Journal of Clinical and Experimental Neuropsychology 2001, Vol. 23, No. 01, pp. 32±48

1380-3395/01/2303-032$16.00 # Swets & Zeitlinger

Functional Neuroimaging and Episodic Memory: A Perspective Scott W. Yancey and Elizabeth A. Phelps

Department of Psychology, New York University, NY, USA

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ABSTRACT One area of research that has signi®cantly bene®ted from the recent development of functional neuroimaging techniques is the study of memory. In this review we explore what has been learned about the neural basis of normal memory function using these techniques. We focus on episodic memory, which is characterized by the ability to consciously recollect memories for facts or events. We highlight three neuroanatomical regions that have been linked to episodic memory: The hippocampal complex, the prefrontal cortex and the amygdala. For each of these regions, we discuss the behavioral methods of assessment and speci®c episodic memory processes, particularly encoding and retrieval. Finally, we brie¯y comment on the potential clinical applications for this research and other memory systems.

The study of memory, or understanding how the human mind stores and retrieves information, has been a primary focus of psychological and neuroscienti®c literature for the past century. The fruits of this research have yielded the notion that memory is not a unitary superstructure, but rather that memory is divided between a variety of separate, interacting neural systems, each contributing to unique aspects of memory. A classic and well-documented distinction is between memory that is accessible to conscious awareness and can be declared (i.e., explicit or declarative) and memory that is non-conscious and is expressed indirectly (i.e., implicit or non-declarative, see Schacter & Tulving, 1994). This distinction has primarily arisen from the study of patients with brain injury, most notably the famous case of patient H.M. These patients have allowed researchers to study which cognitive and psychological processes are dissociable from one another based upon what parts of the brain are damaged versus what parts are spared. Despite the great theoretical and conceptual gains made through the study of patients with

brain lesions, there are limitations to this method. First, studying a damaged brain does not reveal what the damaged portion does, rather, it reveals what the remaining intact parts can accomplish. Second, naturally occurring lesions are imprecise and very rarely damage a discrete portion or anatomical region of the brain. Instead, the lesions usually involve partial or complete damage to a variety of anatomical regions, including neural pathways that connect different regions or ®bers of passage. This, therefore, inhibits the researcher's ability to describe and attribute a loss of function in a patient with brain damage to a single structure. Third, most studies of patients with brain injury are limited to single cases or a small sample of similar cases. Given the variability in memory abilities across individuals, these small samples limit the conclusions that can be drawn to the striking and obvious impairments and do not allow for more subtle investigations of memory processes. Finally, brain injuries are often permanent and static. It is only possible to assess the changes in memory output following an injury. Given this, one cannot draw conclusions about

Address Correspondence to: Elizabeth A. Phelps, New York University, Department of Psychology, 6 Washington Place, New York, NY 10003, USA. Tel.: (212) 998 8337. Fax: (212) 995 4349. E-mail: [email protected]

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the different stages of mnemonic processing that may be related to distinct neural systems. Although studies of patients with brain injury have provided the framework of multiple memory systems with unique contributions and have identi®ed some brain structures involved in different mnemonic processes, additional techniques are needed to understand the precise roles of the regions and how they interact in everyday memory. Within the past decade, neuroimaging techniques have yielded a new method for the study of the living brain. First, through Positron Emission Tomography (PET) and then functional Magnetic Resonance Imaging (fMRI), brain researchers have gained valuable tools to non-invasively view the workings of the living, healthy brain. These techniques allow for a direct exploration and visualization of how the brain dynamically interacts when presented with a variety of psychological and cognitive tasks. Memory researchers can test speci®c hypotheses about speci®c anatomical regions, in addition to observing interactions among regions. Furthermore, the dynamic nature of PET and fMRI scanning technology allows researchers to examine and test the different stages and changes in the active brain. In the present paper, we will review what has been learned about the neural basis of memory from functional neuroimaging studies. Although this technique is relatively new, it has seen explosive growth resulting in a vast collection of studies examining different aspects of mnemonic processing. Given this, we will focus this review on what is in the colloquial sense thought of as ``memory,'' that is the ability to recollect at will events from our lives. This type of memory for facts and events in our lives is often referred to in the psychological literature as episodic memory (Tulving, 1972). We will begin this review with studies examining structures that have traditionally been associated with episodic memory; the medial temporal lobes (MTL) and, in particular, the hippocampal complex. We will then move on to the role of the prefrontal cortex (PFC) in episodic memory. This region was not traditionally associated with episodic memory performance until the advent of neuroimaging, which is beginning

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to reveal its distinct role in several mnemonic processes. We will then brie¯y discuss what is known about another medial temporal lobe structure, the amygdala, and its unique role in enhancing emotional episodic memories. Finally, we will brie¯y speculate on the potential clinical uses of this basic research using functional neuroimaging to explore memory systems in the human brain. The Hippocampus and Episodic Memory Beginning with Scoville and Milner's (1957) description of impaired memory in patient H.M. following medial temporal lobe (MTL) resection, suspicion has ¯ourished regarding the hippocampus' role in memory. By examining H.M. and other subsequent MTL lesioned patients, a theory developed that the hippocampus was not the center of all memory function, but rather it was the center for episodic memory formation. This conclusion developed because although H.M. and others were severely impaired in forming new autobiographical and semantic memories posttrauma, many of their past memories remained intact. In addition, the domain of the hippocampus was limited to episodic and semantic memory formation. These patients demonstrated learning of certain procedures and stimulus-response relationships, as well as retention of item information when learning was assessed by facilitation of a response based on recent experience (see Schacter, 1987 for a review). Interestingly, these patients could show evidence of learning when memory was assessed indirectly, such as a faster response to a repeated stimulus, but had no conscious recollection of the previous experience at all (e.g., Warrington & Weiskrantz, 1974). Combining these several lines of evidence, researchers developed a theory of the hippocampus' place in the human memory system. They postulated that the hippocampus is the site that mediates the storage of memories for episodes and factual knowledge of the world (Tulving, 1987). This type of memory mediated by the hippocampus has also been referred to as declarative (Squire, 1987) or explicit (Schacter, 1992) memory. Although alternatives and exceptions exist, a vast array of neuropsychological, neuroscienti®c, and psychological literature has contributed support for this theory.

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SCOTT W. YANCEY AND ELIZABETH A. PHELPS

With the advent of functional imaging, a natural place to initiate a study of memory in the human brain was the MTL, and more speci®cally the hippocampal complex, which includes the parahippocampal and perihinal cortices, subiculum, CA ®elds, denate gyrus, and entorhinal cortex. Neuropsychological literature would suggest that tasks designed to invoke and measure episodic memory would induce activation of the hippocampus and related MTL structures. Interestingly, many initial studies did not report any greater activation in the hippocampus and related structures when studying traditional episodic memory paradigms (e.g., Buckner, Petersen, Ojemann, Miezan, Squire, & Raichle, 1995). Several explanations have been put forth to account for these counter-intuitive ®ndings. First, fMRI has limited power to detect a signal with most changes in activation observed resulting from a 1 to 2% difference in signal magnitude between conditions. Unfortunately, the hippocampus resides in a brain region that is subject to more noise in the fMRI signal than other regions. Thus, failure to detect hippocampal activation may re¯ect more of an inherent weakness in fMRI imaging than lack of activity. Another possibility for the lack of activation is the nature of hippocampal neural function itself. It has been suggested that, due to its central position in information processing, the hippocampus is always active, thus there is no relative baseline to compare with the experimental condition. Neuroimaging studies rely on the subtraction method to determine regions that are relatively more involved in one task versus another (see Phelps, 1999 for a discussion). Although the hippocampal complex may be particularly important for memory, there may not be intentional manipulations that signi®cantly increase or decrease activity in this region. Finally, it was suggested that the neural coding in the hippocampus may be so re®ned and subtle that signi®cant differences may be impossible to detect with the current resolution of PET and fMRI imaging. Despite the initial studies that failed to detect hippocampal activation and some of the problems inherent in neuroimaging of this region, a body of literature emerged which did indeed uncover hippocampal activation. These studies revealed a more nuanced assessment of hippocampal func-

tion than previous neuropsychological studies. Based on studies in patients with MTL damage who failed in their efforts to recollect information, it was initially assumed that effort to recollect should result in hippocampal activity. However, the neuroimaging studies to date have generally found that effort was not the key factor in producing hippocampal activation. Rather, success in recollection has generally been shown to be related to activation of the hippocampus. In this review, we will report studies demonstrating hippocampal activation for both encoding and retrieval processes. In short, encoding represents the ®rst stage of mnemonic processing when information is encountered. These studies focus on hippocampal activation at the time the experimental participant is presented with to-be-remembered material. Retrieval is the ®nal stage of memory and these studies focus on hippocampal activation at the time participants are attempting to recall or recognize previously learned material. A third, intermediate stage of memory function is storage or consolidation. At present, no reliable experimental imaging methods exist to study this stage as a process distinct from either encoding or retrieval. This review will focus only on the existing literature for encoding and retrieval. Lastly, a variety of experimental methods have been employed to study encoding and retrieval processes in the hippocampus. These include comparing activation to novel stimuli versus repeated stimuli, novel stimuli versus a resting baseline, processing novel stimuli in one task versus another, and processing one type of stimuli versus another type of stimuli. In addition, new event-related fMRI techniques have allowed researchers to correlate hippocampal activation with the success of later memory performance. For both encoding and retrieval, studies using these different methodologies will be reviewed. Episodic Encoding and the Hippocampus Repetition Comparisons Repetition comparisons have been derived from the assumption that, at time of encoding, there is much more information to be encoded from a novel stimulus than from stimuli that have been repeatedly viewed by the participant. This para-

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digm provides the bene®t of keeping both the encoding task and stimulus class constant, eliminating these possible sources of variance. Translating this assumption into imaging paradigms, signi®cant novelty driven activations have been found for scenes (Gabrieli, Brewer, Desmond, & Glover, 1997; Stern et al., 1996; Tulving, Markowitsch, et al., 1994), words (Kopelman, Stevens, Foli, & Grasby, 1998), object-noun pairs (Rombouts et al., 1997), and word pairs (Dolan & Fletcher, 1997). In accordance with the usual hemispheric differences found throughout neuroscienti®c literature, lateralization occurs for verbal tasks (i.e., they are left lateralized), whereas scene activations appear bilaterally. Rest Comparisons Another method for measuring the amount of hippocampal activation during episodic tasks is to compare it to a baseline condition where the participant is at rest. This rest condition should ensure, in theory, a minimal amount of psychological activity, thereby providing a relatively uniform backdrop to measure episodic encoding. Indeed, relative to rest, signi®cant activation at encoding has been found for visual patterns (Roland & Gulyas, 1995) and faces (Kapur, Friston, Young, Frith, & Frackowiak, 1995). Processing Comparisons These studies examine how, using the exact same stimuli, memory performance is affected by varying task demands, thereby eliminating many perceptual and attentional confounds. A common processing comparison task is the depth of processing paradigm. It is commonly reported in psychological literature that, using the same stimuli, tasks which demand semantic (or deep) encoding of presented stimuli yield better subsequent memory performance than non-semantic (or shallow) tasks (Craik & Lockhart, 1972). For example, by requiring the participant to use the stimulus ``red'' in a sentence (deep processing) would yield greater success for that stimulus on subsequent recall or recognition tests than simply having the participant determine if the stimulus ``red'' is in upper or lower case letters (shallow processing). Building upon this theory, imaging studies have postulated that, using the same sti-

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muli, hippocampal activation will be signi®cantly greater for deeper levels of processing tasks than shallow processing tasks. Greater activation for deeper processing has been found for both words (Vandenberghe, Price, Wise, Josephs, & Frackowiak, 1996; Wagner, Schacter, et al., 1998), and line drawings (Henke, Buck, Weber, & Wieser, 1997; Vandenberghe et al., 1996). Stimulus Comparisons This approach to studying hippocampal encoding processes usually keeps the task demands constant while varying the stimuli. This effectively eliminates the variability that different task demands can place on the hippocampus' activity. For example, a study by Decety et al. (1997) contrasted the encoding of meaningful actions with that of less meaningful actions. Another study examined the encoding differences between various kinds of stimuli (faces, words, and drawings) against a minimal perceptual control such as ®xation or a noise ®eld. An obvious problem with these studies is that differences in the stimuli's perceptual nature, variety, and attention paid could all in¯uence and confound the stimuli's level of encoding regardless of the task demand. Nevertheless, stimuli comparisons are useful for contrasting encoding processes associated with varying classes of stimuli, either by comparison to a common baseline (e.g., Kelley et al., 1998; Martin, Wiggs, & Weisberg, 1997), or by direct comparison between different kinds of stimuli (e.g., Wagner, Poldrack, et al., 1998). When thinking in terms of activation, stimuli that are more meaningful generally yield greater hippocampal activity than less meaningful stimuli. When compared to ®xation points, noise ®elds, or false fonts, hippocampal activation has been observed for words (Kelley et al., 1998; Martin et al., 1997; Price et al., 1994; Wagner, Schacter, et al., 1998), nonsense words (Martin et al., 1997), line drawings (Kelley et al., 1998; Martin, Wiggs, Ungerleider, & Haxby, 1996; Martin et al., 1997; Wiggs, Weisberg, & Martin, 1999), and faces (Kelly et al., 1998). Asymmetrical hemispheric activations were found, with greater left-lateralized activation during encoding of verbal stimuli (Kelley et al., 1998; Martin et al., 1997) while greater right-lateralized activation was found

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during encoding of nonverbal stimuli such as faces (Kelley et al., 1998) and nonsense objects (Martin et al., 1996, 1997). Correlational Performance As the name suggests, this experimental method correlates the level of hippocampal activity during encoding with performance on a later test of memory. In essence, stimuli considered memorable should exhibit high levels of hippocampal activation at encoding and thus be more likely to be remembered on later tests of recall or recognition. These tests may offer the most direct measure of the relationship between hippocampal encoding and memory performance, since direct correlations can be calculated between the level of activation that stimuli elicited and how this translates to successful recall or recognition of the stimuli in subsequent tests. A clear example of this methodology is from two event-related fMRI studies by Brewer et al. (1998) and Wagner et al. (1998), which measured hippocampal activations to presentations of individual scenes or words, respectively (see Fig. 1 For an example image from Brewer et al., 1998). Post scanning, the participants in both studies received recognition tests and were instructed to answer if the presented stimuli were previously seen (old) or novel (new). If they answered old, they had to also indicate if they were more or less certain of this answer. In both studies, hippocampal activation at encoding was greater for well remembered stimuli than for stimuli forgotten. Furthermore, stimuli judged as old but less certain fell into an intermediate range of activation between stimuli well remembered and stimuli forgotten. These studies indicate that the degree of hippocampal activation at encoding directly correlates, and possibly dictates, the success or failure of storing these stimuli into long-term memory. Episodic Retrieval and the Hippocampus Rest Comparisons Using the same reasoning described previously for encoding, rest comparison studies compare activations between episodic retrieval and conditions where participants neither retrieve information nor perform a task. Increased hippocampal activa-

tion has indeed been found during retrieval for spatial information (Ghaem et al., 1997), words (Grasby et al., 1993), faces (Kapur, Friston, et al., 1995), and visual patterns (Roland & Gulyas, 1995). Processing Comparisons The methodology of these studies is similar in nature to the encoding version mentioned earlier. Retrieval comparison studies examine activations associated with episodic retrieval (such as a cued recall or recognition) versus activations for nonepisodic retrieval tasks (such as random or novel word stem completion). For instance, participants would be presented with the word world in the stimulus presentation phase and during the test phase be given the stem wor-, which they would try to complete with a word from the presentation phase. Hippocampal activation for these stimuli would then be compared to a novel word stem stimulus such as bik-, which does not correspond to any previously presented word, and the participants could complete the stem with any word of their choice. Thus, stimulus class is kept constant while task demand varies. Research has shown that there is greater hippocampal activation for episodic retrieval versus matched non-episodic lexical or semantic verbal tasks (e.g., Blaxton, Bookheimer, et al., 1996; Schacter, Alpert, Savage, Rauch, & Albert, 1996; Schacter, Buckner, Koutstaal, Dale, & Rosen, 1997; Squire et al., 1992). In addition, signi®cantly increased hippocampal activation has been found for episodic retrieval relative to viewing stimuli where no operations or tasks were to be performed for ®gural (Schacter et al., 1995; Schacter, Uecker, et al., 1997) and spatial (Maguire, Frackowiak, & Frith, 1996) materials. Correlational Performance In following with the logic used for correlational performance in encoding methodologies, retrieval activations can be correlated with memory performance across participants or even across items in event-related designs. Again, if hippocampal activation correlates to memory performance, then signi®cantly higher activation would be expected for remembered items tested versus forgotten items. A PET study found that greater left anterior hippocampal activation at retrieval correlated

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Figure 1.

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Composite statistical activation maps superimposed on averaged structural MRI slices from six subjects. For all ®gures, the left side of the image corresponds to the left side of the brain. Voxels showing signi®cantly greater activation for scenes than for ®xation are shown as ranging from p < 0.01 (red) to p < 0.0005 (yellow). Taken from Brewer et al., 1998.

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positively with greater recognition memory accuracy (Nyberg, McIntosh, Houle, Nilsson, & Tulving, 1996). An event-related fMRI study found that words which were successfully recollected from a previous study phase exhibited greater posterior hippocampal activation at retrieval than new words correctly identi®ed as not having been seen in the study (Henson, Rugg, Shallice, Josephs, & Dolan, 1999). Anatomical Speci®city within the Hippocampal Complex Thus far, we have discussed the hippocampal activation studies as if the hippocampal complex is one uni®ed structure. However as mentioned earlier, there are a number of substructures that make up the hippocampal complex. Before ending a discussion on the hippocampus and episodic memory, we need to consider the anatomical makeup of the structure and its relation to episodic memory. Although the resolution of most fMRI and PET studies does not allow for the identi®cation of most speci®c substructures within the hippocampal complex, there has been some attempt to identify particular regions of activation within the hippocampus related to different mnemonic processes. A meta-analysis by Lepage, Habib, & Tulving, (1998) reported a fairly consistent pattern with encoding activations being predominantly (91%) in the anterior portion of the hippocampus, while retrieval activations being predominantly (91%) in the posterior portion of the structure. Although these numbers appear strikingly convincing, a follow up meta-analysis by Schacter and Wagner (1999) found far less convincing results. By including several more studies than Lepage et al. (1998) and deleting ones they concluded did not examine memory per se, Schacter and Wagner (1999) found only 58% of encoding activations in the anterior hippocampus, while 80% of retrieval activations were found in the posterior portion. They attribute much of this variability in activation site to con¯icting fMRI and PET results, possibly arising from the inherently different paradigms used when employing each technique. Clearly more work needs to be done to identify the speci®c mnemonic functions related to different regions of the hippocampal complex.

Through examining the previous activation data for encoding and retrieval, it becomes fairly easy to reveal the existence of a relationship between episodic memory and hippocampal function. In general, hippocampal activation seems greater when novel or meaningful episodic stimuli are present versus the contrary. Furthermore, the greater the activation of the hippocampus when viewing or attempting to recall stimuli with these qualities, the more likely successful remembrance will occur. The Frontal Lobes and Episodic Memory Recalling the early stages of neuroimaging, researchers were perplexed by the lack of hippocampal activation on seemingly straightforward tasks of episodic memory. Equally perplexing was the constant and robust activation found throughout the frontal lobes for these exact tasks. A wealth of published reports found frontal lobe activation for both recall and, surprisingly, recognition tests during encoding and retrieval phases (e.g., Craik et al., 1999; Kapur et al., 1994; Shallice et al., 1994; Tulving, Kapur, Markowitsch, et al., 1994). Before discussing the imaging literature in detail, we will brie¯y overview the proposed role of the frontal lobes in episodic memory based on studies with brain-injured patients. Patients who suffer damage to the frontal lobes do not exhibit the pervasive and disabling amnesia that is characteristic of patients with hippocampal lesions. Their memory appears relatively intact. However, their performance on selective episodic memory tasks, speci®cally those that require a great deal of strategic and organizational manipulation, is impaired. To clarify, episodic processes which require memories to be evaluated, transformed, and manipulated seem to evoke the highest degree of impairment for patients with frontal lobe damage (Milner, 1995; Moscovitch and Umilta, 1991; Wheeler, Stuss, & Tulving, 1997). With regard to the standard episodic memory tests of recall and recognition, patients with frontal lobe damage are solely impaired on tests of recall. Recognition tests, whose success depends on stimulus familiarity and not any overt type of memory strategy, are performed equally as well in patients with frontal lobe damage and

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controls. On the other hand, recall tasks, or any other task requiring self-organization or strategies to aid in remembrance, are impaired. This principle is most clearly understood by examining one useful strategy for improving recall for a list of words. When presented with a list of words, a participant may group the list into categories of semantic meaning, such as sports versus furniture. But patients with frontal lobe lesions, despite normal recognition memory for these words, are severely impaired on free recall (Janowsky, Shimamura, Kritchevsky, & Squire, 1989) and exhibit de®cits in the subjective organization that aids recall (Gershberg & Shimamura, 1995; Stuss et al., 1994). Other strategic memory tasks have uncovered de®cits in patients with frontal lobe damage. These tests present material to the participant and require a detailed retrieval of temporal, source, or spatial information. Examples include tests of memory for source (e.g., who presented the information, where it was presented, and which list it was presented in; Janowsky, Shimamura, & Squire, 1989), temporal order, (i.e., which item was presented more recently; Butters, Kaszniak, Glisky, Eslinger, & Schacter, 1994; Milner, 1971; Milner, Corsi, & Leonard, 1991; Shimamura, Janowski, & Squire, 1990), and ®nally frequency, (i.e., which item was presented more often; Angeles-Juardo, JuniqueÂ, Pujol, Oliver, & Vendrell, 1997; Smith & Milner 1988). Using the same group of experimental paradigms discussed in the hippocampal section, neuroimaging activation in the frontal lobes for both encoding and retrieval will be reviewed. Unless speci®c differences are present for the frontal lobe tests, the methodological theory behind each paradigm will follow what has already been described in the hippocampal section. Episodic Encoding and the Frontal Lobes Rest Comparisons Relative to rest, a variety of different tasks that require verbal encoding elicit activation of the left prefrontal cortex, including word generation on the basis of semantic cues (Warburton et al., 1996; Wise et al., 1991) and word generation on the basis of lexical cues (Buckner et al., 1995).

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Processing Comparisons Holding stimuli constant across tasks, greater activation is found in the left prefrontal cortex during encoding for tasks that yield better memory performance. The majority of these studies examined verbal material, however there are several examples of non-verbal frontal lobe activation. Generating words, relative to reading words, results in greater left prefrontal activation (Frith, Friston, Liddle, & Frackowiak, 1991; Klein, Milner, Zatorre, Meyer, & Evans, 1995; Petersen, Fox, Posner, Mintun, & Raichle, 1988; Raichle et al., 1994), as does generating the colors or uses of objects relative to the names of objects (Martin, Haxby, Lalonde, Wiggs, & Ungerleider, 1995). These ®ndings are replicated when comparing the reading of the words that the participants are intentionally trying to encode versus incidental tasks, such as simply reading words without memory instructions (Kapur et al., 1996; Kelley et al., 1998). Semantic tasks, such as abstract versus concrete judgments of stimuli, yield left-lateralized prefrontal activations relative to nonsemantic tasks (such as whether a stimulus word is in upper or lower case letters; e.g., Craik et al., 1999; Demb et al., 1995; Desmond et al., 1995; Demonet et al., 1992; Gabrieli et al., 1996; Kapur et al., 1994; Poldrack et al., 1999; Wagner, Desmond, Demb, Glover, & Gabrieli, 1997). Phonological tasks yield more left prefrontal activation than orthographic tasks (Craik et al., 1999; Poldrack et al., 1999; Rumsey et al., 1997; Shaywitz et al., 1995). Finally, in following with the usual characteristics of hemispheric asymmetry, greater right prefrontal activation has been found for the encoding of faces and other non-verbal materials (Kelley et al., 1998). In the majority of studies examined, activations are primarily found in the left inferior frontal gyrus, but some activation is also present in the middle frontal gyrus. Within the left inferior frontal gyrus, semantic processes are centralized in the anterior and ventral areas (BA areas 45/47) while phonological activations are more common in posterior and dorsal areas (BA areas 44/45) (reviewed by Fiez, 1997; Poldrack et al., 1999). In fMRI studies, lesser right frontal activations in these same tasks are fairly common.

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SCOTT W. YANCEY AND ELIZABETH A. PHELPS

Stimulus Comparisons When compared to a ®xation or other baseline task in which little information is to be encoded, left prefrontal activations are common for verbal material. These left prefrontal activations are seen for the generation of words on the basis of lexical cues (Buckner et al., 1995), semantic decisions (Demonet et al., 1992), reading words (Herbster, Mintum, Nebes, & Becker, 1997; Martin et al., 1996), lexical decisions (Price et al., 1994; Rumsey et al., 1997), phonetic discrimination (Zatorre, Meyer, Gjedde, & Evans, 1996), and passive viewing of words (Bookheimer, Zef®ro, Blaxton, Gailard, & Theodore, 1995; Menard, Kosslyn, Thomson, Albert, and Rauch, 1996; Petersen, Fox, Snyder, & Raichle, 1990; Price et al., 1994). The usual hemispheric asymmetries have been found for the encoding of verbal and nonverbal stimuli in the prefrontal lobes. Left prefrontal activations for intentional encoding were found for words versus right prefrontal activations for textures (Wagner, Poldrack, et al., 1998), intentional encoding for faces (McDermott et al., in press), and visual ®xation (Kelley et al., 1998). Interestingly, intentional encoding for famous faces or line drawing yielded bilateral prefrontal activations relative to ®xation (Kelley et al., 1998, 1999). This interesting anomaly could possibly be understood as the participant giving a verbal description (e.g., a name) to a non-verbal object (e.g., a famous face), thereby activating both verbal and non-verbal circuits. Consequently, the intentional encoding of verbal knowledge can be linked to left prefrontal activations, non-verbal material to right prefrontal activations, and the encoding of non-verbal material that can be linked to verbal representation (e.g., famous faces) with bilateral prefrontal activations. Repetition Comparisons For virtually all repetition studies examining the encoding of verbal material, there has been greater left prefrontal activation for novel displays of items than for subsequent repeated displays. These studies examined repeated abstract/concrete judgments for words (Demb et al., 1995; Gabrieli et al., 1996), repeated verb generation (Raichle et al., 1994), and repeated living/non-living judgments for words and for line drawings

(Wagner, Desmond, Demb, Glover, & Gabrieli, 1997). One study by Gabrieli et al. (1997) examined activation for scenes. As to be expected, there was greater activation for the novel presentation than subsequent in the right prefrontal lobes. Correlational Studies Greater activation was found in the left prefrontal cortex, both posteriorly in BA 6/44 and anteriorly in BA 45/47, for encoding words that would later be well remembered versus words that would later be forgotten (Wagner, Schacter, et al., 1998). In addition, words that would be later distinctly recalled as having been seen in the study phase exhibited signi®cantly greater activation than words being classi®ed as having been seen in the study phase but not distinctly remembered (Henson, et al., 1999). For encoding scenes, greater right prefrontal activation was seen for scenes that would later be remembered versus scenes later forgotten (Brewer et al., 1998). Retrieval and the Frontal Lobes Processing Comparisons Right prefrontal activations consistently occur when participants make episodic retrieval judgments (i.e., cued recall or recognition) for verbal materials in comparison to a number of non-mnemonic tasks including: Semantic tasks, such as word generation (Buckner et al., 1995; Schacter et al., 1996; Shallice et al., 1994; Squire et al., 1992), word reading or repetition (Buckner et al., 1996; Fletcher et al., 1998; Nyberg et al., 1995; Petrides, Alivasatos, & Evans, 1995; Wagner, Desmond, et al., 1998), word fragment completion (Blaxton, Bookheimer, et al., 1996), word-pair reading (Cabeza, Kapur, et al., 1997), semantic judgments (Kapur, Craik, et al., 1995; Tulving, Kapur, Markowitsch, et al., 1994), or a perceptual task (Rugg et al., 1996). For nonverbal materials, right prefrontal activations are also present for tasks involving recognition of faces relative to face matching tasks (Haxby et al., 1993, 1996) and recognition of object identity or location relative to object matching tasks (Moscovitch, Kapur, Kohler, and Houle, 1995).

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Interestingly, the right prefrontal activations mentioned in the above tasks generally fall into two distinct loci of activation, the posterior area (BA 9/46) and an anterior area (BA 10). There is currently no consensus explanation for what causes a particular task to elicit activation in either region. Broadly de®ned, it seems that these activations likely re¯ect two different sets of processes for episodic memory retrieval, but again, what distinguishes the two processes is unclear. Also, many of the verbal retrieval tasks exhibit some left prefrontal activation as well (e.g., Blaxton, Bookheimer, et al., 1996; Buckner et al., 1995; Kapur, Craik, et al., 1995; Petrides et al., 1995; Rugg et al., 1996; Schacter, Alpert, et al., 1996; Tulving, Kapur, Markowitsch, et al., 1994). Stimulus Comparisons Three fMRI studies have examined prefrontal activation during retrieval of different stimulus types. A study by Wagner, Desmond, et al. (1998) compared activation differences for word versus textures, and found predominantly leftlateralized prefrontal activation for recognition of words relative to textures, and predominantly right-lateralized prefrontal activation for textures relative to words. Since this study only examined the relative processing differences of word versus textures, an examination of regions commonly activated in both tasks was not made. A follow up study by Gabrieli, Poldrack, and Wagner (1998) addressed this issue by including a ®xation condition that revealed right prefrontal activation for both words and textures. A third study examined activation for words versus novel faces (McDermott et al., in press). Retrieval activations in the inferior frontal gyri (BA 6/44) were lateralized by stimulus class, with greater activation on the left for words while there was greater activation on the right for faces. There was also activation during retrieval for both words and faces in the anterior cortex (BA 10). Correlational Studies Unlike other correlational studies mentioned previously, retrieval correlational activations in the prefrontal lobes have been varied, complex, and muddied. One event-related fMRI study examined retrieval based activations on an item-by-

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item basis and found both left posterior and right anterior prefrontal activations for episodic memory judgments for both old (studied) and new (not studied) word judgment (Buckner, Koutstall, Schacter, Dale, et al., 1998) this line of evidence, it has been suggested, would indicate that frontal lobe activation represents an attempt to retrieve memories rather than the actual retrieval of a distinct memory. In a similar item-by-item event-related fMRI study, activations were examined during correct memory judgments for old and new words (Henson et al., 1999). For words classi®ed as old, participants had to classify their subjective experience as either a distinct recollection of the presentation of the word (the ``remember'' response); or as one in which they thought the word had been presented but had no distinct recollection of the word's actual presentation (the ``know'' response). Greater anterior and posterior left prefrontal activations were found for well-remembered versus new words, and in a more superior left frontal location greater activation was found for ``remember'' relative to ``know'' words. Neither comparison yielded any signi®cant right prefrontal activation. When ``know'' responses were compared with new words, there was bilateral posterior prefrontal activations. The scattershot nature of these ®ndings does not allow for any uni®ed theory of frontal lobe activation in episodic retrieval. Instead, the only conclusion that can be tentatively drawn is that there are a variety of frontal lobe locations that each have a distinct role in retrieving certain types of episodic memory. When examining the vast array of imaging data for episodic encoding and retrieval in the frontal lobes, ®nding a clear-cut theme or function or purpose for these structures is dif®cult. Despite these problems, it does appear that right prefrontal activation is a common occurrence for all sorts of materials (verbal, nonverbal) and tasks (recall, recognition). But what is not clear is what this common right prefrontal activation means. It has been suggested that it represents the attempt to access memories and make memory judgments. However, it could also represent the successful retrieval of memories. Further study is needed to clarify these competing hypotheses. Lastly, one possible common theme could be the differing

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role of posterior versus anterior frontal lobes structures. Posterior prefrontal lobe areas seem to show material-speci®c activations during episodic retrieval, with left-lateralized activations mediating verbal material and right-lateralizations mediating non-verbal material (Brewer et al., 1998; McDermott et al., in press; Wagner, Desmond, et al., 1998; Wagner, Schacter, et al., 1998). Whereas anterior prefrontal lobe activation appears to mediate material-independent retrieval processes associated with memory tests requiring greater strategic demands (e.g., temporal and spatial judgments) (Demb et al., 1995; Gabrieli et al., 1996; Raichle et al., 1994; Wagner et al., 1997).

There are only two functional neuroimaging studies examining the role of the amygdala in episodic memory for emotional events, one using PET (Cahill, et al., 1996) and the other fMRI (Hamman, Eli, Grafton, & Kilts, 1999). Both of these studies examine activity during encoding and both correlate activity at encoding with later memory performance. The conclusion of these two studies is similar. Activity in the amygdala at encoding was correlated with later recall of the emotional stimuli. This same relationship was not present for the non-emotional stimuli. In other words, activation of the amygdala was related to the selective episodic memory enhancement of emotional material.

The Amygdala and Episodic Memory The amygdala is a small structure in the MTL adjacent to the hippocampus that has been singled out as especially important for memory performance in¯uenced by emotion. Most of what is known about the role of the amygdala in emotional memory has been derived from research on animals. This research has primarily assessed emotional memory using a non-episodic, indirect measure of memory, speci®cally the fear conditioning paradigm, in which a neutral stimulus comes to acquire emotional properties by being paired with an emotional stimulus (see LeDoux, 1996). These animal models of emotional memory have been extended to humans using similar paradigms (see Phelps & Anderson, 1997, for a review). In spite of a general consensus on the amygdala's importance in emotional memory, there are only a few studies exploring the role of the amygdala in episodic memory performance in humans. These studies are based on the premise that episodic memory for emotional stimuli is, in most circumstances, enhanced. It is proposed that the amygdala modulates this enhancement by modulating hippocampal function (McGaugh, 1992). Support for this interpretation comes from studies with brain-injured patients who have damage to the amygdala. Under some circumstances, these patients do not show the normal enhancement of memory for emotional events as assessed by recognition (Cahill, Babinsky, Markowitsch, McGough, 1995; see also Phelps, et al., 1998).

Clinical Implications of Neuroimaging Studies of Episodic Memory Clearly non-invasive, in vivo neuroimaging techniques have been a signi®cant advance for the study of human memory. It has allowed researchers to examine normal, healthy brain operation as never before. But what possibilities does neuroimaging hold for the advancement of clinical practice? Besides the general boon to knowledge that pure research gives to applied clinical practice, does neuroimaging provide some distinct way for the clinician to improve his or her care for the patient? Neuroimaging offers direct applications to clinical practice by providing the clinician with the non-invasive and in vivo bene®ts of fMRI to aid in the diagnosis of psychological and neurological disorders. By being able to view the actual functioning of a patient's brain, a clinician may be able to discern dysfunction or abnormality in certain regions or circuits. Two common clinical disorders traditionally associated with memory and the MTL are epilepsy and Alzheimer's disease. Below we give examples of studies using functional imaging to examine the neural correlates of episodic memory in these clinical populations. These studies are just a demonstration of how functional neuroimaging may aid our understanding and treatment of neurological disorders. One of the most important preoperative procedures for clinicians and their epileptic patients is the localization of diseased tissue, and what functions could be lost as a result of this tissue's removal. Most techniques currently used to make

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these determinations are invasive and, therefore, potentially dangerous. Attempting to avoid the seemingly inevitable risk and possible consequence of standard preoperative evaluation, various neuroimaging techniques have been tested for use as a substitute to the standard invasive techniques (e.g., Bookheimer, 1996; Detre, et al., 1998; Swartz, Halgren, Simplins, & Mandelkern, 1996; Swartz, Simpkins, et al., 1996). For example, an fMRI study of 10 patients with temporal lobe epilepsy (TLE) compared to 8 healthy controls on a nonverbal episodic encoding task revealed several functional abnormalities (Detre et al., 1998). Encoding activation, nearly symmetric in normal participants, was signi®cantly asymmetrical in the patients with TLE. This abnormal asymmetric activation was interpreted as a result of the epileptic condition, and the less active hemisphere was interpreted as the site of the diseased tissue. These ®ndings were also used to offer a preliminary analysis of what psychological functions would be impacted and possibly lost by the region's surgical removal. Another obvious application for using neuroimaging to investigate pathological memory is in the disorder of Alzheimer's disease (AD). This disorder's hallmark symptom is a profound episodic memory impairment, and some of the earliest brain changes in the disease occur in critical memory locations, such as the hippocampus and neighboring regions (Backman, et al., 1999). One PET study compared patients with AD and normal controls on a word stem cued recall task (Backman, et al., 1999). In addition to the AD patients' marked performance de®cit in the episodic memory task, only control participants exhibited activation in the left hippocampal formation. This ®nding seems to indicate a potential direct link between memory impairment and impaired functioning in a distinct anatomical region known to be related to memory. Another PET study examined patients with AD versus controls on a verbal memory task and found the impaired patients with AD to have a glucose metabolism shift from the left to the right temporal lobe hemisphere as opposed to the controls who exhibited the opposite pattern (Miller et al., 1987). This ®nding indicates some type of relationship between functional temporal lobe abnormality

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and impaired memory performance in AD. One last study to be mentioned examined a variety of cognitive tasks and brain activity using PET (Desgranges et al., 1998). The portions of the study that examined verbal episodic memory found that patients with AD exhibited dysfunctional activation in a variety of limbic structures and the parietotemporal and frontal association cortices. Taken collectively, these studies offer guidelines and suggestions as to how the relationship between memory impairment and cortical dysfunction can be realized and examined in Alzheimer's Disease. CONCLUSIONS This review has illustrated the varied and wideranging applications of functional neuroimaging to the study of episodic memory. But episodic memory is not the only type of memory. To keep this review focused and manageable, a host of memory structures and types has been ignored. Some of these are brie¯y outlined below. Working memory, or memory for short-term events and active information processing, is a vastly expanding ®eld of memory research that is usually associated with the prefrontal cortex. For an excellent review of research in working memory, see Goldman-Rakic (1996). For a summary of what has been learned about working memory with functional neuroimaging, see Smith & Jonides (1998). Skill learning is characterized by improvement in performing a task over a number of successive trials, or with practice. Often skills are sensory or motor in nature (e.g., playing the piano or hitting a ball), but they can also be cognitive in nature (e.g., certain types of problem solving). Examples of neuroimaging studies of skill learning are those that have examined neural changes occurring with learning a pattern or sequence of motor responses (see Karni, et al., 1998; Toni, Krams, Turner, & Passingham, 1998). Studies of implicit memory have often examined priming in which a response to a stimulus is facilitated with repeated exposure. Priming is often measured by the decreased speed of response to a stimulus upon repeated presentations. For an excellent review of neuroimaging

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