Experimental Design and Hemodynamics

Functional MRI is dependent on hemodynamic changes rather than the electrical consequences of neural activity. The spatial and temporal characteristics of these hemodynamic effects must be taken into account when designing experiments and analyzing the data from these experiments. The spatial characteristics arise from the underlying vasculature; the temporal characteristics include a delay in the onset of detectable MR signal changes in response to neural activity and a dispersion of the resulting hemodynamic changes over a longer time than that of the initiating neural events.

With regard to the temporal aspects of the hemo-dynamics, fMRI experiments can be classified into two broad categories: block designs and event-related designs. In block designs, the experimental task is performed continuously in blocks of time, typically 20-60 sec in duration. The idea here is to ignore the details of the temporal characteristics by virtue of setting up a "steady state'' of neuronal and hemodynamic change. The fact that there is a brief delay before the MR signal changes are detected is often unimportant when analyzing a long block of steady-state activity. This approach is conceptually simple; it is analogous to older PET experimental designs, and it is of great practical importance for fMRI because it is the optimal technique for detecting small changes in brain activity. The major weakness of block design is the requirement that all the stimuli or task characteristics remain unchanged for tens of seconds, precluding the use of many classic psychological paradigms (such as the "oddball" scheme).

The other major approach, event-related design, makes use of the details of the temporal response pattern in the hemodynamics as well as the largely linear response characteristics associated with multiple stimulus presentations. In event-related designs, the different stimuli are presented individually in a random order (rather than in blocks of similar or identical stimuli) and the hemodynamic response to each stimulus is measured. Event-related designs are further subdivided into spaced single-trial designs and rapid single-trial designs. In spaced single-trial designs, stimuli are presented with a long interstimulus interval

(ISI) relative to the hemodynamic response to a single stimulus. Specifically, an ISI of at least 10 sec, and more typically 12-20 sec, is used in an effort to allow the hemodynamic response to each stimulus to return to its resting state before the next stimulus is presented. This approach is conceptually simple but very inefficient in its use of imaging time, much of which is spent collecting data when the MR signal variation due to hemodynamcs is small or not detectable. (This is not only wasteful of expensive imaging time but also boring for the subject, who is only doing something approximately once every 15 sec.)

In contrast to spaced single-trial designs, rapid single-trial designs take advantage of the linearity and superposition properties of the hemodynamic responses to neural activity. To a first approximation, the hemodynamic changes associated with multiple stimulus presentations are additive and when presented at different times, are simple time shifts of each other. This permits the much more efficient design of experiments in which novel stimuli appear in quasi-random order and with variable ISIs (typically presenting a new stimulus every 1-3 sec). The associated data analysis is more difficult because the hemody-namic responses to the different stimuli overlap in time (and there are consequent weaknesses relative to block designs in terms of the detection of small effects) but the rapid single-trial designs are particularly powerful and useful when it is essential to have random order in the presentation of individual stimuli (i.e., in the situation in which a block design with long periods of the same type of stimulus would not permit the desired comparisons for neural activations). It is also more efficient in the use of imaging time and more engaging (less boring) for the subject.

One final approach to experimental design should be mentioned. All of the previously discussed techniques typically make use of averaging over multiple instances of a given trial type. In block design the trials all occur together, so the averaging is done as much by the hemodynamic and neural systems as by any data analysis software. In event-related designs the averaging over the effects of multiple stimulus presentations is done explicitly in software during data analysis. It is possible, however, to analyze spaced single-trial data on the basis of activation from a single event (rather than averaging over multiple instances of the same trial type). This technique has not been widely applied, primarily because the elicited signals to single stimulus events are generally weak. However, high-field MRI systems, and the selection of experimental paradigms that elicit strong, focal neural activity, have been used to demonstrate the feasibility of singleevent fMRI.

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