Trial Report Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI, 2024, Schönberg

[Dolphin]

Open access
https://journals.sagepub.com/doi/10.1177/0271678X241270528
Research article
First published online August 7, 2024

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI

Laura Schönberg, Abdalla Z Mohamed, Qiang Yu, Richard A Kwiatek, Peter Del Fante, Vince D Calhoun, and Zack Y Shan https://orcid.org/0000-0002-9042-9278 zshan@usc.edu.au-4
https://doi.org/10.1177/0271678X241270528

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive.

We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS.

This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752).

Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets.

The fMRI signal changes between blocks and sets were compared within and between groups.

Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated.

In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs.

These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities.

BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

https://twitter.com/user/status/1821508982361518405

 

[Creekside]

A follow-up to this would be to check PWME who have had the disease for different periods of time. Does this difference show up immediately after developing ME, or is it something that develops over time? That might determine cause vs effect. Also, does the effect correlate with severity?

 

[hibiscuswahine]

Interesting paper

BOLD signals result from neural activities and regional dynamic regulation of blood flow, i.e., neuro- vascular coupling (NVC). Previous studies showed that the BOLD adaptation in HCs was a combination of learning effect and neural adaptation (increased neural computation efficiency), as well as NVC adap- tation.8 This study could not disentangle whether the absence of BOLD adaptation in ME/CFS originated from aberrant neural and/or NVC adaptation. However, no evidence of abnormal neural adaptation in ME/CFS leads to our postulation of impaired NVC. NVC involves an initial feedforward mechanism of glu- tamate activation in neurons and astrocytes of a Ca2þ- dependent signalling pathway and secondary metabolism-driven feedback.25 This releases vasoactive factors which increase local blood flow to ensure the needed energy supply of activated neurons.25 Recent studies have observed impaired Ca2þ-mobilisation in ME/CFS,26,27 suggesting the possible impairment of glutamate-Ca2þ NVC pathways in ME/CFS./QUOTE]

 

[Ravn]

Possibly results from this grant?
https://www.s4me.info/threads/australian-me-cfs-neuroimaging-project-receives-1-2m-govt-grant.12748/

See also this study
https://www.s4me.info/threads/oppos...evealed-by-diffusion-mri-2024-yu-et-al.39661/

On a quick glance this looks to be a good-sized cohort by ME standards, carefully diagnosed, and with well matched controls - notably including for activity

Maybe someone with relevant expertise can comment on the quality of the method and the interpretation of the results?

 

[ME/CFS Skeptic]

in the last quarter, BOLD responses in HCs exhibited a decrease, while those in the ME/CFS group remained similar with a slight increase

 

[Yann04]

@forestglip if interested, controls are sedentary

 

[SNT Gatchaman]

Health Rising write-up here, noting further study in process Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis (2022, Frontiers in Neurology)

 

[SNT Gatchaman]

This looks pretty good on first read through. I thought the hypothesising and interpretation were careful. The equipment and imaging protocols are excellent (Siemens 3T Skyra, using a 64-channel head coil). Patient selection and matching very good, as commented above (with actigraphy-confirmed sedentary HCs).

The authors did note in limitations that this was part of a multi-modality assessment, so the task-functional MRI (tfMRI) was shortened compared to some stand-alone studies, meaning that BOLD adaptation might have been demonstrated if it had run longer. I don't think that's likely and the difference at the assessed timepoints seems important anyway.

 

[SNT Gatchaman]

Some intro abbreviated quotes —

As the exhaustion is experienced not only physically but also mentally, the involvement of the brain in the pathophysiology of ME/CFS is plausible. […] To better understand brain function in patients with ME/CFS, multiple neuroimaging techniques and studies have been performed. Yet, few consistent findings have been observed in ME/CFS. The most frequently reported observation from 11 studies using different neuroimaging techniques is the larger recruitment of brain regions during cognitive tasks

other neuropathologies resulting in diffuse damage, such as traumatic brain injury, have similarly shown augmented functional recruitment despite normal cognitive task performance. […] traumatic brain injury patients showed progressively increased blood oxygenation level-dependent (BOLD) signals over time, while HCs’ BOLD activities decreased after multiple trial repetitions, a phenomenon termed BOLD adaptation.

mechanics of BOLD adaptation are unclear (resulting from the dynamics of neural processing, regional blood flow regulation, or both), it is believed to improve the energy efficiency of neural computations.

Here, we seek to investigate BOLD adaptation in ME/CFS with the hypothesis that sustained cognitive tasks induce BOLD adaptation in HCs but not in patients with ME/CFS. Additionally, we aim to confirm the hypothesis that the neural correlates of cognitive function in ME/CFS will show a larger recruitment of brain areas compared to HCs […] it is particularly pressing in ME/CFS due to the controversies surrounding this ambiguously defined illness.

 

[SNT Gatchaman]

Some discussion abbreviated quotes —

The BOLD signal increased in both ME/CFS participants and HCs during the first three quarters of trials. However, in the last quarter, BOLD responses in HCs exhibited a decrease, while those in the ME/CFS group remained similar with a slight increase.

Patients with ME/CFS showed significantly higher BOLD response changes (2nd set Vs. 1st set) in the second task block than those from HCs. Within group 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. The absence of BOLD adaptation in ME/CFS observed in our study is consistent with findings of previous studies in patients with multiple sclerosis and traumatic brain injury.

BOLD signals result from neural activities and regional dynamic regulation of blood flow, i.e., neurovascular coupling (NVC). Previous studies showed that the BOLD adaptation in HCs was a combination of learning effect and neural adaptation (increased neural computation efficiency), as well as NVC adaptation. This study could not disentangle whether the absence of BOLD adaptation in ME/CFS originated from aberrant neural and/or NVC adaptation. However, no evidence of abnormal neural adaptation in ME/CFS leads to our postulation of impaired NVC.

NVC involves an initial feedforward mechanism of glutamate activation in neurons and astrocytes of a Ca2+ dependent signalling pathway and secondary metabolism-driven feedback.

Accuracy significantly improved and response times significantly decreased from the 1st to the 2nd set in Block 1 in patients, indicating a learning effect. However, no significant differences were observed in accuracy or response times after the 2nd set in Block 1, suggesting the completion of the learning effect. The learning effect was less prominent in HCs, with no significant accuracy differences across sets but significantly reduced response times, extending into the 1st set of Block 2.

The learning effect in HCs aligned well with increased BOLD changes, showing continuous increases until the 1st set of Block 2. In contrast, learning effects in patients ceased after the 2nd set in Block 1, but the increase in BOLD changes continued. Therefore, the absence of BOLD adaptation in patients cannot be explained by the learning effect, supporting our postulation of impaired NVC in ME/CFS.

 

[Kitty]

It does look interesting, thanks for going through it and highlighting those sections.

 

[Turtle]

Some discussion abbreviated quotes —

I literally get a hot head when on my computer, this research could be an explanation.
I need a break after 10 minutes to cool down, when it is hot even sooner.

 

[Ravn]

Is undergoing fMRI similar to standard MRI where you're bombarded by ear-protection-defying noise, and the machine tries to cook you from below while at the same time freeze-drying you from above?

If so, could some of the recruitment of more brain regions found here and in other fMRI studies be due to the struggle to handle the sensory onslaught on top of the cognitive task? In which case, how would you separate the effects between more resources being thrown at sensory vs cognitive processing?

I literally get a hot head when on my computer, this research could be an explanation.
I need a break after 10 minutes to cool down, when it is hot even sooner.

Same here. Hot and also flushed red. Don't know if it's the thinking itself that does it though. Could be the associated being more upright or even the eye muscles working hard, too.
And I suspect it's anyone's guess if this increased blood flow to the skin could be the result of a poorly targeted attempt by the brain to get more blood up into the head region in general in the hope that some of it ends up in the brain itself

 

[Creekside]

Is undergoing fMRI similar to standard MRI where you're bombarded by ear-protection-defying noise, and the machine tries to cook you from below while at the same time freeze-drying you from above?

I didn't notice any significant noise or other stimuli during my head MRI. There was a moderate hum, but that's all. Maybe early machines were worse?

 

[Kitty]

Maybe early machines were worse?

Imagine an industrial-size tumble dryer full of paving setts.

My last one was just before the pandemic, so I don't know about the early bit.

 

[Subtropical Island]

I didn't notice any significant noise or other stimuli during my head MRI. There was a moderate hum, but that's all. Maybe early machines were worse?

Maybe your hearing protection was better? Or better fitted. (With two to three layers of sound protection I think it could be much reduced but if any of them isn’t well fitted, or good quality for the types of sound, that would make a big difference).

Also whether in PEM at the time makes a huge difference.

 

[Ken Turnbull]

So healthy controls could switch to a sort of automatic energy-saving mode to repeat similar tasks? That sounds handy for energy conservation, and the kind of shortcut brains employ a lot.

I wonder whether the same inability to take advantage of this shortcut has been found in any other medical conditions. (Apologies if that is covered and I missed it.)

 

[forestglip]

I wonder whether the same inability to take advantage of this shortcut has been found in any other medical conditions. (Apologies if that is covered and I missed it.)

Yes, according to the paper:

The absence of BOLD adaptation in ME/CFS observed in our study is consistent with findings of previous studies in patients with multiple sclerosis and traumatic brain injury.7,24

From the first reference:

While performing the mSDMT, participants with a TBI showed increased activity, while HCs subsequently showed decreased activity in several regions including the middle frontal gyrus, superior parietal cortex, basal ganglia and anterior cingulate.

 

[Dolphin]

ME Research UK:

A team of researchers including Dr Zack Shan – who is currently working on a research project funded by ME Research UK, have published a paper in the Journal of Cerebral Blood Flow & Metabolism investigating whether specific signals in the brain differ between people with ME/CFS and healthy controls.

Read a summary of the study and findings here: https://tinyurl.com/mu3tx62p

Read the research paper here: https://tinyurl.com/mu2prkce

Read more about Dr Shan’s ME Research UK-funded project here: https://meres.uk/shan062info

https://twitter.com/user/status/1829451493797515267