Brainstem Abnormalities in [ME/CFS]: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings, 2021, Nelson et al

[Sly Saint]

Nelson T, Zhang LX, Guo H, Nacul L,

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.

Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.

Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.

Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.

https://www.frontiersin.org/articles/10.3389/fneur.2021.769511/full

 

[Creekside]

I hope there's some good followup research on this.

 

[Perrier]

This paragraph was interesting to me, as it tries to explain the role of Peroxynitrite nitrite in generating ME and the associated damage: all this a consequence of infection.

Anxious to hear what others here think of this paper. Thanks.

"The review is in favor of the hypothesis that ME/CFS involves brainstem specific astrocyte dysfunctions, contributing to impaired brainstem cerebrovascular autoregulation and reduced blood flow (36, 56). Oxidative stress appears to induce ME/CFS symptoms, associated with reduced blood flow and neuroinflammation. An infection (the most frequently reported trigger for ME/CFS onset) has been linked to peroxynitrite production, a proinflammatory oxygen/nitrogen species (57, 58), triggering neuroinflammation. This can lead to the production of isoprostanes and cause vasoconstriction when the level of antioxidants is insufficient (59). Oxidative stress and increased isoprostanes in ME/CFS have been correlated with clinical symptoms (60). Reduced brain blood flow is common in ME/CFS patients, accompanied by lowered circulation and nutrient/waste exchange (61–65)."

 

[FMMM1]

This paragraph was interesting to me, as it tries to explain the role of Peroxynitrite nitrite in generating ME and the associated damage: all this a consequence of infection.

Anxious to hear what others here think of this paper. Thanks.

"The review is in favor of the hypothesis that ME/CFS involves brainstem specific astrocyte dysfunctions, contributing to impaired brainstem cerebrovascular autoregulation and reduced blood flow (36, 56). Oxidative stress appears to induce ME/CFS symptoms, associated with reduced blood flow and neuroinflammation. An infection (the most frequently reported trigger for ME/CFS onset) has been linked to peroxynitrite production, a proinflammatory oxygen/nitrogen species (57, 58), triggering neuroinflammation. This can lead to the production of isoprostanes and cause vasoconstriction when the level of antioxidants is insufficient (59). Oxidative stress and increased isoprostanes in ME/CFS have been correlated with clinical symptoms (60). Reduced brain blood flow is common in ME/CFS patients, accompanied by lowered circulation and nutrient/waste exchange (61–65)."

Almost becoming a standard reply from me but the GWAS study (Chris Ponting - sampling starting in May) might provide a way to test hypothesis like this. E.g. presumably if this was a common mechanism then there would be clues in the GWAS results.

@Simon M

 

[Trish]

Posts about the DecodeME GWAS study have been moved to this thread:
https://www.s4me.info/threads/decodeme-uk-me-cfs-dna-study-underway.15604/page-33#post-401205

 

[SNT Gatchaman]

Highlighting some quotes read against the concepts of:

1) Lipid metabolism is critical for myelination maintenance (see Myelin lipid metabolism and its role in myelination and myelin maintenance)
2) Impaired myelination in one area of the brain can be compensated in another (see Anti-Correlated Myelin-Sensitive MRI Levels Consistent with Subcortical to Sensorimotor Regulatory Process)

Barnden et al. [...] identified a negative correlation between midbrain WM volume (explained as a loss/shrinkage of glial cells) and the duration of fatigue.

In addition to assuring that the midbrain WM volume was smaller in ME/CFS patients with longer periods of illness onset, the authors further reported an increasing T1W signal level (suggestive of increased myelination) in the ventrolateral thalamus, internal capsule, and prefrontal WM with increased disease severity.

Finkelmeyer et al. [...] reported reduced WM volume in the midbrain and pons in ME/CFS compared to HC.

Other findings included reduced total intracranial volume (TIV), increased TIV-adjusted global GM volume, and decreased TIV-adjusted global WM volume.

Thapaliya et al. applied a novel T1W/T2W ratio (a higher ratio is indicative of higher levels of myelin and/or iron) [...] reported increased ratio in ME/CFS compared to HC in 16 WM regions.

Boissoneault et al. published the first fMRI study on ME/CFS examining the brainstem in 2018 [... ] study showed progressively increased [Functional Connectivity]* between the inferior frontal gyrus (IFG) and the brainstem and several other brain areas (lingual gyrus, cerebellar vermis, cerebellum, parahippocampal gyrus) during the task in ME/CFS patients, in contrast to a decrease in FC involving the IFG in HC (41). Such increase in FC in ME/CFS was associated with higher fatigue level toward the end of the task.

Another fMRI study of the brainstem in ME/CFS confirmed an impairment in brainstem nerve conduction in ME/CFS

The brainstem has only been subject to focused MRI investigations for a decade, with the functional studies seen only since 2018. Even so, the research published so far has demonstrated the critical involvement of the brainstem in ME/CFS associated deficits.

The studies pointed to a reduced WM volume, impairments in myelination, reduced conduction, abnormal FC linking the brainstem and other brain regions, and compensatory brain changes. The research findings also demonstrated a linkage between brainstem abnormalities and other brainstem structures, highlighting myelination impairment and dysregulation underlying the disease. The reports of midbrain WM volume loss, brainstem myelination impairments, and connectivity deficits within the brainstem also indicated brainstem nerve conduction impairment in ME/CFS, even when the brainstem nuclei themselves remained unaffected. Meanwhile, the increased myelination of multiple brain regions (ventrolateral thalamus, internal capsule, and prefrontal, premotor and sensorimotor cortices) showed a compensatory response in maintaining nerve conduction (e.g., increased myelination of tract segments rostral to the brainstem).

---
* Brain Structural and Functional Connectivity: A Review of Combined Works of Diffusion Magnetic Resonance Imaging and Electro-Encephalography (2021)