The lateral prefrontal cortex and human long-term memory

Handbook of Clinical Neurology, Vol. 163 (3rd series) The Frontal Lobes M. D’Esposito and J.H. Grafman, Editors https://doi.org/10.1016/B978-0-12-804281-6.00012-4 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 12

The lateral prefrontal cortex and human long-term memory 1 2

ROBERT S. BLUMENFELD1 AND CHARAN RANGANATH2* Department of Psychology, California State Polytechnic University, Pomona, CA, United States

Center for Neuroscience, Department of Psychology, University of California Davis, Davis, CA, United States

Abstract Recent research has demonstrated that the lateral prefrontal cortex is extensively involved in human memory, including working memory processes that support retention of information across short delays, and episodic long-term memory encoding and retrieval processes. This chapter reviews results from neuroimaging studies of memory, from noninvasive brain stimulation studies of memory, and from studies of memory in patients with prefrontal lesions. The available evidence is consistent with the idea that different prefrontal regions implement cognitive or executive control processes that support working memory and episodic long-term memory encoding and retrieval.

INTRODUCTION Dating back at least to the work of Jacobsen (Jacobsen et al., 1935), researchers have been interested in the functional role of the lateral prefrontal cortex (PFC) in memory. Here we focus on a broad range of evidence regarding the role of prefrontal subregions in episodic long-term memory (LTM) encoding and retrieval, presenting and providing evidence for a general framework for understanding the roles of different prefrontal regions in long-term memory encoding and retrieval. Our view, which is shared by many in the field, is that the contribution of PFC to LTM emerges from its more general role in service of cognitive control. To better appreciate this relationship, we will start off by considering how PFC damage affects memory for events.

EFFECTS OF PREFRONTAL LESIONS ON LTM ENCODING AND RETRIEVAL Neuropsychologic studies of patients with prefrontal lesions Clinicians have long noted that focal prefrontal lesions in humans produce subtle but noticeable memory deficits, and this impression accords with results from

neuropsychologic studies (Stuss and Benson, 1986; Shimamura, 1995; Ranganath and Knight, 2003). In general, patients with PFC lesions are impaired on a wide range of memory tasks that tax executive control during encoding and/or retrieval (Stuss and Benson, 1986; Moscovitch, 1992; Shimamura, 1995; Ranganath and Knight, 2003). For instance, PFC patients exhibit impaired performance on unconstrained memory tests such as free-recall (Jetter et al., 1986; Janowsky et al., 1989a; Eslinger and Grattan, 1994; Gershberg and Shimamura, 1995; Wheeler et al., 1995; Dimitrov et al., 1999). In contrast to healthy control participants, PFC patients do not spontaneously cluster or group recall output according to semantic relationships in a categorized word list (Hirst and Volpe, 1988; Incisa della Rochetta and Milner, 1993; Stuss et al., 1994; Gershberg and Shimamura, 1995). Furthermore, when presented with several study-test trials with the same word list, healthy participants tend to recall items in the same order across recall trials, a phenomenon termed subjective organization (Sternberg and Tulving, 1977). Patients with prefrontal lesions, however, show less trial-to-trial consistency of recall output order compared to controls (Stuss et al., 1994; Gershberg and Shimamura, 1995; Alexander, 2003).

*Correspondence to: Charan Ranganath, Ph.D., 1544 Newton Court, Davis, CA 95616, United States. Tel: +1-530-757-8750, Fax: +1-530-757-8640, E-mail: [email protected]

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Patients with prefrontal lesions also exhibit impaired performance on tests of source memory (Janowsky et al., 1989b; Duarte et al., 2005), memory for temporal order (Shimamura et al., 1990; McAndrews and Milner, 1991; Butters et al., 1994; Kesner et al., 1994; Mangels, 1997), and memory for frequency (Stanhope et al., 1998). Furthermore, PFC patients often fail to spontaneously use common memory strategies and lack insight into their own memory problems (Hirst and Volpe, 1988; Janowsky et al., 1989a; Moscovitch and Melo, 1997; Vilkki et al., 1998). In contrast to these deficits, patients with prefrontal lesions can often perform at near-normal levels when given structured encoding tasks or tests that do not tax strategic retrieval processes. For instance, PFC patients perform better at cued-recall compared to free-recall and have only a mild impairment in item recognition (Wheeler et al., 1995). Moreover, patients can show marked improvements on a variety of recall measures if given sufficient practice or environmental support at encoding or retrieval (Hirst and Volpe, 1988; Incisa della Rochetta and Milner, 1993; Gershberg and Shimamura, 1994; Stuss et al., 1994).

Recollection and familiarity in patients with prefrontal lesions As mentioned earlier, patients with prefrontal lesions tend to show only mild recognition memory deficits. Behavioral research has supported the idea that item recognition can be supported by either the assessment of familiarity, or by the recollection of specific details associated with the item (Yonelinas, 2002). Some researchers have speculated that prefrontal damage may selectively affect recollection (Squire and Knowlton, 1995; Davidson and Glisky, 2002; Gold et al., 2006), based on reports of recollection deficits among the healthy elderly (Davidson and Glisky, 2002) and among amnesic patients with Korsakoff’s syndrome (Squire and Knowlton, 1995). To directly test the role of PFC in recognition memory, it is necessary to directly assess recollection and familiarity in patients with focal prefrontal lesions. One methodologic challenge in addressing this question is that prefrontal lesions are typically unilateral (due to stroke or tumor excision), and therefore patients might rely on the intact hemisphere to support performance. A study by Duarte et al. (2005) dealt with this issue by using a divided-field presentation method to specifically assess memory performance for information that was encoded in the visual field contralateral to the lesioned hemisphere (contralesional) and the field ipsilateral to the lesioned hemisphere (ipsilesional). Thus, if PFC regions contribute to familiarity or recollection, one would expect deficits in these processes to be most substantial when objects were encoded in the contralesional visual field. Patients and controls were tested using the remember-know method, in which they decided

whether each test object was shown during the study phase, and if so, whether they could recollect specific details about the study episode. These data were then used to create quantitative indices of familiarity and recollection for objects encoded in the contralesional and ipsilesional hemifields in each patient and similar indices were created for each visual field in the corresponding age- and education-matched control participant. As shown in Fig. 12.1, patients showed impaired familiarity for objects that were presented in the contralesional field at the time of encoding. Furthermore, although PFC patients did not exhibit deficits in subjective recollection, patients with left frontal lesions exhibited impairments in memory for the context in which each word was encountered (i.e., source memory). Findings from this study demonstrate that, contrary to previous assertions, the PFC is necessary for normal familiarity-based recognition. Additionally, although patients with PFC lesions may have a subjective experience of recollection, they may still exhibit impairments in the ability to use recollected information to make source attributions. This finding makes sense if one assumes that PFC damage affects control processes, rather than memory storage. That is, engagement of PFC-dependent control processes most likely impacts encoding of overall familiarity strength and encoding of distinctive contextual information that would support recollection (Ranganath et al., 2003, 2005a; Blumenfeld and Ranganath, 2006). Furthermore, engagement of PFC-dependent control processes at retrieval most likely affects strategic search and decision processes that influence the retrieval and use of familiarity and recollective information (see also Farovik et al., 2008 for a study demonstrating that ventromedial PFC is critical for recollection in the rodent; Ranganath and Paller, 2000; Ranganath et al., 2003, 2007).

Theoretical accounts of memory deficits following prefrontal lesions Theoretical accounts of memory deficits in patients with prefrontal lesions generally fall into two categories. Some theories emphasize the role of the PFC in selection processes that direct attention toward goal-relevant information and task-appropriate responses. Thus, memory deficits may arise in patients with prefrontal lesions because they are unable to select goal-relevant information or inhibit distracting or interfering items or responses during encoding or retrieval (Luria, 1966; Perret, 1974; Shimamura, 1995). One finding consistent with this account comes from a study of paired associate learning in patients with focal PFC lesions and matched controls (Shimamura et al., 1995). In this study, participants learned a list of word pairs (A–B) and then learned an overlapping list of word pairs (A–C) across several trials. Recall success on the A–C list required subjects to inhibit the A–B pairing and select the appropriate A–C pairing.

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Fig. 12.1. Experimental design and results from Duarte et al. (2005). (A) Participants with lateral prefrontal lesions and controls encoded objects that were briefly flashed to the left or right hemifield, and then performed retrieval tests assessing memory for each item and the task that was performed during encoding. (B) Lesion overlap for patients. Right frontal lesions have been transcribed to the left hemisphere to determine the overlap across all patients. The color scale indicates the percentage of patients with lesions in a specific area. (C) Results showed that subjective measures of recollection (left) were relatively spared in the patients, whereas familiarity (middle) was impaired, particularly for objects encoded in the contralesional visual field. Source memory (right) performance was also impaired in patients with left frontal lesions.

Critically, patients with PFC lesions showed a disproportionate decrease in recall performance between the first trial of A–B learning compared to the first trial of A–C learning (i.e., a measure of proactive interference), as compared to controls. Furthermore, during cued recall of the

A–C list, PFC patients recalled significantly more intrusions from the A–B list. These finding suggest that patients with prefrontal lesions were unable to inhibit the influence of previously learned associations during encoding or retrieval of new associations.

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The second category of theories to explain memory deficits following prefrontal lesions emphasizes the role of the PFC in guiding spontaneous organization of information (Milner et al., 1985; Hirst and Volpe, 1988; Incisa della Rochetta and Milner, 1993; Gershberg and Shimamura, 1995). In psychology, “organization” refers to memory strategies that emphasize the forming or utilizing of relationships among items in a list during encoding and/or retrieval. Some common organizational strategies during encoding include categorizing words in a list according to semantic features, imagining two or more items interacting, or forming a sentence out of two or more words. Organizational processes do not facilitate LTM by enhancing features of specific items in memory, but rather by promoting memory for associations among items. The organizational account described here can explain free-recall deficits seen in patients with PFC lesions, because free recall is thought to rely heavily on organization of information in the study list. One study directly tested this hypothesis by comparing performance of patients with lateral prefrontal lesions and healthy controls on learning of lists of words that were either semantically related or unrelated (Gershberg and Shimamura, 1995). Patients with PFC lesions showed impaired recall of items from both related and unrelated lists. Furthermore, the patients failed to demonstrate normal levels of subjective organization and failed to show semantic clustering following study of semantically related lists, two indices of organizational processing during encoding. Interestingly, recall and clustering performance increased for semantically related word lists when patients were explicitly asked to make a category judgment during encoding or when they were provided with the category names at test or both. The same was not true for the healthy controls, who performed at similar levels regardless of whether they were given cues or instructions. This pattern of results suggests that patients were capable of using semantic information to guide encoding and retrieval, but that they lacked the ability to spontaneously use semantic organizational strategies. In contrast, controls were spontaneously using organizational strategies during encoding and/or retrieval. These findings, and others (Hirst and Volpe, 1988; Incisa della Rochetta and Milner, 1993; Stuss et al., 1994; Alexander et al., 2003), suggest that LTM deficits following prefrontal lesions may emerge partly from a failure to organize information during encoding and capitalize on organizational structure during retrieval. Many researchers have suggested that both selection and organizational processes depend on the functioning of the PFC, and there are several studies that have found support for both the interference and organizational accounts in the same study (Hirst and Volpe, 1988;

Stuss et al., 1994; Gershberg and Shimamura, 1995; Shimamura et al., 1995; Alexander et al., 2003). One question that cannot be addressed by the neuropsychologic evidence is whether selection and organization depend upon the same regions of PFC, because these studies typically used subject groups that have significant heterogeneity in lesion size and location. However, in light of the evidence from imaging studies of white matter (WM) control processes, it is possible that VLPFC is particularly critical for selection of relevant item information, whereas DLPFC is particularly critical for building of relationships between items in a manner that supports organization. As we will describe in following text, this hypothesis is consistent with results from neuroimaging studies of LTM encoding and retrieval.

FUNCTIONAL NEUROIMAGING OF PFC SUBREGIONS DURING LTM ENCODING Event-related fMRI studies have investigated LTM encoding by identifying “subsequent memory” or Dm (difference due to memory) effects (Paller and Wagner, 2002). In these paradigms, brain activity is monitored during the performance of an incidental encoding task (i.e., semantic processing of a single word). Following scanning, a surprise memory test is administered, and brain activation during encoding is analyzed as a function of later memory success or failure. For example, participants might be given a semantic encoding task in the scanner and then, once out of the scanner, they receive an item recognition test on the items they studied. The results can then be used to contrast brain activity during successful vs unsuccessful encoding. The overwhelming majority of these studies implicates regions of VLPFC, most prominently pars triangularis (
BA 45) in LTM encoding, and a smaller subset of studies finds DLPFC activity associated with subsequent LTM (Blumenfeld and Ranganath, 2007). We have argued that this broad pattern in the encoding literature reflects an important distinction in the processing roles of these regions (Blumenfeld and Ranganath, 2006, 2007; Ranganath and Blumenfeld, 2007; Blumenfeld et al., 2011). In particular, we have theorized that VLPFC subregions (see Fig. 12.2 regions colored red: BA 44, 45, 47/12), via their role in selecting distinctive, goalrelevant item information in WM, will support LTM in a wide variety of contexts. In contrast, DLPFC subregions (see Fig. 12.2 regions colored green: BA 9, 9/46, 46), via their role in selecting and transforming goalrelevant item–item relational information in WM, will specifically support the encoding of item–item relationships in LTM. This item/relational framework has broad support in the literature. In particular, DLPFC activity has been found

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Fig. 12.2. A lateral view of the human brain, illustrating functional differentiation within the PFC along the rostrocaudal and dorsoventral axes. Based on the literature reviewed here, we have proposed that lateral PFC is organized into two distinct gradients of function along the rostrocaudal axis. Areas in VLPFC (depicted in red) are involved in the selection of goal-relevant item information. From caudal to rostral, these VLPFC areas are involved in selecting goal-relevant item information at progressively higher levels of item-feature abstraction. This functional gradient is depicted as a red color gradient from caudal (dark red) to rostral (light red). Areas in DLPFC (depicted in green) are involved in selecting goalrelevant relational information in service of an action plan. From caudal to rostral, DLPFC areas are involved in selecting goal-relevant relational information at progressively higher levels of temporal abstraction or conditional/relational complexity. This functional gradient is depicted as a green color gradient from caudal (dark green) to rostral (light green). RLPFC (yellow) is depicted at the apex of dorsal cognitive control processing—involved in the selection of the most temporally abstract or relationally complex goal-relevant information. In this way RLPFC may be involved in selecting cognitive sets that determine which item-feature information and relational information are appropriate targets for selection.

to predict subsequent LTM during encoding conditions that emphasize processing of item–item relational information in a range of studies (Summerfield and Mangels, 2005; Addis and McAndrews, 2006; Blumenfeld and Ranganath, 2006; Murray and Ranganath, 2007; Qin et al., 2007; Blumenfeld et al., 2011). One such study provides evidence that DLPFC activation is related to successful LTM encoding, specifically under conditions that emphasize processing of relationships between items (Blumenfeld and Ranganath, 2006). In this study, participants were scanned during the performance of two WM tasks (Fig. 12.3A). On “rehearse” trials, participants were presented with a set of three words and required to maintain the set across a 12-s delay period, in anticipation of a question probing memory for the identity and serial position of the items. On “reorder” trials, participants were

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required to rearrange a set of three words based on the weight of the object that each word referred to. They maintained this information across a 12-s delay period in anticipation of a question probing memory for serial order of the items in the rearranged set. Although both rehearse and reorder trials required maintenance of the three-item set, reorder trials additionally required participants to compare the items in the set and transform the serial order of the items. Thus reorder trials forced participants to actively process relationships between the items in the memory set, whereas rehearse trials simply required maintenance of the memory set across a delay. Analyses of subsequent recognition memory performance showed that there were significantly more reorder trials in which all three items were recollected than would be expected, based on the overall item hit-rates alone (Fig. 12.3B). The same was not true for memory for rehearse trials, for which the proportion of trials on which all three items were subsequently recollected was no different than would be expected by the item hit-rates alone. These findings suggest that, on reorder trials, processing of the relationships among the items in each memory set resulted in successful encoding of the associations among these items. Consistent with the idea that the DLPFC is involved in processing of relationships between items in WM, fMRI data revealed that DLPFC activation was increased during reorder trials, as compared with rehearse trials (Fig. 12.3C). Furthermore, DLPFC activation during reorder, but not rehearse trials, was positively correlated with subsequent memory performance. Specifically, DLPFC activation was increased on reorder trials for which 2–3 items were later recollected, as compared with trials for which 1 or 0 items were later recollected. Critically, no such relationship was evident during rehearse trials. In contrast, activation in a posterior region of left VLPFC (BA 44/6) was correlated with subsequent memory performance on both rehearse and reorder trials. Thus, results from this study suggest that DLPFC and VLPFC may play dissociable roles in LTM encoding. DLPFC activation may specifically promote successful LTM formation through its role in processing of relationships among items, whereas VLPFC activation seems to promote LTM formation under a broader range of conditions. Several subsequent studies have addressed key limitations in this first study by Blumenfeld and Ranganath (2006). One such limitation was the fact that, although we found evidence that DLPFC activity during reorder trials promoted LTM for item–item associations, we did not directly measure subsequent item–item relational LTM. Furthermore, beyond being more relational, the reorder condition led to more recollection and to greater LTM overall; thus a possibility could exist that DLPFC tracks high levels of item LTM strength rather than relational processing per se. Murray and Ranganath (2007)

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Fig. 12.3. Experimental design and results from Blumenfeld and Ranganath (2006). (A) Schematic depiction of the two tasks performed during fMRI scanning. (B) Behavioral results, showing that participants recalled significantly more triplets from each reorder trial (yellow) than would be expected based on the overall hit rate. This finding suggests that, on reorder trials, memory performance was supported by associations among the items in the memory set. (C) fMRI data showing that DLPFC (top) exhibited increased activation during the delay period of reorder trials for which 2–3 items were subsequently remembered (solid yellow), as compared with trials in which 0–1 items were remembered (dashed yellow). No such effect is seen on rehearse trials (gray lines). At bottom, activation in a region of posterior VLPFC (pVLPFC) is plotted, showing that delay period activation in this region during both rehearse and reorder trials was predictive of subsequent memory performance.

directly investigated the encoding and subsequent LTM for item–item relationships held in WM and found that DLPFC activity was enhanced specifically for subsequently remembered compared to forgotten item–item relationships. To rule out the possibility that item strength or recollection was driving subsequent memory effects in DLPFC, we conducted a separate study that used an fMRI encoding task with one condition that promoted strong LTM for distinctive item information and another condition that promoted strong LTM for distinctive item–item relationships. Consistent with our view, we found that DLPFC activity was associated with successful encoding of subsequent item–item associations in LTM and not for item-specific details. Results from other studies have demonstrated the specific nature of DLPFC contributions to memory encoding by comparing the relationship between activation and subsequent performance on free recall and item recognition memory tests (Staresina, 2006; Long et al., 2010). As described earlier, item recognition tests are often insensitive to memory for inter-item associations in LTM, whereas recall performance is significantly influenced by encoding of inter-item associations (Tulving, 1962). Consistent with a role for DLPFC in encoding inter-item associations, Staresina and Davachi (2006) found that DLPFC activation was specifically

enhanced during encoding of items that were recalled compared to those that were not. DLPFC activation was not correlated with subsequent item recognition performance. In contrast, encoding time activation in VLPFC was positively correlated with subsequent memory performance on both the recall and the recognition tests. These results are consistent with the idea that DLPFC activation will contribute to subsequent LTM performance specifically under retrieval conditions that are sensitive to memory for associations among items. Another study examining PFC contributions to encoding and subsequent recall also found differences between VLPFC and DLPFC that is consistent with a role of DLPFC involved in relational encoding. In this study, by Long et al. (2010), words were presented in short study lists, and encoding and free recall were both scanned. Several measures of subsequent recall were examined, including item recall and extent of semantic clustering of recall output. Semantic clustering occurs when participants recall semantically related items in a study list together, making use of embedded relational information during encoding to later guide their recall output. As mentioned previously, this type of memory is thought to be highly influenced by relational encoding. Indeed, Long et al. (2010) found that DLPFC, and not VLPFC,

THE LATERAL PREFRONTAL CORTEX AND HUMAN LONG-TERM MEMORY activation during encoding correlated with the extent to which participants semantically clustered during subsequent recall. Interestingly, in contrast to the result of Staresina and Davachi (2006), VLPFC activation was correlated with item recall, but not DLPFC activation. One reason for this difference may have been the use of short encoding lists in Long et al. (2010) study. Short lists lead to higher overall performance, and, as such, recall of individual items might not additionally benefit from relational encoding. Thus results from fMRI studies of subsequent recall are consistent with a dorsoventral division of labor, in which DLPFC regions are specifically associated with relational encoding processes that build item–item associative information in LTM that disproportionately contributes to subsequent recall vs recognition and drives semantic clustering of recall.

FUNCTIONAL NEUROIMAGING OF PFC SUBREGIONS DURING LTM RETRIEVAL Regions in DLPFC, VLPFC, and RLPFC are routinely activated during memory tasks (Fletcher and Henson, 2001; Ranganath and Knight, 2003; Ranganath et al., 2003; Ranganath, 2004), but these studies have not shown a consistent relationship between prefrontal activation and successful retrieval. This is not surprising, however, if PFC activation reflects control processes that are engaged during retrieval tasks even when retrieval fails (Ranganath et al., 2000, 2007; Dobbins et al., 2002; Simons et al., 2005b). If different prefrontal regions contribute to different control processes, then it may be more fruitful to compare and contrast activation between retrieval conditions that are more or less likely to engage these processes, rather than contrasting activation between successful and unsuccessful retrieval (Fletcher and Henson, 2001). Results from such studies have converged in many respects with results from studies of WM and LTM encoding in implicating VLPFC in item processing and DLPFC in relational processing. One study conducted by Fletcher and colleagues is particularly relevant, in that they observed a double dissociation between the roles of VLPFC and DLPFC across two LTM retrieval tasks. In this study, positron emission tomography was used to measure prefrontal activation during two different retrieval tests. In one condition, the study lists were structured lists of 16 single words that were organized according to an overall theme and then broken down into four subcategories. For these lists, participants were given a free recall test, with the instruction to use the organizational structure of the list to guide retrieval. In the other condition, the study lists consisted of 16 category-exemplar word pairs (e.g., “fruit–banana”). For these lists, participants performed

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a cued recall test, in which they had to recall the appropriate exemplar in response to each category name (e.g., “fruit–?”). These two retrieval conditions differed in terms of the control processes that should be engaged during retrieval. In the free recall condition, participants were encouraged to use relational processing in order to generate appropriate retrieval cues, whereas in the cued recall condition, the specific cue was already provided. However, in the cued recall condition, presentation of a category name would presumably activate many semantic associations, and therefore item-based selection processes would be required to resolve this conflict (Thompson-Schill et al., 1997; Wagner et al., 2001). Critically, the authors found a double dissociation between activation within the PFC, such that DLPFC activation (BA 46) was increased during the free recall condition, whereas VLPFC activation (BA 44) was increased during the cued recall condition. This finding is strongly consistent with findings from WM and LTM encoding studies suggesting that VLPFC regions implement processes that modulate activation of item representations, whereas DLPFC regions implement processes that activate representations of relationships among items. In addition to more lateral regions of PFC, areas in RLPFC (BA 10, see Fig. 12.2 region in yellow for approximate location) also exhibit increased activation during LTM retrieval, and particularly during source memory tasks that require retrieval of detailed information (Nolde et al., 1998; Fletcher and Henson, 2001; Ranganath and Knight, 2003). An interesting finding that emerged from many of these studies is that RLPFC activation is often not contingent on successful retrieval, or even on the difficulty of the retrieval decision (Henson et al., 1999; Rugg et al., 1999; Ranganath and Paller, 2000; Dobbins et al., 2002, 2003; Simons et al., 2005a,b; Ranganath et al., 2007). As noted earlier, RLPFC activation during WM tasks tends to be associated with the demand to select or maintain a cognitive set that dictates what information is relevant for selection. Cognitive models of memory retrieval suggest that this may be particularly relevant for accurate performance on source memory tasks (Johnson et al., 1993, 1997; Mather et al., 1997; Norman and Schacter, 1997; Marsh and Hicks, 1998). This is because episodic memories are complex and consist of multiple characteristics (e.g., records of perceptual information in multiple modalities, cognitive operations, actions, affective reactions, etc., Johnson et al., 1993). In many instances, a potential retrieval cue can activate several potential memories, including information that is irrelevant to a particular source decision (Koriat and Goldsmith, 1996; Johnson, 1997; Koriat et al., 2000). Source memory decisions therefore demand the selection of an

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appropriate cognitive set in order to constrain retrieval of information associated with a cue and to narrow down the criteria for subsequent decision processes (Johnson et al., 1993; Mather et al., 1997; Norman and Schacter, 1997; Marsh and Hicks, 1998). This set would be initiated in response to a retrieval cue in order to constrain retrieval of information associated with the cue and narrow down the criteria for subsequent decision processes (this process has been described as setting decision criteria, feature weights, or a retrieval orientation) (Johnson et al., 1993; Johnson and Raye, 1998; Rugg and Wilding, 2000). We hypothesize that RLPFC is critical for selecting cognitive sets, and that source memory decisions constitute an example of when this process must be engaged. One way of testing this idea is to contrast RLPFC activation between retrieval tasks that vary in terms of the specificity of the memory decision that is to be made (Ranganath and Paller, 2000; Ranganath et al., 2000). In one such study, brain activity was contrasted between a retrieval task that required participants to make a general item recognition decision vs a retrieval task that required participants to make a recognition decision specifically based on the match between the visual features of test items relative to studied items (Fig. 12.4). Not surprisingly, participants were slower and less accurate at responding to previously studied items in the more specific test condition. However, for unstudied items, accuracy and reaction times were comparable across the two test conditions. Results showed that activation in left RLPFC was increased during the more specific test, as compared with the more general test. What is more remarkable, however, is that activation during specific test trials were also increased for new items that were not seen during the study phase, despite the fact that behavioral performance was the same across the two test conditions. Thus, RLPFC activation during specific test trials reflected the need to constrain retrieval of information associated with each test item and to narrow down the criteria for subsequent decision processes. In this sense, RLPFC activation in source memory tasks might be analogous to activations in WM tasks in which one must select and maintain sets of rules that dictate the items or relationships that are currently relevant (Braver et al., 2003; Bunge et al., 2003; Sakai and Passingham, 2003). Relevant to this idea, some researchers have suggested that RLPFC may be involved in maintaining an “episodic retrieval mode”—a cognitive set that ensures that stimuli will be treated as cues for episodic retrieval (Lepage et al., 2000; Rugg and Wilding, 2000; Buckner, 2003). This view is supported by recent functional imaging studies showing sustained anterior prefrontal activity during episodic retrieval tasks, sometimes extending

Fig. 12.4. Experimental design and results from Ranganath et al. (2000). Participants studied objects that were shown in a large or small size, and then at test were shown objects that were either larger or smaller than the studied objects. In the “General” test condition, participants were instructed to make a decision as to whether each object was studied, whereas on specific test trials, participants were additionally instructed to decide whether each test object was larger or smaller than the studied objects. In a region of left RLPFC, shown in the lower right panel, activation was increased for both old and new items in the specific test, as compared with the more general test condition (lower left panel).

across multiple retrieval trials (Duzel et al., 2005; Lepage et al., 2000; Velanova et al., 2003). Additionally, retrieval mode-related activation in RLPFC appears to depend on the degree of control that is required in a given episodic memory test (Velanova et al., 2003). These findings are consistent with the idea that RLPFC is more generally involved in selection and maintenance of cognitive sets that support accurate episodic retrieval and source monitoring.

NONINVASIVE STIMULATION OF PFC DURING LTM ENCODING Recent studies have used repetitive transcranial magnetic stimulation (TMS) to probe the role of PFC in LTM encoding (see Floel and Cohen, 2007 for review). The majority of these studies find that TMS to PFC disrupts memory encoding (Floel et al., 2004; K€ohler et al., 2004; Rossi, 2004; Gough, 2005; Kahn et al., 2005; Rossi et al., 2006; Manenti et al., 2009; Gagnon et al., 2010; Innocenti et al., 2010; Machizawa et al., 2010; Balconi, 2013). As reviewed earlier, neuroimaging studies indicate that different regions of lateral PFC

THE LATERAL PREFRONTAL CORTEX AND HUMAN LONG-TERM MEMORY might contribute to memory encoding in different ways. Unfortunately, most TMS studies have not used approaches that allow precise targeting of PFC subregions (e.g., MRI-guided stereotaxic localization). To address this limitation, Blumenfeld et al. (2014) conducted a TMS study in which MRI-guided stereotaxic localization was used to precisely localize mid-VLPFC (
BA 45) and mid-DLPFC (
BA 9/46). They hypothesized that TMS to VLPFC should impair item encoding, whereas TMS to DLPFC would not affect encoding of item information. Participants in this study were prompted to semantically encode individually presented nouns. This task, adapted from Wagner et al. (1998), emphasizes the deep encoding of item information and places minimal demands on encoding relations among items. A mixed design was used such that participants were randomly assigned to a PFC condition (DLPFC vs VLPFC) and received TMS on two separate sessions (PFC vs vertex). A critical aspect of this study is that items with similar semantic features were distributed equally across studied and foil lists. This manipulation ensured that participants could not base retrieval solely

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on shared semantic features (i.e., relational information), and instead, participants needed to use item-specific information to correctly reject foil items. Consistent with our framework, almost every participant in the VLPFC group exhibited an impairment in subsequent item memory during VLPFC TMS compared to vertex TMS (Fig. 12.5). Interestingly, this disruption was seen specifically in the false alarm rate (i.e., VLPFC TMS increased false alarms), suggesting that TMS impaired participants’ ability to encode item-specific information. In contrast, mid-DLPFC elicited no significant effect on item recognition and, if anything, TMS appeared to enhance subsequent item recognition (Fig. 12.5). Thus, taken together, this TMS study provides strong evidence that subregions along the dorsoventral axis of PFC make different contributions to LTM encoding.

CONCLUSIONS AND FUTURE PROSPECTS Converging evidence from neuropsychology and neuroimaging supports the idea that prefrontal regions play an

Fig. 12.5. Results from Blumenfeld et al. (2014). Left top: mean raw d0 values computed for DLPFC, VLPFC, and their respective vertex sessions. Left bottom: difference in DLPFC–vertex and VLPFC–vertex performance. Results show significant subsequent item LTM disruption following VLPFC but not DLPFC TMS during encoding. Right: TMS effects for individual participants. Each plot depicts difference in d0 comparing PFC TMS vs vertex TMS. Negative values (disruption) are plotted toward the left and positive values (enhancement) are plotted toward the right. Right top: majority of participants in VLPFC group show item LTM disruption with VLPFC TMS. Right bottom: majority of participants in DLPFC group show item LTM enhancement with DLPFC TMS.

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important role in LTM encoding and retrieval. VLPFC may support LTM encoding by enhancing the strength and distinctiveness of item information, whereas the DLPFC may support encoding by building associations among items. During retrieval, VLPFC may support the ability to resolve competition in order to retrieve relevant items from memory, whereas DLPFC may support the ability to use relational information to guide successful retrieval and to inhibit previously learned associations. Additional evidence suggests that RLPFC may support the selection of rules to determine the dimensions on which a retrieval cue and retrieved information should be processed. Although recent work has revealed a great deal about lateral prefrontal contributions to memory, there are important unresolved questions. One important question concerns how PFC subregions interact with one another and with posterior cortical regions. Given the functional role for RLPFC suggested previously, it would seem that RLPFC should modulate activation in corresponding regions of DLPFC and VLPFC, depending on the task set that is to be implemented (Sakai and Passingham, 2003). Furthermore, to the extent that VLPFC implements processes that select features of relevant items, one might expect that VLPFC should show increased connectivity with posterior areas that represent those features (Gazzaley et al., 2004). DLPFC regions, however, might process relational information in a number of ways. For instance, it is possible that DLPFC processes relational information by directly modulating activation in posterior cortical areas (Summerfield et al., 2006), perhaps by modulating the relative timing of neural firing within and across different areas (Shastri, 1996). Another possibility is that the posterior parietal cortex maintains dynamic relational bindings on line (Vogel et al., 2001), and that DLPFC can alter these bindings through its interconnections with parietal regions (Wendelken et al., 2008). A third possibility is that the DLPFC might modulate activation of relationships between items through its interactions with VLPFC (Blumenfeld and Ranganath, unpublished observations). Of course, none of the three accounts are mutually exclusive, and much more research needs to be done to address this fundamental question. Our review has focused on lateral prefrontal regions, but accumulating evidence has suggested that ventromedial PFC (VMPFC) subregions (areas 10, 11, 14, 25) € ur also play a critical role in memory processes (Ong€ et al., 2003). Research on these areas has generally focused on their contributions to decision-making, but these areas are extensively interconnected with medial temporal regions (hippocampal area CA1, perirhinal cortex, and entorhinal cortex) that are critical for LTM

(Kondo et al., 2003; Ranganath and Ritchey, 2012). Neuroimaging results (Ranganath and D’Esposito, 2005; Zeithamova and Preston, 2010; Ranganath and Ritchey, 2012; Zeithamova et al., 2012; Preston and Eichenbaum, 2013; van Kesteren et al., 2013; Bowman and Zeithamova, 2018) and studies of patients with ventromedial lesions (Rapcsak et al., 1996, 1999; Johnson et al., 1997; Moscovitch and Melo, 1997; Schnider and Ptak, 1999; Schnider et al., 2000; Gilboa et al., 2006, 2009; Gilboa and Marlatte, 2017; Gilboa and Moscovitch, 2017; Spalding et al., 2018) are consistent with the idea that these areas contribute to memory. Interestingly, though, unlike lateral PFC regions, these regions rarely demonstrate subsequent memory effects during LTM encoding or retrieval success effects. Rather, VMPFC activation has been found during successful category learning (Bowman and Zeithamova, 2018), successful transitive inference (Spalding et al., 2018), tasks that explicitly require retrieval of memory schema (van Kesteren et al., 2010, 2013), and during memory monitoring tasks (Gilboa et al., 2009; Gilboa and Moscovitch, 2017; Bonasia et al., 2018). One common feature of these tasks is that they either require or benefit from flexible, goal-relevant processing of item and/or context schemas. That is, these tasks prominently feature more holistic rather than detailed processing of items and context. As such, extant theories have posited that VMPFC regions are involved in and critical for encoding and retrieval of schemas during LTM decisions. There are several important questions that remain unaddressed, however. For instance, although current theories of VMPFC function do incorporate findings in the rodent LTM literature (Preston and Eichenbaum, 2013), current theories have yet to incorporate findings in the nonhuman primate electrophysiological literature. In particular, these studies link VMPFC (areas 10, 11 and 14 specifically) to value comparison or value-based decision-making processing (Rudebeck et al., 2006, 2008, 2013; Rudebeck and Murray, 2011) during reward-based learning or reward preference tasks. Thus it is not clear how representations of schema relate to representations of stimulus value (Rudebeck and Murray, 2011). Another question is that, given the large psychologic literature that finds schemas aid in encoding and retrieval (Bartlett, 1932; Anderson, 1981; see van Kesteren et al., 2012), why are VMPFC regions so rarely implicated in the fMRI encoding and retrieval literature? Could this be a methodologic issue (i.e., related to the sensitivity of typical encoding or retrieval fMRI paradigms) or a conceptual one? And, finally, given differences in cyto-architecture, whitematter pathways, and homology between rostral “granular” and caudal “agranular” VMPFC (Insausti and € ur et al., 2003; Neubert et al., 2015), Muñoz, 2001; Ong€

THE LATERAL PREFRONTAL CORTEX AND HUMAN LONG-TERM MEMORY future research should be directed toward investigating how the functions of VMPFC differ along its rostrocaudal axis. In conclusion, human neuropsychology and neuroimaging research has revealed significant insights into the roles of different regions of PFC in different kinds of memory processes. We have presented an integrative framework to characterize these roles, but further research needs to be done to flesh out this framework and to address several important, and as yet unresolved, questions. Given the fact that disturbances in memory and prefrontal functioning are associated with normal aging (Tisserand and Jolles, 2003), cerebrovascular disease (Wu et al., 2002; Nordahl et al., 2005, 2006), and in psychiatric (Cohen and ServanSchreiber, 1992; Glahn et al., 2005) and neurologic (Elliott, 2003; Levin and Hanten, 2005; Neary et al., 2005) conditions, addressing these questions will be of fundamental importance.

ACKNOWLEDGMENTS The authors would like to acknowledge support from the Vannevar Bush Faculty Fellowship program sponsored by the Basic Research Office of the Assistant Secretary of Defense for Research and Engineering and funded by the Office of Naval Research through grants N000141510033 and N00014-16-1-2511. Additional support was provided by a Multi-University Research Initiative Grant (ONR N00014-17-1-2961) from the Office of Naval Research and NIH Grant 5R01MH105411. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Office of Naval Research, the US Department of Defense, or the US Public Health Service.

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