Individual differences in cognitive flexibility.

I s it better to be flexible, or persistent? A colleague once said that the secret to success in science is perseveration (no, not mere perseverence—that wouldn’t get you very far at all). Yet we all believe that the highest levels of cognitive function are associated with extreme flexibility—the ability to juggle many things at once and not get hung up on just one. Indeed, this ability to juggle the many demands of being a scientist are seemingly even more important these days than perseverating on one important deep problem. Clearly, these two poles of flexibility and perseverence (aka stability) both have benefits and costs (even in the world beyond the ivory tower), and it would make sense that, at a population level, individuals might be differentially distributed across this spectrum to cover our collective bases (1). Samanez-Larkin et al. (2) provide an important advance in understanding the biological basis for these individual differences, leveraging the powerful technique of dopamine (DA) receptor availability measurements under radioligand positron emission tomography (PET) imaging. This technique is uniquely important for understanding the function of DA (and other neuromodulators) in humans, by virtue of being able to noninvasively assess both DA receptor availability and differences in DA levels, across different brain areas. Interestingly, they found that individual differences in cognitive flexibility were predicted by baseline DA D2/D3 receptor availability in the prefrontal cortex (PFC), parietal cortex, and thalamus, whereas amphetamineinduced DA release in the anterior striatum additionally predicted individual differences (and partially mediated the cortical and thalamic effects). Interpreting these results requires wading into a complex sea of countervailing effects of dopamine and dopamine receptors across the striatum and PFC, as nicely reviewed by Cools and D’Esposito (3). Broadly speaking, consistent with a variety of data, D1 receptors in the PFC are associated with greater stability, whereas D2 receptors promote flexibility. However, the opposite pattern seems to hold in the striatum: D1 receptors promote flexibility, and D2 promotes stability. Furthermore, in the striatum, DA activation of D2 receptors has an overall inhibitory effect, whereas it is excitatory on D1. Putting this all together, we see that Samanez-Larkin et al. (2) bowled a perfect strike: they found D2 baseline availability effects on flexibility in PFC but not in the striatum, whereas they found increased DA levels in the striatum associated with greater flexibility, which would presumably lead to greater D1 receptor activation. If someone ever figures out a way to image D1 receptor availability using PET, then one would predict the opposite pattern, in which flexibility is associated with greater D1 baseline availability effects in striatum and lower levels of D1 availability in the PFC. As emphasized by Cools and D’Esposito (3), these opposing dynamics in PFC versus striatum provide a nice opportunity for the commonly seen U-shaped