The ensemble that plays together, stays together.

It has long been known that the medial temporal lobe is crucial for the formation and retrieval of episodic memories. This region includes the hippocampal formation (the hippocampus proper and subiculum) and the underlying entorhinal, perirhinal, and parahippocampal cortices, all of which receive a unique complement of cortical inputs. How best to characterize the precise roles of these different brain regions and their interactions is of central concern in understanding the medial temporal lobe contributions to episodic memory. Using functional magnetic resonance imaging (fMRI) to assess brain activity while subjects performed an episodic retrieval task, Giovanello et al. (2004) have contributed two important pieces to this puzzle. First, their findings show that the hippocampal formation is differentially recruited when subjects are asked to make memory decisions about the conjunctive relationship (in this case, the co-occurrence) of two stimuli compared to decisions about each stimulus independently. Second, their data demonstrate that the extent to which the hippocampus is activated also depends critically on whether the two stimuli were actually previously paired. In this study, subjects encoded a series of word pairs by forming sentences that contained the two words. At retrieval, subjects were asked to engage in two different tasks: an “Item” task that asked subjects to report whether the two test words had been previously presented and an “Associative” task that asked subjects to report whether the two items had been previously presented together. Giovanello and colleagues collected fMRI data during this retrieval phase, demonstrating that the hippocampus shows greater BOLD signal increase when subjects performed the Associative task compared with the Item task. Furthermore, greater BOLD increase within the Associative task was seen to “intact” word pairs (i.e., test words were paired during the study phase) compared to both “rearranged” (i.e., both test words were presented during the study phase but paired with a different word) and to novel word pairs. The implications of these findings are twofold. First, they add to a growing literature demonstrating the involvement of the hippocampus in conjunctive processing (i.e., making decisions about conjunctions between stimuli) above and beyond item processing (i.e., making decisions about individual stimuli). More specifically, these findings underscore the hypothesis that the role of the hippocampus in episodic memory is in the creation of an ensemble of activity that is a filtered representation of all activity in the cortical and subcortical mantle during the moment to moment processing of events. In this way, each singular hippocampal representation might, in essence, act as a mirror reflection of all other activity in the brain and it is through this process that multiple elements of an episode might get bound into a single, conjunctive representation (Norman and O’Reilly, 2003). Second, these results demonstrate not only that the hippocampus is preferentially engaged during conjunctive processing, but also that activity in the hippocampus signals when previously associated stimuli appear together again or are “intact.” Taken together, these findings suggest that hippocampal processes can be modulated by our attentional orientation or goals and is further sensitive to the external environment, namely the repetition of the co-occurrence of conjunctions between stimuli (i.e., a “match”). Intriguingly, it might be the case that the hippocampus can signal an external “match” in the environment regardless of where or how our attention is being focused. Greater engagement of the hippocampal formation during the Associative orienting task complements results from single cell recordings in rats and monkeys demonstrating that hippocampal neurons primarily code for the associations between stimuli and not for individual stimuli (Brown and Aggleton, 2001; Wirth et al., 2003). This is in contrast to the neighboring perirhinal cortex where, instead, neurons have been shown to code for the familiarity or recency of individual items (Brown and Aggleton, 2001). Extending these findings from animal models, a growing number of neuroimaging studies have now shown that the human hippocampus is more active during encoding when attention is oriented towards conjunctions of stimuli rather than to each individual stimulus (Davachi and Wagner, 2002; Henke et al., 1997). Importantly, the magnitude of hippocampal activation during conjunctive encoding has been shown to affect memory formation as many of these studies have demonstrated correlations between hippocampal activation during encoding and later conjunctive memory as measured by recall, paired associate recognition or source recollection (Sperling et al., 2001; Strange et al., 2002; Davachi et al., 2003; Jackson and Schacter, 2004; Ranganath et al., 2004). Of these studies, a small number have also provided evidence for a dissociation between hippocampal and perirhinal encoding processes. Namely, it has been shown that hippocampal and perirhinal cortical engagement can be modulated differentially by task demands to attend either to the conjuncDepartment of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, Massachusetts. Correspondence to: Lila Davachi, Department of Psychology, New York University, New York, NY 10003. E-mail: lila.davachi@nyu.edu Accepted for publication 5 December 2003 DOI 10.1002/hipo.20004 HIPPOCAMPUS 14:1–3 (2004)