Review Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis 2023 Lee et al

[Andy]

Highlights

• Neuroinflammation is the most convincing hypothesis for ME/CFS pathophysiology, explaining its multifaceted symptoms and pathological features.
• Across various neuroimaging techniques, including MRI, MRS, PET, and EEG, the frontal cortex was the most frequently observed region.
• Our meta-analysis data showed that not only the insula and thalamus showed significant hypoactivity, but also the limbic system.
• Cortical-limbic disconnection leads to the abnormalities of metabolite and brain waves, which eventually contribute to main symptoms of ME/CFS.

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by an elusive etiology and pathophysiology. This study aims to evaluate the pathological role of neuroinflammation in ME/CFS by conducting an exhaustive analysis of 65 observational studies. Four neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and positron emission tomography (PET), were employed to comparatively assess brain regional structure, metabolite profiles, electrical activity, and glial activity in 1529 ME/CFS patients (277 males, 1252 females) and 1715 controls (469 males, 1246 females). Clinical characteristics, including sex, age, and fatigue severity, were consistent with established epidemiological patterns.

Regional alterations were most frequently identified in the cerebral cortex, with a notable focus on the frontal cortex. However, our meta-analysis data revealed a significant hypoactivity in the insular and thalamic regions, contrary to observed frequencies. These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS. Furthermore, we discuss the regions where neuroinflammatory features are frequently observed and address critical neuroimaging limitations, including issues related to inter-rater reliability. This systematic review serves as a valuable guide for defining regions of interest (ROI) in future neuroimaging investigations of ME/CFS.

Open access, https://www.sciencedirect.com/science/article/pii/S1568997223002185

 

[Creekside]

I wonder whether they've considered what sort of dysfunction could cause the results. What I mean is that a widespread dysfunction of one type of cell might cause one pattern of study results (slight reduction of neuron firing rate) while dysfunction of just a few cells in a region might cause a different result (just a few cells, but they're not firing at all). One large bomb on a battlefield causes a different pattern than the same amount of explosives used in bullets. If you measure results by number of craters at least 3' deep, you might say "Nothing of note here" despite thousands of dead bodies with bullet wounds.

Just pointing out limitations of such studies.

 

[Hutan]

Jin-Seok Lee ab, Wakiro Sato c, Chang-Gue Son ab
a Research Center for CFS/ME, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea
b Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea
c Department of Immunology, National Center of Neurology and Psychiatry, Tokyo, Japan

We've seen papers by Wakiro Sato before - he seems to take a neuroimmunology approach to ME/CFS and recognises the importance of PEM. I'm not sure if we have seen ME/CFS-related papers from the two Korean authors before. This paper looks as though it is a literature review before a new study is done, so we might see more from this group.

I haven't looked at the paper yet, but my impression of a lot of neuroimaging work in ME/CFS is that it's still in the 'grasping at straws' category, and that there is huge scope for the expectations of the researchers and other factors that aren't a direct result of the disease to affect outcomes. So, I tend to think that doing a meta-analysis of brain imaging studies is going to be a bit of a garbage in-garbage out scenario. I could be wrong.

These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS.

I'm not keen on that framing given the weakness of the evidence, suggesting as it does that people with ME/CFS have problems with reason and emotion. As others have said, the thoughts that a person with a contested disease might have while having a brain scan will probably be quite different on average to the thoughts that a healthy control, possibly someone handy in the hospital who has been used as a control in other brain imaging studies, would have. So, functional brain imaging can be expected to show differences in brain activity patterns that aren't a direct consequence of the disease.

 

[SNT Gatchaman]

From a total of 131 articles identified initially, 65 studies met the inclusion criteria, encompassing data derived from four distinct neuroimaging technologies: 41 studies utilized MRI, 10 employed MRS, 10 utilized EEG, and 4 employed PET.

A total of 3,244 participants (746 males and 2,498 females) were enrolled, comprised of 1,529 ME/CFS patients (277 males and 1,252 females), 382 diseased controls (161 males and 221 females), and 1,333 healthy controls (308 males and 1,025 females). The mean duration of illness in ME/CFS patients was reported as 8.5 ± 4.3 years, and they were diagnosed based on the Fukuda CDC criteria (58 out of 64 studies) mainly. Fatigue assessment within these studies utilized various tools, including the Chalder Fatigue Scale (CFS) in 9 articles, the Checklist Individual Strength (CIS) in 3 articles, the Fatigue Severity Scale (FSS) in 6 articles, the Multidimensional Fatigue Inventory (MFI) in 5 articles, and the Visual Analogue Scale-fatigue (VAS) in 6 articles. Fatigue scores ranged from 53.0 to 93.9, compared to a range of 17.4 to 30.8 in healthy controls.

 

[Woolie]

They are rather loose and free with their conclusions! They found reduced activity in the insular and thalamic regions, but then they go all out and say that:

These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS."

I don't know how they decided that the insula and thalamus are involved in "bridging reason and emotion". The insula most likely plays a role in evaluating bodily states and other inputs that might indicate pain, illness, or alternatively physiological changes associated with emotional states. The thalamus is a relay station for a bunch of cortical areas. Neither has anything to do with "reason", whatever the F that is.

Its not really that helpful to talk about the "limbic area" at all in this day and age, and even if you can forgive that, they include in it lots of structures that have little in common - including for some weird reason, the basal ganglia, which hasn't ever really been considered part of it.

Some weird errors. They can't seem to decide if the cingulate cortex is part of "cortex" or "sub-cortex". Its part of the cortex. And the insula, precuneus lingual gyrus and angular gyrus are assigned to "sub-cortex", but these regions are actually part of the cortex.

The increased activity in cingulate cortex is a common finding in abnormal populations. It is a region that signals when people increase their level of effort on a particular task. The finding probably indicates participants are applying increased effort (relative to controls) when performing the task or complying with the researchers' instruction.

 

[Woolie]

I haven't looked at the paper yet, but my impression of a lot of neuroimaging work in ME/CFS is that it's still in the 'grasping at straws' category, and that there is huge scope for the expectations of the researchers and other factors that aren't a direct result of the disease to affect outcomes. So, I tend to think that doing a meta-analysis of brain imaging studies is going to be a bit of a garbage in-garbage out scenario. I could be wrong.

You're not wrong, @Hutan.

 

[DigitalDrifter]

A study upon Amygdala and Insula Retraining (AIR) reported dramatic improvements in fatigue and QoL among 21 ME/CFS patients [33].

This paper praised a brain retraining program which is a huge red flag for me. Reference 33 points to a study of Fibromyalgia and Chronic Fatigue not CFS or ME.