Friday, 4 April 2014

Does it matter that we do not know the link between neuronal signals and the BOLD response?

In recent weeks there have been a couple of articles that have revisited the question of the importance (or not) of the results of fMRI studies ( and For me the importance of fMRI to address any research question is dependent on the degree to which the hypothesis requires specific predictions about the underlying neuronal signals. In general, the more any hypothesis is dependent upon specific neuronal parameters the less convincing the results and conclusions of that study will be. Currently, we still do not know with any confidence how the BOLD signal in humans is modulated by neuronal firing rate and/or by modulations in the amplitude of the local field potentials at different frequencies. In addition, we have virtually no data that addresses how any relationships between the neuronal measures and the BOLD signal might differ in different brain regions. Indeed Harris et al. (2011) wrote “In particular, BOLD signals need not directly report spiking activity in the imaged area, but instead reflect the many factors associated with neural activity that lead to an increase in blood flow. Most importantly, neurotransmitters released during synaptic activation are now known to directly influence local blood flow and it is thought that the BOLD signal may most closely reflect the excitatory synaptic component, rather than the action potential component, of neural activity”. Therefore, it would seem that it would be prudent to reduce the weight given to fMRI results that purport to reflect changes to specific parameters of the underlying neuronal signal. A good case study that demonstrates the difficulty in relating neuronal signal modulations to BOLD signal modulations is the history of using fMRI to investigate the presence (or not) of mirror neurons in humans. Which is still unresolved.

However, not all fMRI experiments have hypotheses that are based on specific predictions about the underlying neuronal signals. Indeed, it is interesting to note that the examples given in support of fMRI research by Matt Wall ( are examples of such research. Here, the fMRI signal is employed as a biomarker, without any attempt to explain or link any modulations in the BOLD signal to specific neuronal parameters. So, does it matter that we do not know the link between neuronal signals and the BOLD response? I would say – it depends. It depends on whether your hypothesis makes specific predictions about the underlying neuronal signal or not. If it does then it clearly does matter that the link between neuronal signals and the BOLD response is not known. If not, then it does not matter.

What ever your thoughts this paper is well worth a read.

Harris JJ, Reynell C, Attwell D. (2011) The physiology of developmental changes in BOLD functional imaging signals. Dev Cogn Neurosci. 1(3):199-216.

1 comment:

  1. James,

    Many thanks for the comment - really valuable. My thought is that ideally fMRI researchers should keep all the issues you highlight at the front of their minds when making interpretations of their data. That's easier said than done though - sometimes it's easy to get carried away by a nice result!

    It's a tricky issue - of course you're absolutely right that we desperately need to develop a better understanding of exactly what the BOLD response is and how it relates to neural activity - the issue that it's never been documented how BOLD differs in different brain regions is just one of many gaps in our knowledge. At the same time, a lot of work has shown that there *is* a relationship of some kind between BOLD and neural activity. Researchers need regular reminders that the issue is not as settled as we'd like it to be.

    For me, some of the most interesting and thoughtful fMRI research are those papers that seek to dig a little deeper and try to infer something about the underlying neural response. fMRI-adaptation studies are a good example of this (nice review here: I've often wondered why more people don't use adaptation designs; though of course they have their own set of associated problems.

    Which brings me back to the conclusion of that Conversation/Guardian article - no one research methodology is enough. In order to make progress with tackling the issues you mention, we'll need to use all the tools in our toolbox, and fMRI is just one of them.

    Thanks again for the comment - and I'll be reading that Harris et al. paper tomorrow!