BOLD signal changes can oppose oxygen metabolism across the human cortex, 2025, Epp et al.

[Chandelier]

BOLD signal changes can oppose oxygen metabolism across the human cortex

Spoiler: Authors

Epp, Samira M.; Castrillón, Gabriel; Yuan, Beijia; Andrews-Hanna, Jessica; Preibisch, Christine; Riedl, Valentin

Abstract​

Functional magnetic resonance imaging measures brain activity indirectly by monitoring changes in blood oxygenation levels, known as the blood-oxygenation-level-dependent (BOLD) signal, rather than directly measuring neuronal activity.
This approach crucially relies on neurovascular coupling, the mechanism that links neuronal activity to changes in cerebral blood flow.
However, it remains unclear whether this relationship is consistent for both positive and negative BOLD responses across the human cortex.
Here we found that about 40% of voxels with significant BOLD signal changes during various tasks showed reversed oxygen metabolism, particularly in the default mode network.
These ‘discordant’ voxels differed in baseline oxygen extraction fraction and regulated oxygen demand via oxygen extraction fraction changes, whereas ‘concordant’ voxels depended mainly on cerebral blood flow changes.
Our findings challenge the canonical interpretation of the BOLD signal, indicating that quantitative functional magnetic resonance imaging provides a more reliable assessment of both absolute and relative changes in neuronal activity.

Web | DOI | PDF | Nature Neuroscience

 

[Chandelier]

40 percent of MRI signals misinterpreted

Interpretation of numerous MRI data may be incorrect: blood flow is not a reliable indicator of brain activity.

www.tum.de

Why blood flow is not a reliable indicator of the brain's energy requirements​

40 percent of MRI signals do not correspond to actual brain activity​

For almost three decades, functional magnetic resonance imaging (fMRI) has been one of the main tools in brain research. Yet a new study published in the renowned journal Nature Neuroscience fundamentally challenges the way fMRI data have so far been interpreted with regard to neuronal activity. According to the findings, there is no generally valid coupling between the oxygen content measured by MRI and neuronal activity.

 

[Hutan]

This is interesting. I've just read the brief article so far.

PD Dr. Valentin Riedl, now Professor at FAU, and his colleague Epp examined more than 40 healthy participants during their time at TUM. Each was given several experimental tasks – such as mental arithmetic or autobiographical memory recall – which are known to produce predictable fMRI signal changes in distributed brain regions. During these experiments, the researchers simultaneously measured the actual oxygen consumption using a novel quantitative MRI technique.

Depending on the task and the brain region, the physiological results varied. Increased oxygen consumption – for instance in areas involved in calculation – did not coincide with the expected rise in blood flow. Instead, the quantitative analyses showed that these regions met their additional energy demand by extracting more oxygen from the unchanged blood supply. Thus, they used the oxygen available in the blood more efficiently without requiring greater perfusion.

So, these results depend on the accuracy of the 'novel quantitative MRI technique' to reliably determine actual oxygen consumption.

But, if they are right, it suggests another thing that could be going wrong in ME/CFS brains. Oxygen may be getting into the blood vessels in the brain normally, but there might be a problem in the ability of neurons to access that oxygen during periods of higher demand.

It's a good reason to retain a high level of skepticism about brain imaging research in ME/CFS for now, I think.

According to Riedl, these insights also affect the interpretation of research findings in brain disorders: “Many fMRI studies on psychiatric or neurological diseases – from depression to Alzheimer’s – interpret changes in blood flow as a reliable signal of neuronal under- or over-activation. Given the limited validity of such measurements, this must now be reassessed. Especially in patient groups with vascular changes – for instance due to aging or vascular disease – the measured values may primarily reflect vascular differences rather than neuronal deficits.” Previous animal studies already point in this direction.

The researchers therefore propose complementing the conventional MRI approach with quantitative measurements. In the long term, this combination could form the basis for energy-based brain models: rather than showing activation maps that depend on assumptions about blood flow, future analyses could display values indicating how much oxygen – and therefore energy – is actually consumed for information processing. This opens new perspectives for examining aging, psychiatric, or neurodegenerative diseases in terms of absolute changes in energy metabolism – and for understanding them more accurately.

 

[ScoutB]

Oxygen may be getting into the blood vessels in the brain okay, but there might be a problem in the ability of neurons to access that oxygen during periods of higher demand.

Haven't even skimmed the paper properly yet, but I'm wondering if it could help explain the slightly counterintuitive results of that BOLD study on pwME. That other paper found that when healthy controls used certain areas of the brain to complete tasks, oxygen flow to those area actually reduced over time (or over repetitions of the task). Meanwhile pwME maintained the same or even increased the level of oxygen. (That's my layman's understanding anyway, correct me if I misunderstood).

In that other study they said

This study could not disentangle whether the absence of BOLD adaptation in ME/CFS originated from an aberrant neural and/or neurovascular coupling adaptation.

If this new study holds up, maybe it implies something about that question? Too foggy right now to think things though.

 

[SNT Gatchaman]

Yep, this paper will be important and of particular relevance to us, esp. via the NIH study and Walitt et al.'s claim of effort preference, with the right TPJ finding when testing grip strength.

It's one of those baked-in assumptions in almost every fMRI study (that neuron activity = increased blood flow) and you will get weird looks and shrugs when you point out it can also be a confounder.

See eg thread Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI (2024)

(It also may be very relevant to FND studies which are focusing on fMRI, eg BOLD signal variability as potential new biomarker of functional neurological disorders)

 

[Turtle]

Yep, this paper will be important and of particular relevance to us, esp. via the NIH study and Walitt et al.'s claim of effort preference, with the right TPJ finding when testing grip strength.



See eg thread Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI (2024)

(It also may be very relevant to FND studies which are focusing on fMRI, eg BOLD signal variability as potential new biomarker of functional neurological disorders)

That's what you get when using a normal word "functional" and give it the opposite meaning: "dysfunctional."
It's a real disease say psychologists, doctors shrug it off.
BPS'ers using fMRI might have bitten off more than they can chew.

I imagine Walitt scrambling all 70+ co-authors to find out if TPJ and effort preference, as @SNT Gatchaman mentioned, are under scrutiny now.

 

[Sean]

According to the findings, there is no generally valid coupling between the oxygen content measured by MRI and neuronal activity.​

Interesting.

 

[SNT Gatchaman]

I've posted a brief summary in the neurovascular coupling thread.

 

[SNT Gatchaman]

I imagine Walitt scrambling all 70+ co-authors to find out if TPJ and effort preference, as @SNT Gatchaman mentioned, are under scrutiny now.

Well the authors may not be scrambling, but their paper states —

showed that blood oxygen level dependent (BOLD) signal of PI-ME/ CFS participants decreased across blocks bilaterally in temporoparietal junction (TPJ) and superior parietal lobule, and right temporal gyrus in contradistinction to the increase observed in HVs

The reality might be that the reduced BOLD signal indicates increased metabolic activity.

This paper said —

Contrary to the canonical BOLD response model, we found that approximately 40% of brain voxels with significant ∆BOLD exhibited opposing changes in oxygen metabolism. Specifically, voxels with positive ∆BOLD showed decreased ∆CMRO2, whereas those with negative ∆BOLD exhibited increased ∆CMRO2. By measuring the BOLD signal, CBF, OEF and CMRO2 in the same session, we uncovered distinct neurovascular mechanisms in regions with concordant versus discordant responses. Discordant voxels primarily regulate oxygen demand via ∆OEF, whereas concordant voxels display a larger increase in ∆CBF, aligning with canonical predictions. Moreover, discordant voxels demonstrated lower baseline CMRO2 and OEF, indicating that their baseline oxygen supply is sufficient to meet higher metabolic demands. In conclusion, we identified two distinct hemodynamic responses to neuronal activity changes, influenced by baseline OEF and metabolism.

At the least this paper renders Walitt et al.'s temporoparietal junction data uninterpretable and the effort preference conclusion unsupportable. Particularly in a patient group in whom cardiovascular dysfunction is common, cerebrovascular dysfunction evident and in whom abnormal metabolism, oxygen transport and mitochondrial dysfunction are strongly suspected.

 

[Turtle]

Well the authors may not be scrambling, but their paper states —



The reality might be that the reduced BOLD signal indicates increased metabolic activity.

This paper said —



At the least this paper renders Walitt et al.'s temporoparietal junction data uninterpretable and the effort preference conclusion unsupportable. Particularly in a patient group in whom cardiovascular dysfunction is proven and in whom abnormal metabolism, oxygen transport and mitochondrial dysfunction are strongly suspected.

Could they rebuke with Walitt +70 saw it first?

 

[SNT Gatchaman]

Featured prominently on Hacker News today. Including this comment referencing the famous salmon paper —

I remember reading a paper back in grad school where the researchers put a dead salmon in the magnet and got statistically significant brain activity readings using whatever the analysis method à la mode was. It felt like a great candidate for the Ig Nobel awards.

Which got some replies from "prefrontal" —

That was our paper! We showed that you can get false positives (significant brain activity in this case) if fMRI if you don't use the proper statistical corrections. We did win an Ig Nobel for that work in 2012 - it was a ton of fun.

When we published the salmon paper, approximately 25-35% of published fMRI results used uncorrected statistics. For myself and my co-authors, this was evidence of shaky science. The reader of a research paper could not say with certainty which results were legitimate and which might be false positives.

Among other challenges, when we first submitted the poster to the Human Brain Mapping conference we got kicked out of consideration because the committee thought we were trolling. One person on the review committee said we actually had a good point and brought our poster back in for consideration. The salmon poster ended up being on a highlight slide at the closing session of the conference!