Inhibition INCREASES the BOLD Response ('nuff said)

In the early days of functional magnetic resonance imaging (fMRI), researchers were eager to point out that the hemodynamic response measured by fMRI may correspond rather directly to neural firing. Recently, a number of researchers have attempted to remind the larger neuroimaging community that the hemodynamic response reflects metabolic/energetic demands, and this might very well more strongly reflect the firing of inhibitory interneurons that oppose the action of the excitatory pyramidal neurons we more commonly think about. This kind of confusion has consequences: many have argued that below-baseline activation of a cortical area reflects inhibition of that area, even though such inhibition might be expected to increase the BOLD response owing to the energetic demands of inhibitory interneurons.

A new Nature paper by Lee et al definitively shows the mistake in this kind of claim, using a combined fMRI and optogenetic method, though the take-home is a little understated for my tastes and appears to have been lost in some of the excellent discussions of this paper throughout the blogosphere. So let's flesh it out:

The authors used cell-type specific promoters to genetically engineer a photoreceptor into excitatory neurons, and engineered a slightly different photoreceptor into inhibitory interneurons. These photoreceptors respond to different wavelengths of light, which can be delivered fiberoptically; this, in turn, permits the simultaneous use of fMRI to determine what the effect of selective activation of inhibitory interneurons is on the hemodynamic response measured by fMRI.

The results were clear: the volume of tissue showing BOLD increases following stimulation of interneurons was nearly three times as large as the volume of surrounding tissue showing decreases in BOLD (1.7mm^3 vs 0.6mm^3, respectively). In addition, even in this smaller volume, the observed % decrease in BOLD was less than half as large as the observed % increase in BOLD relative to what was seen in the larger volume (~5% vs ~2%). So activation of inhibitory interneurons in a particular area should be expected to primarily increase the local BOLD response, both in terms of the volume of tissue affected and the magnitude of that effect.

This "read" on the paper is consistent with a 2007 review paper on what hemodynamic activity reflects, from some of the biggest names in the field.

I'm happy that neuroscience is progressing so quickly that logical arguments of this importance can be definitively settled using cutting-edge techniques, just 2 years later. Now, if only we could stop talking about below-baseline activations as reflecting inhibition... unless someone can point out long-range inhibitory projections (especially in cortex), in which case the debate will rage on.

Of course, it probably will anyway.

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I've been confused by this paper, and confess I've not read it carefully. The authors describe this paper as if it supports the mainstream read fMRI activity = excitation; the paper itself seems to downplay the parvalbumin/inhibitory results. From where in the paper did you pull the numbers you quote? The finding that inhibitory activity also results in fMRI activation would be an important finding, the authors seem unwilling to support this interpretation.

Thanks Tal!

Svs: this stuff is all coming from the supplemental information (e.g., FigS4c).

However, there was a full 3.0mm^3 of inhibitory cells which should have been activated by the light. This makes the 1.7mm^3 look pretty odd.

Compare that to the 10-20mm^3 that was observed when stimulating excitatory neurons, and the results are less than clear cut. Although the prober careful analysis hasn't been presented in the paper, the authors should have the data needed. Should we look at the larger scale activations as the result of excitatory neurons while the local variation driven mostly by inhibitory cells?

The negative edge also complicates everything significantly. I would assume it's the center of the inhibitory neurons that was positive while the edges were negative. What is different about those neurons? It must be something about the spatial layout and perhaps the activation pattern. Obviously there is a negative component to inhibitory neurons effect on BOLD, and how that component behaves in natural processing is far from worked out.

There's certainly a lot more that we could learn about this topic.

Hi KevinH - Nice observations and good point, but keep in mind that Chr2-EYFP may not be as effective (it's newer and trickier, I'm told): opsin expressing region was *only* 3mm^3 relative to much more for the excitatory cells, and the transduction in inhibitory cells was 17% less effective (72.7% of PV positive cells expressed it, relative to 89% of CaMKIIalpha over a much larger area, as you note).

I also disagree in principle that "obviously there is a negative component to inhibitory neurons' effect on BOLD." BOLD is energetic, and in principle inhibitory neurotransmission could induce larger metabolic demands than excitatory transmission (indeed, that's what Buzsaki, Raichle et al have argued). What evidence do you have that the opposite is so obvious?