Progress in understanding functional imaging signals.

M ore than a century ago, Roy and Sherrington observed that a change in regional cerebral blood flow (CBF) could reflect neural activity (1). This concept is a basis for modern functional brain imaging technologies including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), intrinsic optical imaging, and near infrared optical tomography. These methods have been extensively used to map various brain functions in humans and animals on a spatial scale of 50 micrometers to a few centimeters. To understand functional maps as ‘‘meaningful’’ neurophysiological parameter(s), a chain of events from behavior to functional signal recording should be understood (see Fig. 1). Task and or stimulation induce synaptic and electric activities in localized regions, which will trigger changes in metabolic and hemodynamic responses including CBF. Then, brain mapping techniques detect a change in one or many vascular parameters, which can be displayed as a colorful functional image. However, the exact relationship between neural activity and a functional imaging signal is not wellunderstood. Therefore, understanding the physiological sources of the functional imaging signals is critically important as summed by Raichle, ‘‘We have at hand tools with the potential to provide unparalleled insights into some of the most important scientific, medical, and social questions facing mankind. Understanding those tools is clearly a high priority’’ (2). This critical issue was investigated by Caesar et al. (3) in this issue of PNAS using rat cerebellum as a model, where excitatory and inhibitory neural activities in Purkinje cells can be controlled by climbing fiber and parallel fiber stimulations, respectively. When excitatory and inhibitory neural activities were independently modulated, CBF was detected by laser Doppler flowmeter. One important observation by Caesar et al. (3) is that blood flow response induced by neural activity is correlated with postsynaptic field potential activities, regardless of type of stimulus. Similar findings were also observed in rat somatosensory cortex and monkey visual cortex (4–8). The same conclusion was drawn whether inhibitory and excitatory stimuli were combined or either stimulation was used alone. Inhibitory synaptic activity increased CBF without producing any spiking activity (4), demonstrating that the action potential, by itself, does not significantly contribute to the CBF change. It should be noted that there is an alternative opinion that the spike activity is indeed an energy-consuming process and increases CBF (9). Generally, spiking patterns and rates (which can be measured by single-unit recordings) are the major interest of most neuroscientists. How can we interpret hemodynamic-based functional signals as a population of action potentials? It seems that we cannot consider