Despite a rapidly-growing scientific and clinical brain imaging literature based on functional MRI using blood oxygenation level dependent (BOLD)1 signals, it remains controversial if BOLD signals in a particular region can be caused by activation of local excitatory neurons2. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications3. Using a novel integrated technology unifying optogenetic4–13 control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIα-expressing excitatory neurons, either in neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (ofMRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that ofMRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations14 and fMRI with electrical stimulation which will also directly drive afferent and nearby axons, this ofMRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-employed fMRI BOLD signal, and the features of ofMRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.
Functional magnetic resonance imaging (fMRI) has been widely used for imaging brain functions. However, the extent of the fMRI hemodynamic response around the active sites, at submillimeter resolution, remains poorly understood and controversial. With the use of perfusion-based fMRI, we evaluated the hemodynamic response in the cat visual cortex after orientation-specific stimuli. Activation maps obtained by using cerebral blood flow fMRI measurements were predominantly devoid of large draining vein contamination and reproducible at columnar resolution. Stimulusspecific cerebral blood flow responses were spatially localized to individual cortical columns, and columnar layouts were resolved. The periodic spacing of orientation columnar structures was estimated to be 1.1 ؎ 0.2 mm (n ؍ 14 orientations, five animals), consistent with previous findings. The estimated cerebral blood flow response at full width at half-maximum was 470 m under single-stimulus conditions without differential subtraction. These results suggest that hemodynamic-based fMRI can indeed be used to map individual functional columns if large-vessel contributions can be minimized or eliminated.
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