Trial Report A Multimodal Magnetic Resonance Imaging Study on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Feasibility and Clinical Correlation, 2024, Kaur

[Dolphin]

https://www.mdpi.com/1648-9144/60/8/1370

A Multimodal Magnetic Resonance Imaging Study on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Feasibility and Clinical Correlation

by
Raminder Kaur
1,2,
Brian Greeley
1,
Alexander Ciok
1,2,
Kashish Mehta
1,2,
Melody Tsai
3,4,
Hilary Robertson
5,
Kati Debelic
5,
Lan Xin Zhang
1,
Todd Nelson
1,2,
Travis Boulter
4,5,
William Siu
6,
Luis Nacul
3,4,7,* and
Xiaowei Song
1,2,*


1
Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada
2
Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
3
Women’s Health Research Institute, Vancouver, BC V6H 3N1, Canada
4
Complex Chronic Diseases Program, BC Women’s Hospital, Vancouver, BC V6H 3N1, Canada
5
ME/FM Society of BC, Vancouver, BC V6J 5M4, Canada
6
Medical Imaging, Royal Columbian Hospital, New Westminster, BC V3L 3W7, Canada
7
Department of Family Practice, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
*
Authors to whom correspondence should be addressed.
Medicina 2024, 60(8), 1370; https://doi.org/10.3390/medicina60081370
Submission received: 12 July 2024 / Revised: 15 August 2024 / Accepted: 19 August 2024 / Published: 22 August 2024
(This article belongs to the Section Neurology)

Abstract

Background/Objectives:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neurological disorder characterized by post-exertional malaise. Despite its clinical relevance, the disease mechanisms of ME/CFS are not fully understood. The previous studies targeting brain function or metabolites have been inconclusive in understanding ME/CFS complexity. We combined single-voxel magnetic resonance spectroscopy (SV-MRS) and functional magnetic resonance imaging (fMRI). Our objectives were to examine the feasibility of the multimodal MRI protocol, identify possible differences between ME/CFS and healthy controls (HCs), and relate MRI findings with clinical symptoms.

Methods:

We enrolled 18 female ME/CFS participants (mean age: 39.7 ± 12.0 years) and five HCs (mean age: 45.6 ± 14.5 years). SV-MRS spectra were acquired from three voxels of interest: the anterior cingulate gyrus (ACC), brainstem (BS), and left dorsolateral prefrontal cortex (L-DLPFC). Whole-brain fMRI used n-back task testing working memory and executive function. The feasibility was assessed as protocol completion rate and time. Group differences in brain metabolites and fMRI activation between ME/CFS and HCs were compared and correlated with behavioral and symptom severity measurements.

Results:

The completion rate was 100% regardless of participant group without causing immediate fatigue. ME/CFS appeared to show a higher N-Acetylaspartate in L-DLPFC compared to HCs (OR = 8.49, p = 0.040), correlating with poorer fatigue, pain, and sleep quality scores (p’s = 0.001–0.015). An increase in brain activation involving the frontal lobe and the brainstem was observed in ME/CFS compared to HCs (Z > 3.4, p’s < 0.010).

Conclusions:

The study demonstrates the feasibility of combining MRS and fMRI to capture neurochemical and neurophysiological features of ME/CFS in female participants. Further research with larger cohorts of more representative sampling and follow-ups is needed to validate these apparent differences between ME/CFS and HCs.

Keywords:
myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); brain function; brain metabolites; single-voxel magnetic resonance spectroscopy (SV-MRS); task-phase functional magnetic resonance imaging (fMRI)

https://twitter.com/user/status/1827486631428759683

 

[SNT Gatchaman]

Despite increasing research efforts, MRI findings on ME/CFS remain inconclusive. Combining MRS and fMRI techniques can allow for neurochemical quantification and neuro-hemodynamic investigations within the same session. This can provide insights linking brain metabolites and functional activity to a potentially better understanding of ME/CFS. Here, we conducted a study that combines SV-MRS and fMRI techniques together with other behavioral and clinical measures. However, a multimodal MRI protocol can be challenging for participants with ME/CFS who suffer from fatigue and pain; therefore, our first aim was to assess the feasibility of the protocol, i.e., how well ME/CFS participants completed the study.

Regarding feasibility, in each participant group, the rate for completing the one-hour MRI protocol, was 100%.

Effort preference.

 

[SNT Gatchaman]

I can't see the supplementary materials yet, so I'm not sure what level of brain fog the patients had. They met either IOM or CCC.

Results (fMRI) —

Each fMRI task condition (i.e., 1-back and 2-back) evoked distributed brain activation that involved the visual, motor, supplementary sensory, and prefrontal cortices in both ME/CFS and HC groups. During each task condition, ME/CFS showed increased brain activation than HCs, particularly involving the frontal pole, ACC gyrus, and BS regions

From discussion —

Our NAA results contribute to that of the other studies investigating MRS in ME/CFS. Brooks and colleagues reported a reduced concentration of NAA in CFS (n = 7) than in age matched controls (n = 10) [41]. Although this seems to conflict with the findings from our study, it is important to note that their data were acquired from the right hippocampal area, a subcortical brain region on the opposite hemisphere from the VOI in the current study. In a more recent study with a larger sample, Thapaliya and colleagues demonstrated a high NAA level in the posterior cingulate cortex in long COVID patients who displayed some ME/CFS-like symptoms (alongside elevated glutamate) in patient groups compared to controls [42]. The finding was interpreted as a compensatory response to brain inefficiency in patients, with increased glucose and oxygen utilization under infection-triggered osmotic stress. Similar to the current study, associations between neurochemical and clinical severity measures were found, linking neurochemistry to neuropathology, overlapping long COVID and ME/CFS [42]. Future studies comparing metabolites from the same VOIs across multiple brain regions key to ME/CFS will enhance result validation and interpretation.

[41] Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome. (2000, British Journal of Radiology)
[42] Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans (2020, NeuroImage: Clinical)

We also observed an overall greater level of fMRI activation in ME/CFS during the task that engaged working memory, despite the same level of accuracy and reaction time as HCs. This finding aligns with the previous research. For instance, Shan and colleagues reviewed that across ten studies, ME/CFS participants recruited additional brain regions during a variety of cognitive tasks to achieve the same task performance as control participants [11]. This suggests individuals with ME/CFS engage the same brain regions more extensively compared to HCs, possibly associated with a compensatory mechanism to counteract impairments or dysfunction [11,43].

[11] Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS: a systematic review (2020, Journal of Translational Medicine)

Which might be more than simply the absence of progressive efficiencies that HCs demonstrate in Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI (2024, Journal of Cerebral Blood Flow & Metabolism) —

Patients with ME/CFS showed significantly higher BOLD response changes (2nd set Vs. 1st set) in the second task block than those from HCs. Withingroup analyses indicated that these increases were mainly driven by a decline in BOLD signals in HCs, known as BOLD adaptation, potentially improving the energy economy.

So overall, this points to an impairment or inefficiency in brain function that can be compensated for, though presumably at cost (ie PEM-cognitive). The compensation allowing for equivalent performance to HC is in patients with mild enough ME that they can tolerate the testing. With current technology, I doubt it's going to be possible or indeed ethical to repeat this with more severely affected patients, but I suspect the differences would be much more pronounced and more easily able to point us in the right direction.

 

[Hutan]

Group differences in brain metabolites

Magnetic resonance imaging (MRI) techniques have been employed to study brain metabolites (using proton 1H magnetic resonance spectroscopy (MRS)) or activity (using functional MRI-fMRI) in ME/CFS [11–15]. MRS quantifies the concentration of major metabolites by analyzing their resonate frequencies [16,17]. The most studied neuronal metabolites include N-acetyl aspartate (NAA), a marker for neuronal viability; creatine (Cr), essential for neuronal energy; phosphocholine (PCh), involved in membrane synthesis; myo-inositol (Ins), necessary for membrane function; and glutathione (GSH), a marker for oxidative stress. MRS imaging allows for the simultaneous acquisition of data from larger areas, whereas single voxel MRS (SV-MRS) focuses on a localized voxel of interest (VOI) with a higher signal-to-noise ratio [16–18].
....
Previous MRS imaging studies have suggested widespread metabolite abnormalities in ME/CFS compared to HCs, while SV-MRS revealed lowered Cr and GSH levels in the anterior cingulate gyrus (ACC) [14,15]. In addition, a reduced NAA to Cr ratio in the left dorsolateral prefrontal cortex (L-DLPFC) has been correlated with an increased frequency of pain symptoms in ME/CFS [21].

Previous MRS imaging studies have suggested widespread metabolite abnormalities in ME/CFS compared to HCs, while SV-MRS revealed lowered Cr and GSH levels in the anterior cingulate gyrus (ACC) [14,15]. In addition, a reduced NAA to Cr ratio in the left dorsolateral prefrontal cortex (L-DLPFC) has been correlated with an increased frequency of pain symptoms in ME/CFS [21].
....
Based on the current research highlighting the significant involvement of ACC, BS, and L-DLPFC in ME/CFS, we conducted MRS measurements from these three specific brain regions.

So, magnetic resonance spectroscopy only in three regions of interest: anterior cingulate gyrus (ACC), left dorsolateral prefrontal cortex (L-DLPFC) and the brain stem (BS).

Patient selection looks to have been fine - i.e. from a registry, diagnosis confirmed by physician interview, PEM required. The age range of the patient participants was very wide (24-68 years) and there were only 5 healthy controls, so, that's not ideal; the authors acknowledge that this study was only preliminary. What isn't okay though is that there is no mention of blinding the assessment of the imaging. That's a problem, as there is quite a lot of processing where bias could creep in. Hopefully they can fix that in their next study - perhaps it was done and just wasn't mentioned.

Multiple metabolites were examined for potential quantification, including NAA, Cr, PCr, PCh, Ins, GSH, gamma-aminobutyric acid (GABA, an inhibitory neurotransmitter), glutamine (GLN, a neurotransmitter precursor amino acid), glutamate (GLU, an excitatory neurotransmitter), and N-acetyl aspartyl glutamate (NAAG, a modulator of glutamatergic neurotransmission) [18]. Metabolites were expressed in institution units. Metabolites were excluded from further analysis if the Cramer-Rao lower bounds for model fitting were >50% to ensure good quality of fitting [29].

A difference in the level of NAA between ME/CFS and HCs was observed within the DLPFC VOI (OR = 8.49, p = 0.042, which did not reach the corrected threshold of significance with multiple comparisons; Table 2), but not the other two VOIs. No statistical differences were identified in any other metabolites in any VOIs (Figure 2).

So, it doesn't sound as though they found very much in terms of brain metabolite differences, perhaps hampered by the small size of the healthy control cohort.
NAA is N-acetyl aspartate, which they noted earlier was a marker of neuronal viability and the DLPFC is the left dorsolateral prefrontal cortex - it was found to be higher in the ME/CFS group. I guess the fact that they didn't find differences in the metabolites they looked for is useful information. Table 2 gives results for 10 metabolites in each of the three brain regions. And yes, of the 30 comparisons, the NAA in the DLPFC is the only one remotely significant.

Googling about NAA, it does seem to be recognised a measure of neuronal health and function, and is correlated with common measures of cognitive intelligence (higher levels = higher cognitive intelligence). The DLPFC is involved in complex thinking, abstract reasoning, executive function. So, what could be happening here is that we are just seeing a sampling bias. The type of people who are more likely to sign up to a patient registry and participate in research are more likely to be of above average intelligence. The difference with the small healthy control cohort wasn't huge and there were overlaps, but may reflect differences in selection, and so mean intelligence.

The researchers correlated findings with all sorts of measures. There did seem be some correlation between measures of symptoms e.g. fatigue and NAA, but that might just be the result of an even stronger selection bias for cognitive intelligence in people with worse fatigue. That seems possible: people who understand the importance of research are likely to be more motivated to participate. (Actually, looking at the charts, the correlation is mostly the result of the healthy controls tending to have lower NAA and lower symptom burden.)

So, I'm not really seeing any finding here that can't be explained by a participant selection bias. If there really was a difference in average cognitive abilities in the two groups, then it does create problems for comparisons with fMRI cognitive investigations such as the n-back studies.

NAA in the L-DLPFC appeared to be higher in ME/CFS than HCs, though this novel and unexpected finding requires validation with larger sample cohorts for improved statistical power to survive the false positive adjustment of multiple comparisons. NAA is present solely in neurons and is a source of glutamate metabolism for critical neuronal and nutrient cell functions [16,38]. Within this context, stable NAA suggests that participants with ME/CFS have a functioning, relatively responsive L-DLPFC. However, considering that the ME/CFS group reported greater overall fatigue and pain compared to the HC group, it is likely that the NAA level may represent a potentially negative downstream effect of ME/CFS pathophysiology. This is supported by the observed positive correlations between the L-DLPFC NAA and the pain and sleep scores in the ME/CFS group (Figure 4). At this time, it remains unknown whether ME/CFS involves a unique metabolite profile. Given the sample size, how the metabolites in ME/CFS and HCs compare in these brain regions warrants verification in future longitudinal studies with larger cohorts and repeated measures over the course of the disorder. Further research can then target how such a profile is linked to the underlying neural immune inflammation or other hypothesized mechanisms [2,14,39,40].

The authors don't seem to have considered this obvious possible explanation (that their patient sample had better mean inherent cognitive capacity and therefore neuronal integrity than the controls), instead offering a vague hand-wavy "it is likely that the NAA level may represent a potentially negative downstream effect of ME/CFS patholophysiology".

They go on to note that another small study actually found lower levels of NAA in the CFS cohort, but in a different brain region, while another study found a high NAA level in yet another brain region.

Our NAA results contribute to that of the other studies investigating MRS in ME/CFS. Brooks and colleagues reported a reduced concentration of NAA in CFS (n = 7) than in age- matched controls (n = 10) [41]. Although this seems to conflict with the findings from our study, it is important to note that their data were acquired from the right hippocampal area, a subcortical brain region on the opposite hemisphere from the VOI in the current study. In a more recent study with a larger sample, Thapaliya and colleagues demonstrated a high NAA level in the posterior cingulate cortex in long COVID patients who displayed some ME/CFS-like symptoms (alongside elevated glutamate) in patient groups compared to controls [42]. The finding was interpreted as a compensatory response to brain inefficiency in patients, with increased glucose and oxygen utilization under infection-triggered osmotic stress. Similar to the current study, associations between neurochemical and clinical severity measures were found, linking neurochemistry to neuropathology, overlapping long COVID and ME/CFS [42]. Future studies comparing metabolites from the same VOIs across multiple brain regions key to ME/CFS will enhance result validation and interpretation.

So, of the 'group differences in metabolites' in the three parts of the brain that were examined, I don't think there is really any difference that we can point to and say 'this is implicated in ME/CFS pathology'. I guess more studies with bigger and better matched cohorts might be useful, especially if other parts of the brain were examined.

 

[SNT Gatchaman]

Googling about NAA, it does seem to be recognised a measure of neuronal health and function, and is correlated with common measures of cognitive intelligence (higher levels = higher cognitive intelligence).

Yes for the first part, I'm not sure for the second. I've always thought of it in terms of a marker for neuronal health (so reduced = bad, apart from Canavan), but that there would be a ceiling on its role in better than normal functioning. I guess it depends on how much intelligence is dependent on multiple individual neuronal function/efficiency vs the size/complexity of the network of neuronal connections*.

Moderate relationships between NAA and cognitive ability in healthy adults: implications for cognitive spectroscopy (2014, Frontiers in Human Neuroscience) —

In our study, we found that quantitative estimates of NAA in cortex did not correlate strongly or significantly with standardized measures of IQ constructs. The small correlations we obtained between NAA concentration and measures of cognitive function echo other findings that have reported weak associations between IQ and neurometabolite variables in healthy cohorts

---
* Are Bigger Brains Smarter? Evidence From a Large-Scale Preregistered Study (2018, Psychological Science)

 

[Hutan]

Yes, that paper:

Moderate relationships between NAA and cognitive ability in healthy adults: implications for cognitive spectroscopy (2014, Frontiers in Human Neuroscience)

was the one I was looking at too. And they did find a relationship between the cerebral NAA and cognitive abilities, as the title suggests. With respect to actual measured IQ, the abstract goes on to say:

We found correlations between NAA and IQ that were within the range reported in previous studies. However, the magnitude of these effects was significantly modulated by the stringency of data screening and the extent to which outlying values contributed to statistical analyses.

I haven't looked further into the paper, but it sounds as though they finessed things with respect to those 'outlying values'. And of course, IQ measurement is horribly biased and problematic. Putting measured IQ aside though, I think the core point remains - there is a likely relationship between cerebral NAA levels and cognitive ability (i.e. intelligence) in broad terms, and there is also a likely bias in the cognitive ability of participants volunteering for research studies. I think that cerebral NAA:cognitive ability relationship is particularly likely to be true when the part of the brain that is being assessed is involved in higher-level cognitive tasks. This ME/CFS study did not find differences in the NAA levels in the brain stem, which isn't known for its involvement in higher-level cognitive tasks.

Of course, it may well be just a random result, but I do think that these authors should have at least noted that the higher NAA in the DLPFC may be a result of a bias in the cognitive abilities of the participants in their sample when they were hypothesising about what the finding might mean.

I think the finding is good news for people with ME/CFS. Good levels of cerebral NAA are not suggestive of damage to the brain.

 

[SNT Gatchaman]

This one could probably do with a glossary.

ACC Anterior cingulate cortex
BOLD Blood oxygen level dependent
DLPFC Dorsolateral prefrontal cortex
GABA Gamma-aminobutyric acid
GLN Glutamine
GLU Glutamate
GSH Glutathione
MRI Magnetic resonance imaging
MRS Magnetic resonance spectroscopy
NAA N-acetyl aspartate
NAAG N-acetyl aspartyl glutamate
PCh Phosphocholine
PCr Phosphocreatine
SV Single voxel (MR Spectroscopy)
VOI Voxel of interest

 

[Ash]

This one could probably do with a glossary.

ACC Anterior cingulate cortex
BOLD Blood oxygen level dependent
DLPFC Dorsolateral prefrontal cortex
GABA Gamma-aminobutyric acid
GLN Glutamine
GLU Glutamate
GSH Glutathione
MRI Magnetic resonance imaging
MRS Magnetic resonance spectroscopy
NAA N-acetyl aspartate
NAAG N-acetyl aspartyl glutamate
PCh Phosphocholine
PCr Phosphocreatine
SV Single voxel (MR Spectroscopy)
VOI Voxel of interest

Oh thank god. And you too.