Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome 12-17

Neuroinflammation, Fatigue and Pain Lab Stop

We were having a case of déjà vu as we drove around the surprisingly large campus. Getting into the NIH to see Avindra Nath had been a nightmare.  It turned out that the NIH would only allow the big van through one access point and we’d ended up mortifyingly late to our appointment. Now here we were in another big campus with what my partner felt were inadequate directions. 

 I thought Jarred and I had it going, though. He said he would meet us at the parking lot and let us through the gate, but there were lots of parking lots. Plus, because we couldn’t stop, we had to keep driving around the campus and hope we met up with him at the right parking lot at the right time. It did seem a little dicey but I was confident I’d figured it out.

My partner, though, wasn’t having it with the sketchy directions or the reliance on male directional genes.  She could see it happening – we were going to be late again.

“Men,” she said, “how do you ever get anything done?”

As it turned out, Jarred and I were in sync: we both showed up at the gate at about the same time and he led us into his surprisingly large facility. Once again, we forgot to take pictures, but our timing couldn’t have been better; Younger had just wrapped up one of the most exciting studies in memory.

But first a little history…

 Neuroinflammation – The Japanese Way

Researchers have thought for decades that neuroinflammation is probably present in chronic fatigue syndrome (ME/CFS), but it’s only recently that the technology has been able to pick up the lower levels of neuroinflammation believed present in diseases like ME/CFS and fibromyalgia. The Japanese were the first to take a crack at it. 

 They have long believed that inflammation produces central fatigue (fatigue emanating from the brain), which plays a major role in ME/CFS. In 2013, Watanabe proposed that inflammation in the brain was whacking the “facilitation system” which pops up when we are fatigued to boost signals from the motor cortex to keep our muscles moving. He also hypothesized that an inhibition system was turning up the fatigue in ME/CFS.

A 2016 study rounded the circle when it found evidence of reduced dopaminergic activity from a part of the brain (the basal ganglia) which activates the motor cortex. That fit in just fine with Miller’s results, which suggested that problems with the basal ganglia could be producing both the fatigue and the motor activity problems in ME/CFS.

The big breakthrough came in 2014 when the Japanese startled just about everyone with a PET scan study which found widespread neuroinflammation in the brains of ME/CFS patients. The study was small (n=19) but the findings appeared strong. 

The neuroinflammation was widespread but was highest in the areas of the brain (thalamus, amygdala, midbrain, hippocampus) that had shown up in ME/CFS before. Plus, the Japanese were able to link specific regions of inflammation to specific symptoms. Inflammation in the thalamus was associated with cognitive impairment, fatigue and pain; inflammation in the amygdala was associated with cognitive issues; and inflammation of the hippocampus was associated with depression.

Anthony Komaroff called the findings the most exciting in decades. The Japanese began a much larger (n=120) neuroinflammation study. This year they published a large number of papers on ME/CFS in the Japanese Journal, “Shinkei Kenkyu No Shinpo” (Brain and Nerve). One of the papers was specifically on neuroinflammation but the findings have not yet been published in English journals.

Neuroinflammation – The Younger Way

Jarred Younger – who runs the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham has also long believed that neuroinflammation plays a major role in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

In 2015, he noted what a hot subject neuroinflammation had become.  Seven years ago, he said, there was almost nothing on the microglia at the pain conferences. Now they’re loaded with presentations on microglia.

These immune cells are sensitive to so many factors and can be triggered in so many ways that virtually any stressor, from an infection to toxins to psychological stress, can potentially trigger a state of microglial sensitization in the right individual. With their ability to produce dozens of different inflammatory mediators, Younger believes that the difference between ME/CFS and FM could simply come down to small differences in how the microglia are tweaked.

Both diseases could be triggered by high rates of immune activation which, over time, sensitizes the microglia to such an extent that they start pumping out inflammatory factors at the first sign of a stressor.

New Non-Invasive Technique

Younger had just finished up his ME/CFS brain thermometry study. He used a new, less invasive way of assessing the brain called magnetic resonance spectroscopic thermometry (MRSt). The technique, which aims to create a thermometer for the brain, uses a magnetic resonance imaging (MRI) scanner. While Younger was assessing the temperature of the brain, he was also examining its chemical makeup.

Using temperature as a measure of inflammation, Younger is taking the temperature of the brain.

My partner asked him how he glommed onto the heat mapping idea?  It turned out that Younger had been trying for quite some time to find a non-invasive way to assess neuroinflammation.  He needed a technique he could safely use again and again in his longitudinal (Good Day/Bad Day) studies.

None of the present techniques, however, fit the bill; they were all heavily invasive. The PET scan approach uses radiation to image the brain. Another approach using magnetized nano particles is supposed to be safe but it still requires putting little bits of metal into peoples’ brains…

After hitting several dead ends, he hypothesized that because inflammation produces temperature increases, he could try and create a heat map of the brain. Looking through the literature, he realized that thermometry was already being used in the brain to assess stroke and cancer patients. It turns out that the brain’s attempts to repair the damage from stroke and cancer results in huge temperature increases. The stroke and cancer researchers, though, were just focused on small areas of the brain.

Because Younger didn’t know exactly where in the brain to search in ME/CFS, that technique wouldn’t work for him. He had to develop a method that would produce a heat map and a chemical signature of the entire brain, and found a Florida researcher who developed a way to do that.

With this technique, it takes just 20 minutes in the machine to get an entire 3-D heat and chemistry map of an ME/CFS patient’s brain. After The Solve ME/CFS Initiative (SMCI) provided funding, he got to work and ultimately scanned the brains of 15 ME/CFS women and 15 age and sex matched healthy controls.

Widespread Neuroinflammation Found in ME/CFS Patients’ Brains

“The markers were truly elevated” Jarred Younger

It turned out that Younger’s brain-wide search technique was right on. Looking at single areas of the brain in ME/CFS patients would have produced misleading data. It turned out there was no single area or even a group of areas in the brain that were abnormal in ME/CFS: most of the brain was.

Younger found lactate – a product of anaerobic metabolism – widely distributed across the brains of people with ME/CFS. He opened a chart showing an amazing array of lactate-engorged brain regions. He picked out a few: the insula, hippocampus, thalamus, and putamen, which had particularly high levels. They were virtually the same regions the Japanese had found in their 2015 study. The fact that the temperature increases overlapped with the lactate increases provided further confidence that Younger had identified some key areas.

The cingulate cortex – which Younger called the “seat of suffering” was particularly inflamed.

The interior cingulate cortex, in particular, which Younger called “the seat of suffering” in the brain, showed up in spades. It’s associated with a lot of nasty symptoms (malaise, fatigue and pain) and it’s shown up in both ME/CFS and fibromyalgia studies in the past. The high choline signal in that region of the brain suggested that inflammation there was producing a pattern of destruction and replacement; i.e. quite a bit of damage – even possibly neuronal damage – was happening there.

Overall, the lactate levels weren’t as high as in other diseases – they were just consistently present. Younger didn’t expect to see really high levels; really high lactate levels would have meant irretrievably damaged neurons – the kind of neuronal damage seen in M.S., Parkinson’s and Alzheimer’s – the kind of neuronal damage that is really hard to reverse. The fact that Younger saw inflammation in ME/CFS but not neuron-destroying inflammation is good news indeed for people with ME/CFS.

It’s possible that some damage such as neuronal reprogramming and synaptic pruning could be occurring, but determining that would take an autopsy.  (Some groups are collecting ME/CFS brains at a couple of autopsies that have been done.)

Remarkably, the healthy controls didn’t show evidence of a single analyte such as lactate being elevated or a single area of the brain being heated up. It’s highly unusual to find zero evidence of an abnormality in the healthy controls. Usually the results of studies apply to groups, not individuals; some healthy controls typically will have findings that are similar to the MEC/CFS patients and vice-versa, but not here – the two groups were absolutely distinct.  Even though this was a small study, such black/white results strongly suggest that neuroinflammation of the brain is a key element of ME/CFS.

Lactate

Magnetic spectroscopy studies have found increased lactate in the ventricles of the brain in ME/CFS before but not in the brain itself.  Shungu’s spectroscopy studies have, in fact, produced some of the most consistent results in all of ME/CFS research. Three times he’s probed the ventricles and three times he’s found increased lactate.  Shungu, however, is examining an area just outside of the brain. His findings may indicate inflammation is present in the brain or it could be confined to the cerebral spinal fluid. 

Younger’s new approach looked at the entire brain and found signs of inflammation almost everywhere. When asked what could cause that, Younger said that any neurodegenerative/ neuroinflammatory disorder like MS or a severe brain injury that tweaks the microglia (immune cells in the brain) enough to produce a sustained period of inflammation, burns up the oxygen in the system. Once that happens, the cells resort to anaerobic metabolism and lactate builds up just as it does in the muscles during exercise.

My partner asked another intriguing question. (Thank god her brain was functioning.) What about intervention studies?  What about whacking ME/CFS patients with exercise and seeing what happens to their brains? Younger, it turned out, had already laid the groundwork for that study.

Therapeutic Implications

Documenting that neuroinflammation is present and is affecting functioning in ME/CFS could have dramatic treatment implications.  It could lead the scientific and medical communities to focus less on drugs that target the nervous system and more on ways to reduce inflammation. For example, attempts could be made to modify current anti-inflammatories so that they pass through the blood brain barrier (most do not). Health Rising will focus on some way that might happen in a future blog.

Fast Mover

Throughout this process, Younger has moved extremely quickly. He completed the thermometry study as quickly as possible, and then as the dramatic results began to come in, rapidly applied for a nice, fat ROI grant from the NIH. The results were so convincing, in fact, that he didn’t wait for them all to come in and applied for the grant using half the data from the study.

It’s hard to imagine that that grant application won’t get funded.  When it is, Younger will have plenty of money to pursue the neuroinflammation angle further, including challenging ME/CFS patients with exercise – something he’s never done before – and seeing what that does to the inflammation in their brain. It’ll be fascinating to see if it rises, how long the inflammation lasts, how it tracks with post-exertional symptoms, and where it’s most evident.

Cause?

Younger speculated that people with ME/CFS have an immune-triggered metabolic disorder.  The widespread neuroinflammation provides a clue, he thinks, to what’s going on. That pattern suggests that immune cells are breaching the blood-brain barrier in multiple areas; like a flood overwhelming a dike they’re essentially pouring through gaps across the brain. Why that may be happening he’s not sure, but his next step in ME/CFS is to demonstrate that that’s happening. How he proposes to do that is the subject of the next blog.  

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