McNab and colleagues provide groundbreaking evidence showing that cognitive training with working memory tasks over a five-week period impacts D1 dopamine receptor availability in prefrontal cortex. Links between prefrontal D1 receptor function and working memory are often thought to be one-directional, i.e., that better D1 function supports better working memory, but here the authors show that working memory practice reciprocally affects D1 receptors.

An influential body of empirical and theoretical research suggests that an optimal level of prefrontal D1 receptor stimulation is required for working memory function (e.g., Seemans and Yang, 2004). Because acute pharmacological targeting of prefrontal D1 receptors reliably alters working memory, causal directionality from D1 to working memory remains evident. Nevertheless, these findings cast several other studies in a new light. Namely, when a population exhibits impaired (or enhanced) working memory and PET studies indicate differences in dopaminergic function, it is no longer clear which variable is the main driving factor. For example, those who engage in cognitively demanding tasks on a day-to-day basis may show better working memory and dopaminergic correlates may be reactive rather than causal. Finally, the possibility cannot be completely discounted that the observed changes in D1 receptor binding may reflect a learned increase in prefrontal dopamine release; this would explain the general tendency for D1 receptor availability to decrease with cognitive training, due to competition with endogenous dopamine.

The McNab study also finds that only cortical D1 receptors, and not subcortical D2 receptors, were altered by cognitive training. The significance of this null effect of D2 receptors is not yet clear. First, all tasks used in the training study involved recalling the ordering of a sequence of stimuli and repeating them back when probed. While clearly taxing working memory, these tasks did not require subjects to attend to some stimuli while ignoring other distracting stimuli, and did not require working memory manipulation. Both manipulation and updating are characteristics of many working memory tasks, particularly those that depend on and/or activate the basal ganglia. Indeed, previous work by the same group (McNab and Klingberg, 2008) showed that basal ganglia activity is predictive of the ability to filter out irrelevant information from working memory. Similarly, Dahlin et al. (2008) reported that training on tasks involving working memory updating leads to generalized enhanced performance in other working memory tasks, and that this transfer of learned knowledge is predicted by striatal activity. These results are consistent with computational models suggesting that the basal ganglia act as a gate to determine when and when not to update prefrontal working memory representations and are highly plastic as a function of reinforcement. Thus, future research is needed to test whether training on filtering, updating, or manipulation tasks leads to changes in striatal D2 receptor function.

References:

McNab, F. and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103-107. Abstract

Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L. & Nyberg, L. (2008). Transfer of learning after updating training mediated by the striatum. Science, 320, 1510-1512. Abstract

Seamans, J.K. and Yang, C.R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1-57. Abstract

View all comments by Michael J. Frank

This is an important article that describes profound changes in the dopamine D1 receptor binding potential after working memory training in healthy male controls. The study rests on prior work that has demonstrated changes in brain volume with practice (e.g., Draganski and May, 2008), and dopamine can be released at the synapse in measurable amounts even during, dare I say, fairly trivial activities (e.g., playing a video game (Koepp et al., 1998). The present study demonstrated that binding potential of D1 receptors decreased in cortical regions (right ventrolateral frontal, right dorsolateral PFC, and posterior cortices) with training, and the magnitude of this decrease correlated with the improvement during training. Binding potential of D2 receptors in the striatum did not change. Unfortunately, D2 receptors in the cortex could not be measured with raclopride.

Two points come to mind. One is theoretical—how long would such a change remain, i.e., is it transient or is it fixed? This has implications for understanding practice-related phenomena and their transfer or consolidation. The second is technical. A number of studies have shown that practice can change not only the magnitude of a physiologic response, but also its location (see Kelly and Garavan for a review, 2005). Thus, the circuitry involved in learning a task may be different than the circuitry involved in implementing a task after it is well learned. By constraining areas to those activated in fMRI during initial working memory engagement, it is possible that other critical areas were not monitored for binding potential changes.

References:

Draganski B, May A. Training-induced structural changes in the adult human brain. Behav Brain Res . 2008 Sep 1 ; 192(1):137-42. Abstract

Kelly AM, Garavan H. Human functional neuroimaging of brain changes associated with practice. Cereb Cortex . 2005 Aug 1 ; 15(8):1089-102. Abstract

Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature . 1998 May 21 ; 393(6682):266-8. Abstract

View all comments by Terry Goldberg