Download Prefrontal Cortex and Long-Term Memory Encoding: An Integrative

Prefrontal Cortex and Long-Term Memory
Encoding: An Integrative Review of Findings
from Neuropsychology and Neuroimaging
ROBERT S. BLUMENFELD and CHARAN RANGANATH
Center for Neuroscience and Department of Psychology, University of California at Davis
Recent findings have led to a growing appreciation of the role of the lateral prefrontal cortex (PFC) in
episodic long-term memory (LTM). Here, the authors will review results from neuropsychological and neuroimaging studies of humans and present a framework to explain how different regions of the PFC contribute to successful LTM formation. Central to this framework is the idea that different regions within the
PFC implement different control processes that augment memory by enhancing or attenuating memory for
certain aspects of a particular item or event. Evidence reviewed here suggests that ventrolateral regions of
the PFC contribute to the ability to select goal-relevant item information, and that this processing strengthens the representation of goal-relevant features of items during LTM encoding. Dorsolateral regions of the
PFC may contribute to the ability to organize multiple pieces of information in working memory, thereby
enhancing memory for associations among items in LTM. Thus, dorsolateral and ventrolateral regions of the
PFC may implement different control processes that support LTM formation in a complementary fashion.
NEUROSCIENTIST 13(3):280–291, 2007. DOI: 10.1177/1073858407299290
KEY WORDS
Working, Organization, Selection, Frontal, Lobes, Associative, Episodic, Memory
Memorizing phone numbers, remembering past conversations, finding where you left your keys—these are the
kinds of daily activities that depend on the ability to form
coherent episodic memories. Recent research in neuropsychology and neuroimaging has highlighted the
importance of the prefrontal cortex (PFC) in promoting
successful episodic long-term memory (LTM) formation,
although its precise role remains poorly understood. Here,
we will review this evidence and present a theoretical
framework for understanding how different regions of the
PFC contribute to episodic memory encoding. Central to
this framework is the idea that different regions in the PFC
implement different control processes that augment memory by enhancing or attenuating certain aspects of a particular item or event.
Our review will have three main sections. First, we will
begin by discussing results from studies of memory in
patients with focal PFC lesions that converge on the idea
that specific deficits in cognitive control underlie the LTM
impairments in PFC patients. Next, we will review results
from neuroimaging studies of cognitive control, which
suggest that these different cognitive control processes
are performed by distinct PFC regions. Finally, we will
review the neuroimaging literature on episodic memory
This work was supported by PHS grant 1R01MH068721.
Address correspondence to: Robert S. Blumenfeld, UC Davis Center
for Neuroscience, 1544 Newton Ct, Davis, CA 95616 (e-mail: roblume
@ucdavis.edu).
280
encoding and consider how our framework can help to
clarify the role of the PFC in LTM encoding.
Effects of Prefrontal Lesions
on LTM Encoding
Clinicians have long noted that focal prefrontal lesions in
humans produce subtle but noticeable memory deficits,
and this impression accords well with results from neuropsychological studies (Milner 1962; Stuss and Benson
1986; Shimamura 1995; Ranganath and Knight 2003).
In general, patients with PFC lesions show impairments
on a wide range of memory tasks that tax executive control during encoding and retrieval. For instance, PFC
patients exhibit impaired performance on unconstrained
memory tests such as free-recall (Jetter and others 1986;
McAndrews and Milner 1991; Eslinger and Grattan 1994;
Stuss and others 1994; Moscovitch and Winocur 1995;
Wheeler and others 1995; Dimitrov and others 1999; see
Box 1). In contrast to healthy control participants, PFC
patients tend not to spontaneously cluster or group recall
output according to the semantic relationships within a
categorized word list (della Rocchetta 1986; Hirst and
Volpe 1988; della Rocchetta and Milner 1993; Stuss and
others 1994; Gershberg and Shimamura 1995). When presented with several study-recall blocks of the same word
list, PFC patients show less consistency of recall output
order from trial to trial (i.e., “subjective organization”; see
Box 1) compared to controls (Stuss and others 1994;
Gershberg and Shimamura 1995; Alexander and others
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Prefrontal Cortex and Memory Encoding
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ISSN 1073-8584
Box 1. Memory Measures in Behavioral Research
In behavioral studies, episodic memory is usually assessed by testing memory for lists of items such
as words (Ebbinghaus 1885/1964). With this approach, memory can be tested in a number of ways.
One is free-recall, in which participants are simply asked to recall as many items as they can remember from the study list. Organizational strategies strongly impact recall performance, and this impact
can be measured by analyzing the characteristics of items that are recalled and the order in which
they are recalled. For example, if participants are given lists of categorically related words to memorize, they tend to recall semantically related items together even if these items were distributed across
the study list. This phenomenon, called semantic clustering, can provide a quantitative index of organization in memory. A related phenomenon, subjective organization, is seen in studies in which the
same list is repeatedly studied and tested. In this situation, participants will tend to recall sets of items
in the same order across different recall trials. This tendency is thought to reflect the fact that participants form associations between items during encoding, and subsequently make use of these associations to guide retrieval (Sternberg and Tulving 1977).
Another paradigm used in many memory studies is “paired-associate learning.” In these studies,
pairs of items are studied together, and then memory for these associations is tested. For example,
memory for a studied word pair (A-B) can be tested via cued recall (A-?) or associative recognition (AB or A-D?). Relevant to the studies discussed in our review, learning of a previous association (A-B)
makes it more difficult to learn a new, overlapping association (A-C) (Barnes and Underwood 1959).
This phenomenon is called “proactive interference,” and it may reflect competition between the previously learned association and the new association. Accordingly, overcoming proactive interference
requires the engagement of controlled selection processes to resolve this competition.
2003). In addition, patients with PFC lesions exhibit
impairments on tests of source memory (Janowsky and
others 1989b), memory for temporal order (Milner and
others 1985; Shimamura and others 1990; Kesner and others 1994), recency (Milner and others 1991), frequency
(Stanhope and others 1998), and associative learning
(Shimamura and others 1995; Swick and Knight 1996;
Dimitrov and others 1999). Furthermore, PFC patients
often lack insight into their own memory problems and fail
to spontaneously use common memory strategies (Hirst
and Volpe 1988; Janowsky and others 1989a; Moscovitch
and Melo 1997; Vilkki and others 1998).
In contrast to these deficits, patients with prefrontal
lesions can often perform at near-normal levels when
given structured encoding tasks or tests that do not tax
strategic retrieval processes. For instance, PFC patients
perform better at cued-recall compared to free-recall and
can perform similarly to control subjects on item recognition (Kesner and others 1994; Stuss and others 1994;
Swick and Knight 1996; Dimitrov and others 1999;
Alexander and others 2003; but see Wheeler and others
1995). Moreover, patients can show marked improvements on a variety of recall measures if given sufficient
practice or environmental support at encoding or retrieval
(Hirst and Volpe 1988; della Rocchetta and Milner 1993;
Stuss and others 1994; Gershberg and Shimamura 1995).
In general, theoretical accounts have stressed that LTM
impairments associated with PFC damage arise as a consequence of deficits in control processing rather than from
a primary deficit in memory storage (Ranganath and
Knight 2003). Some theories emphasize the role of the
PFC in “selection” processes that direct attention toward
goal-relevant information and task-appropriate responses
(for reviews, see Milner and others 1985; Stuss and
Benson 1986; Miller and Cohen 2001). Thus, memory
deficits may occur in patients with prefrontal lesions
because they are unable to select relevant information or
inhibit distracting or interfering items or responses during
encoding or retrieval (Luria 1966, 1973; Perret 1974;
Shimamura and others 1995). One finding consistent with
this account comes from a study of paired-associate learning (see Box 1) in patients with focal PFC lesions and
matched controls (Shimamura and others 1995). In this
study, participants learned a list of word pairs (“A-B”) and
then learned an overlapping list of word pairs (“A-C”)
across several trials. Recall success on the second list
required subjects to inhibit the well-learned A-B pairing
and select the appropriate A-C pairing. Consistent with
the selection account, patients with PFC lesions showed a
significant and disproportionate decrement in recall performance between the first trial of A-B learning compared
to the first trial of A-C learning (i.e., a measure of proactive interference). Furthermore, during cued recall for the
A-C list, PFC patients recalled fewer appropriate targets
and recalled significantly more words from the A-B list.
These findings are consistent with the idea that PFC
lesions induce difficulties in resolving competition
between items in memory, possibly due to impairments of
controlled selection processes.
Other theories emphasize the role of the PFC in guiding
spontaneous organization of information during the
encoding and retrieval of memories (Petrides and Milner
1982; Milner and others 1985; della Rocchetta and Milner
1993; Gershberg and Shimamura 1995). Specifically,
“organization” refers to memory strategies that emphasize
comparison or transformation of relations among items
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that are to be learned (Bower 1970; Hunt and Einstein
1981). Some common organizational strategies during
encoding include categorizing words in a list according to
semantic features (Hunt and Einstein 1981), imagining
two or more items interacting (Bower 1970), or forming a
sentence out of two or more words. Organization during
encoding does not facilitate LTM by enhancing features
of specific items in memory, but instead promotes memory for associations among items (Bower 1970; Begg
1979; McGee 1980). Accordingly, a number of measures
can be used to estimate the impact of organization on
LTM performance (see Box 1).
In support of the notion that PFC is critical for organization in memory, studies have demonstrated that patients
with prefrontal lesions do not spontaneously organize
information or make use of effective organizational strategies during encoding or retrieval (Hirst and Volpe 1988;
della Rocchetta and Milner 1993; Stuss and others 1994;
Gershberg and Shimamura 1995; Alexander and others
2003) and that they show deficits on many memory measures that are sensitive to organization. For instance,
Gershberg and Shimamura (1995) compared patients with
relatively focal lesions to the dorsolateral PFC and healthy
controls on learning of lists of words that were either
semantically related or unrelated. Relative to controls,
patients were less likely to exhibit subjective organization
or semantic clustering (see Box 1) during recall of lists of
semantically related words. Interestingly, recall and clustering performance increased for semantically related
word lists when patients were explicitly asked to make a
category judgment during encoding, or when they were
provided with the category names at test, or both. In contrast, healthy controls performed at similar levels regardless of whether they were given encoding instructions or
retrieval cues. This pattern of results suggests that patients
were capable of using semantic information to guide
encoding and retrieval, but they lacked the ability to spontaneously use semantic organizational strategies. In contrast, controls were spontaneously using organizational
strategies during encoding and/or retrieval. These findings,
and others (Hirst and Volpe 1988; della Rocchetta and
Milner 1993; Stuss and others 1994; Alexander and others
2003), are consistent with the idea that LTM deficits following prefrontal lesions may result from a failure to
organize information during encoding and capitalize on
organizational structure during retrieval.
Many researchers have suggested that both selection
and organizational processes depend on the functioning of
the PFC, and there are several studies that reported findings consistent with both the selection and organizational
accounts (Hirst and Volpe 1988; Stuss and others 1994;
Gershberg and Shimamura 1995; Shimamura and others
1995; Alexander and others 2003). One question that cannot be addressed by the neuropsychological evidence is
whether selection and organization depend upon the same
regions of the PFC, because these studies typically used
subject groups that have significant heterogeneity in
lesion size and location. There are hints in the extant neuropsychological literature to suggest that patients with
deficits in subjective organization and recall clustering
tend to have damage to the dorsolateral PFC (Eslinger and
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Grattan 1994; Gershberg and Shimamura 1995; Alexander
and others 2003; but see Stuss and others 1994).
Nonetheless, the neuropsychological evidence cannot conclusively resolve this issue because studies have typically
used patient groups that have significant heterogeneity in
lesion size and location.
Functional Neuroimaging of
Cognitive Control
Several functional magnetic resonance imaging (fMRI)
studies have found support for the notion that selection
mechanisms and organizational control mechanisms are
processed by different regions of the PFC (D’Esposito,
Postle, Ballard, and others 1999; Postle and others 1999;
Petrides 2000a; Wagner, Maril, and others 2001; Glahn
and others 2002; for review, see Fletcher and Henson
2001). Specifically, neuroimaging studies of working
memory (WM) and cognitive control have suggested that
regions within the ventrolateral PFC (VLPFC: BA
,44,45,47,47/12) and regions in the dorsolateral PFC
(DLPFC: BA 9,46) may implement control processes that
support memory encoding in a complementary fashion.
VLPFC and Selection Processes
Results from neuroimaging studies of proactive interference resolution (Jonides and Nee 2006), response inhibition (Aron and others 2004), verb generation (Buckner
2003; Thompson-Schill and others 2005), and semantic
and nonsemantic classification (Wagner and Davachi
2001; Badre and others 2005) are consistent with the
idea that VLPFC might be particularly important for
implementing “selection” processes that direct attention
toward goal-relevant information or inhibit the influence
of irrelevant information on behavior.
Some support for this view has come from studies that
used the “recent-probes task” (Monsell 1978) to examine
the role of VLPFC in resolving proactive interference. In
this task, participants must maintain a set of four letters
over a short delay and subsequently evaluate whether a
test probe was in the memory set. Proactive interference
is manipulated by varying the familiarity of the probes
across trials. For instance, on some trials, the probe letter
is not in the current memory set but was in the memory
set on the previous trial. To perform accurately on these
“recent negative” trials, participants must inhibit the high
familiarity of the probe to make the correct negative
response. Imaging studies have consistently shown that
activation in the left mid-VLPFC (BA 44, 45; see Fig. 1)
is increased on these trials, relative to trials with nonrecent negative or positive probes (e.g., Jonides and others
1998; D’Esposito, Postle, Jonides, and others 1999;
Bunge and others 2001; Mecklinger and others 2003;
e.g., Nelson and others 2003; Postle and Brush 2004;
Postle and others 2004; Badre and Wagner 2005; see
Jonides and Nee 2006 for review).
Another line of evidence consistent with the selection
account has come from fMRI studies of verb generation and
semantic classification (Buckner 2003; Thompson-Schill
and others 2005). For instance, one study (ThompsonSchill and others 1997) examined PFC activity associated
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require less control and that the anterior regions of the
VLPFC are additionally recruited during selection tasks
that require considerably more control (Gold and Buckner
2002; Gold and others 2005; but see Badre and others
2005). Interestingly, some studies have found that the activation of VLPFC subregions are influenced both by materials and by the amount of controlled selection (Badre and
others 2005; Gold and others 2005). This suggests that
although both of these accounts have some explanatory
power, more research will be required to find the best way
to characterize the functions of VLPFC subregions.
DLPFC and Organization
Fig. 1. Subregions of the human prefrontal cortex (PFC).
The dorsolateral prefrontal cortex (DLPFC) (BA 9, 46) is
shown in green, and the ventrolateral prefrontal cortex
(VLPFC) (BA 44, 45, and 47/12) is shown in red. The blue
dashed line indicates the approximate borders between
the DLPFC and VLPFC. White dashed lines indicate the
approximate borders between the subregions of the
VLPFC.
with selection processing across three different semantic
tasks. Within each task, selection demands were varied
within each of these conditions by increasing the competition among response alternatives. For example, in the high
selection condition of the comparison task, participants had
to compare a target noun (e.g., tooth) to two highly related
probe nouns (e.g., tongue and bone) and decide which probe
was most similar to the cue along a specific dimension (i.e.,
color). However, in the low-selection condition, participants
could make this comparison based on global similarity
between the target and probe words. Across all three tasks,
a common region of the left mid-VLPFC (BA 44, 45) exhibited increased activation during blocks of high-selection trials, suggesting a role for this region in the selection of
semantic features of items.
Results from some fMRI studies have shown that more
activation in relatively more anterior and ventral regions of
the VLPFC (BA 47/12, 45; see Fig. 1) is enhanced during
selection of semantic information, whereas activation in
the posterior and dorsal VLPFC regions (BA 44, 6; see Fig.
1) is enhanced during processing of semantic, phonological, or orthographic attributes of words (e.g., Poldrack and
others 1999; Bokde and others 2001; Roskies and others
2001; Wagner, Pare-Blagoev, and others 2001; Dobbins
and others 2002; McDermott and others 2003; Badre and
others 2005; Bunge and others 2005; Dobbins and Wagner
2005; but see Otten and Rugg 2001b and Gold and
Buckner 2002). Not all studies, however, have observed
this type of material-specific dissociation within the PFC
(e.g., Barde and Thompson-Schill 2002). An alternative
view that has been proposed is that the extent and location
of VLPFC activity depends on the degree of controlled
selection that must be engaged (Buckner 2003). Research
consistent with this notion has found that posterior regions
of the VLPFC show recruitment during selection tasks that
Unlike VLPFC, DLPFC is not robustly recruited during
tasks that solely require selection of task-relevant information. Instead, evidence from neuroimaging studies suggests
that DLPFC is involved in organization—that is, the comparison or transformation of relationships among items that
are active in memory (D’Esposito, Postle, Ballard, and others 1999; Postle and others 1999; Wagner, Maril, and others 2001; Barde and Thompson-Schill 2002; Glahn and
others 2002; Bor and others 2003; Veltman and others
2003; Cannon and others 2005; Blumenfeld and Ranganath
2006; Crone and others 2006; Mohr and others 2006). For
example, DLPFC activation is reported in “manipulation”
tasks that involve sequencing of information that is being
maintained in WM (D’Esposito, Postle, Ballard, and others
1999; Postle and others 1999; Postle and D’Esposito 1999;
Wagner, Maril, and others 2001; Blumenfeld and
Ranganath 2006) or monitoring of previous responses
when selecting a future response (Petrides 2000a, 2000b;
Stern and others 2000). DLPFC activation has also been
reported in studies of “chunking” (Bor and others 2003;
Bor and others 2004), the process by which multiple separate pieces of information are organized into fewer units of
information (Miller and others 1960).
One study of verbal WM highlights the selective role
of DLPFC in organization (Postle and others 1999). In
this study, participants were scanned during three tasks
that required maintenance of verbal information across
an eight-second delay period. In two conditions, participants had to maintain the identity and the serial position
of either two (“forward 2” trials) or five (“forward 5” trials) letters. In the third condition, participants were
prompted to rearrange a set of five letters in alphabetical
order and to maintain the identity and serial position of
the rearranged set of letters (“alphabetize 5” trials).
Whereas forward 5 and forward 2 trials differed primarily in terms of the amount of information to be maintained, alphabetize 5 and forward 5 trials differed
primarily in the kind of processing that was engaged.
Specifically, alphabetize 5 trials placed greater demands
on organizational processing, because these trials
required participants to use the “alphabetize” rule to
transform the serial order relationships among the items.
Results from this study showed that, for each subject,
DLPFC activation was increased during the delay period
of alphabetize 5 trials, as compared with forward 5 trials. DLPFC activation in this study could not be attributed to WM maintenance demands, because it did not
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significantly differ between forward 2 and forward 5 trials. This pattern of results has been replicated in other
studies with verbal (D’Esposito, Postle, Ballard, and others 1999; Wagner, Maril, and others 2001; Barde and
Thompson-Schill 2002; Blumenfeld and Ranganath
2006) and spatial (Glahn and others 2002; Mohr and others 2006) stimuli, suggesting that DLPFC activation is
more specifically increased during tasks that require
organization of information that is active in WM.
Additional evidence for the organizational account of
DLPFC function comes from neuroimaging studies of
“chunking” (Bor and others 2003; Bor and others 2004).
For example, in one study, participants were scanned
while memorizing a sequence of four spatial locations
within a 4 × 4 grid of red squares (Bor and others 2003).
Critically, on some trials, the spatial arrays exhibited a
coherent structure, in that an element in the sequence
was either on the same column, row, or diagonal as the
element preceding it. The resulting sequences therefore
appeared geometrically regular and were more readily
organized into single shapes. In contrast, on other trials,
the elements within the sequence did not exhibit any
geometric structure. Behavioral performance was higher
on structured trials, presumably because participants
were able to exploit the structure to organize, or chunk,
the spatial sequences. Critically, DLPFC activation was
increased on structured, as compared to unstructured,
trials even though the structured task was easier. This
finding suggests that, rather than simply reflecting nonspecific demands related to task difficulty, DLPFC activation is more specifically sensitive to demands for
organizational processing.
Functional Neuroimaging of LTM Encoding
We began this review by summarizing findings indicating
that PFC lesions may impair selection and organization
processes that facilitate LTM encoding. Neuroimaging
studies of cognitive control have suggested that VLPFC is
recruited during tasks that require the selection of specific
item information, whereas DLPFC is additionally recruited
during tasks that require organizational processing. As we
will describe below, these findings may provide critical
insights into the ways in which lateral prefrontal regions
contribute to successful LTM formation.
Subsequent Memory Effects and the PFC
Event-related fMRI studies have investigated LTM
encoding by identifying “subsequent memory” or “difference due to memory” effects (see Paller and Wagner
2002 for review). In these studies, activation during
encoding of a particular item or set of items is analyzed
as a function of later memory success or failure. Regions
where activation is increased during encoding of items
that are subsequently remembered (relative to activation
during encoding of items that are subsequently forgotten) are thought to play a role in promoting successful
LTM formation.
As shown in Figure 2 and Table 1, studies using
the subsequent memory paradigm have demonstrated
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Fig. 2. Prefrontal activations reported in 37 fMRI studies
of long-term memory (LTM) formation. Each green dot
represents an activation peak in an analysis that reported
increased activation during encoding of items that were
subsequently remembered, as compared with items that
were subsequently forgotten (i.e., a “subsequent memory
effect”). Each red dot represents an activation peak in an
analysis that reported increased activation during encoding of items that were subsequently forgotten, as compared with items that were subsequently remembered
(i.e., “a subsequent forgetting effect”). Of the 150 local
maxima associated with subsequent memory, only 18 fall
within the dorsolateral prefrontal cortex (DLPFC) (BA 46
and 9) compared with 132 in the ventrolateral prefrontal
cortex (VLPFC) (BA 6, 44, 45, and 47). Furthermore, 10 of
the 11 local maxima associated with subsequent forgetting fall within the DLPFC. L = left; R = right.
significant prefrontal involvement in LTM encoding.
Inspection of the spatial distribution of activation peaks
(or “local maxima”) from these studies also suggests
that the degree of involvement seems to differ between
different PFC subregions. The data provide overwhelming support for the notion that the VLPFC contributes
to LTM formation. Out of 150 local maxima associated
with subsequent memory within the PFC, 132 fall within
the VLPFC. Furthermore, all but two studies that
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Table 1.
Prefrontal Activation in Studies of LTM Encoding
A. Remember > Forgotten Contrasts
Study
Baker and others 2001
Blumenfeld and Ranganath 2006
Brassen and others 2006
Buckner and others 2001
Chee and others 2002
Clark and Wagner 2003
Davachi and others 2001
Dolcos and others 2004
Erk and others 2003
Fletcher and others 2003
Garoff and others 2005
Henson and others 1999
Jackson and Schacter 2004
Johnson and others 2004
Kensinger and Schacter 2005
Kirchhoff and others 2000
Macrae and others 2004
Maril and others 2003
Morcom and others 2003
Otten and Rugg 2001a
Otten and others 2001
Otten and others 2002
Prince and others 2005
Ranganath and others 2004
Raye and others 2002
Reber and others 2002
Reynolds and others 2004
Sergerie and others 2005
Sommer and others 2005
Sperling and others 2003
Staresina and Davachi 2006
Summerfield and others 2006
Uncapher and Rugg 2005
Wagner and others 1998
Weis and others 2004
de Zubicaray and others 2005
Study Description
Activated
Prefrontal
Regions
Semantic (abstract) vs. structural (uppercase)
Organizational processing
Item memory and free-recall
Encoding during retrieval
Word frequency
Novel word learning
Maintenance vs. elaborative rehearsal
Arousal, valence, and emotion
Emotional processing
Levels of processing
Specific vs. general encoding
Recollection and familiarity
Associative memory
Refreshing
Emotion and reality monitoring
Novelty and content dependency
Self-referential processing
Feeling of knowing
Effect of aging
Content dependency
Levels of processing
Item vs. task processing
Associative memory
Recollection and familiarity
Refreshing
Encoding effort
Item vs. task processing
Emotional processing of faces
Object-location associations
Face-name associations
Associative memory and free recall
Face-house associative binding
Memory durability
Semantic processing
Temporal lobe & cerebellum during encoding
Word frequency and strength effects
VLPFC
VLPFC, DLPFC
VLPFC, DLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC, DLPFC
VLPFC
VLPFC
DLPFC
DLPFC, VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
VLPFC
DLPFC
VLPFC
VLPFC
VLPFC, DLPFC
VLPFC, DLPFC
VLPFC
VLPFC, DLPFC
VLPFC, DLPFC
VLPFC
VLPFC
VLPFC
VLPFC
Study Description
Prefrontal
Regions
B. Forgotten > Remember Contrasts
Study
Clark and Wagner 2003
Daselaar and others 2004
Kensinger and Schacter 2005
Otten and Rugg 2001b
Wagner and others 1998
Novel word learning
Forgetting
Emotion and reality monitoring
Content dependency
Semantic processing
DLPFC
VLPFC, DLPFC
DLPFC
DLPFC
DLPFC
A, Studies that revealed local maxima in prefrontal regions where activity during encoding was greater for items that were
subsequently remembered than for items that were subsequently forgotten. B, Studies that revealed local maxima in prefrontal regions where activity during encoding was greater for items that were subsequently forgotten than for items that
were subsequently remembered. LTM = long-term memory; VLPFC = ventrolateral prefrontal cortex; DLPFC = dorsolateral
prefrontal cortex.
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reported subsequent memory effects reported local maxima within the VLPFC. Given that the ability to select
relevant item information is essential for many forms of
goal-directed cognitive processing, including memory
encoding, it makes sense that the VLPFC activity should
be strongly linked to memory encoding in a wide variety
of behavioral contexts. These findings will be discussed
in more detail below.
The imaging literature seems to tell a different story
about the DLPFC. Out of 150 local maxima throughout
the PFC, only 18 fall within the DLPFC. Furthermore,
some studies have reported that DLPFC activation was
increased during encoding of items that were subsequently forgotten, as compared with those that were subsequently remembered (i.e., a “subsequent forgetting”
effect). These findings do not seem to support the notion
that the DLPFC contributes to LTM encoding. However,
a close analysis of the studies summarized in Table 1
reveals that the majority of imaging studies have used
encoding and retrieval tasks that deemphasize organizational processing. As described below, DLPFC activation should be associated with successful LTM encoding
specifically under encoding and/or retrieval conditions
that emphasize organization.
VLPFC and Selection during LTM Encoding
As shown in Figure 2, there is overwhelming support for
the notion that the VLPFC supports LTM encoding.
Behavioral research suggests that engaging selection
processes at the time of encoding can strongly impact the
strength or distinctiveness of a memory for the relevant
item (Craik and Lockhart 1972; Hunt and Einstein 1981).
For instance, rehearsing an item (Naveh-Benjamin and
Jonides 1984; Greene 1987; Davachi and others 2001;
Raye and others 2002; Ranganath and others 2005) or
attending to its high-level or semantic features (Craik and
Lockhart 1972) can improve its subsequent memorability.
Given that most fMRI studies emphasize encoding and
retrieval of individual items, and that selection processes
figure so prominently in these contexts, it makes sense
that the VLPFC has been so consistently implicated in
successful memory formation.
As noted in the “VLPFC and Selection Processes”
section above, anterior regions of the VLPFC (BA
47/12, 45; see Fig. 1) have been implicated in tasks that
require high levels of control and/or selection of semantic information (i.e., “deep” processing; cf. Craik and
Lockhart 1972), whereas more posterior regions of the
VLPFC (BA 44,6) have been implicated in tasks that
require less control during selection and/or selection of
phonological or orthographic information (i.e., “shallow” processing). Interestingly, some LTM encoding
studies have found corresponding patterns of subsequent
memory effects in the VLPFC. For instance, some studies have found that more anterior regions of the VLPFC
(BA 47/12, 45) showed subsequent memory effects for
items studied under deep encoding conditions (e.g.,
Wagner and others 1998; Baker and others 2001; Otten
and others 2001; Fletcher and others 2003; Ranganath
and others 2004), whereas more posterior regions of the
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VLPFC (BA 44, 6) showed equivalent subsequent memory effects following both deep and shallow encoding
(Baker and others 2001; Fletcher and others 2003).
However, the literature is not consistent in this regard, as
several studies have failed to find such a dissociation in
the PFC (Baker and others 2001; Davachi and others
2001; Otten and others 2001; Otten and Rugg 2001a; but
see Fletcher and others 2003). Thus, more research is
needed to further characterize how VLPFC subregions
contribute to LTM encoding.
Until now, we have highlighted how selection processes,
putatively implemented by the VLPFC, may support successful LTM formation in a very wide range of behavioral contexts. However, there are some situations in
which selection processing may be deleterious to memory formation. For example, if selection processes direct
attention away from items that are to be encoded,
VLPFC activation can be negatively correlated with subsequent memory performance (Otten and others 2002;
Reynolds and others 2004). In one such study, participants were scanned while performing several blocks of
encoding trials, and subsequent memory was tested outside of the scanner (Otten and others 2002). Consistent
with many previous studies, VLPFC activity was
increased during encoding of items that were later remembered, as compared to those that were later forgotten.
However, in this report, a different analysis method was
used to examine sustained activity across each block of
trials that was not specifically related to item processing.
Interestingly, this sustained activity in the VLPFC across
each block of encoding trials was negatively correlated
with subsequent memory for the items in each block.
This suggests that when processing is directed away
from specific items, VLPFC activity will be negatively
correlated with subsequent memory performance.
DLPFC and Organization in LTM Encoding
As mentioned above, organizational processing during
encoding is thought to be an important determinant of
later memory (Bower 1970; Sternberg and Tulving 1977;
Hunt and Einstein 1981), and patients with lesions that
include the DLPFC are thought to have deficits in spontaneous usage of organizational strategies. Given that imaging studies have implicated the DLPFC in control
processes that support organization in WM, it is surprising that few studies have reported DLPFC subsequent
memory effects and that some studies have reported subsequent forgetting effects in the DLPFC. This pattern of
findings is consistent with at least two possibilities: 1) the
DLPFC implements processes that do not typically promote successful LTM formation or 2) most previous studies were insensitive to detect the way in which the DLPFC
contributes to LTM formation. Relevant to the latter possibility, most LTM encoding studies have used encoding
tasks that orient attention toward specific attributes of single items and away from relationships between items. In
these studies, engaging in organizational processing during encoding was irrelevant or possibly deleterious to later
memory performance (i.e., because allocating resources
toward processing the relationships among items might
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Fig. 3. Dorsolateral prefrontal cortex (DLPFC) activity during working memory (WM) organization predicts successful
long-term memory (LTM) formation (Blumenfeld and Ranganath 2006). (a) Schematic depiction of the two tasks performed during fMRI scanning. (b) Behavioral results, showing that participants recalled significantly more triplets from
each reorder trial (yellow) than would be expected based on the overall hit rate. This finding suggests that, on reorder
trials, memory performance was supported by associations among the items in the memory set. (c) fMRI data showing
that DLPFC (top) activation was increased during the delay period of reorder trials for which two to three items were
subsequently remembered (solid yellow), relative to trials in which zero to one items were remembered (dashed yellow).
No such effect is seen on rehearse trials (gray lines). At bottom, activation in a region of the posterior ventrolateral prefrontal cortex (“pVLPFC”) is plotted, showing that delay period activation in this region during both rehearse and reorder
trials was predictive of subsequent memory performance.
take attentional resources away from processing the distinct features of the items themselves; Bower 1970; Begg
1979; McGee 1980). Accordingly, it is possible that the
encoding conditions in many previous imaging studies
were not conducive to revealing subsequent memory
effects in the DLPFC. The retrieval tests used in subsequent memory paradigms might also be a relevant factor.
Most imaging studies of encoding assess LTM with tests
of item recognition memory (see Box 1). However, organization facilitates memory by enhancing associations
among items (Bower 1970; Begg 1979; McGee 1980).
Thus, averaging encoding activation as a function of subsequent item recognition performance might mask the
role of the DLPFC in successful LTM encoding.
If the DLPFC contributes to LTM encoding through its
role in organizational processing, the ability to detect this
contribution may depend on the kinds of encoding and
retrieval tasks that are used. Indeed, in studies that used
encoding tasks that encouraged formation of inter-item
associations (Sommer and others 2005; Summerfield and
Mangels 2005; Blumenfeld and Ranganath 2006), or
studies that used retrieval tests that are sensitive to memory for associations among items (Brassen and others
2006; Staresina and Davachi 2006), DLPFC activity during encoding was positively correlated with subsequent
memory performance.
In one such study (Blumenfeld and Ranganath 2006),
we found evidence that DLPFC activation is related to
successful LTM encoding specifically under conditions
that emphasize organization. In this study, participants
were scanned while they performed two WM tasks: On
“rehearse” trials, participants were presented with a set of
three words and were required to maintain the set across
a 12-second delay period, in anticipation of a question
probing memory for the identity and serial position of the
items (see Fig. 3). On “reorder” trials, participants were
required to rearrange a set of three words based on the
weight of the object that each word referred to. They
maintained this information across a 12-second delay
period (see Fig. 3) in anticipation of a question probing
memory for serial order of the items in the rearranged set.
Although both rehearse and reorder trials required maintenance of the three-item set, reorder trials additionally
required participants to compare the items in the set and
transform their serial order. Consequently, reorder trials
required substantial organizational processing on each
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287
trial, in addition to WM maintenance. Analyses of results
from a postscan recognition memory test showed that
there were significantly more reorder trials in which all
three items were recollected than would be expected
based on the overall item hit-rates alone (see Fig. 3). In
contrast, the proportion of rehearse trials on which all
three items were subsequently recollected was no different than would be expected by the item hit-rates. These
findings suggest that active organization of the memory
set on reorder trials resulted in successful encoding of the
associations among the items in each set.
Consistent with the notion that the DLPFC is involved
in organization in WM, analyses of fMRI data revealed
that DLPFC activation was increased during reorder trials,
as compared with rehearse trials (Fig. 3). Furthermore,
DLPFC activation during reorder, but not rehearse, trials
was positively correlated with subsequent memory performance. Specifically, DLPFC activation was increased
during the delay period of reorder trials for which two to
three items were later recollected, relative to trials for
which one or no items were later recollected. Critically,
no such relationship was evident during rehearse trials. In
contrast, activation in a posterior region of the left VLPFC
(BA 44, 6) was correlated with subsequent memory performance on both rehearse and reorder trials. Thus, results
from this study suggest that DLPFC activation promotes
successful LTM formation through its role in organizational processing during encoding.
A study by Summerfield and colleagues (2006) provides further evidence for the role of the DLPFC in LTM
formation. In this study, participants learned associations between faces and houses by using a mnemonic
(“he lives in this house”). Results showed that DLPFC
and VLPFC activation was enhanced during encoding of
pairs that were subsequently remembered. In addition,
posterior regions thought to be involved in perception of
faces (the “fusiform face area”; Puce and others 1995;
Kanwisher and others 1997) and houses (the “parahippocampal place area”; Aguirre and others 1998; Epstein
and Kanwisher 1998) showed subsequent memory
effects. Functional connectivity analyses demonstrated
that the correlation between the DLPFC, FFA, and the
PPA was increased on trials that led to successful memory for the face-house pairing. This suggests that the
DLPFC may promote memory for associations through
increased connectivity with regions that represent the
items that are to be associated.
Results from another recent study demonstrated the specific nature of DLPFC contributions to memory encoding
by comparing the relationship between activation and subsequent performance on free recall and item recognition
memory tests (Staresina and Davachi 2006). As described
above, recognition tests are often insensitive to detecting
the presence of inter-item associations in LTM, whereas
recall performance is significantly influenced by organization during encoding (see Box 1). Critically, DLPFC activation was specifically enhanced during encoding of items
that were recalled compared to those that were not.
DLPFC activation was not correlated with subsequent item
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recognition performance. In contrast, encoding time activation in the VLPFC was positively correlated with subsequent memory performance on both the recall and the
recognition tests. These results are consistent with the idea
that DLPFC activation will contribute to subsequent memory performance specifically under retrieval conditions
that are sensitive to memory for associations among items.
Before concluding, it is important to address potential
challenges to our proposal that the DLPFC contributes to
LTM formation via its role in organization. A few studies
have reported increased DLPFC during processing of
items that were subsequently forgotten, relative to items
that were subsequently remembered. Importantly, many
of the studies that reported forgetting effects examined
encoding of single items and used encoding and retrieval
tasks that directed processing toward specific features of
the individual items (Otten and Rugg 2001b; Wagner and
Davachi 2001; Clark and Wagner 2003; Daselaar and others 2004; Kensinger and Schacter 2005). As mentioned
above, these conditions deemphasize organizational processing, which according to our proposal, will reduce the
contribution of the DLPFC in LTM formation. Moreover,
to the extent that organizational processing competes with
item encoding (Begg 1979; McGee 1980; but see Hockley
and Cristi 1996), DLPFC forgetting effects may reflect
task-irrelevant processing that interferes with successful
memory formation. Indeed, during item-specific encoding
conditions, organizational processing (and hence DLPFC
activity) may need to be inhibited to promote item memory (Daselaar and others 2004). Future research should
test this intriguing yet speculative proposal.
Conclusion
In conclusion, we have reviewed evidence suggesting
that different regions of the PFC implement cognitive
control processes that support successful LTM encoding.
Neuropsychological research has suggested that the PFC
supports LTM encoding by supporting controlled selection of goal-relevant item information as well as organization among items. Neuroimaging studies have
suggested that these cognitive control processes may
depend upon distinct regions of the PFC. For instance,
studies investigating resolution of proactive interference
and semantic categorization suggest that the VLPFC
may be disproportionately involved in controlled selection of item information. Studies investigating manipulation, transformation, or chunking of multiple items in
WM provide evidence for the notion that the DLPFC
may be disproportionately involved in organizational
processing. Recent imaging studies suggest that the
roles of these prefrontal regions in cognitive control are
directly linked to their roles in LTM encoding. More
specifically, results from functional imaging studies
investigating LTM suggest that the VLPFC may support
LTM formation through its role in selecting relevant
item information, whereas the DLPFC may support
LTM by building associations among items that are
active in memory.
Prefrontal Cortex and Memory Encoding
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