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Journal of Clinical and Experimental Neuropsychology
2001, Vol. 23, No. 01, pp. 32±48
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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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NEUROIMAGING AND EPISODIC MEMORY
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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SCOTT W. YANCEY AND ELIZABETH A. PHELPS
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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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NEUROIMAGING AND EPISODIC MEMORY
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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SCOTT W. YANCEY AND ELIZABETH A. PHELPS
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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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NEUROIMAGING AND EPISODIC MEMORY
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).
Downloaded By: [New York University] At: 19:51 13 July 2009
NEUROIMAGING AND EPISODIC MEMORY
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-
41
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
Downloaded By: [New York University] At: 19:51 13 July 2009
42
SCOTT W. YANCEY AND ELIZABETH A. PHELPS
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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NEUROIMAGING AND EPISODIC MEMORY
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
43
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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44
SCOTT W. YANCEY AND ELIZABETH A. PHELPS
studies of priming, see Schacter, Buckner, & Koustaal (1998). Lastly, research in emotional learning often assesses fear conditioning, in which a
neutral stimulus comes to elicit an emotional response by virtue of being paired with an emotional
stimulus. Consistent with animal models of fear
conditioning (see LeDoux, 1996, for a review),
neuroimaging studies have found activation of the
amygdala during the acquisition of conditioned
fear (Buchel, Morris, Dolan, & Friston, 1998;
LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998).
For this review we focused on what we normally mean when we refer to ``memory'' in
everyday speech, that is, the ability to consciously
recollect memories for events. This review highlights that a network of brain regions makes distinct contributions to the normal operation of the
episodic memory system. This normal operation
may be altered in certain clinical populations.
By understanding the mechanisms involved in
the normal operation of episodic memory, and
determining how they malfunction in patient
populations, we can begin to gain insight into
the unique functional neuroanatomical signatures
related to different clinical disorders.
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