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Study Presents Alternative Findings

Neuroinflammation seemed like a slam dunk for ME/CFS – until this study showed up.

Neuroinflammation has almost seemed like a slam dunk in chronic fatigue syndrome (ME/CFS). Nakatomi’s small 2014 study (n=19) set the stage when it reported finding widespread neuroinflammation.

A widespread, low-level neuroinflammatory problem seemed like a match for a disease characterized by a wide variety of symptoms (fatigue, pain, cognition, sleep). Tony Komaroff called the Nakatomi finding potentially the most important in decades.

Since then, several studies have suggested that neuroinflammation is indeed present in ME/CFS, as well as fibromyalgia (FM) and Gulf War Illness (GWI). Shungu’s consistent findings of increased lactate levels in the brain’s ventricules, William’s dUPTase studies, Miller’s findings of basal ganglia deactivation, Hornig’s findings of altered cerebral spinal fluid cytokines, and Baraniuk’s CSF miRNA study all suggested that neuroinflammation was present.

Add to those the many hypothesis papers that have cited neuroinflammation as a potential cause of the symptoms in ME/CFS and fibromyalgia and you’ve got what seems to be a foregone conclusion:  neuroinflammation MUST be present in ME/CFS/FM and similar diseases.

Fibromyalgia, Chronic Fatigue Syndrome, Gulf War Illness – the Widespread Neuroinflammation Diseases

Nancy Klimas’s models indicated that the first drug in her two-drug combo for GWI and ME/CFS should be focused on quieting down neuroinflammation. Health Rising has devoted over 25 blogs to the subject of neuroinflammation and has several pages devoted to potential neuroinflammatory fixes.

Microglial Inhibiting Drugs, Supplements and Botanicals to Combat Neuroinflammation

 

That speculation regarding neuroinflammation, though, has rested upon a pretty thin evidentiary reed. Until this Dutch study appeared, though, only Jarred Younger’s 30-person thermography and metabolite study more or less attempted to directly assess neuroinflammation, Younger, using a new technique, found elevated temperatures in widespread areas of the brain and then validated his findings by using MRS spectroscopy.

Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS)

While only a few studies have directly attempted to assess neuroinflammation the evidence to date suggests it is probably present. Until now, though, no one has attempted to replicate Nakatomi’s small study results.

The Dutch Study

It seems remarkable that for a subject that has aroused so much interest and so many hopes, it’s taken 7 years for someone to attempt to replicate the 2014 study. In the 2021 “No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195” paper, Dutch researchers attempted to replicate and improve on the first PET scan study.

The Dutch researchers proposed a familiar scenario:  an inflammatory hit from the original infectious event had reset the immune cells of the brain (the microglia). Now primed to act at the slightest disturbance, they were constantly producing the classic signs of “sickness behavior” (fatigue, pain, cognitive and sleep problems) – so often seen during the infection and so common in ME/CFS, FM, and GWI.

Like the Japanese study before it, the Dutch study was very small (n=16). Although the authors noted that better tracers are now available, the study used the same radioactive tracer that Nakatomi did. The study differed in that it added a post-infectious arm of Q fever patients, only assessed women, used a better-matched the authors thought, healthy control group, and an older patient set. (While the study required that symptoms reached a certain severity, it did use the Fukuda criteria). Finally, the researchers used a different, and they felt more accurate, reference point in the brain to assess their findings.

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On the whole, the study seemed better designed than the 2014 study – plus it had the advantage of assessing a known post-infectious cohort. Because the study was so small, though, the authors noted that any of the differences between it and the Nakatomi study could have had an effect.

No Neuroinflammation!

The study found no evidence of neuroinflammation at all in either the ME/CFS group or the Q fever group. Some symptom scores were correlated with increased activity in some parts of the brain in the Q-fever patients but very little correlation was found between symptom scores, and microglial activation in the ME/CFS patients. In other words, the study was pretty much of a bust regarding neuroinflammation and ME/CFS.

Odd Man Out?

Neuroinflammation

Loggia’s pet scan study found ample evidence of neuroinflammation in fibromyalgia.

It’s difficult to know what to make of this study. While the study appears to have improved methodologically on Nakatomi’s 2014 study, its results – particularly when ME/CFS’s sister diseases are taken into account, leave it an odd man out. Nakatomi’s and Younger’s studies in ME/CFS as well as PET scan studies of fibromyalgia, Gulf War Illness, and migraine all report finding a rather unusual signature – widespread areas of inflammation in the brain (and in many of the same brain regions).

Loggia is a key figure. Having investigated neuroinflammation in many other diseases (chronic pain, depression, anxiety, autism, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington’s disease), Loggia has a long track record in neuroinflammation and has found similar neuroinflammatory signatures FM, GWI and migraine neuroinflammation.

While the basis for neuroinflammation in ME/CFS is still pretty slim – resting on just a few studies – thus far the evidence, notwithstanding this study’s results, still supports the idea that similar patterns of neuroinflammation are happening in ME/CFS, fibromyalgia, GWI, and other diseases.

While neuroinflammation makes a lot of sense, it should be noted that neuroinflammation is not needed to explain ME/CFS, FM, or other diseases. In the last of their ever-expanding series of hypothesis papers, Klaus Wirth and Carmen Scheibenbogen have found a way to explain the neurological symptoms of ME/CFS without ever calling neuroinflammation into play at all.

Time will tell if they are correct, but a great hypothesis should be able to explain all aspects of a disease and, so far, that’s what Wirth and Scheibenbogen, over three publications, have been able to do in their impressive effort. (A blog on their latest hypothesis paper is coming up).

The Future

future neuroinflammation studies

The future – as it so often seems – should tell us much. Very large long COVID studies underway should be particularly illuminating.

The small Dutch study, notwithstanding, most evidence suggests that neuroinflammation is occurring in ME/CFS.  The good news is that the future is, indeed, coming and it should tell us much. At least two major NIH-funded studies are underway.

Dikomo Shungu’s “Oxidative Stress and Neuroinflammation: Co-conspirators in ME/CFS Pathophysiology” study using PET scans and MRS spectroscopy, began in 2017, and should have ended, if all went well, in August of this year.

Jarred Younger’s “Measuring neuroinflammation in chronic fatigue syndrome with whole-brain magnetic resonance spectroscopy” study began in 2019 and is slated to end in 2024. Younger’s three-part study will search the entire brain using MRS for signs of neuroinflammation, will employ a good-day/bad-day approach to see if worsened symptoms are associated with neuroinflammation, and will do a PET scan study for neuroinflammation.

A first-of-its-kind Stanford study, “Imaging inflammation in the whole body and brain of ME/CFS patients“, is going whole hog – scanning and assessing microglial activation in the body and the brains of people with ME/CFS. The study encouragingly states that “our encouraging preliminary data shows increased [11C]DPA-713-PET signal in multiple brain regions of severe ME/CFS patients compared to healthy controls.” This smaller, exploratory R21 study began in December of last year and should be ending up now.

A 200-person long COVID study, “Understanding the long-term impact of COVID-19 on the brain through advanced MR imaging and spectroscopy“, brings us to a whole new level. This is surely just the first of many VERY large long-COVID studies that will be assessing neuroinflammation, neurodegeneration, hypoxia/ischemia, and other potential brain issues.

Other studies are surely underway, of which, Nakatomi’s larger and long-delayed ME/CFS follow-up validation study looms the largest.

Plus, studies in other diseases are underway. A fibromyalgia study that is using PET scans to determine if cannabidiol (CBD) reduces microglial activation should tell us both about neuroinflammation in FM and whether CBD can help. My experience with cannabis products suggests it just might.

Conclusion

A new and improved Dutch version of Nakatomi’s 2014 neuroinflammation study found no neuroinflammation at all in either ME/CFS or post-Q fever syndrome. While the study was quite small, the result is a reminder that whatever the popularity of the neuroinflammation hypothesis, it rests on a rather small direct evidentiary basis.

Besides Jarred Younger’s duo thermography/MRS study, the best evidence for neuroinflammation in ME/CFS probably lies in Loggia’s neuroinflammation findings in fibromyalgia, Gulf War Illness, and migraine. An accomplished neuroscientist with many neuroinflammation studies under his belt, Loggia’s findings of a rather unusual brain signature (widespread neuroinflammation) in FM, GWI, and migraine jives well with Nakatomi’s and Younger’s findings of the same.

While these studies provide indirect evidence of neuroinflammation in ME/CFS, more and larger studies that directly assess neuroinflammation are clearly needed to determine.  Thankfully, several large NIH-funded studies are underway, including a 5-year study that was slated to wrap up a couple of months ago. Very large neuroinflammation studies are also expected in long COVID, one of which – a 200-person study – has started.

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