Working memory-related hippocampal deactivation interferes with long-term memory formation

Abstract

Previous findings indicate that the hippocampus does not only play a role in long-term memory (LTM) encoding, but is important for working memory (WM) as well, in particular when multiple items are being processed. A recent study showed that maintenance of multiple items was associated with hippocampal activation (hippocampus-dependent WM), while maintenance of individual items induced hippocampal deactivations (hippocampus-independent WM). Here, we used two complimentary approaches to investigate whether WM-related activity patterns occur also during LTM encoding of sequentially presented items and whether they are related to the primacy effect, i.e., improved LTM encoding of items presented at the beginning of the list. Intracranial electroencephalogram in epilepsy patients and functional MRI in healthy subjects were recorded during a word-list learning task. As expected, the proportion of successfully encoded items was higher at the beginning of the list than at later list positions. Items at the beginning of the list which were subsequently forgotten were associated with negative blood oxygen level dependent responses and positive direct current slopes, corresponding to hippocampal deactivations, suggesting that they were not processed in hippocampus-dependent WM. These deactivations were absent for items later in the list and for subsequently remembered items. These data show that if processing of items at the beginning of the list is accompanied by hippocampal activity patterns previously observed during hippocampus-dependent WM, these items are subsequently remembered. However, deactivations of the hippocampus as previously observed during WM maintenance of individual items predicts failure of LTM encoding.

Figure 1.

A, Overview of the paradigm. After presentation of 12 consecutive words, a number between 80 and 90 was presented and subjects had to count backward by three aloud. After 30 s of this distraction task, there was a free recall phase in which subjects loudly pronounced all words they remembered. B, C, Timing of the paradigm in the iEEG (B) and fMRI (C) version of the experiment.

Figure 2.

Recall performance as a function of list position. A, Primacy effect in the group of healthy control subjects which were investigated with fMRI. B, Primacy and recency effects in the group of epilepsy patients with intracranial EEG electrodes.

Figure 3.

Position-dependent shifts of DC potentials. The slope of the DC potential in the hippocampus depends on list position for subsequently forgotten items, but not for subsequently remembered items.

Figure 4.

Position-dependent BOLD responses in the hippocampus. Time course of BOLD activity in anatomically defined regions of interest in the bilateral hippocampus (A). B, For subsequently forgotten items, there was a deactivation during presentation of the first item, which was reduced for later list positions. C, For subsequently remembered items, no deactivation was apparent. The time period selected for statistical analysis is marked in light gray.

Figure 5.

Position effects in the anterior cingulate cortex. For both subsequently forgotten and remembered items, we observed an increased activation of the anterior cingulate cortex (remembered: MNI −3/39/15; forgotten: MNI −3/36/15).

Figure 6.

Alternative model: position effects in the hippocampus and cingulate cortex. Contrast of activity during presentation of the seventh and first item in anatomically selected regions of interests in bilateral hippocampus (left and middle column) and anterior cingulate cortex (right column). For subsequently forgotten items presented at the first list position, there was a negative BOLD response in the left hippocampus, which was absent at the seventh list position (A, left column). No negative BOLD responses occurred in the right hippocampus (A, middle column) and for subsequently remembered items (B, left and middle column). On the whole-brain level, there was an increased activation in the anterior cingulate cortex at the seventh as compared with the first list position regardless of subsequent memory (right column).