A quadratic regression analysis of the relationship between prefrontal activation and striatal dopamine function across the whole sample, independent of group, indicated that this followed an inverted U-shaped curve (Figure 4). Thus, prefrontal activation was maximal in subjects with midrange levels of dopamine function, but less marked in subjects in whom dopamine function was either relatively low or relatively high. This relationship is similar to the inverted U relationship between prefrontal cortical function during working memory tasks and afferent dopamine activity described in experimental animals and in healthy human subjects.11,19,61 According to this model, there is a dopamine activity level that is optimal for efficient working memory function, corresponding to the peak of the inverted U curve.19,62- 63 The opposite direction of the correlations between Ki and prefrontal activation in the ARMS and control groups can be interpreted as reflecting their different positions on the putative inverted U curve. In the ARMS group, in whom dopaminergic function is relatively elevated, most subjects would tend to lie to the right of the curve's peak, where the efficiency of prefrontal function is relatively low. Within this group, the greater the Ki, the further the subject lies to the right of the curve, the less efficient their prefrontal function, and the weaker the activation.64 Conversely, in the controls, most subjects lie to the left of the curve's peak. Within this group, the greater the Ki, the closer the subject lies to the peak of the curve, the greater the prefrontal efficiency and the level of activation. While we observed a significant correlation between striatal dopamine function and prefrontal activation, there was no evidence of a correlation between dopamine function and performance of the N-back task. Although the inverted U-shaped curve that relates prefrontal function to dopamine activity was originally defined on the basis of neurophysiological, rather than behavioral, measures of prefrontal function,63 a relationship between dopamine activity and performance of another task putatively mediated by prefrontal cortex (the Wisconsin Card Sorting Test) has also been reported.25 Task performance can be seen as an indirect measure of the underlying prefrontal physiology and may be influenced by a range of additional factors. It is thus not surprising that we were able to detect a relationship between dopamine function and prefrontal activation, but not with task performance. The latter might have been evident if there had been significant group differences in task performance and if the study had been powered to detect differences at the behavioral, as opposed to the physiological, level. In line with this neurochemical pattern, we found that, within the ARMS sample, those lying to the right of the peak of the inverted U-shaped curve showed greater recruitment of superior frontal, medial frontal, and parietal areas than those positioned on the left side of the peak. The greater engagement of these areas can be interpreted as a compensatory response to maintain normal task performance in the face of elevated dopamine activity. The finding that prefrontal function is related to the level of striatal dopamine function in controls as well as in patients, and that the relationship in both groups may follow a common curve, suggests that there is a continuum across controls and subjects with an ARMS with respect to prefrontal and dopamine function. This may reflect the composite psychopathological status of the ARMS group, which includes subjects with true prodromal signs (who will later develop psychosis) and subjects who are at high risk but will not develop psychosis.65 The participants in the present study have not yet been followed up for a sufficient period (at least 2 years is required50) to determine their long-term clinical outcome, and the extent to which the findings relate to the subsequent onset of psychosis remains to be determined. Clinical follow-up of the ARMS sample may clarify whether subjects who subsequently develop psychosis lie furthest to the right of the curve's peak.