Functional MRI (fMRI) is a powerful technique for measuring subtle magnetic resonance changes in active neurons, but it does have limitations. One commonly used fMRI method called BOLD, or blood oxygen level-dependent MRI, measures decreases in deoxyhemoglobin content in the vicinity of active neurons. However, BOLD has limited resolution because deoxyhemoglobin in surrounding blood vessels can interfere with the measurement. Now, in today's Science, researchers in Ralph Freeman's lab at the University of California, Berkeley, demonstrate that the resolution of this technique may be dramatically improved by focusing on transient increases in deoxyhemoglobin, which occur immediately upon neural activation.
These increases, causing an initial dip in the BOLD signal, are followed by a delayed decrease in deoxyhemoglobin, which results as oxygenated hemoglobin rushes in from surrounding blood vessels to replenish the active area. This delayed decrease in deoxyhemoglobin elicits the stronger BOLD resonance that is typically used to measure neural activity. But what does the "initial dip" tell us?
Some researchers have proposed that the dip directly results from oxygen consumption by neurons (see Malonek and Grinvaid 1996), but this contention has remained controversial, and alternative hypotheses such as changes in blood volume also explain the dip. Now, first author Jeffrey Thompson and colleagues addressed this issue directly, by simultaneously measuring oxygen consumption and neural activity.
At the heart of their experiment was a combined oxygen electrode/platinum electrode sensor, which measures the electrical activity of a single neuron and the oxygen concentration in its immediate vicinity (30 μm radius). Thompson and colleagues trained this sensor on a single neuron in the visual cortex. Neurons in the visual cortex are exquisitely sensitive to optical stimuli from particular directions or specific eyes, and the authors used this selectivity to show that oxygen consumption correlated beautifully with electrical spikes from this one neuron. Stimuli that failed to elicit neural spikes also failed to register O2 changes, while the number of electrical spikes correlated with the magnitude of O2 loss. In addition, Thompson et al. iced the cake by recording delayed increases in O2 that explain the delayed BOLD signal.
The data confirms that the dip is indeed due to oxygen consumption, and would, in principle, seem to open the door for the BOLD dip to be used as a legitimate-and spatially more accurate-measure of neuronal activity. In practice, however, "there are still important gaps in our understanding of neuronal metabolism, with important consequences for interpreting BOLD fMRI signals," cautions John Mayhew, University of Sheffield, England, in an accompanying commentary. For example, he points out that there is considerable heterogeneity in the density of capillaries and the number of mitochondria in the brain. Other problems may also need to be ironed out, the authors write, as the initial dip is not always observed.—Tom Fagan
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