Left lateral prefrontal cortex (PFC) is consistently activated in neuroimag
ing studies of memory encoding. Its role, however, remains unclear. We desc
ribe two functional magnetic resonance imaging (fMRI) studies addressing th
is question. In the first we used a blocked experimental design to explore
the effect of repeated encoding of word paired associates. Initial presenta
tion of word pairs was associated with left ventrolateral PFC activation th
at attenuated with subsequent presentations of the same lists. When well-le
arned lists were presented with word pairs rearranged, a left PFC activatio
n, greater than that associated with the initial presentation, was observed
. In a second experiment, the formation of these associative relationships
was explored using an event-related design. Two types of word pairs were pr
esented: closely related (e.g., Ring...Queen) and distantly related (e.g.,
Net...Ship). The same region of left PFC was differentially sensitive to th
ese two event-types, showing a greater response for distantly related pairs
. We suggest that left PFC activity, at memory encoding, reflects operation
s necessary to the formation of meaningful associations in the service of o
ptimal learning. A crucial feature of such associative processing lies in s
electing appropriate, and inhibiting inappropriate, semantic attributes of
the study material. (C) 2000 Academic Press.