the model is that it is a temporary situation to deal with infection: inflammation –> sickness behaviour –> removal of pathogen –> restoration of normal behaviour.
The key steps leading to sickness behaviour are:
- White blood cells recognize invading pathogens. (At this point, the cells use receptors that identify generic ‘foreign’ markers, such as bacterial cells walls, rather than recognising specific bugs such as the flu virus.)
- The white blood cells release cytokines in the body.
- Immune-to-brain communication takes signal to the brain (either via the blood, or the nerves innervating the site of the body in which the inflammatory response takes place.
- This activates microglia – the brain’s innate immune cells – which release more cytokines into the brain. So activation of immune cells in the body leads to activation of immune cells in the brain.
- This leads to more biological changes and, ultimately, to sickness behaviour, including fatigue.
The first evidence that microglia played a critical role came in 1992, when a study showed that microglia produced IL-1 in the brain in response to inflammation in the rest of the body. Subsequent work using fMRI brain imaging shows that inflammation leads to microglia being activated throughout the brain within a few hours.
- [Neuroinflammation: Putting the ‘itis’ back into Myalgic Encephalomyelitis – Back to the Future For Chronic Fatigue Syndrome?
- The Fatigue and Pain Producers: Could Glial Cells Be ‘It’ in Chronic Fatigue Syndrome and Fibromyalgia?
- Microglial Inhibiting Drugs to Combat Neuroinflammation]
Professor Dantzer made the point that while sickness behaviour is normally a standard set of responses driven by infection, it is affected by the environment too. This is the “motivational state” view of sickness behaviour. Normally, when we are sick the world no longer matters to us, what matters is taking care of our injured bodes – exactly what our brains wants us to do – but in extreme situations this can be overridden, as the following experiment showed.
Female mice with young pups injected with LPS at room temperature will show lethargy typical of sickness behaviour, and won’t respond if the pups’ nest is removed. However, if pups are dispersed in the cage, the female mice will overcome their sickness and bring back their pups to the stack of cotton wool they normally use to build the nest.
If the experiment is repeated with the temperature reduced to a chilly 6 degrees centigrade, then the mother mouse will react to the harsher circumstances threatening her pups and not only bring back her dispersed pups to the stack of cotton wool and make use of the material to rebuild the nest. So behaviour depends not just on inflammation, but the environment too. Or, as Professor Dantzer said “Inflammation-induced sickness is a motivational state that reorganizes the priorities of the sick individual”. And those priorities are flexible according to the environment.
Professor Dantzer said that up to this point he’d described normal, ‘healthy’ sickness behaviour. It’s normal to feel sick in response to an infection in the same way it’s normal to feel afraid in response to a threat.
- The brain has an ‘immunostat’ that recognises the immune response in the body – this is the origin of sickness behaviour.
- This reorganises sick animal’s priorities.
- Crucially, sickness behaviour is normally fully reversible.
Then Professor Dantzer moved on to what might go wrong when we don’t recover, asking the crucial question “Is chronic fatigue or depression a form of sickness disorder?”
Inflammation: Unpicking its Roles in Fatigue, Sickness and Depression
“To be healthy is to be able to become ill and recover from it…” (Georges Canguilhem: “être en bonne santé, c’est pouvoir tomber malade et s’en relever”)
Historically, much sickness behaviour research has focused on inflammation causing depression rather than fatigue. However, what doctors call ‘depression’ has different elements, and fatigue counts as a big part of it:
- Mood symptoms including feelings of sadness, irritability and crying
- Affective/cognitive symptoms including self-dislike, guilt and worthlessness
- Neurovegetative symptoms, which include the CFS/ME symptoms of fatigue, problems with sleep and concentration.
Professor Dantzer showed a fascinating slide based on the work carried out by his former student, Lucile Capuron. This slide broke down how different types of symptoms appeared at different times in cancer patients given the cytokine interferon-alpha as therapy. The fastest response comes from flu-like symptoms (malaise) that appear rapidly with each repeated dose (but fade fast due to anti-fever drugs).
But within a few days the neurovegetative symptoms start, including fatigue, sleep problems and difficulty concentrating. After a week or so both mood and cognitive symptoms cut in.
This means that when researchers said they found ‘depression’ in response to inflammation, sometimes they only meant fatigue and other CFS/ME-like symptoms.
[This collapse of boundaries between fatigue and other symptoms has clearly muddled our understanding of disorders like ME/CFS and depression. We saw how that collapse confused, until recently, the difference between the fatigue and post-exertional malaise found in multiple sclerosis and ME/CFS in
- A “Fatigue” Disorder No More? – What Multiple Sclerosis Taught Us About Fatigue and Chronic Fatigue Syndrome“.
Are increased rates of depression found in ME/CFS? Overviews suggest yes. Is ME/CFS distinct from depression? This blog
- “How to Prove to Your Doctor You’ve Got Chronic Fatigue Syndrome (ME/CFS) And Are Not Just Depressed“
indicates that it is. It’s clear that the inflammation Dantzer is talking about can contribute to both mood and other symptoms – in the same disorder . It’s a tangled web.]
A study on an inflammation-linked disorder called Metabolic Syndrome found that there was a link of inflammation with depression overall, but that while there was a significant link for the neurovegetative symptoms, the link with mood and affective symptoms was not statistically significant.
Deconstructing Fatigue – What Exactly Does Inflammation Affect?
Professor Dantzer argues if we really want to understand the biology we need to go further and ‘deconstruct’ even fatigue. The idea is to break it into the ‘neurobehavioural units’ corresponding to the way the brains works. Fatigue, said Professor Dantzer, could be seen as having two elements:
- The physical ability to do things
- Motivation: willingness or wanting desire to do things.
He said that patients they see at his cancer centre have more problems with motivation, but he also believes biological systems underpin both elements of fatigue.
[So cancer induced fatigue appears to affect “motivation” more. Does that mean their fatigue is more “psychological”? Not at all. Miller’s long string of studies on the effects of IFN-a suggests that inflammation may in ME/CFS and other disorders, inhibit the reward center of the brain – the basal ganglia. The motivational problems in the cancer fatigue patients may very well have a physiological origin. That doesn’t mean, though, that mind/body approaches may not be helpful. They could able to take advantage of the brains plasticity to alter it’s functioning.
- See Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome for more on Miller’s findings]
Professor Dantzer gave the example of motivated behaviour and how it is affected in different ways by different aspects of inflammation. Motivated behaviour can be broken into two steps. In the case of feeding, there is
- a ‘seeking’ phase of accessing the food, then
- a ‘taking’ (or consummatory phase of eating it.
So in predators, like cats, this would be hunting and eating. It turns out that different parts of the brain are involved in theses seeking vs taking steps.
An experiment helped show the difference and how inflammation can affect both steps but at different times. If rats pressed a lever five times (seeking behaviour) they were rewarded with tasty food (the rat equivalent of “very nice wine from Bordeaux” said Professor Dantzer, who is French). The rats had free access to normal rather bland laboratory food (“like wine from Bristol”, suggested Professor Dantzer, who was speaking in a lecture hall in Bristol).
Healthy rats press the lever to get the “Rat Bordeaux”. When rats were injected with a cytokine to cause inflammation and tested ninety minutes later during the peak of sickness, they ate less ‘Rat Bordeaux’ (the food that required more energy-requiring seeking behaviour of lever-pressing), but still ate easy-access boring food (simple taking behaviour). This fits with physical exhaustion.
However, the results were different when they did a similar study on mice at a later stage (one day on) where depression would have cut in for mice. This study used grain (unexciting food) or chocolate (which mice apparently love). A single lever press was needed for grain, but ten presses were needed for chocolate. This time the LPS-injected mice injected worked less than healthy mice overall, but more of what they ate was chocolate, even though it was more work. It was if the problem was motivation – they were less likely to respond overall, but if they opted for engaging in an effort, then this effort needed to be for a big incentive rather than a small one.
Similar studies have been done in humans, though they used money instead of chocolate as the incentive. Professor Dantzer said the beauty of this approach was they could study motivation both in animals and humans (and run experiments in animals that wouldn’t be possible in humans).
Orexin – The key to Inflammation-related Fatigue
Professor Dantzer finished his presentation by describing a recently-discovered system in the hypothalamus of the brain that plays a key role in regulating energy levels – and could be a target for drugs to treat fatigue. The orexin system senses metabolic status and the balance between feeding and energy expenditure. It responds to glucose as well as leptin, a key molecule signalling energy levels that has been implicated in CFS/ME).
[Younger’s research suggests leptin, a substance tied to both metabolism and microglial activation, could be a key driver of the immune activation found in ME/CFS. Younger, who is now director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama, recently scored a major NIH grant to extend his research into leptin and immune activation in ME/CFS.
- See Tweeting the Stanford Symposium for more on leptin and ME/CFS ]
The orexin system also plays a role in sleep versus wakefulness. Unlike healthy rats, those given LPS fail to become more active at night. What’s really interesting is that the reduction in activity correlates with reduced levels of orexin. However, rats given orexin as well as LPS don’t show any reduction in activity, suggesting that orexin plays a key role in activity levels.
Orexin as a Treatment for Fatigue?
Researchers suspected that orexin may play a similar role in the cancer-related fatigue resulting from chemotherapy. They found that giving mice chemotherapy did indeed lead to lower levels of activity, indicating fatigue and a reduction in their orexin levels.
Crucially, giving mice orexin alongside the chemo restored their activity levels, again suggesting reduced orexin played a central role in fatigue. He said that there are now drugs for narcolepsy targeting the orexin system, and perhaps they could one day be used for fatigue too.
Professor Dantzer said his group are working on a test of orexin as a treatment for cancer-related fatigue.
Professor Dantzer summed up by saying how hard it was to study a disorder characterized by symptoms, and urged a more detailed approach, probing what is really happening in the brain:
“It’s time now to deconstruct fatigue. We cannot continue to label patients; we have to find out how their brain is working, what is behind chronic fatigue. We are doing that now in cancer patients. There is no reason not to do it in CFS/ME.”
Finally he pointed out the challenge ahead: “We know what causes fatigue, we still do not know what is responsible for the chronification of fatigue”.
This article covers most of the points in the presentation, but does not aim to be a comprehensive summary.
[article by Simon McGrath, thanks to Professor Dantzer for his amendments and approval]
recently died after raising more than £1 million for ME/CFS research.
Simon McGrath tweets on ME/CFS research: @sjmnotes