The Functional Neuroanatomy of Episodic Memory: The Role of the Frontal Lobes, the Hippocampal Formation, and Other Areas

8, 198–213 (1998) NI980359

NEUROIMAGE ARTICLE NO.

The Functional Neuroanatomy of Episodic Memory: The Role of the Frontal Lobes, the Hippocampal Formation, and Other Areas Be´atrice Desgranges,*,† Jean-Claude Baron,* and Francis Eustache*,† *INSERM U320 and University of Caen, †Department of Neurology, CHU Coˆte de Nacre, 14033 Caen Cedex France Received December 29, 1997

INTRODUCTION Because it allows direct mapping of synaptic activity during behavior in the normal subject, functional neuroimaging with the activation paradigm, especially positron emission tomography, has recently provided insight into our understanding of the functional neuroanatomy of episodic memory over and above established knowledge from lesional neuropsychology. The most striking application relates to the ability to distinguish the structures implicated in the encoding and the retrieval of episodic information, as these processes are extremely difficult to differentiate with behavioral tasks, either in healthy subjects or in braindamaged patients. Regarding encoding and retrieval, the results from most studies converge on the involvement of the prefrontal cortex in these processes, with a hemispheric encoding/retrieval asymmetry (HERA) such that the left side is preferentially involved in encoding, and the right in retrieval. However, there are still some questions, for instance, about bilateral activation during retrieval and a possible specialization within the prefrontal cortex. More expected from human and monkey lesional data, the hippocampal formation appears to play a role in both the encoding and the retrieval of episodic information, but the exact conditions which determine hippocampal activation and its fine-grained functional neuroanatomy have yet to be fully elucidated. Other structures are activated during episodic memory tasks, with asymmetric activation that fits the HERA model, such as preferentially left-sided activation of the association temporal and posterior cingulate areas in encoding tasks and preferentially right-sided activation of the association parietal cortex, cerebellum, and posterior cingulate in retrieval tasks. However, this hemispheric asymmetry appears to depend to some extent on the material used. These new data enhance our capacity to comprehend episodic memory deficits in neuropsychology, as well as the neural mechanisms underlying the age-related changes in episodic memory performances. r 1998 Academic Press

1053-8119/98 $25.00 Copyright r 1998 by Academic Press All rights of reproduction in any form reserved.

Episodic memory is a cognitive system which, according to Tulving, makes it possible to record, store, and retrieve the memories of events as well as their temporal and spatial context. While this definition was put forward in 1972, the concept of episodic memory and certain of its characteristics had already been described at the end of the past century (e.g., W. James, 1890). Likewise, the birth of the neuropsychology of episodic memory preceded the actual adoption of the term. Indeed, the earliest cognitive and neuroanatomical information about episodic memory originated from the study of patients suffering from the permanent amnesic syndrome (Squire, 1992, for review). The neuropsychological approach to episodic memory still continues, for instance, with the study of Alzheimer’s disease (Desgranges et al., 1996). In accordance with results from investigations in nonhuman primates (Squire, 1992), the neuropsychological studies have emphasized the medial temporal cortex and diencephalic structures as key structures in episodic memory. Recently, the neuropsychological paradigm has been supplemented by functional imaging techniques, such as positron emission tomography (PET) and functional MRI (fMRI). Using these tools, two different approaches have been developed: (i) the study of resting cerebral metabolism (glucose or oxygen consumption) and (ii) the activation paradigm. The former, which reflects baseline integrated synaptic activity, can be assessed by PET with the aim of mapping cell dysfunction and damage in brain areas still structurally intact (see, e.g., Penniello et al., 1995). This approach has permitted new insights into the structures whose microscopic pathology underlies episodic memory impairment in the amnesic syndrome (Fazio et al., 1992; Lucchelli et al., 1994), normal aging (Eustache et al., 1995b; Baron et al., 1997), and Alzheimer’s Disease (Perani et al., 1993; Desgranges et al., 1998). By inference, this approach also has implications about both the structures involved in normal memory processes and the

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design of structural models and as such is comparable to the standard neuropsychological paradigm. The activation paradigm can be performed with either PET or fMRI. Its use in the healthy subject is a new approach as, for the first time, it is possible to obtain information ‘‘directly’’ concerning the functional neuroanatomy of cognitive processes. Recently, episodic memory has been the subject of intense research with this approach. Although reports initially emphasized the role of the prefrontal cortex, that of the hippocampal formation has been the main focus lately. Studies have also shown the involvement of many other structures, of which are the temporo-parietal association cortex, the cerebellum, and the cingulate cortex. However, because of the rapid accumulation of reports in this field, it would be almost impossible to have an integrated view on the respective role of these different brain structures in episodic memory. The purpose of the present review is therefore to examine specific aspects of present knowledge from activation studies, with an attempt to relate some of the findings with established data from the neuropsychological literature. The articles published to date in peer-review journals have been analyzed, regardless of the imaging method (i.e. PET or fMRI) and the kind of paradigm (e.g., hierarchical, correlative). Tables 1 and 2 summarize the results regarding the hierarchical paradigms, while studies that used other paradigms will be reported in the text only. 1. EPISODIC MEMORY AND THE PREFRONTAL CORTEX Although observations made in brain-damaged patients have long pointed out the involvement of the frontal lobes in the strategic aspects of memorization (e.g., Moscovitch, 1989), it is well established that frontal lobe damage does not result in major difficulty in the standard clinical tests for episodic memory (Shimamura et al., 1992). In contrast with the neuropsychological data, PET activation studies have documented a major engagement of the prefrontal cortex in memory processes and shown its differential role in encoding and retrieval, two processes which are particularly difficult to distinguish with clinical memory tests (see Section 6). 1.1. Functional Asymmetry of the Prefrontal Cortex Although prefrontal activation during memory tasks was already reported in the pioneer studies of Squire et al. (1992) and Grasby et al. (1993a), this finding went relatively unnoticed. In the Squire et al. (1992) study (see also Buckner et al., 1995), 15 words were presented on a screen, the instruction being to scale their pleasantness. A few minutes later, 20 trigrams, of which 10 were distractors, were presented, the explicit instruction

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being to use them as cues for recalling the words of the initial list. This task caused, among other things, an activation of the right prefrontal cortex. Grasby et al. (1993a) studied the encoding and recall of lists of words. In a first task, 15 words were presented three times, a supraspan task which brings into play both short-term and episodic memory in the form of the recency and the primacy effects, respectively. The second task was identical but used nine lists of 5 words, a subspan task which involves the same cognitive processes save for episodic memory. The supraspan– subspan comparison demonstrated a bilateral activation of the dorsolateral prefrontal cortex. In both reports, the activation of the prefrontal cortex in relation with episodic memory was attributed to the use of strategies, without further elaboration at the time. In the spring of 1994, the London and Toronto teams simultaneously published landmark papers establishing the role of the prefrontal cortex in episodic memory. The former (Shallice et al., 1994) used a complex paradigm designed to study encoding and retrieval separately, the encoding furthermore being intentional, while the latter published a general theory (Tulving et al., 1994a) based on articles that concerned incidental encoding (Kapur et al., 1994) and the retrieval of episodic information (Tulving et al., 1994b). 1.1.1. Encoding (Table 1) Shallice et al. (1994) separately studied the encoding and the retrieval of verbal material (15 pairs of words, each pair consisting of a category and an examplar). Encoding was intentional in this task, which required that automatic semantic processing be controlled. To this end, the same task was also performed under ‘‘difficult’’ conditions that prevented encoding in episodic memory thanks to a competing task. The comparison (easy–difficult), aimed at isolating the encoding process, showed an activation of the left dorsolateral prefrontal and posterior cingulate cortices. In the Kapur et al. (1994) study, the encoding was incidental. The paradigm was designed to manipulate depth of encoding so as to detect CBF differences between superficial and deep encoding. The instructions were respectively an orthographic and a semantic processing of words presented visually without instruction for memorization. As expected, memorization of the items (assessed after the scan) was better in deep than in superficial encoding. The subtraction (deep– superficial) showed an activation in the left inferior prefrontal cortex (see below for further discussion about this finding). 1.1.2. Retrieval (Table 2) In order to assess the retrieval of episodic information, Shallice et al. (1994) controlled for the automatic intervention of semantic processes by comparing a cued

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TABLE 1 Brain Structures Activated During Intentional Encoding in Episodic Memory, as Compared with Control Tasks (in Brackets) in Young Healthy Subjects Verbal

Prefrontal cortex Hippocampal region Parietal cortex Temporal cortex Occipital cortex Precuneus Cerebellum Anterior cingulate cortex Posterior cingulate cortex Thalamus

Nonverbal

1

2

3

4

5

6

7

L

L L

L

L

L R

BR B

B

L

L

8

9

L

L L

B L B

R L L

L

R

B L

Note. The numbers refer to published articles; only hierarchical paradigms are reported, using either PET (1–8) or fMRI (9). R, right; L, left; B, bilateral; BR, bilateral with right predominance. 1, Shallice et al., 1994, and Fletcher et al., 1995 (passive listening of words); 2, Kapur et al., 1996 (reading of words); 3, Nyberg et al., 1996c (object location encoding); 4, Dolan and Fletcher, 1997 (listening ‘‘old’’ words); 5, Grady et al., 1995, and Haxby et al., 1996 (face matching); 6, Roland and Gulya´s, 1995 (rest); 7, Maguire et al. 1996 (non topographical encoding); 8, Owen et al., 1996b (retrieving object features); 9, Stern et al., 1996 (viewing of a single complex picture).

recall task (recall of words from paired associates) with semantic retrieval task (generation of words belonging to the category of furniture). The comparison (cued recall–semantic recall) revealed an activation of the right prefrontal cortex and the precuneus, bilaterally (see Fletcher et al., 1995a, for a full description of this study). Tulving et al. (1994b) examined the recognition of verbal information by manipulating the degree of familiarity of the stimuli: during PET scanning, sequences of either new or familiar (‘‘old’’) sentences (listened to 24 h previously without being instructed to memorize) were presented binaurally (distractor sentences, either old or new, were also presented immediately before and after scanning). Having been made aware immediately before each PET session of the mainly new or familiar character of the sentences to be heard, the subjects had to mentally count the sentences which were in the minority, the performance accuracy being monitored at debriefing. The (old–new) subtraction showed extensive activation of the right dorsolateral prefrontal cortex. 1.1.3. The HERA Model The results obtained by Kapur et al. (1994) and Tulving et al. (1994b) together with a review of the literature led this team to propose a model they called HERA (for hemispheric encoding–retrieval asymmetry), which assigns a preferential role to the left prefrontal cortex in the encoding, and to the right one, in the

retrieval of episodic information (Tulving et al., 1994a), this fitting well the Shallice et al. (1994) findings. However, because all the paradigms on which they based the role of the left prefrontal cortex in episodic encoding involved semantic processing of verbal stimuli (whether it be categorical judgement, production of words associated with a target word, or verbal fluency), it was somewhat audacious to interpret the activation of the left prefrontal cortex in terms of episodic encoding rather than semantic processing. The researchers’ key argument was that any retrieval of information (episodic or semantic) results in an automatic entry in episodic memory: the subject encodes the event (‘‘having carried out the task’’) in its spatio-temporal context, which the instruction turns, or does not turn, into a memorization task. In other words, in the original account of the HERA model, the hypothesis of greater involvement of the left prefrontal cortex in episodic encoding paradoxically rested on CBF modifications observed during semantic tasks which were believed to result in incidental encoding (see Nyberg et al., 1996a, for review). However, as stated above, left prefrontal activation was observed by Shallice et al. (1994) in a word encoding paradigm that controlled for semantic processing. Furthermore, since 1994, left prefrontal activation has been confirmed in intentional encoding of verbal material (Kapur et al., 1996, see below) and observed in the encoding of nonverbal material (object location, Owen et al., 1996a; unfamiliar faces Grady et al., 1995; Haxby et al., 1996). Yet, this issue is still the matter of some controversy. For instance, Kapur et al. (1995b) and Stern et al. (1996) could not reproduce the finding, while Roland and Gulya´s (1995) found that the intentional encoding of colored geometric patterns led to a bilateral prefrontal activation (see also Klingberg and Roland, 1998). In contrast to the above role of the left prefrontal cortex in encoding, activation of the right prefrontal cortex in the retrieval of episodic information has been extensively demonstrated with paradigms using either free-recall, cued-recall, or recognition of diverse stimuli (e.g., sentences, drawings of objects, words, faces, smells, colored geometric patterns, Table 2) (see Buckner et al., 1996a, for a comparison of activation caused by the recall of words and images and Tulving et al., 1994a, and Nyberg et al., 1996a, for reviews). Thus, in conflict with the well-established notion from lesional neuropsychology of a preferential involvement of the right hemisphere in the processing of visuo-spatial stimuli (Tranel and Damasio, 1995), the activation literature suggests that the role of the right prefrontal cortex in retrieval is not material-specific. 1.2. Limitations of the HERA Model Although the prefrontal cortex is a vast cerebral region within which functional specializations have

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TABLE 2 Brain Structures Activated during Episodic Memory Retrieval Tasks, as Compared with Control Tasks (in Brackets) in Young Healthy Subjects Verbal Free recall 1 2

3

4

Nonverbal

Cued recall 5

Recognition

6 7 8 9 10 11 12 13 14 15

Prefrontal cortex B BR R BR R R R R BR BR R Hippocampal region R R B Parietal cortex B R B Temporal cortex L B B L Occipital cortex B L R Precuneus L B B L R R R Cerebellum B B B L L L L L Ant cingulate cortex L L L R L R M L Post cingulate cortex R R Thalamus B B B L B L

R B

B

R L

L

L L L

M

R R

L B

B

L B R

L

R

B B

L

Recognition

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

R BR BR R B

FR

M L

B L

L

L B

R B L B B L

R BR R BL R B R R R R R B B L B B

B B

B

L

Note. The numbers refer to published articles; only hierarchical paradigms are reported, all with PET. R, right; L, left; B, bilateral; BR, bilateral with right predominance; BL, bilateral with left predominance; M, medial; FR, free recall; 1, Grasby et al., 1993 (subspan); 2, Grasby et al., 1993 (rest); 3, Andreasen et al., 1995b (rest); 4, Andreasen et al., 1995c (rest); 5, Petrides et al., 1995 (word repetition); 6, Squire et al., 1992 (word stem completion); 7, Shallice et al., 1994, and Fletcher et al., 1995 (word repetition); 8, Buckner et al., 1995 (word stem completion); 9, Petrides et al., 1995 (word repetition); 10, Schacter et al., 1996a, low recall (word stem completion); 11, Schacter et al., 1996a, high recall (word stem completion); 12, Ba¨ckman et al., 1997 (word stem completion); 13, Cabeza et al., 1997a (word reading); 14, Tulving et al., 1994b (listening new sentences); 15, Andreasen et al., 1995a (word reading); 16, Kapur et al., 1995a (living/nonliving decision on words); 17, Nyberg et al., 1995 (word reading); 18, Cabeza et al., 1997a (word reading); 19, Cabeza et al., 1997d (temporal-order retrieval); 20, Fujii et al., 1997 (word repetition); 21, Rugg et al., 1997 (word recognition after shallow encoding); 22, Petersson et al., 1997 (fill in contours of predrawn designs); 23, Schacter et al., 1995 (viewing new possible objects); 24, Grady et al., 1995, and Haxby et al., 1996 (face matching); 25, Moscovitch et al., 1995 (perceptual discrimination of patterns of drawings); 26, Roland and Gulya´s, 1995 (rest); 27, Owen et al., 1996b (encoding object features); 28, Tulving et al., 1996 (viewing new pictures); 29, Henke et al., 1997 (to judge whether a square or a rectangle was presented); 30, Uecker et al., 1997 (passive viewing of possible objects).

been demonstrated, both in man (e.g., Petrides et al., 1993) and in the animal (Fuster, 1996), the HERA model ‘‘describes a very general functional pattern of the prefrontal cortices’’ (Cabeza and Nyberg, 1997). Furthermore, because the HERA model is based on studies using hierarchical paradigms, it may assign too restrictive roles to particular areas, especially with respect to the part played by the left prefrontal cortex in retrieval. These two points will be dealt with in succession below. 1.2.1. Functional Specialization within the Prefrontal Cortex? Within the prefrontal cortex, activation studies have reported relatively variable coordinate peaks from one study to another (see Nyberg et al., 1996a, for review). Studies that focused on encoding emphasize the involvement of the left anterior inferior frontal gyrus (particularly BA 45 and 46). Kapur et al. (1996) suggest that this region, which is activated in the case of intentional as well as incidental encoding of verbal and nonverbal material, plays a part as soon as deep semantic processing occurs. These authors also found a selective activation of the posterior mid-dorsolateral frontal cortex (BA 6 and 44) in relation with rote-rehearsal of pairs of

words, which brings subvocal rehearsal of working memory into play. Likewise, Busatto et al. (1997), using fMRI, have recently observed a left prefrontal activation, essentially within Broca’s area, during an intentional encoding, which ‘‘might reflect the use of inner speech by subjects to aid encoding.’’ With regard to retrieval, activation of the right anterior prefrontal cortex (BA 10 and 46) would subtend any kind of episodic retrieval, while activation of the posterior prefrontal cortex would depend on the type of information to be recalled—on the left for verbal and on the right for nonverbal material (Buckner and Petersen, 1996). This view is mainly based on the Buckner et al. (1995, 1996a) and Grady et al. (1995) studies, but the findings of Petrides et al. (1995) can equally be seen along this view. The latter authors compared the CBF data acquired during the free recall either of a series of 20 words studied 10 min beforehand (new) or of five pairs of overlearned words. In comparison with a word-repetition task, both tasks activated the right anterior prefrontal cortex (BA 9 and 46). The new–overlearned comparison showed activation in the left posterior prefrontal cortex (BA 45), which, according to the authors, suggests that this region plays a role in the strategic component of the retrieval of informa-

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tion stored in episodic memory. The Buckner and Petersen (1996) scheme is advantageous because it reconciles both the predications of the HERA model and data regarding hemispheric asymmetries and the kind of material. It predicates a stronger asymmetry for verbal than nonverbal material, which, however, has not been confirmed (see Table 1 and Cabeza and Nyberg, 1997). Moreover, McIntosh et al. (1997), reanalyzizing the data from Nyberg et al. (1995), found that separate areas within the right prefrontal cortex may support different functions: area BA10 being involved in the retrieval mode and areas BA 45/47 in retrieval success. Finally, Nyberg (1998) proposed that the right anterior prefrontal cortex would be involved in all memory tasks, and the right posterior prefrontal cortex, in the more difficult retrieval conditions. To these uncertainties about functional specialization of distinct prefrontal subregions can be added the question of whether this brain area even plays a specific role in episodic memory, or if it exerts a more general computational duty (Cabeza and Nyberg, 1997, for review and MacLeod et al., 1998). Further studies are needed, including the study of connectivity between the various activated areas, to shed new light on this issue (see McIntosh et al., 1997). 1.2.2. Role of the Left Prefrontal Cortex in Retrieval? According to the HERA model, the left and right frontal lobes play a differential, though nonexclusive, role in encoding and retrieval, respectively. However, according to Buckner (1996) this model (or at least the interpretation of it which is sometimes given) underestimates the role of the left prefrontal cortex in the retrieval of episodic information. The existence of activation of the left frontal lobe common to encoding and retrieval has been largely neglected, probably because of the subtraction method (Buckner, 1996; Buckner and Petersen, 1996). A bilateral activation of the prefrontal cortex during episodic retrieval has, however, been observed in several studies (Table 2). Although Ba¨ckman et al. (1997) linked this finding to the greater demand of the test used in those studies, i.e., cued recall rather than recognition, there is some evidence to contradict this view: thus, several studies using a cued recall paradigm have shown a selective right prefrontal activation (Squire et al., 1992; Shallice et al., 1994; Buckner et al., 1995; Petrides et al., 1995; Cabeza et al., 1997a), while others using a recognition paradigm did find a bilateral activation (Andreasen et al., 1995a; Kapur et al., 1995a; Roland and Gulya´s, 1995; Tulving et al., 1996). Two other hypotheses have been put forward to account for this occasional activation of the left prefrontal cortex during retrieval tasks. The first emphasizes the notion of predominant processing of verbal material by the left hemisphere, which would explain why this activation often shows up with re-

trieval of verbal material (Buckner and Petersen, 1996) and more particularly in paradigms calling for a lexicosemantic processing, as in the stem-cued recall tasks (Nyberg et al., 1996a). The second hypothesis involves a phenomenon of ‘‘active ongoing encoding process’’ of information (Andreasen et al., 1995c). These authors (Andreasen et al., 1995a,b,c, 1996) published a series of studies based on the same experimental paradigm, according to which the CBF measurements were carried out during retrieval of information acquired intentionally either 1 week previously and refreshed the day before or 1 min before. They manipulated the information to be memorized (series of words, stories, faces), the retrieval (recognition or free recall), the presentation modes (visual or auditory), and finally the reference task (reading, gender categorization, or ‘‘resting’’). Despite these variations and protocols, all far from the ideal hierarchical paradigm, the results concurred extremely well (Table 2) and in particular the recall of recently acquired information resulted in an activation of the left prefrontal cortex which was greater and more extensive than if information was acquired 1 week previously, and which may therefore reflect ongoing encoding of the just-presented information. If true, this interpretation means that the data yielded by paradigms of recognition which use distractors should be interpreted with caution (e.g., Kapur et al., 1995a; Roland and Gulya´s, 1995), as the distractors might themselves be capable of triggering automatic encoding processes by virtue of their novelty. Therefore, still today, the specificity of the left prefrontal cortex in the process of retrieval has not been established, but these findings emphasize the risk of neglecting phenomena which are potentially important because of the exclusive use of the subtraction method. 1.3. Prefrontal Cortex and Retrieval Processes: The Search Hypothesis A widespread belief about the role of the prefrontal cortex in cognitive activities concerns the implementation of strategies. Whether this general function may also apply to the processes of encoding and retrieval is an intriguing issue. This hypothesis has been the subject of specific studies, in particular in the area of retrieval. For instance, recent studies have contrasted, within retrieval, the processes of strategic search and ecphoric recall, the latter being more automatic and characterized by a matching of the recall cues and the engram which favors the retrieval of information (Tulving, 1983). Thus, one would expect that only the former would call upon the prefrontal cortex. Accordingly, Schacter et al. (1996a) found that the recall of words seen only once and processed superficially (‘‘low recall’’) was associated with a bilateral prefrontal blood flow increase, which was explained by the search effort demanded by the task; however, activation of the left

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prefrontal cortex could just as well be explained by the ‘‘ongoing encoding phenomenon’’ (see above). Other studies have, on the contrary, emphasized the involvement of the prefrontal cortex in all memory search activities, whether they be effortful or not, effective or not. Kapur et al. (1995a) measured the CBF during two tasks involving the visual recognition of words, of which one was characterized by a large proportion (high-target condition) and the other a low proportion (low-target condition) of target items. In comparison with a control task of semantic characterization, both tasks induced activation of similar amplitude in the right dorsolateral prefrontal cortex, related to the retrieval attempt. Similarly, in the Nyberg et al. study (1995), 80 words were first processed according to either a semantic or a perceptive criterion, and then CBF measurements were carried out during recognition tasks involving the words processed semantically, the words processed perceptively, or never-processed words. As compared to the silent reading of words, the three recognition tasks showed activation in the right prefrontal cortex indicating that the involvement of this region ‘‘is related to retrieval attempt rather than to retrieval success’’ (see below for a discussion about success). Likewise, Cabeza et al. (1997a) demonstrated similar activation in the right prefrontal cortex in cued recall as compared to recognition. Petrides et al. (1995) compared the recall of a series of 20 words studied 10 min previously and that of five overlearned pairs of words, which differed by their degree of difficulty and therefore by the strategic component of retrieval. In comparison with word repetition, both recall tasks activated the right dorsolateral prefrontal cortex (the left prefrontal cortex was also activated in the difficult retrieval condition, again consistent with encoding prolongation). Overall, therefore, the right prefrontal cortex appears engaged by memory search activity, whether it be effortful or not, and the magnitude of the ‘‘search effort’’ does not seem to have significant influence on the magnitude of the activation. As mentioned above, Nyberg et al. (1995) found no effect of retrieval success on right prefrontal activation. Rugg et al. (1996), however, found different effects. Using a recognition paradigm which manipulated the density of target items (as in the Kapur et al. study (1995a)), and which included a recognition condition with entirely new items (as in the Nyberg et al. study (1995)), these authors showed that CBF in the right prefrontal cortex and bilateral frontopolar cortex covaried with increasing density of the word targets. According to them, the right prefrontal cortex does play a part in memory search, but the more successful the search the greater its activation, possibly reflecting a process of item verification. However, the same authors (Rugg et al., 1997) recently reported data that suggest that prefrontal activation is less dependent on retrieval

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success than on the intentional feature of retrieval. The recent study of McIntosh et al. (1997) may reconcile these two opposing views, insofar as area BA10 would be involved in the retrieval mode and areas BA 45/47 in retrieval success. 2. EPISODIC MEMORY AND THE HIPPOCAMPUS As already stated, the involvement of the hippocampus in episodic memory is well established by lesional neuropsychology and ablation studies in monkeys (Squire, 1992; Tulving and Markowitsch, 1997). Likewise, significant correlations between reduced resting energy metabolism in the hippocampal region and impaired episodic memory have been shown in normal aging (Eustache et al., 1995b), Alzheimer’s disease (Perani et al., 1993; Desgranges et al., 1998), and progressive amnesia (Lucchelli et al., 1994; Miceli et al., 1996). However, PET activation studies in the healthy subject have demonstrated that the hippocampal formation is not systematically involved during episodic memory tasks (see Tables 1 and 2), an unexpected finding highlighted in earlier reviews (e.g., Cabeza and Nyberg, 1997; Fletcher et al., 1997). Explanatory hypotheses stressed either technical limitations such as the inadequate spatial resolution of the imaging devices or the nature of the hippocampal activation, too weak, diffuse, and transient to be reliably detected (Fletcher et al., 1995b; Andreasen et al., 1995a). Another hypothesis set forth by Haxby (1996) suggested that the absence of hippocampal activation could be directly related to the subtraction method insofar as reference tasks systematically involve encoding, no matter the cognitive activity demanded. However, none of these hypotheses accounted for the fact that the pioneer studies of Squire et al. (1992) and Grasby et al. (1993a), both based on the subtraction paradigm, did clearly demonstrate hippocampal activation (Table 2). In the first, cued recall of visually presented words caused (apart from the right prefrontal activation already mentioned) activation of the right hippocampus and parahippocampal gyrus (this right-sided activation was interpreted as reflecting the use of visual rather than semantic characteristics of the cues). In the latter, in addition to the supraspan–subspan comparison (see above) which canceled activation common to the two tasks, the supraspan task was compared with the resting state, which demonstrated activation of the bilateral thalamus and right parahippocampal gyrus. Consistent with Haxby’s view, however, are the findings of correlated hippocampal CBF and performance. Thus, Grasby et al. (1993b) reanalyzed their data from the free recall of word lists of variable length (2 to 13 words), but this time the statistical processing was based on the ‘‘graded response paradigm,’’ establishing correlations between cognitive performance and CBF

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changes. They found significant positive correlations between long-term memory scores, expressed as the number of words recalled from the center of the serial position curve (i.e., ‘‘uncontamined’’ by primacy or recency effects) and hippocampal CBF (bilaterally but with a left-sided predominance). In yet another article (Grasby et al., 1994), the same authors showed significant correlations between left hippocampal/parahippocampal CBF and list length for the supraspan lists (8 to 13 words). However, as the memory tasks used in Grasby’s studies involved both the encoding and the recall of information, a precise cognitive basis of the hippocampal formation activations observed could not be inferred. Since these early studies, however, significant hippocampal activation has been reported in many investigations, which have tested specific hypotheses about the function of the hippocampus in episodic memory by means of sophisticated paradigms. Some have assessed the detection of new information, and others the encoding versus the recall—in particular ecphoric—of episodic information. 2.1. The Hippocampus and Novelty Detection Tulving et al. (1996) suggest that the hippocampus may play a key role in the detection of novelty. They base their argument on an experiment constructed after the ‘‘old vs new’’ paradigm which they used in their 1994 article (see above), but this time using illustrated scenes rather than verbal material. They found that a network of structures was involved in the detection of new scenes, made up of the hippocampus, the parahippocampal gyrus, the medio-dorsal thalamus, and the anterior cingulate cortex, a ‘‘right expanded limbic system.’’ They suggest that novelty detection constitutes a stage preliminary to encoding proper (a higher level process subserved by the neocortex, in particular left frontal). Yet, the lack of hippocampal activation in their 1994b study (listening to new sentences), would suggest that the hippocampus is less sensitive to novelty in the verbal than the visual mode. However, recent work supports the idea that the left hippocampus is sensitive to novelty in the verbal domain (Dolan and Fletcher, 1997; Fujii et al., 1997), and the right one, in the verbal as well as visual domains (Martin et al., 1997). For instance, in the former study, subjects heard 12 paired associates (e.g., dog–boxer), and then, CBF measurements were made during four conditions, subjects being instructed to memorize all the presented items: (1) pairs containing a new category (e.g., sportsman–dog), (2) pairs containing a new exemplar (e.g., dog–labrador), (3) entirely new pairs (e.g., food–biscuit), and (4) old pairs (dog– boxer). As compared with old pairs, the presentation of pairs containing a new word induced left prefrontal activations, while the presentation of entirely new

pairs essentially activated the left hippocampus and parahippocampal region. Thus, this latter region would be sensitive to both the novelty of the stimuli and the context in which they appear, while the left prefrontal cortex comes into play in the establishing of semantic links between the items. 2.2. The Hippocampus and Encoding In contrast with the findings just described, several lines of evidence suggest that the presentation of new stimuli is not always enough to trigger hippocampal activation and attribute a broader role for the hippocampus in the encoding of at least certain types of information. In the study carried out by Maguire et al. (1996), no hippocampal activation was detected during an intentional memorization of filmed events, contrary to the memorization of routes, which was associated with bilateral parahippocampal and right hippocampal activations. Likewise, Aguirre et al. (1996), using fMRI, found bilateral parahippocampal gyri activation during the encoding of topographic information, and rightsided and bilateral hippocampal activations were recorded during the intentional encoding of faces (Grady et al., 1995) and of complex colored pictures (Stern et al., 1996), respectively. The idea, suggested by Stern et al. (1996) and others (e.g., Tulving et al., 1996; Rugg et al., 1996; Fletcher et al., 1997), that the hippocampus appears to be more solicited if the data processed is visuo-spatial and complex rather than verbal (perhaps because the presentation of familiar words does not require the formation of new representations) would be consistent with the hypothesis originating in animal experimentation (e.g., Nadel, 1994) of the particular involvement of the hippocampus in the processing of spatial data. However, Owen et al. (1996b), who specifically tested this hypothesis, did not find hippocampus activation during the encoding of the characteristics of objects and their spatial localization. Moreover, a recent study showed that the right parahippocampal gyrus was activated during learning of an environment containing salient objects but not during learning of an empty environment (Maguire et al., 1998). Conversely, Haxby (1996) mentions three sets of unpublished results showing increased left medial temporal activity during the encoding of verbal material when compared with tasks ‘‘that divert attention from the linguistic features of the stimuli,’’ suggesting that in some circumstances, the hippocampus is indeed sensitive to verbal material. Accordingly, the intentional encoding of pairs of words resulted in the activation of the left medial temporal region including the hippocampus (Kapur et al., 1996), while Nyberg et al. (1996c) demonstrated a significant increase in left hippocampal CBF during the intentional encoding of words, as compared to encoding of either their location on a screen or their order of presentation (first or second list). Finally, Martin et al.

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(1997) studied incidental encoding of different types of material and showed that the left medial temporal lobe activation varied as a function of meaning (greater activity for real than for nonsense words and objects), and that the right one varied as a function of stimulus form (greater activity for objects than words). Overall, therefore, hippocampal region activation occurs during the encoding of various types of stimuli, with left-sided predominance for words and right-sided for faces and objects and bilateral activations when complex spatial or visual material is involved (Table 1). A different view has been recently advanced by Henke et al. (1997) who propose that the hippocampus would be particularly involved in the establishment of associations between items. In their study, among four experimental conditions (establishing associations between faces and houses; encoding single items; novelty detection; retrieving associations), only the first, which was an incidental encoding, was associated with a right hippocampal and parahippocampal activation. Further studies will be needed to refine the precise topography of these activations within the hippocampus itself and in the various parts of the parahippocampal regions. 2.3. The Hippocampus and Recall The early study of Squire et al. (1992), although not designed specifically for this purpose, already favored the idea of hippocampal involvement in the recall of episodic information (see above). Recently, this has been established in a series of studies that purposely tested this hypothesis (Table 2), and which used various test material such as verbal stimuli (e.g., Schacter et al., 1996a; Fujii et al., 1997; Rugg et al., 1997), line drawings (Schacter et al., 1995; Petersson et al., 1997; Uecker et al., 1997), geometric patterns (Roland and Gulya´s, 1995), and topographical information (Owen et al., 1996a). The right hippocampus was also found to be involved in the retrieval of well-learned topographical memories, possibly of a ‘‘semantic’’ nature, as shown by a recent study using taxi drivers of many years’ experience (Maguire et al., 1997). Yet, in several studies, there was no significant activation of the hippocampal region during episodic memory retrieval (Table 2). To explain this, Schacter et al. (1996a) implicated the nature of the tasks, which would involve primarily the prefrontal cortex when the retrieval requires a demanding search strategy. They base this hypothesis on a study in which the cued recall of words which had previously been presented on four occasions and undergone in-depth semantic processing (‘‘high recall’’) caused bilateral flow increases in the hippocampal formation, while a condition involving difficult recall (words presented only once and processed superficially—‘‘low recall’’) was associated with a bilateral blood flow increase in the prefrontal cortex. Thus, within episodic recall, the prefrontal cortex and the hippocampus would be espe-

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cially involved in effortful retrieval and in effortless conscious recollection, respectively. In support of this, Nyberg et al. (1996b), using a correlative paradigm, also found that the involvement of the left medial temporal cortex in the recognition of words was greater after deep than after superficial encoding. Nyberg’s findings have been recently confirmed by Rugg et al. (1997) and extended to incidental retrieval, suggesting a ‘‘relative automaticity of hippocampally-mediated retrieval,’’ and by Fujii et al. (1997), who reported right parahippocampal gyrus activation during easy verbal recognition tasks. In the nonverbal domain, Owen et al. (1996a) demonstrated right hippocampal region activation in a task of object-location retrieval which was correctly executed (98% mean correct). Therefore, all these five studies tend toward the idea that the hippocampal activity is more related to the success of the recall than to the search effort. This idea, attractive as it may be, does not, however, take account of certain findings. Thus, several studies which used ‘‘easy recall’’ tasks did not show hippocampal activation (Petrides et al., 1995; Kapur et al., 1995a; Rugg et al., 1996). Furthermore, Grasby et al. (1994) showed significant positive correlations between hippocampal activation and performances in a task involving effortful retrieval of a list of words. Finally, Petersson et al. (1997) have recently shown activation bilaterally in the hippocampus proper and the parahippocampal gyri during the free recall of a series of nonverbalizable abstract drawings, this activation being greater during retrieval with new than with overlearned stimuli. Overall, therefore, it remains unclear at present whether the hippocampus has an exclusive role in encoding or in recall, no single model being able to account for all the available data. 2.4. A Double Role for the Hippocampus: Encoding and Retrieval? Apart from the encoding–retrieval dichotomy, several investigators have proposed that the hippocampus plays different roles according to the side (right or left) and to the part of the structure in its rostro-caudal axis. For instance, according to Schacter et al. (1995), the left hippocampus would be mainly sensitive to the novelty of the stimuli and involved in encoding, and the right hippocampus in recall processes. These authors found greater hippocampal/parahippocampal activation on the right during recognition of three-dimensional objects and on the left during a pseudorecognition task involving new stimuli only (consequently more likely to trigger encoding than retrieval). These results were confirmed by Uecker et al. (1997). Likewise, Fujii et al. (1997) have reported parahippocampal gyrus activation predominant on the left in the detection of new, as compared to previously presented, stimuli and on the right in retrieval processes. Regarding the rostro-

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caudal axis, Roland and Gulya´s (1995) reported bilateral activation of the anterior hippocampus during the encoding of colored geometrical patterns, and of the posterior hippocampus during the recognition of these stimuli among distractors, suggesting that the hippocampus is involved in both encoding and retrieval, but with a rostro-caudal gradient. However in this work, the recognition among distractors involved the presentation of new stimuli, which could have set off automatic novelty detection and encoding; moreover, there was no significant hippocampal activation during the ‘‘mental recall’’ of the target stimuli. Finally, Stern et al. (1996) reported posterior hippocampus activation in an encoding task, which would contradict the Roland and Gulya´s (1995) findings. A metaanalysis of data pooled from four PET studies involving a total of 48 subjects revealed that the medial temporal lobes (including left perirhinal and bilateral entorhinal cortices and right parahippocampal gyrus) were more active during encoding than during retrieval (Tulving and Markowitsch, 1997). However, beyond the encoding–retrieval dilemma, recent studies emphasize the role of the hippocampal region in the processing of specific information, such as spatial data (see above), or in the establishment of associations among items, regardless of whether these processings occur during encoding—incidental (Henke et al., 1997) or intentional (Maguire et al., 1998)—or during retrieval (Owen et al., 1996a). 2.5. General Comments about the Hippocampal Region The uncertainties that still remain regarding the exact role of the medial temporal lobe structures in episodic memory are exacerbated by both the extreme complexity of this structure and the small size of its component parts. Thus, the stereotactic coordinates of the activation peaks are often insufficient for a precise anatomical localization according to the subcomponents of the hippocampal regions, and this is made worse by the process of spatial normalization and filtering used in intersubject averaging softwares (Friston, 1995; Kapur et al., 1996). Consequently, the anatomical terminology used (e.g., ‘‘medial temporal structures,’’ ‘‘hippocampal region,’’ ‘‘hippocampal formation,’’ ‘‘hippocampus proper’’) makes comparison among the articles sometimes difficult. For instance, both Maguire et al. (1996, 1998) and Aguirre et al. (1996) found that visual learning of topographical information activated the parahippocampal gyrus, but only the former reported an activation of the hippocampus proper, which could reflect subtle differences in the task itself (realworld vs virtual environment, respectively). Even differences in timing within the paradigms employed may be important, as suggested by Petersson et al. (1997), who underlined the dynamic aspect of the involvement of the hippocampus in memory process. Thus, both im-

proved spatial resolution and improved temporal resolution will be necessary to further our understanding of the role of hippocampal region in memory, and fMRI may be the technique of choice to achieve this goal. Thus, in a recent fMRI study, the parahippocampal cortex was found to be involved in the encoding of novel pictures, and the subiculum in the recognition of words and pictures (Gabrieli et al., 1997). Future work should also try and specify further the exact role of perihippocampal structures, such as the perirhinal and entorhinal cortices (Klingberg et al., 1994; Owen et al., 1996a) and the amygdala. Regarding the former, their key role as obligatory relay between the neocortex and the hippocampus, and as the structures earliest affected in aging (Vermersch et al., 1995) and Alzheimer’s disease (Braak and Braak, 1991) should make it an important focus of research. For example, Klingberg et al. (1994) have reported activation of the entorhinal cortex in associative memory. Regarding the amygdala, its role in episodic memory has probably been underestimated following works carried out on monkeys. Thus, Cahill et al. (1996) suggested an involvement of the amygdala in the memorizing of emotional information. A recent study has also shown activation of the amygdala during the retrieval of autobiographical information (Fink et al., 1996). In both studies, there was preferential right-sided activation, suggesting that the HERA model also extends to this structure. 3. EPISODIC MEMORY AND OTHER CEREBRAL STRUCTURES In addition to the prefrontal cortex and hippocampus, a number of other cerebral structures appear to be involved in episodic memory processes, and above all the posterior (temporo-parieto-occipital) association cortex, the cerebellum, and the cingulate cortex (Tables 1 and 2). We will now review the evidence regarding each one of these structures. 3.1. The Posterior Association Cortex As shown in Tables 1 and 2, activation of the posterior association cortex has often been reported in episodic memory tasks and various interpretations have been proposed. For instance, the parietal cortex would be involved in the processing of spatial (Tulving et al., 1994b) or temporal (Cabeza et al., 1997d) information, and the inferior temporal cortex would be a storage site for mnemonic representations (Andreasen et al., 1995c). According to Cabeza et al. (1997a), greater activation of the right inferior parietal cortex in recognition than in cued recall could reflect a greater implication of perceptive operations in the recognition task. Kapur et al. (1995a) suggested that, like the right prefrontal cortex, the parietal cortex could be involved in search strategy. Nyberg et al. (1996a) have recently

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proposed to incorporate within the HERA model regions other than the prefrontal cortex—an ‘‘extended HERA’’ model. In support of this scheme, several studies have shown activations of the left temporal cortex during encoding of words (Shallice et al., 1994; Dolan and Fletcher, 1997), faces (Grady et al., 1995), and object location (Owen et al., 1996b), while the retrieval of words, faces, objects, or scenes activates the parietal cortex, either bilaterally (e.g., Andreasen et al., 1995a; Cabeza et al., 1997a) or unilaterally on the right (e.g., Kapur et al., 1995a; Tulving et al., 1996; Schacter et al., 1996a) (see Table 2). Moscovitch et al. (1995) have emphasized right inferior parietal activations during object location recall (dorsal pathway) and right inferior temporal activation during object identity recall (ventral pathway). Owen et al. (1996b) replicated these data concerning the dorsal and ventral pathways in recall and extended them to the encoding of the characteristics of the objects and their location, though they could not reproduce the asymmetry of the HERA model. A particular region of the posterior association cortex, the posterior medial parietal cortex (at or near the precuneus), seems to play a special role in the retrieval of episodic information (Table 2). The widely given interpretation for this intriguing finding implicates the more general role played by this structure in mental imagery (Mellet et al., 1995; Platel et al., 1997). For instance, Fletcher et al. (1995c) found that precuneus activation during recall of words depended on their imageability, suggesting involvement of visual imagery. Kapur et al. (1995a) compared two tasks involving the visual recognition of concrete imageable words, one characterized by a large and the other by a small proportion of target items. An activation in the right parietal cortex in the region of the precuneus was present in the former only. This ecphoria effect may reflect reactivation of stored visual representations but also some visual imagery activity, conducive to the recognition of items. However, based on the Schacter et al. (1996a) study, Buckner et al. (1996a) raised a different hypothesis, that of the involvement of the precuneus in ‘‘retrieval effort.’’ In the study of Schacter et al. (1996a) already described above, activation of the right precuneus was indeed observed during the condition of difficult retrieval (low recall) when compared with a condition of easy retrieval (high recall). But overall the most convincing hypothesis regarding the role of the precuneus, remains that of the imageability of the items to be memorized, which may have been at play in the low recall condition of Schacter et al. (1996a). 3.2. The Cerebellum Activation of the cerebellum has been repeatedly documented during episodic memory tasks (Table 2). A role for the cerebellum in cognitive activities is now

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widely recognized, even if not yet fully understood (Schmahmann, 1991; Fiez 1996, for reviews). It may play a role in the modulation of cognitive functioning (Schmahmann, 1991), the temporal programming of willful acts and language (Ingvar, 1994, for review), and the mechanism of subvocal rehearsal (Fiez et al., 1996), but none of these functions has a direct link with episodic memory. Likewise, the well-established role of the cerebellum in explicit learning of motor (Jenkins et al., 1994) and cognitive skills (Raichle et al., 1994) would not easily account for the occurrence of cerebellar activation in episodic retrieval tasks with a single trial (e.g., Grady et al., 1995; Schacter et al., 1996a). According to some authors, however, the cerebellum would play a specific role in episodic memory. Thus, Schacter et al. (1996b) proposed that the cerebellum might, like the prefrontal cortex, be involved in ‘‘retrieval effort’’ and inhibition of nonrelevant information, and Andreasen et al. (1995c) underlined the close anatomical (crossed) connections between the cerebellum and the prefrontal cortex (Middleton and Strick, 1994), so that the right cerebellum could, like the left prefrontal cortex, belong to a general memory circuit involved in the encoding of information. However, the available data suggest that activation of the cerebellum would seem to be more specific to retrieval than to encoding (Tables 1 and 2) and to concern predominantly the left cerebellar hemisphere; hence the recent extension of the HERA model to the cerebellum (Cabeza et al., 1997a). Clearly, further studies are needed to clarify the exact computational role of this structure in episodic memory. 3.3. The Cingulate Cortex Consistent with lesional neuropsychology (Valenstein et al., 1987), activation of the posterior cingulate cortex has been occasionally observed in episodic memory tasks (Tables 1 and 2). However, a precise role for this area cannot be extracted from the pattern of results, with activations noted during both encoding (Shallice et al., 1994) and retrieval (Petrides et al., 1995; Owen et al., 1996b), though with asymmetrical activation fully consistent with the HERA model (Tables 1 and 2). Activation of the anterior cingulate cortex is almost constant in episodic memory tasks (Tables 1 and 2), though greater for cued recall than for recognition (Cabeza et al., 1997a). Across studies, the hemispheric asymmetries observed would be determined more by the type of stimuli (i.e., verbal vs nonverbal) than by the memory processes at play (i.e., encoding vs retrieval). Several cognitive functions have been attributed to the anterior cingulate cortex, which according to Fletcher et al. (1995a) might be explained by its extensive connections with neocortical and subcortical structures. Thus, involvement of this structure has been established in divided attention (Pardo et al.,

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1990; Corbetta et al., 1990; Bench et al., 1993), in various anticipatory states (Murtha et al., 1996), and in the initiation and selection of responses (Cabeza et al., 1997a). Although all of these different functions might apply during episodic memory paradigms, a recent study by Nyberg et al. (1996c) documented activations of this structure when retrieval of the temporal feature of the items (‘‘when’’) was compared with the recall of their object and location features (‘‘what’’ and ‘‘where’’), suggesting a specific role for the anterior cingulate cortex in the temporal component of episodic memory. 4. SYNTHESIS: A GENERAL EPISODIC MEMORY NETWORK As shown above, findings from activation studies concerning the prefrontal cortex and functional asymmetry have been very convergent, even though a recent metaanalysis indicates that retrieval processes are more lateralized than encoding processes (see Tulving and Markowitsch, 1997). Regarding the hippocampus, it seems to be involved in both encoding and retrieval of recently acquired information (but see Maguire et al., 1997), but the exact conditions which determine hippocampal activation have yet to be determined. Finally, in addition to these two structures and despite many still obscure points, the pattern of activations across studies indicates the existence of a relatively wide neuronal network underlying episodic memory (Andreasen et al., 1995a; Nyberg et al., 1996c; Cabeza et al., 1997a). Recently, Nyberg et al. (1996d) put forward a model for the interrelations among the different structures of this network based, not just on the activations observed, but on the deactivations as well. Using a network analysis, they suggest that deactivation reflects the inhibitory influence of the regions which are involved in the current cognitive processing on those which are not. Cognitive processes which are irrelevant to the task would thereby be inhibited. For instance, word recognition would activate the right prefrontal cortex which in turn would inhibit the left prefrontal cortex. The reverse pattern would be observed during the encoding of information, assuming that encoding and recall operate in an antagonistic manner (Nyberg et al., 1996a). According to this model, one part of the network would be active whatever the task, while other parts would be more specific to the type of processing taking place (e.g., ecphoric recall vs retrieval effort) or the type of information to be memorized (Buckner et al., 1996a; Nyberg et al., 1996c; Cabeza et al., 1997d). Both Nyberg et al. (1996c) and Cabeza et al. (1997d) report structures which activate specifically with the processing of the fundamental features of episodic memory (i.e., what, where and when), and structures which activate independently of these features. Within this general network, the prefrontal cortex and the hippo-

campal formation hold a privileged position and would seem to play roles which can be dissociated both in encoding (Dolan and Fletcher, 1997) and retrieval (Schacter et al., 1996a; Cabeza et al., 1997d). For instance, the latter study even suggests that temporalorder retrieval (‘‘when’’) is more dependent on prefrontal cortex, and item retrieval (‘‘what’’) is more dependent on the medial temporal region. 5. AGE EFFECTS ON THE NETWORK Because of the known effects of aging on episodic memory performance, the effects of age on the organization of the neuronal networks underlying episodic memory have attracted considerable interest, though only few articles have been published thus far. Grady et al. (1995) first showed that aging affects the activation pattern underlying the process of encoding of faces, aged subjects not showing the right hippocampus and left prefrontal activation observed in young subjects; the activation pattern did not differ significantly during the face recognition task, and there were no age differences in reaction time but significant difference was found in recognition performances. Schacter et al. (1996c) studied the effect of aging using the high vs low recall protocol of their previous study described above (Schacter et al., 1996a). The old subjects recalled less words than the young in both conditions. Aging did not affect the normal hippocampal activation in the highrecall task, but induced abnormal patterns in the left prefrontal cortex in the low-recall task: instead of the activation in the anterior prefrontal region observed in young subjects, elderly people showed posterior frontal activation in the vicinity of Broca’s area. These findings, which are compatible with the idea of a vulnerability of the frontal lobes in normal aging (Craik, 1990), suggest that the search strategies engaged in by elderly subjects differ from those used by younger subjects, with for instance activation of Broca’s area possibly reflecting articulatory rehearsal mechanisms in compensation for the loss of search strategies based on semantic categorization. The discrepancy between the findings of the Grady et al. (1995) study and that of Schacter et al. (1996c) regarding the aging effects on prefrontal cortex activation during retrieval tasks may be due to differences in the paradigm used, namely recognition and cued recall, respectively, in that it is well-known that recognition is less affected in normal aging and therefore would depend less upon the frontal lobe than cued recall. The other discrepancy between Grady et al. (1995) and Schacter et al. (1996c) concerns the hippocampus, as the former authors reported loss of hippocampal activation in aged subjects during the encoding of faces, while the latter found normal activation in this region during word recall, but again differences in paradigm may be implicated. Cabeza et al.

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(1997b) have compared young adults and high-functioning elderly people in tasks of encoding, recognition, and cued recall of verbal material. Their findings strengthen the hypothesis of a recourse to different strategies in the two groups, elderly subjects showing lesser left and right prefrontal activation during encoding and retrieval, respectively, but stronger activation in the insula during encoding, the precuneus during recognition, and the left prefrontal cortex during cued recall. Though the effects of age on performances were not significant in this study, these findings can be interpreted as reflecting less effective cognitive strategies and/or functional reorganization with aging, i.e., ‘‘agerelated changes in effective connectivity in the neural network underlying the task’’ (Cabeza et al., 1997c). Finally, Ba¨ckman et al. (1997), using the earlierdescribed cued-recall paradigm of Squire et al. (1992), underlined the similarities rather than the differences in prefrontal activation patterns between elderly and young subjects, although there was age-related difference in cued recall and selective activations in each group were observed, such as left cerebellum and Wernicke area in the young subjects and bilateral medial temporal cortex in the older, which, however, ‘‘must be regarded as preliminary findings.’’ Taken together, all four studies about aging and episodic memory suggest that the asymmetry of the HERA model tends to decrease and additional areas are often recruited in elderly subjects as a mechanism to ‘‘compensate’’ for the loss of efficiency of the network. However, this ‘‘compensatory’’ process may result in longer reaction times (Grady and Haxby, 1995). The problems of interpretation regarding the reorganization of neuronal networks raised by these PET activation studies in aging are further complicated in episodic memory disorders such as Alzheimer’s disease (Becker et al., 1996; Herbster et al., 1996). 6. ACTIVATION STUDIES AND NEUROPSYCHOLOGY

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fully by such patients either because they in fact involve processes other than episodic memory per se (e.g., semantic memory, see for example, Swick and Knight, 1996), or because they do not require the recourse to autonoetic consciousness (Wheeler et al., 1997). It may also be that the prefrontal cortex is not necessary for episodic memory processes because of postlesional large scale reorganization. Thus, a new look at memory performance in frontal damaged patients is now required, and Wheeler et al. (1995) recently reported frequently impaired free recall and, to a lesser extent, recognition, after frontal lobe damage. Regarding the functional asymmetry which forms the basis of the HERA model, it proves very difficult to test in the clinic due to the almost impossible separation of encoding from retrieval in classic memory tasks. However, Markowitsch (1995), reexamining the earlier literature regarding retrograde amnesia, concluded that the available data would be consistent with the HERA model, with right-sided frontal lesions inducing episodic memory impairment, and left-sided ones, semantic memory deficit. This author, as well as Kroll et al. (1997), further emphasize the role of the temporal pole in the memory of old events and suggest that this region may have been overlooked in activation studies, either because of technical problems (i.e., topography), or because the cognitive paradigms have used neutral and very recently learned information. To explain the inconsistent activation of the hippocampal area during episodic memory tasks, methodological issues have been raised (see above). However, neuropsychology has documented that hippocampal damage is not a prerequisite for episodic memory impairment, as damage to other parts of Papez circuit may induce permanent amnesia (e.g., diencephalic amnesia). Conversely, it now appears that most recent studies of episodic memory regularly demonstrate hippocampal activation, so that the discrepancies are more apparent than real. 6.2. Complementarity

6.1. Apparent Discrepancies Both congruent findings and discrepancies between the results of activation studies and established knowledge from neuropsychology have been mentioned throughout the above review. However, the most conspicuous differences, i.e., the somewhat unexpected role of the frontal cortex and the inconsistent activation of the hippocampal area during episodic memory tasks, deserve further comments. Regarding the prefrontal cortex, the impairment of performance in episodic memory tasks in patients with frontal damage has either been neglected, or attributed to deficits in complex strategies rather than to the processes of encoding, storage or retrieval (Wheeler et al., 1997). However, some of these clinical tests might be performed success-

Regardless, it remains that the activation and the neuropsychology paradigms do not really assess the same information, as the former reveals the brain structures involved in a given task, while the latter reveals the brain structures necessary to perform the task after brain reorganization (Eustache et al., 1995a). Thus, the two approaches are complementary rather than competing, and each can serve as a feeder to the other. Thus, the finding from activation studies in the young healthy subjects may allow a better understanding of the memory decline of aging (e.g., impaired encoding has been proposed as a mechanism for this decline in the view of the activation pattern, Grady et al., 1995), as well as in particular brain-damaged subjects (e.g., a patient with a lesion confined to the

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right thalamus and a severe and durable deficit of episodic memory showed bilateral hypometabolism in the mesial frontal regions, Della Sala et al., 1997). Likewise, the findings of frontal hypometabolism in two cases of transient global amnesia (Baron et al., 1994; Eustache et al., 1997) and the positive correlations found between episodic memory performance and frontal resting brain glucose utilization in Alzheimer’s disease (Desgranges et al., 1998) have been interpreted in the light of earlier activation studies. For instance, the somewhat unexpected finding in early 1994 (i.e. before the HERA model was published) of right frontal hypometabolism in a case of TGA (Baron et al., 1994) was nevertheless interpreted in terms of episodic memory processes based on the then available memory activation studies. Activation studies in single-case brain-damaged patients, together with the combined use of the resting metabolism paradigm, should allow to directly visualize the neural substrates of cognitive impairment and compensatory behavioral strategies induced by each patient’s individual pathological process (Buckner et al., 1996b), bridging the two paradigms and bringing out a new functional approach to the neuropsychology of episodic memory. REFERENCES Aguirre, G. K., Detre, J. A., Alsop, D. C., and D’Esposito, M. 1996. The parahippocampus subserves topographical learning in man. Cereb. Cortex, 6:823–829. Andreasen, N. C., O’Leary, D. S., Arndt, S., Cizadlo, T., Hurtig, R., Rezai, K., Watkins, G. L., Ponto, L. L. B., and Hichwa, R. D. 1995a. Short-term and long-term verbal memory: A positron emission tomography study. Proc. Natl. Acad. Sci. USA 92:5111–5115. Andreasen, N. C., O’Leary, D. S., Arndt, S., Cizadlo, T., Rezai, K., Watkins, G. L., Ponto, L. L. B., and Hichwa, R. D. 1995b. PET studies of memory. I. Novel and practiced free recall of complex narratives. NeuroImage 2:284–295. Andreasen, N. C., O’Leary, D. S., Cizadlo, T., Arndt, S., Rezai, K., Watkins, G. L., Ponto, L. L. B., and Hichwa, R. D. 1995c. PET studies of memory. II. Novel versus practiced free recall of word lists. NeuroImage 2:296–305. Andreasen, N. C., O’Leary, D. S., Arndt, S., Cizadlo, T., Hurtig, R., Rezai, K., Watkins, G. L., Ponto, L. L. B., and Hichwa, R. D. 1996. Neural substrates of facial recognition. The Journal of Neuropsychiatry Clin. Neurosci. 8:139–146. Ba¨ckman, L., Almkvist, O., Andersson, J., Nordberg, A., Winblad, B., Reineck, R., and Långstro¨m, B. 1997. Brain activation in young and older adults during implicit and explicit retrieval. J. Cognit. Neurosci. 9:378–391. Baron, J. C., Petit-Taboue´, M. C., Le Doze, F., Desgranges, B., Ravenel, N., and Marchal, G. 1994. Right frontal cortex hypometabolism in transient global amnesia. A PET study. Brain 117:545–552. Baron, J. C., Desgranges, B., Landeau, B., Mezenge, F., Petit-Taboue´, M. C., and Eustache, F. 1997. Mapping with SPM the neurobiological basis of episodic memory impairment of normal aging: A PET study of resting brain glucose utilization (rCMRGlc). NeuroImage 5:621.

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