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.