Health Update – an unsympathetic Forest Service employee booted me out of my campsite, leading to yet another move. That exacerbated my symptoms (nausea, cold sweats) and set me back.
The Oura ring findings were interesting. First came the poorer sleep and higher resting heart rates. Then after the activity was over in the PEM period, my resting heart declined to my pathologically low levels, my HRV shot up (not a good thing), and my blood pressure dip dropped dramatically during sleep (a sign of stress).
My Oura readings are normalizing, and I am recovering more quickly than expected – a good sign after all that work!
Recent studies clearly implicate the brain in the movement problems in ME/CFS.
This is the last in a series of blogs on recent brain imaging studies in ME/CFS and long COVID and Aregawi/Goldstein study “Central noradrenergic deficiency in post-infectious chronic fatigue: neurobehavioral correlates” may be the best of them all.
At the end of this blog, we’ll bring together recent brain imaging studies and see whether and how they may inform one another and move these fields forward.
Health Rising reported on Dr. Goldstein’s plenary lecture at the IACFS/ME’s 2025 conference.
A self-proclaimed “cataholic” (i.e., catecholamine researcher), Goldstein is the real deal. Now an NIH researcher emeritus, over his career Goldstein has co-authored more than 600 research articles and several books (“Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine,” “Dysautonomias: A Handbook for Patients”, “Stress, Catecholamines, and Cardiovascular Disease”, “The Autonomic Nervous System in Health and Disease”, “Principles of Autonomic Medicine”, and “The Dysautonomia Project“). It’s good to have a researcher of his stature interested in ME/CFS.
A self-described “cataholic”, Goldstein is an expert on catecholamines like norepinephrine.
Norepinephrine drives the sympathetic nervous system (SNS) or fight-or-flight system. We’ve always assumed that the SNS is dominant in ME/CFS while its regulator – the parasympathetic nervous system (PNS) – has gotten hammered.
Goldstein’s lecture suggested that a weakened and destabilized norepinephrine system, perhaps driven by low energy (ATP) production, could be having vast effects on ME/CFS.
Instead of dominating, the sympathetic nervous system, or fight-or-flight system, is actually struggling. The SNS is getting turned on, but it also quickly poops out, causing its regulator, the parasympathetic nervous system (PNS), to lay low. In this scenario, a balky SNS is the problem – not an underperforming PNS. Symptomatically, this could produce an overstimulated, overwhelmed, wired, and tired state, characterized by unrefreshing sleep, among other symptoms.
Norepinephrine is produced in the brain by the locus coeruleus (LC) – a small bundle of neurons found deep in the brainstem – which gets hit early and hard during an infection. Not surprisingly, given its role in producing the “stress hormone”, norepinephrine, it immediately responds to stress of all kinds.
The Study
So here we are with the actual paper, which expands significantly on Goldstein’s presentation. (A summary of the paper was featured on the NIH’s Science Highlights page on LinkedIn).
The number of ME/CFS patients is still pitifully low (n=16), but the rest of the study has been dramatically expanded. We have a handgrip test, an orthostatic intolerance assessment, more symptom assessments, and more controls (34 long COVID patients, 32 Parkinson’s disease patients, and 40 healthy controls).
The study’s superpower was its decision to assess norepinephrine and dopamine, along with their metabolites, directly in the cerebrospinal fluid. Of course, simply measuring norepinephrine levels – the standard assessment in ME/CFS – isn’t sufficient – the body is more complex than that. This is because a lot happens before NE is taken up into the cerebrospinal fluid.
The locus coeruleus – a small bundle of neurons perched on top of the brainstem – is the only place in the brain where norepinephrine is produced. Look how far connections from it extend across the brain. (Image from Diego69 – Wikimedia Commons).
Norepinephrine is produced in the noradrenergic neurons on the locus coeruleus. It starts with tyrosine → (broken down into) DOPA → (broken down into) dopamine → (broken down into) norepinephrine.
When the sympathetic nervous system needs more juice, NE is released into the synaptic cleft between neurons. It’s then rapidly recycled back into the neuron via the NET transporter and metabolized into its byproducts before it ever gets into the cerebrospinal fluid.
If the NET transporter isn’t working well, high levels of NE will seep into the cerebrospinal fluid, making it look like NE activity is high when it’s simply not being recaptured by the neuron. Alternatively, if the NE transporter is in overdrive, transporting large amounts of NE back into neurons, the resulting low CSF NE levels do not necessarily indicate low NE activity.
We need a test that assesses how much NE is actually flowing through the neurons. Because once NE returns to the neuron, it is metabolized into DHPG and MHPG, these readings tell us how much NE is actually cycling through the system. That gives us a good readout of actual NE activity.
The main source of NE activity assessed in this study, however, is a metabolite called MHPG. Because MHPG is the final stage of NE breakdown or metabolism, it tells us the most about how NE cycles through the system. The authors referred to MHPG as “the predominant analyte” in their NE assessment.
They summed cerebrospinal fluid NE, DHPG, and MHPG levels to form a “norepinephrine pathway index.” They did the same thing with the dopamine and its metabolites.
- NE pathway index = NE + DHPG + MHPG
- DA pathway index = DA + DOPAC + HVA
Very Low NE Pathway Activity
Notice the dramatic drop in the NE pathway in ME/CFS, long COVID and (left) the normal dopamine pathway results for MECFS and Long COVID but a big drop in Parkinson’s (center), and a finding suggesting that PEM is affected (right)
Only 16 ME/CFS patients participated in the study, but the probability factor, which assesses how likely a result was due to chance, was so low (p=.00055) that, even with the low participant numbers, it was VERY clear that the two groups were different. (There was about a1 in 1,800 chance that the results were the result of random sampling.) Plus the MHPG finding (P=.00044) was similar. (This was a group finding. Interestingly, not everyone with ME/CFS had dramatically lower NE metabolite levels: there are subsets here, too.)
We don’t know if these findings will translate into the ME/CFS population at large but they show that at least with this group, the average NE pathway index was very different from that found in the healthy controls.
The norepinephrine index was reduced in the long COVID patients, but the probability factor was not as extreme (p=.05). Norepinephrine metabolites were also dramatically reduced in the Parkinson’s disease patients (p<.0001).
Normal Dopamine Pathway Levels
The dopamine pathway index, on the other hand, was normal in both the ME/CFS and long COVID patients. (It wasn’t in the Parkinson’s patients.)
In a way, the normal dopamine levels were encouraging because if ME/CFS patients were simply stressed, inactive, or taking certain medications, both the NE and dopamine pathways might have been affected. Instead, the reduced NE findings and the normal dopamine findings zeroed in on something particular to ME/CFS and long COVID.
Handgrip Test
This NIH group loves the handgrip test, and Health Rising recently covered a prior handgrip study which suggested to the authors that the fatigue in ME/CFS is at least in part driven by the brain. The recent Australian study, Health Rising covered, also aligned with that finding. It reported a striking deficit in the supplementary motor area, which plans and carries out movement.
The researchers combined the ME/CFS and long COVID groups and found that reduced NE pathway activity correlated with reduced ability to maintain handgrip force; i.e., the lower the NE metabolite levels, the shorter the time they could maintain a strong handgrip.
Note how essential a role norepinephrine plays in many of the problems associated with ME/CFS and long COVID: it’s needed for arousal, attention, effort, movement, autonomic nervous system regulation, sensory processing, and cognition.
We have a nice correlation, but the brain is a complex organ, and many factors could be preventing ME/CFS and long COVID patients from being able to sustain muscular force and becoming fatigued so quickly. They include inadequate motor drive from the brain (motor cortex, supplementary motor area), motivation, effort, autonomic nervous system, muscle metabolism, and nerve transmission, but the authors will focus on a particularly intriguing one: energy production.
The ATP Question
Notice how on the left side of the image dopamine flows freely into the cytoplasm of the cell while norepinephrine has to be transported out of the vesicles – an ATP-intensive process.
Norepinephrine is the “arousal” neurotransmitter. Among other things, it gets the body moving and the mind concentrating. While it doesn’t generate ATP, it eats up lots of energy.
This is because the conversion of dopamine to norepinephrine takes place inside vesicles found in the cell. In order to get from the cytoplasm of the cell into the vesicles, norepinephrine has to be transported by an ATP-dependent proton pump called VMAT2 (vesicular monoamine transporter 2). That pump uses up a lot of energy.
Note that dopamine doesn’t require this step to be used. It’s already present and available in the cell. The authors propose that the normal dopamine levels but low norepinephrine levels suggest the cell simply doesn’t have enough energy (ATP) to replenish norepinephrine.
It’s a nice hypothesis, given that dopamine and norepinephrine are part of the same pathway (Tyrosine → DOPA → dopamine → norepinephrine), but only norepinephrine levels, which require ATP, were affected.
This all makes sense, but this study can only point to that possibility. We need more refined studies to determine that.
A recent study, however, does appear to bolster that hypothesis. The recent long COVID study, which got Jarred Younger very excited and was covered by Health Rising, measured high-energy phosphate metabolism in the living brain.’
While the study did not directly measure ATP, the reduced ATP/phosphocreatine ratios found suggested that low energy stores were present in the cingulate cortex – which just happens to be filled with neurons extending from the locus coeruleus (LC). Both the LC and cingulate cortex participate in many of the same features (effort, motivation, autonomic nervous system regulation, cognition, and pain) that plague people with ME/CFS and long COVID.
Effort Preference Redefined?
The findings cast the “effort preference” finding in Nath’s deep phenotyping paper, which sparked so much controversy, in a new light. Many people interpreted the effort finding to suggest that ME/CFS patients weren’t trying hard enough.
These findings, though, suggest a physiological basis for the “effort preference” issue. Parts of the brain we need to engage in exertion – no matter how large or small – may not have the energy they need to work well. That could make everything more effortful.
If Aregawi and Goldstein are right, that may all be due to that old bugaboo – a lack of energy production – that particularly kicks in during exertion.
Other Possibilities
The catecholamine pathway – like everything in the body its complex!
The energy production problem hypothesis is a nice fit given other study findings, but other possibilities exist. Less active or damaged LC neurons or problems with NE synthesis could reduce NE availability. Looking more broadly, neuroinflammation could be affecting the NE pathway. Or, as an earlier blog suggested, damaged muscles could be telling the brain to stop activating them.
There’s also Hwang’s 2023 WASF3 mitochondrial finding. A future blog will catch up on that.
Finding out which, if any, of these hypotheses fits is not rocket science. A follow-up study that included 31P-MRS brain energetics assessments (recently performed in long COVID), cerebrospinal fluid NE/DHPG/MHPG levels, a handgrip test, and an exertional challenge could tell us a lot.
If low baseline brain energy levels predicted reduced norepinephrine pathway levels after exertion, that could suggest energy production was the driver. A finding that a decreased ability to sustain a handgrip test was correlated with reduced brain energy and norepinephrine pathway levels would provide more evidence.
The NIH – Still Behind the 8-Ball
Nath said more papers would come out of the intramural study, and this is at least the third paper to do so. It’s good to see these papers; they are moving the field forward, but the intramural study was designed to give the NIH solid ground to dramatically increase ME/CFS funding.
With the NIH continuing on its 30 plus year path of neglecting ME/CFS, advocates are turning to Congress to force it to fund ME/CFS.
These findings clearly call for larger, more comprehensive studies, but no grants have been approved for these researchers and, more importantly, no major grant packages exist. Right now, it looks like the NIH is continuing with its “50-year” plan for solving ME/CFS; i.e., it will fund a couple of studies every year that can’t even begin to cover the gamut of possibilities and propel the field forward inch by inch. The alternative is that it keeps its word, finally gets serious, and provides major grant packages that produce timely progress.
We could be surprised, but with NIH funding levels dropping rather than increasing since long COVID came on the scene, there’s no evidence that the NIH will do anything other than continue its 30-plus-year pattern of criminally neglecting the ME/CFS community.
As always, Congress is the hope, and ME/CFS advocates are pushing for $50 million in the 2027 appropriations bill to fund the ME/CFS roadmap. Accomplishing that would be a HUGE win. As the bill is usually due by the end of September, we will hopefully know its fate soon.
- Next up – Jarred Younger talks on ME/CFS
