The prefrontal cortex (PFC) is assumed to contribute to goaldirected episodic encoding by exerting cognitive control on medial temporal lobe (MTL) memory processes. However, it is thus far unclear to what extent the contribution of PFC-MTL interactions to memory manifests at a structural anatomical level. We combined functional magnetic resonance imaging and fiber tracking based on diffusion tensor imaging in 28 young, healthy adults to quantify the density of white matter tracts between PFC regions that were activated during the encoding period of a verbal free-recall task and MTL subregions. Across the cohort, the strength of fiber bundles linking activated ventrolateral PFC regions and the rhinal cortex (comprising the peri-and entorhinal cortices) of the MTL correlated positively with free-recall performance. These direct white matter connections provide a basis through which activated regions in the PFC can interact with the MTL and contribute to interindividual differences in human episodic memory.functional MRI | tractography | hippocampus | perirhinal cortex | entorhinal cortex E pisodic memory (1) is the ability to encode, store, and recall events in their spatial and temporal context. Human lesion studies (2, 3) have demonstrated that episodic memory function is critically dependent on the hippocampus and neighboring structures of the medial temporal lobe (MTL), and functional neuroimaging experiments have shown that episodic memory encoding is associated with activations of the MTL and regions of the prefrontal cortex (PFC) (1, 4, 5).During encoding, both MTL and PFC regions show stronger activity for items that are later recalled compared with items that are forgotten [difference because of memory (DM)] (for reviews see refs. 6 and 7). It had long been hypothesized that coactivation of PFC and MTL structures might indicate that both regions cooperate during encoding and that activated PFC regions might be anatomically connected to MTL structures by white matter tracts (8). Via these fiber tracts, PFC regions might exert top-down control on MTL structures (9, 10) that act as gateways to the hippocampus, most notably the entrorhinal and perirhinal cortices (ERC and PRC, respectively, jointly referred to as the rhinal cortex) (7).Although intriguing, the possibility of a direct anatomically based functional interaction between PFC regions and the ERC and PRC during successful encoding is not without doubt. Activity patterns that reflect successful encoding in functional MRI (fMRI) studies are most frequently observed in the ventrolateral and dorsolateral PFC (VLPFC and DLPFC, respectively) (6, 7). However, studies in nonhuman primates suggest that the strongest PFC projections to the ERC and PRC arise in the orbitofrontal cortex (11-13). In contrast, structural connectivity between DLPFC/VLPFC and the MTL is light (10-13). Therefore, the question whether prefrontal areas that show encoding-related activity patterns are connected with the ERC and PRC is particularly relevant in humans.Diffusion tensor im...