Elsevier

NeuroImage

Volume 25, Issue 4, 1 May 2005, Pages 1224-1231
NeuroImage

Hippocampal activations during encoding and retrieval in a verbal working memory paradigm

https://doi.org/10.1016/j.neuroimage.2005.01.038Get rights and content

Abstract

Though the hippocampus has been associated with encoding and retrieval processes in episodic memory, the precise nature of its involvement in working memory has yet to be determined. This functional magnetic resonance imaging (fMRI) study employed a verbal working memory paradigm that allows for the within-subject comparison of functional activations during encoding, maintenance, and retrieval. In each trial, participants were shown 5 target words and, after an 8 s delay, a series of probe words. Probe words consisted of target matches, phonetically or semantically related foils, or foils unrelated to the target words. Both the left and right hippocampi showed higher mean activation amplitudes during encoding than maintenance. In contrast, the right dorsolateral prefrontal cortex (DLPFC) showed greater activation during maintenance than encoding. Both hippocampal and DLPFC regions were more active during retrieval than maintenance. Furthermore, an analysis of retrieval activation separated by probe type showed a trend toward greater bilateral hippocampal activation for probes related (both semantically and phonetically) to the target than for unrelated probes and still greater activation for target matches. This pattern suggests that there may be roles for the hippocampus and DLPFC in working memory that change as function of information processing stage. Additionally, the trend towards increased involvement of the hippocampus with the increase in relatedness of the probe stimuli to the information maintained is interpreted to be consistent with the role of the hippocampus in recollection-based retrieval in long-term memory and may indicate that this role extends to working memory processes.

Introduction

Several lines of evidence support the involvement of the hippocampus in long-term memory (LTM), including reports of memory impairments following hippocampal damage in both humans and animals (Cave and Squire, 1992, Scoville and Milner, 1957), and hippocampal activation in human neuroimaging studies of episodic memory (e.g. Eldridge et al., 2000). More specifically, the hippocampus has been associated with encoding and retrieval of items in LTM (Lepage et al., 1998, Schacter et al., 1999). The involvement with encoding has been proposed to be in part due to the binding together of separate stimuli into a combined representation that includes information about the relationship between the stimuli (Cohen et al., 1999, Davachi, 2004). Hippocampal activation during retrieval has been frequently discussed as it relates to recognition memory, in particular to recollection of specific aspects of an episode (Manns et al., 2003, Squire et al., 2004).

Traditionally, this hippocampal association with LTM was thought to be at the exclusion of any involvement in working memory (WM). Indeed, there is evidence that hippocampal damage may leave basic WM functioning intact (Cave and Squire, 1992, Overman et al., 1990, Sidman et al., 1968, Wickelgren, 1968) and that WM and LTM can be independently impaired (Janowsky et al., 1989, Warrington and Baddeley, 1974). However, it has also become clear that under normal circumstances WM and LTM do not function in isolation. Rather, LTM and WM functions interact in some way, as information stored in LTM can be applied to a current problem-solving task and influence performance on WM tasks (Forde and Humphreys, 2002, Gathercole and Baddeley, 1989, Hodges et al., 1994, Hulme et al., 1991). Many cognitive models of WM have been adapted to incorporate an intersection with LTM processes (e.g. Baddeley, 2000, Cowan, 2000, Ericsson and Delaney, 2000).

Additional evidence for an overlap between WM and LTM comes from investigations of the neuroanatomical structures implicated in each type of processing. In particular, functional investigations of hippocampal activity have suggested that structures associated with LTM may also be implicated in WM. Animals with hippocampal lesions can show alterations in WM performance (Zola-Morgan and Squire, 1986) and hippocampal activity has been demonstrated during WM tasks in behaving laboratory animals (Friedman and Goldman-Rakic, 1988, Sakurai, 1994). Furthermore, functional magnetic resonance imaging (fMRI) studies have shown hippocampal activations during WM in humans (Cabeza et al., 2002, Davachi and Wagner, 2002, Kato et al., 1998, Monk et al., 2002, Ranganath and D'Esposito, 2001). A question of great importance is how to reconcile demonstrations of WM–LTM interactions and hippocampal activations during WM with findings of preserved working memory performance in amnesiacs. Although it has been demonstrated that amnesic patients show intact performance on basic working memory tasks such as the digit span (Cave and Squire, 1992, Sidman et al., 1968, Wickelgren, 1968), there is a paucity of data on whether more subtle aspects of WM are affected, such as the longer WM span for real words than non-words observed by Hulme in healthy patients (Hulme et al., 1991), or influences of semantic information on memory span. If the hippocampus is found to be involved in these more complex aspects of WM but not to be necessary for more basic processes, such a result would help to reconcile the finding of hippocampal activations during WM with the data showing that subjects without a hippocampus can still perform basic WM tasks.

The discrepancies in the neuropsychological and animal findings over whether WM is impaired after hippocampal damage invite further exploration of hippocampal activations during WM using fMRI in healthy, non-lesioned subjects. Since the hippocampus has been implicated in episodic binding during encoding and recollective retrieval functions in LTM, the most parsimonious prediction is that its role in WM may also involve these processes.

Existing functional imaging studies of WM have not allowed for clear parsing of the different process stages (i.e. encoding, maintenance, retrieval); rather, these studies have collapsed analyses across stages (e.g. encoding + maintenance or retrieval + baseline) (Cabeza et al., 2002, Davachi and Wagner, 2002), focused the analysis only on a subset of the stages (Monk et al., 2002), or incorporated additional factors such as novelty (Ranganath and D'Esposito, 2001) or scene complexity (Park et al., 2003). However, tasks without such secondary factors have demonstrated hippocampal activations in time periods that include encoding (Cabeza et al., 2002, Davachi and Wagner, 2002, Monk et al., 2002) and retrieval (Cabeza et al., 2002). Further evidence for hippocampal involvement during encoding and retrieval comes from single-unit recording studies in which hippocampal cells fired for encoding and retrieval but not maintenance (Deadwyler et al., 1996, Hampson and Deadwyler, 2003). However, human fMRI studies clearly differentiating each stage of activation are needed to resolve this issue.

Assuming the hippocampus has a role in WM, a second issue is whether the hippocampus is performing a function of a similar nature across these phases of WM and LTM. During encoding in WM, the hippocampus may be functioning much as it would in LTM by binding the information and experience into an episode, even if in the context of the task, the episode only needs to be maintained for a brief period of time (e.g. Postle, 2003). Similarly, the hippocampal role in WM retrieval may be associated with its involvement in the recollective aspect of retrieval in LTM (Davachi, 2004, Eldridge et al., 2000, Manns et al., 2003, Nemanic et al., 2004). Its role during retrieval in WM may be to recollect specific items out of the material being maintained and recognize whether they match the probe. This issue can be addressed by incorporating different levels of recollection into the framework of a WM task.

This study uses verbal stimuli (non-novel, familiar words) to investigate the phasic role of the hippocampus in WM using a within-subjects design. Foil types presented during retrieval varied in the degree of relatedness of the probe to the target. This manipulation was designed to assess the nature of the information being accessed during the retrieval phase and whether it contained an episodic-like trace.

Section snippets

Participants

Thirteen healthy adult subjects (7 female, 6 male; age (mean +/− SD) = 24.08 +/− 3.48) participated in this study. All subjects gave written informed consent before their participation on a protocol approved by the Internal Review Board of the University of California, Los Angeles.

Cognitive paradigm

The cognitive task is adapted from a paradigm used by Jonides et al. (1998). In each trial, subjects were shown a set of 5 unrelated target words displayed in pink capital letters; each word was displayed for 1 s with

Behavioral data

Behavioral measures of accuracy and reaction time were acquired for all subjects, although due to a button-box failure, data from one of the subjects were unusable. However, this subject performed normally on the out-of-scanner training session. Accuracy did not significantly vary by probe type (P = .191). The average overall accuracy was 95.2 ± .08% correct. Reaction times were 813.8 ± 77.5 ms for phonetic foils, 821.92 ± 80.7 ms for semantic foils, 834.3 ± 91.9 ms for target matches, and

Discussion

The design of this task allowed for the assessment of hippocampal activation during encoding, maintenance, and retrieval stages of verbal WM within-subjects. The principal findings are that hippocampal activity during this verbal WM task is specifically associated with the encoding and retrieval of information, but not with its maintenance. In addition, hippocampal activation shows a tendency to vary according to whether the probe stimulus is related to the initially seen target. Such a pattern

Conclusions

In this study, we found a role for the hippocampus in WM that appears to be much like its role in long-term episodic memory, indicating that it may be involved in encoding and retrieval in general rather than only during LTM tasks. Additionally, the activity during WM may occur in concert with the activity in the pre-frontal cortex with each contributing uniquely to the distinct phases of WM. The finding that a region associated with LTM is selectively active during WM may provide a

Acknowledgments

This research was supported by grant MH65079 from the National Institute of Mental Health (NIMH), by grant RR00827 to the FIRST Biomedical Informatics Research Network (BIRN, http://www.nbirn.net), that is funded by the National Center for Research Resources (NCRR) at the National Institutes of Health (NIH), and by a gift to the UCLA Foundation from Garen and Shari Staglin. The authors wish to thank David Glahn, Ph.D., Russell Poldrack, Ph.D., Kristin Herzberg, Vikas Rao, and Tyler Lesh, as

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