How does ventrolateral prefrontal cortex (VLPFC) control mnemonic processing? Alternative models propose that VLPFC guides top-down (controlled) retrieval of knowledge from long-term stores or selects goal-relevant products of retrieval from among competitors. A paucity of evidence supports a retrieval/selection distinction, raising the possibility that these models reduce to a common mechanism. Here, four manipulations varied semantic control demands during fMRI: judgment specificity, cue-target-associative strength, competitor dominance, and number of competitors. Factor analysis revealed evidence for a metafactor that accounted for common behavioral variance across manipulations and for functional variance in left mid-VLPFC. These data support a generalized control process that selects relevant knowledge from among competitors. By contrast, left anterior VLPFC and middle temporal cortex were sensitive to cue-target-associative strength, but not competition, consistent with a control process that retrieves knowledge stored in lateral temporal cortex. Distinct PFC mechanisms mediate top-down retrieval and postretrieval selection.

Learning and memory in humans rely upon several memory systems, which appear to have dissociable brain substrates. A fundamental question concerns whether, and how, these memory systems interact. Here we show using functional magnetic resonance imaging (FMRI) that these memory systems may compete with each other during classification learning in humans. The medial temporal lobe and basal ganglia were differently engaged across subjects during classification learning depending upon whether the task emphasized declarative or nondeclarative memory, even when the to-be-learned material and the level of performance did not differ. Consistent with competition between memory systems suggested by animal studies and neuroimaging, activity in these regions was negatively correlated across individuals. Further examination of classification learning using event-related FMRI showed rapid modulation of activity in these regions at the beginning of learning, suggesting that subjects relied upon the medial temporal lobe early in learning. However, this dependence rapidly declined with training, as predicted by previous computational models of associative learning.

Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRI study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism.