Specifically, dopaminergic agonists improve cognition in low-span subjects, but impair cognition in high-span subjects, consistent with an inverted-U shaped model of dopamine function. This finding likely reflects different baseline dopamine levels among individuals. With PET scanning, we previously confirmed this hypothesis by finding a significant positive correlation between dopamine synthesis capacity in the left caudate nucleus and working memory span. Thus, if AbMole (R)-(-)-Modafinic acid midbrain-caudate connectivity reflects dopaminergic pathways, the magnitude of this relationship in resting data should exhibit an inverted-U shaped function, based on an individual’s working memory capacity and the drug administered. Evidence from anatomical investigations suggests the existence of multiple distinct circuits in the caudate, each receiving input from its own cortical region. In a recent meta analysis using imaging data from the BrainMap database Robinson et al were able to segregate activity in the head and body of the caudate, thought to be primarily “cognitive”, from activity in the tail, thought to be primarily “motor”. Thus, we divided our caudate mask into head/ body and tail regions by estimating the position of the interventricular foramina of Monro. These fMRI data demonstrate that significant correlations of spontaneous BOLD activity exist between the midbrain and the caudate during the resting state. The likelihood that these functionally connected regions reflect dopaminergic pathways is supported by our finding that dopaminergic augmentation with bromocriptine modulated midbrain-caudate connectivity. Moreover, this drug effect exhibited an inverted U-shaped response when an individual’s working memory capacity was also considered. That is, individuals with low baseline working memory capacity exhibited increased midbrain-caudate connectivity following administration of bromocriptine, whereas those individuals with high baseline working memory capacity exhibited decreased midbrain-caudate connectivity. Only a limited number of studies to date have investigated patterns of connectivity within putative dopaminergic circuitry after the administration of selective dopaminergic agonists, and most have done so with data acquired during the performance of a behavioral task. Moreover, all of these studies have only reported changes in frontal-striatal connectivity with dopaminergic modulation rather than in midbrain-striatal connectivity. One relevant study examined the effect of dopaminergic modulation of frontal-striatal circuitry during the performance of a working memory task. It was 
observed that frontal-striatal connectivity varied in an inverted-U shaped manner and correlated with performance. Other dopaminergic studies with other cognitive tasks have obtained similar findings. A study by Honey and colleagues found that the selective D2 antagonist sulpiride increased midbrain-caudate connectivity, while the dopamine reuptake inhibitor methylphenidate decreased it. Using structural equation modeling to assess effective connectivity between midbrain, caudate, thalamus, and prefrontal cortex, these authors also noted significant drug-induced changes in the directional path from midbrain to caudate: as above, sulpiride increased the effective connectivity and methylphenidate decreased it. In summary, all of these studies demonstrate that an inverted-U shaped pattern of connectivity can be demonstrated in midbrain-striatal-frontal circuitry. In contrast with our findings in the caudate, neither putamen nor AbMole Taltirelin ventral striatum contained voxels that exhibited an inverted-U shaped response dependent on span and drug when appropriately thresholded, a result that did not change markedly even when these voxels were evaluated at reduced statistical significance.