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standing the dynamics of neuronal/vascular coupling. Similarly, although it has been known for some time that there is a rapid onset of increased tissue oxygen in both primary sensory (visual) and higher-order (language) cortex in humans after stimulation (7), the exact temporal ordering, indeed even the fundamental relationship, between changes in oxygen metabolism and the hemodynamic parameters of blood flow and blood volume is still to be fully defined.

These issues have importance beyond their obvious physiological interest. For example, although a wide range of data support the notion that large-scale changes in hemodynamics occur within 2 to 3 sec of underlying neuronal events, several recent reports, including those using both optical (8) and MRI techniques (9, 51), note that there may be subtle, but observable, changes in these physiological parameters in times of a few hundred milliseconds after neuronal stimulation. The origin of such changes remains controversial, but is critical to understanding whether even more precise timing information may be obtainable by using these hemodynamic and metabolic measures, and to understanding the quantitative relationship between these physiological changes and the degree of underlying neural activity.

Dynamic Physiology and fMRI

Whatever its ultimate origin, the link between increased neuronal firing and changes in cerebral hemodynamics and metabolism is certainly a rapid one. Although early efforts at human functional brain imaging relied (and continue to rely) on the anatomic correspondence between neuronal activity and hemodynamics, nuclear tracer technologies, both positron emission tomography and single photon emission computed tomography, typically lacked the temporal resolution to take advantage of the temporal elements of this physiological linkage (10, 11). The earliest functional activation studies with MRI, which used exogenous paramagnetic tracers to map changes in cerebral blood volume, had similar limitations, allowing interrogation of changes in brain state with temporal sampling measured across several minutes (12).

This situation changed radically with the concurrent development of two advances in MRI. First, though initially described early in the history of MRI (13), very rapid MRI techniques were refined only to the point of human use at high field (1.5 Tesla) by the end of the 1980s (14). These techniques are capable of acquiring complete two-dimensional images after a single radio frequency excitation (by using echo planar imaging or other k-space trajectories such as spiral scanning). It was in fact this development that allowed for the initial studies of cerebral blood volume by using exogenous tracers (15), and thus was the key technical development for the first functional MR images of brain activity, by using contrast agents (12).

Second, two new “endogenous” contrast mechanisms were described. One of these mechanisms was based on changes to the net longitudinal magnetization within an organ produced by changing tissue perfusion. Originally described by Detre, Koretsky, and colleagues at Carnegie Mellon University (16), these first experiments now have spawned a whole host of quantitative methods, broadly named arterial spin labeling techniques, capable of measuring CBF with high spatial and temporal precision. The second of these mechanisms was based on changes in the transverse magnetization produced by local changes in the magnetic susceptibility induced by changing net tissue deoxyhemoglobin content. Labeled BOLD contrast for blood-oxygen-level-dependent changes by Seige Ogawa of Bell Labs (17), these early experiments demonstrated that, as had been observed in vitro by Thulborn et al. (18). changes in blood oxygenation induced changes in blood MR signal intensity in vivo.

It was the combination of these endogenous contrast mechanisms with rapid imaging technology that inspired a veritable revolution in human brain mapping. The first successful demonstrations of human brain activation were performed by combining high-speed imaging and both arterial spin labeling and BOLD contrast mechanisms (1922). These initial demonstrations showed that the changes in MRI signal intensity within activated cortical regions could be reliably measured by using equipment designed for high signal sensitivity. Of greater importance for this discussion, these demonstrations revealed that the MR signal changes were truly dynamic, with MRI signal changes occurring only seconds after the neuronal activity onset (see Fig. 1; ref. 20). Thus these earliest experiments were often shown as cine (movie) images, allowing visualization of the temporal dimension to tomographic human brain functional imaging. Dynamic fMRI was born.

Despite the early recognition that these dynamic fMRI experiments were fundamentally different from previous hemodynamically based functional imaging methods, these early studies typically used experimental paradigms that could have been easily performed by using previous nuclear technologies. Specifically, most experiments were performed by using extended periods of “on” versus “off” activations—so-called block designs—which had been the stalwart of functional studies of sensory and higher cortical function using positron emission tomography and single photon emission computed tomography for more than a decade. Nevertheless, although such block designs are a necessity when imaging hemodynamics by using techniques that require a quasi-equilibrium physiological state for periods upward of 1 min, they were clearly not required for fMRI experiments, where activity was detectable within seconds of stimulus onset.

Movement away from blocked designs was gradual and aided by a number of studies exploring fMRI signal responses to brief stimulus events. Blamire et al. (23), for example, showed that a stimulus duration of as little as 2 sec could produce detectable signal changes. Under such a situation, the observed signal changes were actually after the stimulus offset, owing to the few-second rise time of the hemodynamic response. Bandettini and colleagues (24) demonstrated signal changes to even shorter task events. Subjects were instructed to make finger movements for durations ranging from 1/2 sec to 5 sec. In all situations, including the brief 1/2-sec movement duration, clear signal increases were detected. A number of similar studies of motor and visual stimulation followed (2528). The use of visual stimulation allowed the limits of duration

FIG. 1. Adapted from Kwong et al. (20). BOLD contrast signal change is shown for a region of visual cortex during stimulation (on) and during rest (off). These data originally were used to demonstrate the application of BOLD contrast fMRI in normal human subjects. As can be seen, the rise time of the signal (indicated with arrows) is very rapid and has occurred after just a few seconds of stimulation, indicating that shorter stimulus events should be detectable.



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