“We’re seeing things in the front of the brain, we’re seeing issues in the back of the brain, we’re seeing a lot of things in between…this is a brain-wide issue”. It’s safe to say that the ME/CFS brain is an inflamed brain.”  Jarred Younger

Jarred Younger couldn’t resist. He’s usually pretty deadpan, but there it was – a big smile as he started the “New Results: The ME/CFS brain is inflamed” video. Younger made the proviso that this was a first pass of his data and that things could change, but I would be shocked if Younger talked about results he wasn’t very confident in. He certainly looked happy in this video.

Younger has been asserting that neuroinflammation was a big deal – perhaps THE big deal – in ME/CFS for over ten years. Younger has been so confident that neuroinflammation is a big deal in diseases like ME/CFS and FM that ten years ago, when he opened his new lab at the University of Alabama at Birmingham, he called it “The Neuroinflammation, Pain and Fatigue Laboratory“.

Younger has hypothesized that hypersensitive microglia in the brains of ME/CFS/FM and long-COVID patients have been pumping out inflammatory cytokines and immune factors in response to the slightest stressors, and are responsible for the fatigue, pain, and other symptoms in these diseases.

For all the hullabaloo over neuroinflammation, though, it’s amazing how little direct evidence of widespread neuroinflammation there is. While quite a few brain studies suggest neuroinflammation is present, I could find only three papers that attempted to directly measure it across the brain.

The first attempt to directly measure it, Nakatomi’s small 2014 PET scan paper concluded that widespread neuroinflammation was present and quickly became a kind of cause celebre in the ME/CFS world. Somehow it took another seven years for a small PET scan study (n=16) to show up, but this time, using the same not-so-accurate radioactive tracer that Nakatomi did, it found no evidence of neuroinflammation.

Next, Younger’s innovative 2020 thermal mapping MRI and spectroscopy study found widespread areas of increased temperature and metabolites that were indicative of neuroinflammation.

PET scans, which highlight activated microglia, are considered the gold standard for assessing neuroinflammation. Now we had two small PET scan ME/CFS studies – one which found neuroinflammation and one which didn’t.

So while we’ve been acting, talking, and thinking as if neuroinflammation is, of course, present in ME/CFS, we haven’t directly proved that it’s present at all. With Younger’s use of a newer, more accurate radiotracer, it looks like his PET study is going to break the tie.

An Inflamed Brain 

Please note that as I attempt to dig deeper into Younger’s findings, I add many things he did not discuss in the video.

Both Sides Now – Sites of Bilateral Inflammation in ME/CFS Patients’ Brains

Younger started with areas of the brain featuring bilateral inflammation, i.e., inflammation found on both sides of the brain. Bilateral inflammation is considered worse than unilateral inflammation because in unilateral inflammation, one side of the brain can sometimes compensate for the poor functioning of the other side.

The Insula!

Inflammation in the insula alone could have been enough to cause ME/CFS.

Younger said we could have stopped right at the insula! The insula is so significant that inflammation in it alone could cause the ME/CFS symptoms. Highlighting the insula’s impact on the human experience, Younger said the insula is responsible for sensory information, bodily feelings, and most importantly, “how your emotions and your sensations and your understanding of yourself are integrated in how you ultimately feel”. The insula is responsible for making the assessment, “are you feeling well?”, to your consciousness.

Plus, because the insula also processes autonomic nervous system (ANS) signals and regulates the ANS, an inflamed insula could help produce the dysautonomia so common in these diseases. The insula is considered the “bridge” between internal bodily states and “adaptive physiological responses”; i.e., autonomic nervous system activity.

In ME/CFS, both physical and mental stressors (exertion) have been shown to increase activation of the insula, and produce an increased sensitivity to threats, increased vigilance, impaired attention, brain fog, unrefreshing sleep, and emotional distress.

The insula has been better studied in fibromyalgia, where it has been called a “central hub” in the disease. Increased default mode network activity, autonomic dysregulation, increased pain, brain fog, reduced attention,  and increased

An Interoception Interlude

The idea that problems with interoception play a role in ME/CFS is not new. In 2008, in “An extended concept of altered self: chronic fatigue and post-infection syndromes“, James Jones of the CDC proposed that post-infectious fatigue states were primarily diseases of interoception.

Jones proposed that the brains of people with post-infectious illnesses were stuck in a chronic and maladaptive state of “illness behavior”. The pathogen was gone, but the brain was acting as if it was still present.

Jones’s hypothesis – that the body was essentially well but the brain was not – was controversial (and perhaps not surprisingly, he was the sole author of the paper). Jones did not, however, assert that the body was unaffected, and cited a range of biological findings (glucose and lipid metabolism, neuroendocrine issues, brain imaging findings (including the insula and thalamus) which he believed were caused by the brain’s maladaptation.

Jones’s interoception hypothesis never caught on, and the research community mostly dropped it.

Precuneus

Precuneus. (Image from Dr. Johannes Sobotta, Wikimedia Commons.)

The precuneus’s close integration with the insula, and the notorious default mode network, would likely result in difficulty in focusing one’s attention and increased feelings of fatigue, pain, and unpleasant body sensations. If it seems you’re never free from negative body sensations and have trouble getting beyond them and concentrating on other things, dysregulation of the insula, precuneus, and default mode network could be the reason why.

Parahippocampus

Younger explained that bilateral inflammation of the parahippocampus has been shown in other diseases to be associated with fatigue. We see a theme emerging: like the precuneus and the insula, the parahippocampus is associated with the default mode network and interception. The parahippocampus also interacts with the limbic system, which could be amplifying sensations of fatigue, and producing anxiety and other unwelcome mental states.

Structural changes shown in parahippocampus, insula and other brain regions in fibromyalgia. (Borsook D, Moulton EA, Schmidt KF, Becerra LR. (Image from Borsook D, Moulton EA, Schmidt KF, Becerra LR. Creative Commons, Wikimedia)

Medial orbitofrontal cortex

The fun continues with the medial orbitofrontal cortex – yet another brain region associated with the insula. Younger found “a lot of microglial inflammation” on both sides of the medial orbitofrontal cortex, which is also associated with the basal ganglia – a brain region that has been linked to ME/CFS in the past.

Inflammation in the medial orbitofrontal cortex finds a new way to keep ME/CFS patients isolated by reducing the sensation of “reward” – a key motivating factor – and by increasing “effort”.

Younger noted that when you have a fever and can’t get out of bed, activated microglia in the medial orbitofrontal cortex are one reason why.

Other Areas of Bilateral Inflammation

Younger said “lots of the other regions” such as the temporal lobe (headaches, sensory and auditory disturbances, mood swings) feature bilateral inflammation in ME/CFS, but he would talk about those some other time.

Unilateral (One-Sided inflammation)

More hits come with inflammation in the seat of fear and anxiety – the amygdala. (The amygdala had to be in there, didn’t it?) Cognition and attention take a hit with an inflamed right medial frontal gyrus. For its part, a tweaked posterior cingulate activates the default mode network – the center of rumination – which is basically kryptonite to getting things done.

Moving on, inflammation in the left hippocampus impacts learning and memory, but then we come to the left thalamus, which Younger called a “critically important” brain region that relays all sensory information that flows through the brain. Problems in the thalamus alone, he said, could explain ME/CFS.

Inflammation, Here, There, and Seemingly Everywhere

AI Perplexity image of the inflamed ME/CFS brain found by Jarred Younger.

So there you have it – neuroinflammation, Younger said, in the front, back, and in-between areas of the ME/CFS brain. At the beginning of his talk, Younger said the inflammation in the insula alone could be responsible for ME/CFS – and then added on about ten other brain regions.

That seems a little daunting! Then again, this disease was never going to be explained by something subtle. It was always going to get pretty ugly at some point – and the sooner the better. The fact that Younger found so much suggests he’s really onto something.

If Younger believed neuroinflammation was a key to ME/CFS/FM ten years ago, he’s pretty darn sure now. He believes there is now enough neuroimaging data for us to know that neuroinflammation is what we need to be targeting in ME/CFS, stating:

“We have to find or develop treatments that reduce brain inflammation if we’re going to improve ME/CFS.”

Younger started off the video with a big smile. He’s excited about what’s happening with this disease, and promised more is to come.

Younger said he hoped to have more “exciting news” on the clinical trials front soon. Also, he said there is so much going on right now that it’s hard for him to decide what to talk about each week (:)). Plus, there are a lot of “good things” on his plate right now. It’s all good news and all the more reason to stay tuned.

(Talk about a full plate. Besides the brain inflammation findings, Younger is working on his “brain invasion” study, a big “Good Day/Bad Day” study, the tFUS ultrasound device, a Gulf War Illness clinical trial, and who knows what else.)

More PET Findings Coming?

It sounded like Younger will be writing up his findings fairly soon, and we may also be in for some more PET findings. Years ago, Watanabe was reportedly in the midst of a large validation study and did publish a neuroinflammation paper in Japanese in 2018, but we’ve been waiting for the study results for so long that we can probably give up on that now.

Three years ago, Michelle Jones at Stanford was in the second year of the 2-year NIH-funded study PET scan study of the entire body. Preliminary data show increased microglial activation/neuroinflammation in “multiple brain regions of severe ME/CFS patients compared to healthy controls.”  The study was due to end in 2022. Hopefully, the results will be published soon.

The Perfect Post-Infectious Syndrome Brain?

The brain Younger described seems designed to keep one from participating in life.

Has Younger just uncovered the perfect post-infectious syndrome brain? When we get an infection, the brain – not the pathogen, but the brain – in a process known as “sickness behavior”, produces symptoms, feelings, and emotions that are designed to stop us from spreading the infection, and conserve our energy so that the immune system can kill the pathogen.

This period of “sickness behavior” is supposed to end when the pathogen is vanquished, but the idea that it may have become entrenched in postinfectious diseases like ME/CFS dates back decades. The ME/CFS brain that Younger just described seems like it was designed to ensure that sickness behavior’s prime directive is carried out: the person is kept from participating in life and passing on an infection.

What kind of brain would produce that? Perhaps the brain the Jarred Younger’s new PET scan revealed.

A brain that ramps up symptoms – most especially fatigue – and body sensations to keep one from exerting oneself – and to keep one’s attention focused inwards rather than outwards. A brain designed to increase effort, blunt the “rewards” that typically move us, and reduce motivation.

A hypervigilant, anxious, and unsure brain that amplifies danger and fear and, when we step over the line, whacks us with more symptoms. A cognitively impaired brain with a short attention span keeps us from engaging in the tasks we used to engage in. A brain that impairs restful sleep keeps us in a fatigued state.

This is the type of brain that Younger found.

Two AI Engine Takes

Just for the fun of it, I asked AI Perplexity and ChatGPT, without mentioning ME/CFS or long COVID.

“What symptoms and kinds of illness would a brain with bilateral inflammation of the insular cortex, precuneus, parahippocampus, medial orbitofrontal cortex and temporal lobe and unilateral inflammation in the right amygdala, right posterior cingulate, left thalamus, left hippocampus cause?”

Interestingly, AI Perplexity said it could produce a “profound sickness behavior phenotype”, encompassing global cognitive impairment, abnormal pain experience, disrupted motivation and mood, altered social behavior, etc.

ChatGPT said inflammation in these regions would likely cause “a complex constellation of cognitive, emotional, autonomic, sensory, and behavioral symptoms”. It mentioned brain fog, heart rate and blood pressure instability, problems with short-term memory, lack of pleasure, reduced reward, anxiety, sensory abnormalities, pain, fatigue, sleep problems.

Its top three clinical candidates were autoimmune encephalitis, chronic fatigue syndrome / ME (inflammatory subtype), and long COVID neuroinflammation.

A Brain Inflammation – Energy Production Link?

Since neither ChatGPT nor AI Perplexity mentioned anything regarding energy production, and at some point, the energy production problems in the immune and muscle cells need to be linked to the brain findings, I asked both engines, again, without mentioning ME/CFS or long COVID.

“Could inflammation in these brain regions impair energy production in immune or muscle cells in the body, and, if so, how?”

The answer from both Perplexity AI and ChatGPT was an encouraging “yes”.

How neuroinflammation could translate into problems with energy production in the muscles and immune system. (from ChatGPT)

Perplexity AI: Inflammation in the specific brain regions you listed doesn’t just stay confined to the brain. It actively disrupts central metabolic control, leading to systemic changes in hormone levels, immune cell metabolism, and muscle energy production. The result is impaired energy output, increased fatigue, and reduced physical and cognitive functioning. This mechanism is well documented in conditions like chronic fatigue syndrome (ME/CFS), long COVID, neurodegenerative diseases, and autoimmune illnesses involving these brain areas.

Among other things, AI Perplexity asserted that inflammation in two brain regions – the hypothalamus and insula – involved in controlling the body’s energy balance and metabolic stress responses, could lead to metabolic dysfunction. Plus, neuroinflammation in the brain could increase systemic inflammation, induce insulin resistance, and increase mitochondrial dysfunction.

ChatGPT stated: “Yes”. Through a combination of autonomic dysfunction, neuroimmune signaling, HPA axis disruption, and altered interoception/metabolism, “inflammation in the specific brain regions you’ve listed could plausibly impair energy production in peripheral cells (e.g., immune and muscle cells). These mechanisms are highly consistent with energy metabolism abnormalities observed in conditions like ME/CFS, Long COVID, and post-viral syndromes.

ChatGPT stated that sympathetic nervous system overactivity could ultimately impair mitochondrial function, fatty acid metabolism, and glucose uptake, and reduce ATP production. Neuroinflammation could also cause immune cells in the body to shift to a pro-inflammatory, energy-inefficient metabolic state.

Causes

We don’t know what is causing the microglial activation/neuroinflammation that Younger found. Probably any number of possibilities are present. Note, though, that because many of the inflamed areas of the ME/CFS brain (hippocampus, prefrontal cortex (PFC), anterior cingulate cortex, amygdala, striatum, insular cortex, orbitofrontal cortex, parahippocampal gyrus, thalamus)  seem to be particularly sensitive to inflammation coming from the body, inflammation is a prime suspect.

Treatments

Younger didn’t dwell on specific treatments, but many treatments could potentially reduce neuroinflammation. They range from immune affecting drugs (LDN, IVIG, monoclonal antibodies, etanercept, PPAR Agonists, oxytocin, Donepezil, Abilify, some antidepressants) and supplements (PEA, curcumin, resveratrol, etc.) to things like deep brain stimulation, vagus nerve stimulation, autonomic nervous system affecting drugs (propanolol, etc.), and newer options like suramin, rapamycin, ketamine, as well as brain retraining (eg. “Amygdala and Insula Retraining“) to tamp down the stress response, reduce vigilance, feelings of danger, etc., could potentially help.

Younger noted, though, and I think most of us would agree, that better treatments are needed. Hopefully, Younger’s new study will focus more attention on finding ways to reduce neuroinflammation.