Submax Exercise Provokes Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of PEM in ME/CFS, Rayhan, 2021

Original title: Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Rakib U. Rayhan et al

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.

Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.

Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.

Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714840/

 

Bump.

Anyone here who understands what they did, and the validity of the work itself and the interpretation that this possibly is a biomarker for PEM?
@Woolie @SNT Gatchaman ?

 

Presuming this is a valid finding, my next question I would like answers to are is it secondary or a primary cause. In either case it could be evaluated as diagnostic.

If other diseases are found that show this, but its not general in sick people, and those diseases can easily be differentiated from ME, then it can be considered diagnostic if its shown to be replicable in large numbers.

More work to be done, but its at least an interesting finding.

 

Thanks @Ravn, I'll read through this weekend. No prior knowledge of the DMN, but it is being related to autism, ADHD, non-classical epilepsy, social anxiety and depression.

Here are recent review articles in PubMed.

Note the following in the criticism section of Wikipedia's overview of the DMN.

 

Hi @Ravn, I teach a little about the default mode network (DMN) in my cognitive neuroscience classes. The DMN is a bunch of brain structures which are particulary active "at rest", when the person is not processing any outside stimuli or performing any action. Importantly, these structures are not only active, but their activity is correlated - as activation in one region increases, so too does activation in the other regions and vice versa. That is, they seem to be "talking" to each other.

Its measured using fMRI, so when I say "active" I mean "taking up a lot of oxygen from the blood".

Here is a picture of the regions that are often observed as part of this DMN (we're looking down on the brain from above):



I think the concept of the DMN has some value in helping us understand how people transition between internally-focussed and externally-oriented "modes" of thinking.

But people try to make reverse inferences all over the place. Just because there is significant crosstalk within this network when we are lost in internal thoughts does NOT mean that abnormally marked crosstalk indicates the person is "overthinking" or "symptom focussing" or any of those things researchers say in the literature.

This sort of reasoning has been applied to a lot of unusual populations, but most particularly depression, where abnormally heighted DMN crosstalk is claimed to be evidence of "rumination" (recursive negative thoughts). What a crock. As if you can tell from the network stats what valence the person's thoughts have. Could we even say that people with depression just "overthink" in general? I don't think so, because that claim assumes that the degree of DMN crosstalk is a reliable marker of "overthinking". We have no idea what we actually mean by "overthinking" (how much thinking is too much?), let alone how we would go about testing whether its associated with heightened DMN crosstalk.

So, my guess is that abnormally heightened DMN crosstalk is a more general marker associated with managing some sort of internal challenge the person is facing while under the scanner. That would explain why we see it in such a wide variety of conditions, including not only psychological states like depression, but also chronic pain and chronic illness. It would be too simplistic to say that these people are "overthinking" or even being "overly introspecitve". Both these terms imply some level of control that might not be there, and both make the reverse inference error.

BUT, if used correctly, I think this DMN measure could be a useful in marker of certain bodily states, including PEM - if it is used comparatively within the same person (e.g. Mary is evaluated during PEM and during a non-PEM state and the two are compared). The challnege will be using it without falling into any of the logical traps (e.g, claiming Mary is overly focussed on her symptoms, etc).

 

@SNT Gatchaman, I like your cautious sceptical appraoch to this. But I think the DMN is more than a vascular anomaly, because of the specific structures that are implicated and what we know of their functions - which include the hippocampus (long term memory for personally experienced events), the ventromedial prefrontal cortex (involved in linking memories and cognitions with their emotional associations), the posterior cingulate (internal visual imagery), and the parietal cortex (internally directed attention).

 

Both can be true.