What does the hippocampus do during working-memory tasks? A cognitive-neuropsychological perspective.

In this commentary, we highlight the role of the hippocampus as a binding device that may explain its recruitment during associative working-memory paradigms. Furthermore, we argue that both functional neuroimaging research, as presented in Slotnick (this issue), and carefully designed lesion studies in patients with selective bilateral hippocampal damage are crucial for advancing our understanding of the neural structures and processing involved in human memory in general and disentangling the role of the hippocampus proper and other medial temporal lobe structures in working-memory function and long-term encoding specifically.

Neural substrates of successful working memory and long-term memory formation in a relational spatial memory task.

Working memory (WM) tasks may involve brain activation actually implicated in long-term memory (LTM). In order to disentangle these two memory systems, we employed a combined WM/LTM task, using a spatial relational (object-location) memory paradigm and analyzed which brain areas were associated with successful performance for either task using fMRI. Critically, we corrected for the performance on the respective memory task when analyzing subsequent memory effects. The WM task consisted of a delayed-match-to-sample task assessed in an MRI scanner. Each trial consisted of an indoor or outdoor scene in which the exact configuration of four objects had to be remembered. After a short delay (7-13 s), the scene was presented from a different angle and spatial recognition for two objects was tested. After scanning, participants received an unexpected subsequent recognition memory (LTM) task, where the two previously unprobed objects were tested. Brain activity during encoding, delay phase and probe phase was analyzed based on WM and LTM performance. Results showed that successful WM performance, when corrected for LTM performance, was associated with greater activation in the inferior frontal gyrus and left fusiform gyrus during the early stage of the maintenance phase. A correct decision during the WM probe was accompanied by greater activation in a wide network, including bilateral hippocampus, right superior parietal gyrus and bilateral insula. No voxels exhibited supra-threshold activity during the encoding phase, and we did not find any differential activity for correct versus incorrect trials in the WM task when comparing LTM correct versus LTM incorrect trials.

Brain activation during associative short-term memory maintenance is not predictive for subsequent retrieval.

Performance on working memory (WM) tasks may partially be supported by long-term memory (LTM) processing. Hence, brain activation recently being implicated in WM may actually have been driven by (incidental) LTM formation. We examined which brain regions actually support successful WM processing, rather than being confounded by LTM processes, during the maintenance and probe phase of a WM task. We administered a four-pair (faces and houses) associative delayed-match-to-sample (WM) task using event-related functional MRI (fMRI) and a subsequent associative recognition LTM task, using the same stimuli. This enabled us to analyze subsequent memory effects for both the WM and the LTM test by contrasting correctly recognized pairs with incorrect pairs for either task. Critically, with respect to the subsequent WM effect, we computed this analysis exclusively for trials that were forgotten in the subsequent LTM recognition task. Hence, brain activity associated with successful WM processing was less likely to be confounded by incidental LTM formation. The subsequent LTM effect, in contrast, was analyzed exclusively for pairs that previously had been correctly recognized in the WM task, disclosing brain regions involved in successful LTM formation after successful WM processing. Results for the subsequent WM effect showed no significantly activated brain areas for WM maintenance, possibly due to an insensitivity of fMRI to mechanisms underlying active WM maintenance. In contrast, a correct decision at WM probe was linked to activation in the "retrieval success network" (anterior and posterior midline brain structures). The subsequent LTM analyses revealed greater activation in left dorsolateral prefrontal cortex and posterior parietal cortex in the early phase of the maintenance stage. No supra-threshold activation was found during the WM probe. Together, we obtained clearer insights in which brain regions support successful WM and LTM without the potential confound of the respective memory system.

Early and late stages of working-memory maintenance contribute differentially to long-term memory formation.

The present paper investigated the role of early and late stages of working-memory maintenance, which have been suggested to differentially contribute to long-term memory formation. In experiment 1, we administered a delayed-match-to-sample task, requiring participants to remember line drawings of non-sense three-dimensional stimuli. In the delay phase, participants were either presented with a fixation cross (for 2 or 9s) or with one of two different interference tasks, varying in visual overlap with the target. The interference task was presented 1.5, 4.5 or 7.5s after target offset. Early interfering and early probing disproportionately affected performance on an unexpected subsequent recognition-memory task compared to later interference or probing. This was not modulated by the type of interference task. In Experiment 2, we examined whether the formation of a holistic internal code of the target may be a gradual process. An analogous delayed-match-to-sample task was administered, with interference after 0.5, 2.5 or 4.5s after target offset. The early and middle interference condition similarly disproportionately affected performance compared to later interference. Hence, the present results support the view of a functional dissociation between early and late stages of working-memory maintenance and that early working-memory processes contribute particularly to long-term memory formation.

Distinct neural correlates of associative working memory and long-term memory encoding in the medial temporal lobe.

Increasing evidence suggests a role for the hippocampus not only in long-term memory (LTM) but also in relational working memory (WM) processes, challenging the view of the hippocampus as being solely involved in episodic LTM. However, hippocampal involvement reported in some neuroimaging studies using "classical" WM tasks may at least partly reflect incidental LTM encoding. To disentangle WM processing and LTM formation we administered a delayed-match-to-sample associative WM task in an event-related fMRI study design. Each trial of the WM task consisted of four pairs of faces and houses, which had to be maintained during a delay of 10 s. This was followed by a probe phase consisting of three consecutively presented pairs; for each pair participants were to indicate whether it matched one of the pairs of the encoding phase. After scanning, an unexpected recognition-memory (LTM) task was administered. Brain activity during encoding was analyzed based on WM and LTM performance. Hence, encoding-related activity predicting WM success in the absence of successful LTM formation could be isolated. Furthermore, regions critical for successful LTM formation for pairs previously correctly processed in WM were analyzed. Results showed that the left parahippocampal gyrus including the fusiform gyrus predicted subsequent accuracy on WM decisions. The right anterior hippocampus and left inferior frontal gyrus, in contrast, predicted successful LTM for pairs that were previously correctly classified in the WM task. Our results suggest that brain regions associated with higher-level visuo-perceptual processing are involved in successful associative WM encoding, whereas the anterior hippocampus and left inferior frontal gyrus are involved in successful LTM formation during incidental encoding.

The effects of valence and arousal on associative working memory and long-term memory.

BACKGROUND: Emotion can either facilitate or impair memory, depending on what, when and how memory is tested and whether the paradigm at hand is administered as a working memory (WM) or a long-term memory (LTM) task. Whereas emotionally arousing single stimuli are more likely to be remembered, memory for the relationship between two or more component parts (i.e., relational memory) appears to be worse in the presence of emotional stimuli, at least in some relational memory tasks. The current study investigated the effects of both valence (neutral vs. positive vs. negative) and arousal (low vs. high) in an inter-item WM binding and LTM task. METHODOLOGY/PRINCIPAL FINDINGS: A five-pair delayed-match-to-sample (WM) task was administered. In each trial, study pairs consisted of one neutral picture and a second picture of which the emotional qualities (valence and arousal levels) were manipulated. These pairs had to be remembered across a delay interval of 10 seconds. This was followed by a probe phase in which five pairs were tested. After completion of this task, an unexpected single item LTM task as well as an LTM task for the pairs was assessed. As expected, emotional arousal impaired WM processing. This was reflected in lower accuracy for pairs consisting of high-arousal pictures compared to pairs with low-arousal pictures. A similar effect was found for the associative LTM task. However, the arousal effect was modulated by affective valence for the WM but not the LTM task; pairs with low-arousal negative pictures were not processed as well in the WM task. No significant differences were found for the single-item LTM task. CONCLUSIONS/SIGNIFICANCE: The present study provides additional evidence that processes during initial perception/encoding and post-encoding processes, the time interval between study and test and the interaction between valence and arousal might modulate the effects of "emotion" on associative memory.

The interaction of working memory performance and episodic memory formation in patients with Korsakoff's amnesia.

Both neuroimaging work and studies investigating amnesic patients have shown involvement of the medial temporal lobe during working memory tasks, especially when multiple items or features have to be associated. However, so far no study has examined the relationship between working memory and subsequent episodic memory in patients using similar tasks. In this study, we compared patients with amnesia due to Korsakoff's syndrome (n=19) with healthy controls (n=18) on an associative working memory task followed by an unexpected subsequent episodic memory task. The computerized working memory task required participants to maintain two pairs of faces and houses for either short (3s) or long (6s) delays. Approximately 5 minutes after completion of the working memory task, an unexpected subsequent recognition task with a two-alternative forced choice paradigm was administered. By directly comparing working memory and subsequent episodic memory, we were able to examine long-term encoding processes that may take place after longer delays. As expected, patients performed at chance level on the episodic memory task. Interestingly, patients also showed significantly impaired working memory performance (p<.01), even at short delays. Longer delays did not result in better subsequent memory, indicating that they do not facilitate long-term encoding processes. Our results are discussed in relation to Baddeley's working memory model as the episodic buffer is assumed to be a short-term store for maintaining bound representations. In light of these results, the long-standing view that working memory and long-term memory are strictly dissociated may need to be revisited.

Memory for emotional pictures in patients with Alzheimer's dementia: comparing picture-location binding and subsequent recognition.

Emotional content typically facilitates subsequent memory, known as the emotional enhancement effect. We investigated whether emotional content facilitates spatial and item memory in patients with Alzheimer's dementia (AD). Twenty-three AD patients, twenty-three healthy elderly, and twenty-three young adults performed a picture relocation task and a delayed recognition task with positive, negative, and neutral stimuli. AD patients showed a benefit in immediate spatial memory for positive pictures, while healthy young and older participants did not benefit from emotional content. No emotional enhancement effects on delayed item recognition were seen. We conclude that AD patients may have a memory bias for positive information in spatial memory. Discrepancies between our findings and earlier studies are discussed.