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Published in final edited form as:

Annu Rev Psychol. 2016 ; 67: 105–134. doi:10.1146/annurev-psych-113011-143733.

Episodic Memory and Beyond: The Hippocampus and Neocortex

in Transformation
Morris Moscovitch1,2,3, Roberto Cabeza4, Gordon Winocur2,5,6, and Lynn Nadel7
Morris Moscovitch: [email protected]; Roberto Cabeza: [email protected]; Gordon Winocur:
[email protected]; Lynn Nadel: [email protected]
1Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada
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2Rotman Research Institute, Baycrest Center, Toronto, Ontario, M6A 2E1 Canada
3Department of Psychology, Baycrest Center, Toronto, Ontario M6A 2E1, Canada
4Center for Cognitive Neuroscience, Duke University, Durham, North Carolina 27708
5Department of Psychology, Trent University, Peterborough, Ontario K9J 7B8, Canada
6Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada
7Department of Psychology and Cognitive Science Program, University of Arizona, Tucson,
Arizona 85721

Abstract
The last decade has seen dramatic technological and conceptual changes in research on episodic
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memory and the brain. New technologies, and increased use of more naturalistic observations,
have enabled investigators to delve deeply into the structures that mediate episodic memory,
particularly the hippocampus, and to track functional and structural interactions among brain
regions that support it. Conceptually, episodic memory is increasingly being viewed as subject to
lifelong transformations that are reflected in the neural substrates that mediate it. In keeping with
this dynamic perspective, research on episodic memory (and the hippocampus) has infiltrated
domains, from perception to language and from empathy to problem solving, that were once
considered outside its boundaries. Using the component process model as a framework, and
focusing on the hippocampus, its subfields, and specialization along its longitudinal axis, along
with its interaction with other brain regions, we consider these new developments and their
implications for the organization of episodic memory and its contribution to functions in other
domains.
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Keywords
episodic memory; frontal cortex; hippocampus; parietal cortex; schema; transformation

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the
objectivity of this review.
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INTRODUCTION
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The concept of episodic memory, according to Tulving (1983, 2002), refers to a declarative
memory that contains information specific to the time and place of acquisition (what
laypeople may call an autobiographical episode), as distinguished from semantic memory,
which is concerned with knowledge not tied to its context of acquisition. Recollection, a
process that enables one to relive episodes, is associated with autonoetic consciousness, a
subjective sense of time and of the self as the one who experienced the episode and
possesses the memory. By contrast, the process of knowing enables one to recognize an
event or stimulus as familiar without locating it in time and place. Familiarity-based memory
is associated with noetic consciousness, or at least with a much reduced autonoetic
consciousness. Because these events and processes are what researchers studying episodic
memory mean to capture in a laboratory setting, Tulving referred to the single, unrelated
trials that are the typical memoranda of laboratory experiments as events (or mini-events)
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embedded within the larger episode of the laboratory experiment. For an event to qualify as
an episodic memory, details of the event and of the place in which it occurred must be
present at retrieval, accompanied by autonoetic consciousness that enables reexperiencing
[James 1950 (1890), p. 658; Tulving 1983, 2002; see Rubin & Umanath 2015 for a critique
and alternative].

Tulving’s formulation still governs much of the research on episodic memory and the brain,
but the introduction of new topics, modes of inquiry, more naturalistic approaches and
technologies has added great variety to the landscape. It is this altered landscape that we
wish to capture in our review. Because it is considered central to our understanding of the
brain basis of episodic memory, the hippocampus (HPC) serves as the hub of our article,
much as it is considered the hub of regions dealing with episodic memory. The article
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focuses on four parts: (a) the role the HPC plays in representing the various aspects and
attributes of episodic memory; (b) other structures that are implicated in different aspects of
episodic memory and its transformation to gist and semantics; (c) the contribution of the
HPC and episodic memory to nonepisodic memory functions such as priming, short-term
memory (STM), and semantics and to nonmnemonic functions such as perception, problem
solving, decision making, and language; and finally, and briefly, (d ) the functional and
structural connectivity between the HPC and other regions and networks implicated in
episodic memory.

In the interest of space and timeliness, we favored the most recent references and reviews
over early empirical papers. All figures accompanying the review can be downloaded by
following the Supplemental Material link in the online version of this article or at the
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Annual Reviews home page at http://www.annualreviews.org/. We regret that owing to space

limitations we could not cover in detail, and sometimes not at all, many topics relevant to
episodic memory, such as emotion, reward, individual differences, and lifespan
development.

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COMPONENT PROCESSES AND DYNAMIC HIERARCHIES

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We use a component process model as our framework. Building on Tulving’s ideas, and the
acknowledged role of the HPC in memory, Moscovitch & Winocur (1992; also Moscovitch
1992) proposed that at encoding the HPC obligatorily binds together into a memory trace or
engram (Dudai 2012, Josselyn et al. 2015, Tonegawa et al. 2015) those neural elements in
the medial temporal lobe (MTL) and neocortex that give rise to the multimodal,
multidomain representations that constitute the content of a conscious experience. The
experience includes the accompanying phenomenological awareness and reflects a process
involving the network interactions that make up the experience itself (Moscovitch 1995). In
this view, consciousness, or the phenomenology of experience, is inextricably linked to
episodic memory. The episodic memory trace or engram consists of a bound ensemble of
HPC-neocortical neurons with a sparsely coded HPC component. This is envisioned as a
spatial scaffold or matrix (Nadel 2008, O’Keefe & Nadel 1978) that acts as a pointer or
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index (Teyler & Rudy 2007) to neocortical components that together represent the totality of
the experience, including not only the perceptual, emotional, and conceptual details that
form the content of the experience, but also the processes that imbue it with a sense of
autonoetic consciousness. Because HPC binding is obligatory, storage is random, and only
close temporal contiguity, or close contiguity with a reinstated context, determines the
elements that are bound to each other.

At retrieval, the HPC-neocortical ensemble is reactivated in a two-stage recollection process

by an internal or external cue. The first involves a rapid and unconscious interaction between
the cue and HPC (ecphory), which in turn reactivates the neocortical traces bound with it.
The process may end here or proceed to the second stage. In the second stage, which is
slower and conscious, cortical processes operate on the output of the first stage to reinstate
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the conscious experience of the episode (Moscovitch 2008). Because the HPC-mediated
operations, once initiated, are obligatory, control processes at encoding and retrieval,
mediated by prefrontal cortex (PFC) and related structures, operate on the information
delivered to the HPC and on the output from it to make memory intelligent and goal
directed.

Hippocampus, Neocortical Connections, and Specialization Along Its Long Axis

The HPC sits at the top of a hierarchy of largely cortical systems (the ventral and dorsal
streams) in which later stages integrate information from previous ones, building more
complex representations in the process and influencing the operation of earlier stages
through back projections (Nadel & Peterson 2013) [Supplemental Figure 1 (follow the
Supplemental Material link in the online version of this article or at http://
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www.annualreviews.org/)].

Receiving its input from the entorhinal cortex, which in turn receives its input from the
perirhinal cortex (PRC) and the parahippocampal cortex (PHC), the HPC integrates
information about complex object representations from the PRC and view-specific scene
representations from the PHC into a view-invariant representation that “frames the spatial
relations among the various parts of the environment ” (Nadel & Peterson 2013, p. 1248)
and locates those parts and their features within that spatial frame (Bird & Burgess 2008,

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Hassabis & Maguire 2009, Nadel 2008). HPC-mediated memories are said to reflect
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relational associations (Eichenbaum et al. 2007, Olsen et al. 2012), in that both the separate
elements of some event and their relation retain their distinctiveness.

This framework focuses primarily on representational inputs to the HPC from the posterior
neocortex, and it says nothing about HPC connections to anterior structures such as the
amygdala (emotion), anterior temporal cortex (semantics), and PFC [schemas and working
memory (WM)]. These structures play different, but important, roles in episodic memory
through their interaction with the HPC. We will pay some attention below to the relation of
the HPC to the ventromedial PFC (vmPFC). Readers interested in the interactions between
HPC and lateral frontal cortex during encoding and retrieval should refer to Simons & Spiers
(2003) and Anderson & Huddleston (2012), and to Talmi (2013) on amygdala and emotion.

The HPC creates the same kind of representation throughout its length, but at different
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scales. At the posterior end, its representations capture detailed information about local
spatiotemporal aspects of an experienced event based on input from the posterior neocortex.
At the anterior end, its representations capture global aspects of an event (i.e., the general
context and the emotion and meaning attached to it) based also on interactions with the
anterior neocortex. Thus, these two types of HPC representation arise primarily from
differences in input-output connections along the long axis of the HPC (Poppenk et al. 2013,
Strange et al. 2014) [Supplemental Figure 2 (follow the Supplemental Material link in the
online version of this article or at http://www.annualreviews.org/)]. This framework sets the
stage for investigating the contribution of various HPC subfields to episodic memory (see
below) and for understanding how memories are transformed from detailed representations
to schematic ones at both functional and neurological levels (Penfield & Mathieson 1974).
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Memory Transformation
As Bartlett (1932) noted, memory representations are not static entities but change
throughout an individual’s life with time and experience. As we discuss in the sections that
follow, some memories retain their highly detailed specificity and, as the data suggest,
continue to rely on the HPC and remain recollective; others are transformed through
forgetting or schematization, so that they lose details and retain only the gist or familiarity;
and others become incorporated into a semantic network and acquire its properties. The
latter cases rely more on neocortical structures, with the vmPFC and anterior temporal lobe
prominent among them. In some cases, specific and gist-like representations can coexist,
leading to dynamic interactions and to the dominance of one memory over the other or to the
conversion of one type to the other, depending on circumstances. The neural instantiation of
these memories corresponds to their functional representation, in accordance with what we
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believe is a general principle in cognitive neuroscience: Representations that differ from one
another must necessarily be mediated by different structures (collections of neurons), and
representations mediated by different structures must necessarily differ in some fundamental
way from one another. This principle, which we call functional-neural isomorphism (F-NI),
helps account for patterns of HPC-neocortical involvement during memory consolidation.

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Process-Specific Alliances
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Not all components of the HPC nor of the neocortical (and other) structures with which they
interact are activated at the same time or in all tasks. Instead, we conceive of subsets of
components forming temporary process-specific alliances (PSAs) whose composition is
determined by the moment-to-moment demands of a task. Whereas the posterior neocortical
components, in conjunction with the posterior hippocampus (pHPC), determine the local,
spatio-perceptual aspects of the experience, anterior components of the HPC, in conjunction
with the anterior temporal lobe, PFC, and amygdala, represent conceptual and emotional
aspects. The PSAs also include control structures that regulate encoding and retrieval. All
these memory components can interact with components earlier and later in the hierarchy,
and in other domains, such as language, planning, and decision making, leading to the
involvement of the HPC, and by inference episodic memory, in nonmnemonic functions (see
below).
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The updated component process model makes the following assumptions:

1. During perception, sensory information is progressively bound into feature

clusters in early sensory regions, into integrated objects and contexts in
late sensory and cortical MTL regions, and into complex events binding
objects with their spatiotemporal contexts together with the feeling
(phenomenology) of experience in the HPC.

2. The same regions remain active for a while due to top-down modulation
from the PFC, which allows the persistence of object and context
representations, as well as unified event representations, within WM.

3. During encoding, a fraction of transient representations in WM are

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transformed to a long-lasting format in the cortex and HPC. The HPC

representation points to the location of cortical memory traces (HPC-
cortex PSA). This encoding process is supported by schematic relational
processes in the vmPFC [aHPC-vmPFC PSA; anterior hippocampus
(aHPC)] and semantic processes in the ventrolateral PFC (vlPFC) (vlPFC-
MTL PSA) and anterior temporal cortex.

4. Finally, during retrieval, access to the integrated event representation in

HPC leads to the reactivation of the MTL and posterior cortices, hence to
cortical memory traces (HPC-cortex PSA) (stage 1) and to the awareness
of the recovered memories, involving regions such as the ventral parietal
cortex (VPC) (HPC-VPC PSA) (stage 2). As in the case of encoding
processes, these retrieval processes are supported by control processes
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mediated by the PFC. Oscillatory mechanisms are assumed to contribute

to all these four groups of processes.

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PERCEPTUAL (LOCAL) DETAILS AND EVENT (GLOBAL) ELEMENTS

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Episodic Details and Representations

It is generally agreed that patients with extensive bilateral damage manifest a global
anterograde amnesia that affects acquisition, retention, and retrieval of all episodic
memories. This includes the particular details of the event as well as its theme and general
structure, though it is the episodic details that are most severely affected. When damage is
more restricted, confined to small portions of the HPC, or unilateral, the relative sparing of
acquisition of gist and semantic memory compared to episodic memory is more noticeable
(Winocur & Moscovitch 2011, Winocur et al. 2010).

To measure these aspects of autobiographical memory retrieval, Levine et al. (2002) created
the Autobiographical Interview (AI), whose scoring distinguishes between different internal
details that are unique to the event (perception, emotions, locations) and capture episodic
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aspects of it, and external details, which are not unique to the event and capture more
semantic aspects. Administering the AI to patients with unilateral temporal lobe epilepsy or
lobectomy that included the HPC, St-Laurent et al. (2014) found that memory for perceptual
details was most affected; memory for more global details, such as the story elements that
comprise the series of events within an episode, was also impaired, but not as severely; and
memory for external details was preserved. Using the AI, or a variety of similar tests such as
the Autobiographical Memory Inventory (Kopelman et al. 1989) and the Test Episodique de
Mémoire du Passé autobiographique (TEMPau) task (Piolino et al. 2009), investigators
found the same pattern of impaired episodic but relatively spared semantic aspects of
autobiographical memory in patients with MTL lesions or dysfunction, regardless of
etiology (transient epilepsy, ischemic attacks, degenerative disorders such Alzheimer’s
disease, amnesic variant of minimal cognitive impairment, later stages of frontotemporal
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dementia, and psychiatric and mood disorders; reviewed in Piolino et al. 2009, Viard et al.
2012, Winocur & Moscovitch 2011).

In functional magnetic resonance imaging (fMRI) studies of autobiographical memory, HPC

activation has been shown to be modulated by the number of details or the vividness of the
recalled autobiographical event, which is correlated with internal details (Sheldon & Levine
2013; reviewed in Cabeza & St. Jacques 2007, Svoboda et al. 2006, Winocur & Moscovitch
2011). It is noteworthy that HPC sensitivity to details and vividness was also observed when
recollecting generic and often repeated events such as family dinners (Addis et al. 2004);
this is consistent with findings from patients and suggests a general HPC propensity for
representing details (Rosenbaum et al. 2009, Rubin & Umanath 2015).
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Film clips provide more experimental control than tests of autobiographical memory, yet
they retain a naturalistic quality. The pattern of results obtained with clips in patients with
MTL lesions (St-Laurent et al. 2014), compared to HPC activation in healthy controls in
fMRI studies, was similar to that obtained on recall of autobiographical episodes (Ben-
Yakov & Dudai 2011, Furman et al. 2012, Maguire & Mullally 2013) [Supplemental Figure
3 (follow the Supplemental Material link in the online version of this article or at http://
www.annualreviews.org/)].

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Although the use of more naturalistic stimuli has grown, by far the largest majority of
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studies use unrelated stimuli as the method of choice in studying episodic memory,
sometimes presented in arbitrary contexts and tested almost exclusively by recognition. It is
reassuring, therefore, that similar regions are activated when laboratory memory studies
emphasize recollection (but not familiarity), whether measured subjectively, by asking
individuals to rate the extent to which the item evoked the experience at study (recollection
or know response), or objectively, by asking individuals to recognize elements of the context
in which the stimulus appeared (source memory) (Skinner & Fernandes 2007). Known as the
recollective network, these regions overlap substantially with those activated during recall of
vivid, autobiographical memories (Cabeza & St. Jacques 2007, Rugg & Vilberg 2013,
Svoboda et al. 2006) and include HPC, PHC, medial prefrontal cortex (mPFC), VPC
(angular gyrus), and retrosplenial cortex/posterior cingulate [Supplemental Figure 4 (follow
the Supplemental Material link in the online version of this article or at http://
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www.annualreviews.org/)]. As with more naturalistic tests, the degree of HPC activation is

associated with the amount of detail that is retrieved (Rugg & Vilberg 2013) or its contextual
specificity (Cohn et al. 2009, Sadeh et al. 2012), but not with memory strength, even when
great care is taken to equate recollection and familiarity with strength (Migo et al. 2012,
Montaldi & Mayes 2011; but see Squire & Wixted 2011).

With respect to performance in patients with MTL lesions that include the HPC, Montaldi &
Mayes (2011) and Yonelinas (2013) concluded that even when overall accuracy, an index of
strength, is equated, memory under conditions associated with recollection is selectively
impaired compared to memory based on familiarity (for counterarguments, see Dede et al.
2013, Squire & Wixted 2011). By contrast, familiarity-based memory is impaired and
recollection is preserved following PRC lesions that spare the HPC (Bowles et al. 2010).
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As we noted earlier, recollection, mediated by the HPC, depends on relational yet flexible
associations among disparate (random) and distinct (separable) elements (for reviews, see
Eichenbaum et al. 2007, Olsen et al. 2012, Yonelinas 2013). When associations lose their
relational nature and become unitized (e.g., combining the words fire and dog into firedog),
HPC involvement as inferred from lesion (Quamme et al. 2007) and fMRI (Haskins et al.
2008) is diminished or lost.

Spatial Details and Representations

Because all autobiographical events unfold in a particular spatial context, it has been argued
that spatial context has a privileged status in episodic memory, consistent with the HPC’s
role in spatial memory and navigation (Buzsaki & Moser 2013, Nadel 2008). The scene
construction hypothesis holds that the HPC is necessary for constructing coherent scenes
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that provide the scaffold or framework for supporting memory for events (Hassabis &
Maguire 2009). Studies of patients with HPC lesions and functional neuroimaging studies in
healthy people show that constructing coherent scenes is dependent on the HPC (Maguire &
Mullally 2013). Moreover, there is great overlap among brain regions and networks activated
on spatial tasks and on episodic memory tasks, even when the latter do not have an obvious
spatial component (Spreng et al. 2009). Robin et al. (2015), however, found that even when

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narratives lack information about spatial location, participants spontaneously add them at
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encoding or recall, which may account for some of the overlap.

There is evidence that memory for events is facilitated by familiar spatial information (e.g.,
Robin & Moscovitch 2014), and that regions sensitive to memory for events interact with
regions sensitive to spatial memory in the HPC even at the single-cell level (Miller et al.
2013). In a study that suggests the primacy of spatial over event memory in the HPC,
Chadwick et al. (2010) had participants recall in detail film clips in which two different
events occurred in two distinct spatial locations. Using multivariate pattern analysis (MVPA)
to differentiate neurally the retrieved memories from one another, they found that
classification accuracy for distinct episodes was significantly better than chance only in the
HPC. When required to classify the clips with regard to differences in location as compared
to event content, only locations could be classified accurately, and then only in the HPC.
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Temporal Details and Representations

Time is a central aspect of episodic memory. Events unfold in time just as they unfold in
space. However, evidence for a hippocampal role in forming, maintaining, and retrieving
temporal associations, as well as relating them to events, is controversial: Some consider
time to be a derived property, whereas others consider temporal coding to be a core function
or property of the HPC (Dalla Barba & La Corte 2013, Davachi & Dubrow 2015,
Eichenbaum 2014, Howard & Eichenbaum 2013).

There are at least three aspects of temporal processing that have been addressed in the
literature (Schacter et al. 2012): (a) the temporal tag or signal associated with different
moments in the unfolding of an event, which can also code for duration; (b) the coding for
the temporal order of elements within and across episodes; and (c) the subjective sense of
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time, so that we can identify our experience of the memory as occurring in the near or
distant past or future.

To account for the first two aspects, based on evidence from time cells (Eichenbaum 2014),
investigators have proposed a hippocampal mechanism that could construct a scale-invariant
representation of time over hundreds of seconds; this could serve as the contextual/neuronal
background in which events are embedded via association (Howard & Eichenbaum 2013).
This model can account both for temporal order effects in memory and for the reduction in
temporal precision with temporal distance. Davachi & Dubrow (2015) noted that contiguity
as a determinant of temporal order is better for elements within an event or segment than
across them, pointing to an important role for event segmentation. They also note that
learning a sequence through repeated presentations may rely on pattern completion, with one
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item serving as a cue for eliciting replay of the associated elements. Although both proposals
are broadly consistent with the temporal contiguity aspects of the component process model,
it remains to be explained why, in general, memory for temporal information is very poor in
comparison to memory for spatial information.

Memory for duration and temporal order across very short intervals such as milliseconds,
and across long intervals such as minutes, hours, or days, seems to depend on information
and strategies mediated by extrahippocampal structures (Davachi & Dubrow 2015,

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Moscovitch 1992), among them the cerebellum, PFC, posterior parietal cortex (PPC)
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(Danckert et al. 2007), and basal ganglia. The cognitive processes and neural mechanisms
that underlie our subjective sense of time as past, present, or future are even less well
understood, though some have proposed that the HPC plays a crucial role. The growing
interest in the temporal aspects of memory will hopefully stimulate research that will add to
our meager knowledge of them and resolve some of the controversies.

INTRAHIPPOCAMPAL SPECIALIZATION
Memory Precision, Pattern Separation, and Hippocampus Subfields
Although there is ample evidence that relational associations account for our ability to
recollect the details of an episode, a number of studies suggest that the precision, or high
resolution, of those memories is a critical component even for recognition of single items
such as faces, as long as the items are complex and the targets are distinguished from similar
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lures after a long delay (Craik 1986, Smith et al. 2014a, Yonelinas 2013). To account for this
sensitivity to complexity and precision, investigators have pointed to a fundamental
computational mechanism, called orthogonalization, instantiated in the organization and
operation of the projections between two hippocampal subfields, the dentate gyrus (DG) and
CA3. This orthogonalization, or pattern separation that is dependent on DG, yields distinct
representations that enable memory precision between items (or collections of items) with
overlapping features (Hunsaker & Kesner 2013, Norman 2010) [Supplemental Figure 5
(follow the Supplemental Material link in the online version of this article or at http://
www.annualreviews.org/)]. The efficiency of pattern separation should determine the
precision of the memory and the number of separable details held in memory (Poppenk et al.
2013).
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Recent advances in high-resolution fMRI have allowed investigators to test these ideas more
directly. Bakker et al. (2008) found that DG/CA3 (which were considered together because
they could not be delineated separately) showed the greatest sensitivity to tests of memory
discrimination between highly similar items (which they presumed depended on pattern
separation). CA1, on the other hand, showed a linear response and tracked the similarity
matrix, indicating that the more similar the items were, the more likely they were to be
coded as the same. Pattern separation was related to recollection (Kim & Yassa 2013) in
younger adults. Older adults showed a reduction in DG/CA3 responsivity to pattern
separation but normal CA1 responses, consistent with their poorer ability to distinguish
targets from similar foils at recognition (Yassa et al. 2011). Importantly, the extent of HPC
involvement in distinguishing between target and lures may depend on whether the
differences between them are relational or based on single features (Aly et al. 2013,
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Yonelinas 2013).

The same involvement of HPC subfields is evident in distinguishing among more naturalistic
stimuli. Precision of episodic recall of film clips, as measured by the extent to which
participants could rate the clips as different, was related to the size and activity of the CA3
region (Chadwick et al. 2014) [Supplemental Figure 6 (follow the Supplemental Material
link in the online version of this article or at http://www.annualreviews.org/)]. Comparable
findings were reported by Bonnici et al. (2013) for autobiographical memories in the pHPC,

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where remote, but not recent, memories could be distinguished from one another only in DG
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and CA3.

By contrast, CA1 is presumed to collate information generated through pattern completion

in CA3 and to deliver it back to the entorhinal cortex after having compared it with the
current perceptual input. CA1, therefore, can act as a match-mismatch detector and facilitate
the laying down of new memories and retrieval of old ones (Ben-Yakov et al. 2014).
Selective damage to CA1, therefore, leads to extensive episodic memory loss (Bartsch et al.
2011, Zola-Morgan et al. 1986).

SPECIALIZATION ALONG THE LONGITUDINAL AXIS OF THE

HIPPOCAMPUS
The distribution of the hippocampal subfields is not uniform along the longitudinal axis
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(Malykhin et al. 2010). DG/CA3 ratios are higher in the pHPC than in the aHPC, with
greater CA1 proliferation in the anterior portion. This would suggest more powerful pattern
separation capabilities in the pHPC than in the aHPC, a notion that fits well with recent
work demonstrating greater precision and detail in the grain of HPC representations and
reduced receptive field size of place cells as one moves from anterior to posterior regions
(Strange et al. 2014). Neuroanatomical (Aggleton 2012) and connectivity analysis during
resting state (Ranganath & Ritchey 2012) showed that the pHPC is preferentially connected
to perceptual regions in the posterior neocortex, whereas the aHPC is preferentially
connected to anterior regions, such as the vmPFC and the lateral temporal cortex extending
into the temporal pole and the amygdala, which are associated with the processing of
schemas, semantic information, and social and emotional cues, respectively. These
connectivity patterns could conspire to create unique aHPC and pHPC encoding and
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representational environments, with the aHPC coding information in terms of the general or
global relations among entities, and the pHPC coding information in terms of precise
positions within some continuous dimension (Poppenk et al. 2013) (Supplemental Figure 2).

The evidence generally supports the model (see Poppenk et al. 2013 for review). Whether on
tests of autobiographical memory (Nadel et al. 2013) or on laboratory tests of spatial
memory (Evensmoen et al. 2015), aHPC activity is associated with the general locations
where events occurred or coarse map-like representations of those locations, whereas
activity in the pHPC is associated with local details or finer-grained maps (for comparable
results in rodents see review in Preston & Eichenbaum 2013). Similar effects are found in
studies of real-world navigation in a virtual environment. Greater aHPC activation is
associated with increased distance between sequentially presented landmarks (Morgan et al.
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2011), greater scale of the environment (Baumann & Mattingley 2013), and direction to
goal, whereas pHPC activations are inversely correlated with distance to goal (Howard et al.
2014). Consistent with this model, and with the hypothesis that recollection is associated
with memory for local details, Poppenk & Moscovitch (2011) found that individual
differences in recollection were correlated with the size of the pHPC (and the pHPC/aHPC
ratio), which in turn was related to the functional connectivity of the pHPC with posterior
neocortical regions at rest.

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With respect to autobiographical memory, our framework has much in common with
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Conway’s (2009) nested hierarchical model, in which a conceptual frame provides

contextualizing knowledge that helps locate and organize the local perceptual and spatial
details that comprise the episode [Supplemental Figure 7 (follow the Supplemental Material
link in the online version of this article or at http://www.annualreviews.org/)]. Retrieving the
frame of the episode or the lifetime period in which it occurred, which is a typical first step
in constructing memory for an autobiographical episode, is often associated with aHPC and
neocortical activation, whereas recovering and elaborating the perceptual details of the event
is associated with pHPC activation (McCormick et al. 2013, St-Laurent et al. 2014; for
review and other evidence, see Schacter et al. 2012).

Such differences are also observed when considering global and local aspects of a single
object. The neural suppression that occurs when an object is repeated is seen in the DG/CA3
subfields of the aHPC, but when fine discrimination between targets and similar lures is
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required, then the pHPC is activated (Reagh et al. 2014).

Similarly, encoding novel events, or forming relational associations between random items,
is associated with aHPC activation, possibly because such activities typically involve higher-
order conceptual processing, whereas encoding familiar or repeated events relies less on
such conceptual processes and more on attending to perceptual aspects of the event
(Poppenk et al. 2013). Since repeated events also have a retrieval component, this
formulation is consistent with evidence of differential aHPC and pHPC activation at
encoding and retrieval (Kim 2015).

The global-local hypothesis of anterior-posterior HPC organization that we propose provides

a plausible first approximation of functional organization along the long axis of the HPC
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with respect to episodic memory. Another virtue of this conception of aHPC function is that
it serves as a bridge between detailed episodic representations that are dependent on the
HPC and more schematic, gist-like representations that emerge as memories are transformed
with time and experience (Preston & Eichenbaum 2013, Robin et al. 2015, Winocur &
Moscovitch 2011) and become reliant on extrahippocampal structures, such as the vmPFC
and anterior temporal lobe, that have strong aHPC connections.

MEMORY CONSOLIDATION, TRANSFORMATION, AND ASSIMILATION

Postencoding Consolidation
Episodic memory is dynamic, with significant transformations occurring throughout the
memory’s lifetime (Bartlett 1932, Dudai 2012). In accord with our model, and with the
principle of F-NI, these transformations are accompanied by corresponding shifts in
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underlying neural structures that support different kinds of memory representations.

Studies of postencoding consolidation indicate that different processes are predictive of

better memory for the studied material, such as a spike in HPC activity immediately after the
end of an event (Ben-Yakov & Dudai 2011), event-specific reactivation of encoding
processes during rest (Staresina et al. 2013), and increased connectivity between the HPC
and structures specialized in processing associated stimuli measured at rest after a block of

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associative memory study trials (Tambini et al. 2010). Memory can be reduced by
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interference from other stimuli (Ben-Yakov et al. 2013) or enhanced by emotional stimuli
(Dunsmoor et al. 2015) presented during this postencoding period.

Postencoding processes during sleep have complex effects on memories acquired during the
previous day, and recent work suggests that their impact may be related to the type of
memory examined as well as to the stages of sleep under study (Diekelman & Born 2010,
Stickgold 2013). With respect to episodic memory, there is evidence that recollection can be
preserved or degraded and transformed to familiarity, but the conditions that lead to one or
the other outcome, and the neural mechanisms involved, have yet to be elucidated (Lewis &
Durrant 2011).

Remote Memory
The issue of memory transformation lies at the heart of the debate on the neural
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representation of remote memory, in which changes can occur across weeks, years, and even
decades (Nadel & Moscovitch 1997, Winocur & Moscovitch 2011). The observation that
remote, compared to recent, memories appear to be relatively spared following damage to
the MTL, and the HPC in particular, formed the foundation of the standard consolidation
theory (SCT). This theory states that the HPC serves as a temporary memory structure
needed only until memories are consolidated elsewhere, presumably in the neocortex, where
they are retained and from where they can be retrieved. Although Penfield & Milner (1958)
and Penfield & Mathieson (1974) noted that extra-HPC memories are generalized (gist-like)
and fundamentally different from the detailed, specific memories mediated by the HPC,
some versions of SCT did not make any distinction between the two types of memory. In
other versions, all remote memories were assumed to be incorporated into a neocortical
semantic or schematic network, leaving no HPC-mediated specific episodic memories
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behind (Frankland & Bontempi 2005, McClelland et al. 1995, Wang & Morris 2010).

Drawing on the work of previous investigators, Nadel & Moscovitch (1997) took issue with
each of these interpretations and with evidence that all remote memories are spared
following HPC damage. They noted that individuals can retain detailed remote episodic
memories and that the HPC and related structures are needed for their retention and retrieval,
no matter how old the memories are. Reactivation of old memories leads to the re-encoding
and formation of a rich distributed network of multiple traces in the HPC, which provides
some protection from small, but not large, HPC lesions. Gist-like (semanticized) memories
of episodes as well as semantic memories, mediated as they are by other structures, would
survive HPC damage under any circumstances. The multiple trace theory proposed by Nadel
& Moscovitch (1997) links the type of memory representation (detailed versus gist-like/
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schematic/semantic) with the structure that mediates it (HPC versus neocortex), and it helps
account for the different patterns of retrograde amnesia observed after HPC damage.

Building on ideas from multiple trace theory, Winocur & Moscovitch (2011; see also
Winocur et al. 2010) proposed that some autobiographical and spatial memories in humans,
as well as context-dependent memories in rodents, are transformed with time and experience
from highly detailed, context-specific memories to less detailed, schematic memories that
retain the gist of an experience or event or schematic representation of an environment, but

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not many particulars. These transformed memories are based on representations in extra-
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HPC structures and do not depend on the HPC. Insofar as memories remain detailed and
retain their contextual specificity, they will continue to depend on representations encoded in
the HPC, regardless of their age. Both types of representations can coexist and dynamically
interact, so that a memory that has previously been manifested in a schematic rather than
detailed form can regain its specificity with appropriate reminders and once again engage the
HPC (Winocur et al. 2010, Winocur & Moscovitch 2011).

Appealing to the principle of F-NI, Winocur & Moscovitch (2011) reasoned that a memory
that was once mediated by the HPC and is now mediated by the cortex must differ in accord
with the processing and representational capabilities of these two structures. If the intricate
architecture of the HPC is needed to perform the computations that are central to the
retention and retrieval of precise, detailed, and relational representations of recent memories,
it is difficult to see how comparable representations, only older, could be mediated solely by
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the neocortex, which lacks the requisite architecture.

The debate between adherents of each camp has continued for 20 years and has been
reviewed extensively, so it will only be summarized here. Performance on tests of
autobiographical memory that are especially sensitive to attributes that capture the essence
of episodic memory—such as perceptual details, viewpoint specificity, vividness, judgments
of recollection, and relational associations—suffers after HPC damage or dysfunction,
regardless of etiology and of the amount of time passed since the memory was acquired.
Unless the damage extends to extra-HPC regions, memories for gist or semantic aspects of
personal experiences, public events, and well-known narratives such as bible stories and
fairy tales are relatively well preserved (Winocur & Moscovitch 2011), though memory for
details, even for well-known stories, may be compromised (Kwan et al. 2013, Verfaellie et
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al. 2014). The same is true of spatial memory: Memory for perceptual details needed to
reexperience the environment (scene construction) is lost, whereas schematic memories
sufficient for navigation are retained (Winocur & Moscovitch 2011).

Evidence from fMRI is consistent with this observation. Autobiographical memories that are
detailed and vivid engage the HPC no matter how long ago they were acquired (Winocur &
Moscovitch 2011). Importantly, the pattern of activation along the long axis of the HPC
resembles that observed for recently acquired novel and familiar memories: More recent
memories engage the aHPC and more remote ones engage the pHPC, and the distinction
between recent and remote memories, and among the memories themselves, is mediated by
the posterior DG/CA3 subfield (Bonnici et al. 2013). Likewise, connectivity of the HPC to
other structures in the autobiographical memory network varies with vividness and
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remoteness (Furman et al. 2012, Sheldon & Levine 2013).

The same pattern of decreasing HPC and increasing neocortical activation with remoteness
and accompanying loss of specificity or recollection is found in traditional laboratory tests
of episodic memory with delays of one (Ritchey et al. 2015) to six weeks (Viskontas et al.
2009a; but see Nieuwenhuis & Takashima 2011 for different types of associative memories
that may be schema dependent). Likewise, for remote spatial memory, studies suggest that
what is preserved after HPC damage is a gist-like, schematic representation of the

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environment (essentially a coarse-grained map) that is adequate for navigation but not for
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conjuring up the kind of details that allow for reexperiencing the environment (Rosenbaum
et al. 2000, Winocur & Moscovitch 2011). Consistent with this interpretation, HPC
activation is found during mental navigation in a recently encountered environment but is
diminished or absent when navigating in a familiar environment (Hirshhorn et al. 2012).

Proponents of the SCT argue that extensive retrograde amnesia for autobiographical events
occurs only when lesions of the MTL extend beyond the HPC to include the temporal
neocortex (Squire & Wixted 2011). Although this explanation may account for deficits in
remote memory in some patients, it cannot account for deficits in many others whose lesions
are restricted to the HPC or its projections via the fornix (see review in Winocur &
Moscovitch 2011), or to disruption restricted to CA1 fields in transient global amnesia
(Bartsch et al. 2011). To account for fMRI results, proponents of the SCT have argued that
HPC activity observed while recalling remote memories is related to the re-encoding of
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autobiographical memories retrieved from the neocortex rather than to the memories
themselves (Squire & Wixted 2011). This critique is difficult to refute, though recent
evidence of the different patterns of activation for recent and remote memories in the HPC
and midline structures would argue against a simple re-encoding interpretation (Bonnici et
al. 2013).

Recent and Remote Memory and Memory Transformation in Rodents

The most unequivocal evidence comes from studies of context-dependent (episodic) and
context-independent (gist-like) memory in rodents, where considerable control can be
exerted over the learning environment and over lesion location and extent. These data favor
the transformation hypothesis. Longitudinal studies show a loss of contextual specificity of
memories tested a month after acquisition compared to tests given shortly after learning
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(Winocur et al. 2010). This loss of context specificity is accompanied by a lesser dependence
on the HPC and a higher dependence on the anterior cingulate cortex (ACC) or prelimbic
cortex, the rodent homologue of the vmPFC in humans, as determined by both the effects of
lesions and early gene expression (Frankland & Bontempi 2005, Winocur et al. 2010).
Importantly, providing reminder cues in the long-delay condition a day prior to the test
(Winocur et al. 2010) or periodically reactivating the context (de Oliveira Alvares et al.
2012) restore or maintain contextual specificity, rendering the memory once again HPC
dependent and vulnerable to the effects of HPC lesions.

These findings provide a possible interpretation of system reconsolidation, a process

whereby memories that once were believed to be consolidated in extra-HPC structures
become labile once they are reactivated by a reminder (retrieval cue) and become vulnerable
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once again to the disruptive effects of HPC lesions, protein synthesis inhibitors, or synaptic
interference (Dudai 2012, Nader & Hardt 2009, Wang & Morris 2010).

The fact that specificity and hippocampal dependence could be restored by reminders not
only speaks to the dynamic nature of memory and against the SCT, but also suggests that
some vestige of the original specific memory must be retained by the HPC. Evidence in
support of this hypothesis comes from optogenetic studies in which temporary disruption of
those CA1 cells that encoded the information leads to loss of contextual fear memories even

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at long delays (Goshen et al. 2011, Tanaka et al. 2014), just as CA1 disruption causes remote
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memory loss in humans (Bartsch et al. 2011). Recent studies in which cells that constitute
the memory (engram) are labeled (tagged), reactivated, or suppressed support our hypothesis
that long-term retention of context-dependent memories is mediated by neural ensembles in
the HPC (Josselyn et al. 2015, Tonegawa et al. 2015).

Memory Transformation and the Ventromedial Prefrontal Cortex: Remote Memory and
Schemas
The vmPFC seems to play a special role in mediating remote memories (Frankland &
Bontempi 2005), but its precise nature is not clear. One promising clue to vmPFC function
comes from the work of Tse, Morris, and collaborators (Tse et al. 2007; see Wang & Morris
2010) on schemas, which can be defined as “adaptable associative networks of knowledge
extracted over multiple similar experiences” (Ghosh et al. 2014, p. 12057). Tse et al. (2007)
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showed that the vmPFC is crucial for assimilating new olfactory-location associations into a
spatial schema, which is acquired over many exposures. As a result, the new associations
become independent of the HPC more quickly, relying instead on the ACC/vmPFC.

Such results are interpreted according to a schema modification model (Dudai 2012, Wang
& Morris 2010), which posits that schemas provide the organizing structures that influence
memory formation and retrieval (Bartlett 1932) as well as interpretation of ongoing events.
We propose that the vmPFC, with its reciprocal connections to the aHPC, could act as a hub
binding the global context of events represented in the aHPC and general knowledge,
including that about the self, into a schema that captures what is common to all such events
(see also Benoit et al. 2014). A fundamental function of any schema is to make predictions
about what one should expect to experience in a given context/situation/setting, to aid in
interpreting events that occur there, and to enable one to notice new details that do not fit the
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schema. For example, one may have schemas of what kitchens are like and what one does in
them. Walking into a strange kitchen may produce a novel episodic memory for the kitchen
and for the local events that transpire there; schemas ensure that the experience of being in
the kitchen is not in itself strange but relatively predictable.

Some investigators have suggested that the vmPFC is the consolidated (remote) memory
homologue of the HPC, taking over its function. This notion runs counter to the F-NI
principle. Our proposal is that the vmPFC and HPC may both deal with context, but of
fundamentally different sorts. The HPC binds together local and global contextual
information about a specific event or environment, whereas the vmPFC binds together what
is common across similar events and possibly helps “decide” which among them is relevant
for a particular task (Preston & Eichenbaum 2013).
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A number of predictions follow from this hypothesis:

1. Insofar as retrieval is dependent on the vmPFC without HPC involvement,

the retrieved memory will be gist-like or general, rather than detailed and
specific. This appears to be the case in humans and rodents with HPC
damage.

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2. The vmPFC should interact with the aHPC to encode schematic

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information and to help retrieve detailed information via schema-related

cues (for similar proposals, see Conway 2009, Preston & Eichenbaum
2013, van Kesteren et al. 2012). The vmPFC’s role in retrieval becomes
more prominent as local perceptual details mediated by the pHPC are
degraded, making retrieval more dependent on the global aspects of the
memory represented in the aHPC (Bonnici et al. 2013, Sheldon et al.
2013).

3. Damage to the vmPFC, therefore, should be more evident in tests of

remote, rather than recent, memory, and vary inversely with the specificity
of retrieval cues.

4. The vmPFC may be implicated more as structured events are transformed

or when isolated events are experienced within a structured context, as in
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Tse et al.’s (2007) studies and Takashima et al.’s (2009) human analogue
of them, but not when events are isolated and random as in many
traditional laboratory experiments.

5. Following vmPFC damage, schema formation and representation may

itself be impaired, so that what delineates a schema (e.g., what one does in
a kitchen) is distorted, nebulous, or overinclusive (Ghosh et al. 2014).
Consequently, individuals with vmPFC damage may experience the
present, and reexperience the past, through the lens of distorted or
misapplied schemas, and this may contribute to confabulation, a memory
disorder characterized by the production of patently false information
about autobiographical episodes, personal semantics, historical events, and
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common narratives (Gilboa & Verfaellie 2010, Moscovitch & Winocur,

2002, Schnider 2008, Shallice & Cooper 2012).

Interim Summary
Memories for recent events draw on interactions between schemas, semantics, and
perceptual aspects of an experience, mediated in part by different regions in the anterior and
posterior neo-cortex. These are bound together in relational representations mediated by the
pHPC for local details and the aHPC for global context, accounting for the specificity
characteristic of episodic memory (Craik 1986). Over time, detailed information about local
aspects of the event become degraded or lost, and our memory reports come to rely on more
global aspects mediated by the aHPC in conjunction with schema-related information
mediated by the vmPFC. The latter helps determine performance when the HPC is entirely
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lost. Damage to the vmPFC leads to deficient and distorted use of schemas in memory,
perception, and reasoning.

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CONSCIOUSNESS, THE HIPPOCAMPUS, AND THE LATERAL AND

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POSTERIOR PARIETAL CORTEX

Consciousness is a defining feature of episodic memory, as evidenced by the fact that
performance on a variety of implicit or nondeclarative tests can be normal in patients with
MTL damage and severe episodic memory deficits (Moscovitch et al. 1993). These findings
suggest the following conclusions: (a) The HPC, and by implication recollection, does not
contribute to normal performance on nonepisodic memory tasks such as priming; (b) the
HPC can only process consciously apprehended information; and (c) consciousness
invariably accompanies the retrieval of the detailed information that underlies recollection.
In the last decade, each of these conclusions has been challenged and effectively overturned.

The two-stage model of recollection predicts that priming for relational associations should
be preserved insofar as it draws on information underlying the first rapid, nonconscious
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stage of recollection mediated by the HPC. Recent studies show that priming of relational
associations, measured by manual reaction times (Schacter et al. 2004) or eye movements
(Hannula & Ranganath 2009), is accompanied by HPC activation, is impaired in people with
HPC damage (Olsen et al. 2012), and is more robust for items that are subsequently judged
to be recollected than for familiar ones (Sheldon & Moscovitch 2010). Going one step
further, Henke and collaborators showed that the HPC encodes information presented
subliminally as long as it is relational (Henke 2010).

The Ventral Posterior Parietal Cortex and Subjective Aspects of Memory (Autonoetic
Consciousness)
Consistent with our component process model, studies on nonconscious memory suggest
that engagement of the HPC is not sufficient for explicit recollection or episodic memory,
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and that other structures also need to be recruited. Structures in the frontoparietal network
are among the possible candidates. Here we focus on the PPC, since it has been the object of
much debate concerning its role in episodic memory.

Activation of the PPC, particularly on the left, often accompanies memory retrieval on
laboratory tests of recognition and autobiographical memory (Cabeza & St. Jacques 2007,
Rugg & Vilberg 2013, Svoboda et al. 2006). Of the two major divisions of the PPC, dorsal
parietal cortex (DPC) and VPC, the VPC is associated with successful recollection, source
monitoring, and high-confidence responses, whereas the DPC is associated with familiarity
and low-confidence responses (for other differences between the two divisions, see Cabeza
et al. 2012) [Supplemental Figure 8 (follow the Supplemental Material link in the online
version of this article or at http://www.annualreviews.org/)].
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A number of hypotheses have been proposed to account for VPC involvement in episodic
memory, and recent reviews have discussed extensively their merits and deficiencies
(Berryhill 2012, Cabeza et al. 2012, Rugg & Vilberg 2013). Here, we focus on the
hypothesis that the VPC is implicated in the apprehension of the subjective qualities of
memory (Simons et al. 2010). This hypothesis accounts not only for the reduced and less
detailed recollections of patients with VPC lesions that can be ameliorated by cuing

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(Berryhill 2012, Davidson et al. 2008), but also for the low confidence the patients have in
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their memory even when source accuracy is high (Hower et al. 2014, Simons et al. 2010), an
outcome that can be produced in normal people by deactivating the VPC with theta burst
stimulation (Yazar et al. 2014). These findings raise the possibility that the VPC, perhaps via
its interactions with the frontal cortex, is an essential component for enabling autonoetic
consciousness. It is interesting in this regard that VPC activation accompanies memories that
come to mind involuntarily, either when they are elicited by a cue (Hall et al. 2014) or when
they overcome active suppression (Benoit et al. 2014). It is also noteworthy that the VPC has
been associated with functions that are the hallmarks of autonoetic consciousness: WM and
attention, time perception, feelings of intentionality, and a sense of self associated with
theory of mind (ToM) (see Berryhill 2012, Cabeza et al. 2012). As noted, the VPC is also
linked with the PFC (Prebble et al. 2013), another region that is associated with ToM
(Mitchell 2009) and whose damage, or disconnection, can lead to reduced recollection and
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deactivation of the VPC (Levine et al. 2009).

These findings suggest a dissociation between successful retrieval of the content of episodic
memories and the phenomenological experience that accompanies successful retrieval. It
remains to be determined whether the diminished autonoetic consciousness associated with
VPC and PFC damage or disconnection results from an impaired postretrieval process that,
as part of the second stage of recollection, attributes phenomenological experience to a
detailed memory, or whether it results from loss of the “consciousness feature” of the HPC-
neocortical engram, which VPC codes much as inferior temporal structures code for
perceptual features.

BREAKING DOWN BORDERS AND CONQUERING DOMAINS

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Following the introduction of the concept of episodic memory in 1972, much research has
focused on how to distinguish episodic memory from other cognitive functions in general,
and in particular from other forms of memory, at both the functional and neural levels. Given
the widespread connections of the HPC (Aggleton 2012, Ranganath & Ritchey 2012) and its
position in the component process model, the isolation and encapsulation of episodic
memory could not be sustained. The last decade has seen an imperialist encroachment of
episodic memory and the HPC into various domains, from perception to imagination, and
from decision making to food regulation (Robinson et al. 2013, Rozin et al. 1998). We
highlight four of these domains and consider how they relate to our model (see also Rubin et
al. 2014).

The Hippocampus, Perception, and Working Memory

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The idea that the HPC sits at the end of a perceptual hierarchy, receiving input from lower
levels and projecting back to them, suggests that HPC influence should be felt in perception
and WM, thereby eroding the hard and fast distinction between long-term memory (LTM),
perception, and WM. According to the hierarchical representation model (HRM; Lee et al.
2012), the HPC’s role at the top of the hierarchy and the role of the structures below it are
defined strictly not in terms of memory or perception, but rather (or also) in terms of the
representations they support, consistent with the component process model. Insofar as the

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HPC represents relational information among separable entities, or even among features in
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single complex stimuli, perceptual discrimination based on such features activates the HPC
and is impaired in people with HPC damage (Lee et al. 2012, Yonelinas 2013).

Drawing on their theory stating that the HPC is implicated in scene construction, Mullally et
al. (2012) showed that boundary extension—the normal tendency to reconstruct a scene with
a larger background than actually was presented—was markedly diminished in patients with
HPC lesions compared to controls, even when stimuli were presented as briefly as 200 ms
[Supplemental Figure 9 (follow the Supplemental Material link in the online version of this
article or at http://www.annualreviews.org/)]. In subsequent neuroimaging studies, Chadwick
et al. (2013) showed that boundary extension is accompanied by hippocampal activation
that, in turn, projects down the hierarchy to levels in the visual cortex.

HPC has also been shown to be implicated in STM and WM, especially if precision and
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relational binding are required (Olsen et al. 2012, Yonelinas 2013). Binding errors in
reporting information in STM in people with HPC damage (Pertzov et al. 2013) and
matching a target array of items on a screen with a test array presented shortly afterward was
shown to be associated with HPC activation and to be reduced in people with medial
temporal/HPC damage (Nichols et al. 2006, Olson et al. 2006; but see Talmi et al. 2005) or
atrophy; the reduction was correlated with the extent of posterior hippocampal atrophy for
location and with perirhinal atrophy for objects (Das et al. 2015). Performance on all the
tests was correlated with estimates of recollection, whereas only performance on the object
test was correlated with familiarity.

Though such developments blur the boundaries between LTM, WM, and perception,
obliterating them would obscure the striking differences one sees clinically: Patients with
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HPC lesions rarely complain of perceptual or WM deficits but always complain of episodic
memory deficits, whereas the reverse is true of people with damage to levels that are lower
in the hierarchy. Capitalizing on this observation, Squire and collaborators (e.g., Kim et al.
2015, Squire & Wixted 2011) presented evidence showing that if the lesions were confined
to the HPC and the tests did not implicate LTM, then perception and STM/WM was normal
in patients with HPC lesions (see also Baddeley et al. 2010 and rebuttal in Clark & Maguire
2016; Maguire et al. 2015).

To counter this negative evidence, and the arguments based on it, Yonelinas (2013) and Lee
et al. (2012) have argued, in accord with the HRM, that the complexity of the items and the
precision of the discrimination determine HPC involvement on tests of perception and
STM/WM. Moreover, it is likely that susceptibility to interference increases as one moves up
the hierarchy, and hence the impact on memory is more keenly felt when higher levels are
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damaged. The component process model and the F-NI principle are consistent with either
account, and the resolution of the debate rests on the question of whether HPC-mediated
relational processing applies only to memory or also to perception (see also Clark &
Maguire 2016, Maguire et al. 2015).

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Episodic Simulation, Problem Solving, Empathy, and Decision Making

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One of the most striking findings in recent years points to the large overlap in processes and
structures involved in retrieving episodic memories, imagining future personal events, and
constructing scenes, thereby propelling the HPC into domains it had not occupied previously
(Addis & Schacter 2011, Buckner 2010, Maguire & Mullally 2013, Schacter et al. 2012,
Viard et al. 2012). Because HPC-based memories are relational, their elements could be
recombined to form new associations, which together with constructive processes dependent
on the pHPC (Gaesser et al. 2013) would create new scenarios (Romero & Moscovitch
2012) and construct new scenes (Hassabis & Maguire 2009) in the service of current needs.
Addis, Schacter, and colleagues referred to this as episodic simulation, a cognitive operation
that draws on processes similar to episodic memory to create imagined events [see Maguire
& Mullally (2013), who argue that scene construction is the fundamental process].
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Recent studies have shown that episodic simulation can lead to better social problem solving
(Sheldon et al. 2011), greater empathy (Ciaramelli et al. 2013), and more willingness to help
people in distress (Gaesser & Schacter 2014); in all cases, performance was related to the
vividness or level of detail of the simulation. HPC damage or deterioration with aging leads
to a drop in problem-solving performance (Sheldon et al. 2011) and reduces empathy in
general (Beadle et al. 2013, Davidson et al. 2012), whereas training on recovery of episodic
details improves problem solving (Madore & Schacter 2014). On the other side of the coin,
vivid negative images associated with past events and conjured spontaneously in social
situations contribute to social anxiety (Moscovitch et al. 2013).

Episodic simulation also influences decision making, as illustrated on tests of temporal

discounting (i.e., the tendency to discount rewards if they are delayed). Benoit et al. (2011)
showed that temporal discounting can be reduced by imagining in detail how one would
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spend the money in the future as compared to merely thinking conceptually about its
usefulness; the extent of the reduction is related to vmPFC activation and its functional
connectivity with the HPC. Consistent with the fMRI results, Palombo et al. (2015) showed
that episodic simulation is ineffective in reducing the normal tendency for temporal
discounting in people with amnesia associated with MTL damage (Kwan et al. 2013),
because their capacity for simulation is compromised.

Whereas episodic simulation depends on conscious processes, unconscious stage-one

associative processes mediated by the HPC likely underlie performance on tests of
associative inference. In such tests, participants are shown overlapping pairs of items (e.g.,
AB and BC) and learn to associate A with C though they never co-occur. Shohamy &
Wagner (2008) showed that this effect is mediated by the HPC and occurs at encoding
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without the participant’s awareness, such that when BC is presented, the common element,
B, reactivates the previously learned association, AB, and integrates both with C, a process
they termed integrative encoding. This accords with the principle of obligatory binding of
elements occurring in close temporal contiguity. Similar processes influence reward-based
decisions in which a stimulus (A) acquires value through its secondary association (B) with
monetary reward (C) (Wimmer & Shohamy 2012). The degree to which A comes to be
associated with C is determined also by its interaction with schema-related processes in the
vmPFC and its intrinsic resting-state connectivity with the HPC (Gerraty et al. 2014).

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 Moscovitch et al. Page 21

Similar processes may underlie performance on tests of second-order conditioning in rats

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(Gilboa et al. 2014) and transitive inference in rats and humans who are presented with
overlapping stimulus pairs in which one member of the pair is rewarded (e.g., A > B, B > C,
C > D) and participants must infer how it is related to the other items (Preston &
Eichenbaum 2013). If the latter task is solved by forming relational associations, then the
HPC is necessary, but if it is solved by unitization, then it can be performed without recourse
to the HPC but may still be dependent on the vmPFC and PRC (Ryan et al. 2013).

Such effects cannot be said to be related to full-blown episodic memory, which is defined as
being associated with autonoetic consciousness, but should rather be related to operations of
pattern separation, pattern completion, and associative binding that operate outside of
conscious awareness but presumably underlie both episodic memory and these types of
associative learning, in accord with the two-stage model of recollection and HPC activation.
Consistent with this observation, Reber & Henke (2012) showed that associative inference
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based on integrative encoding can be attained even when AB and BC items are presented
subliminally.

Language and Semantic Memory

Language processing was considered to be preserved in amnesia, at least as far as core
phonological, syntactic, and semantic aspects were concerned (Corkin 2013). By and large,
this view has not changed, though it is fair to say that it has not been thoroughly explored
either. However, in accord with the principle of F-NI, language and semantic memory should
be no different than any other function if they draw on processes and representations
mediated by the HPC. These are most evident in pragmatic uses of language, particularly in
complex social discourse, which requires such HPC-mediated processes as the “flexible use
of relational memory representations dredged from the past, and inserted appropriately into
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the flow of speech, or created rapidly in the present and incorporated effortlessly into the
context that forms the common ground of social discourse” (Duff & Brown-Schmidt 2012).
Discourse analysis reveals that such functions are aberrant or impoverished in amnesic
patients (Race et al. 2015). The paucity of the experiential aspects of episodic memory in
patients with HPC damage is revealed in their greater than normal selection of the definite
over indefinite article and the diminished use of the historical present, a figure of speech in
which a past event is referred in the present tense (e.g., Yesterday, I saw a fire; the fireman
goes into the house, battles the flames…) and whose frequency of usage is correlated with
the number of internal details in their narrative (Park et al. 2011).

As with language, insofar as semantic memory is informed by detailed, precise information

about autobiographical events and allocentric spatial representations, it will be influenced by
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episodic memory representations mediated by the HPC. Evidence from studies of patients
with amnesia and with semantic dementia suggests that people, places, public events, and
even common objects and their names can be imbued with autobiographical significance
(AS) in the sense that they automatically (either with or without conscious awareness)
conjure up recollective information that facilitates naming, recognition, and semantic
judgments. Consistent with the component process model, this AS advantage is lost in
people with MTL damage (for review, see Renoult et al. 2012).

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 Moscovitch et al. Page 22

Renoult et al. (2015) used event-related potentials to explore this phenomenon further. When
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names of famous and nonfamous people were presented to participants in a nonepisodic

fame-judgment task, they found that the amplitude of the N400 varied with the amount of
the semantic, but not episodic, knowledge participants had about the people, whereas the
reverse was true for the late positive component over the parietal electrode, which is
sensitive to recollection.

These sets of findings suggest a novel interpretation of reports by Quiroga and collaborators
(see review in Quiroga 2012), who found that single cells in the human HPC, which they
named concept cells, respond selectively and invariantly to representations of famous people
across modalities. Viskontas et al. (2009b), however, noted that the majority of the cells
respond to people who are personally familiar to the patient. As in studies on AS, the
pictures or names presented to the patients may automatically have evoked a recollective
process, and therefore referring to the cells as AS or episodic cells would be equally
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appropriate.

The contribution of HPC-mediated episodic memory processes is also evident in tests of

semantic fluency. Impaired performance on tests of semantic fluency following temporal
lobe lesions has been shown to be related to HPC damage and not exclusively to lateral
temporal damage as was once believed (Greenberg et al. 2009). This interpretation is
supported by recent evidence from fMRI showing that HPC activation is associated
specifically with the generation of episodic information from which semantic exemplars are
derived, presumably by imagining personal experiences (e.g., evoking one’s kitchen if
required to name kitchen utensils) when the most common exemplars are exhausted
(Sheldon & Moscovitch 2012). Similarly, in a free association task to single words,
responses become more idiosyncratic presumably because they are derived from personal
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episodic memories, whereas in patients with MTL lesions, the responses are fewer and less
idiosyncratic because they rely more on semantic memory (Sheldon et al. 2013). Consistent
with this finding is a report by Addis et al. (2015) showing that performance on tests of
divergent thinking is related to one’s ability to construct episodic simulations and can be
enhanced by inducing episodic specificity (Madore et al. 2015).

Although previously acquired semantic memory, stripped of episodic aspects, can be

relatively spared in HPC patients, the acquisition of new vocabulary, though possible
without the HPC, is laborious and poor (see Corkin 2013), but only if it depends on forming
explicit relational associations between the target item and its name. Acquisition is relatively
preserved, however, through fast mapping, an indirect associative procedure in which the
participant discovers (infers) the association between the item and its name (Sharon et al.
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2011). This fast mapping process may depend on rapid assimilation of the item to pre-
existing schemas or semantic memory networks mediated by neocortex (Coutanche &
Thompson-Schill 2015, Sharon et al. 2011). Item-name associations learned through fast
mapping, however, are prone to catastrophic interference (Merhav et al. 2014). The reverse
pattern, of better acquisition through the explicit route and poor fast mapping, is seen in
patients with anterior temporal lesions that include the perirhinal cortex (Merhav et al. 2015,
Sharon et al. 2011), suggesting that this structure may help mediate fast mapping. Not all
attempts to replicate these fast-mapping results, however, have been successful (e.g., Smith

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 Moscovitch et al. Page 23

et al. 2014b). The reasons for the discrepancies will need to be elucidated if we are to gain a
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better understanding of the neural mechanisms mediating fast mapping (Coutanche &
Thompson-Schill 2015).

The evidence we reviewed indicates that episodic memory, as mediated by the HPC,
contributes more to language and semantics than classical views on dissociable multiple
memory systems would lead us to believe. As with perception and WM, we do not wish to
end by obliterating distinctions that we believe are still useful; rather, based on our
component process model, we propose that the systems are much more interactive than we
once thought, enabling episodic memory and the HPC to influence functions outside their
traditional domain. This interactive approach is increasingly evident in neuroimaging
research, with its current emphasis on networks and on structural and functional connectivity
among nodes in those networks.
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PROCESS-SPECIFIC ALLIANCES SUPPORTING EPISODIC MEMORY

The individual brain regions discussed in the previous sections cannot support episodic
memory unless they interact with each other and with other regions. In functional
neuroimaging studies, these interactions can be indirectly measured as covariation in
activity, or functional connectivity. Functional connectivity can be investigated at the level of
large-scale networks, such as the default mode network (Andrews-Hanna 2012), or at the
level of small networks that are assembled to mediate a specific cognitive operation and
rapidly disassembled when the operation is no longer needed. To postulate one of these
PSAs (Cabeza & Moscovitch 2013), there should be evidence that (a) all regions in the PSA
are associated with the process they are assumed to mediate, (b) each region is associated
with a complementary suboperation of this process, and (c) the regions communicate with
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each other in general and during the process of interest. There are many examples of PSAs
that contribute to episodic memory and fulfill these criteria; here, we mention only two.

The first example is the PSA between the pHPC and VPC during recollective retrieval.
Consistent with the first criterion, meta-analyses of event-related fMRI studies have strongly
linked these regions to retrieval success and recollection (Cabeza et al. 2012). During
retrieval, the pHPC and VPC show a recollection-related activity pattern, whereas a very
different pattern emerges in the aHPC (e.g., Daselaar et al. 2006) [Supplemental Figure 10
(follow the Supplemental Material link in the online version of this article or at http://
www.annualreviews.org/)]. In keeping with the second criterion, the pHPC has been linked
to the recovery of episodic memory details and the VPC to the complementary process of
operating on the recovered information (Cabeza et al. 2012). Finally, fulfilling the third
criterion, the pHPC and VPC have direct white-matter connections and interact very closely
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during rest and during episodic recollection (Cabeza et al. 2012).

Another example is the PSA between the HPC and domain-specific posterior cortices during
encoding and retrieval. Consistent with the first criterion, activity in domain-specific cortices
has been associated with successful encoding of relevant stimuli and with the reactivation of
this information during retrieval (Danker & Anderson 2010). Second, HPC lesions yield
global memory deficits, whereas cortical damage yields domain-specific memory deficits.

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 Moscovitch et al. Page 24

Finally, the HPC and domain-specific cortices are anatomically linked, and there is evidence
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that they are functionally connected during rest (Schlichting & Preston 2014) and during
successful encoding and retrieval processes (e.g., Ritchey et al. 2013) [Supplemental Figure
11 (follow the Supplemental Material link in the online version of this article or at http://
www.annualreviews.org/)].

Given that PSAs are rapidly assembled and disassembled, they require a mechanism that can
quickly control communication between distant brain regions, and the most likely candidate
is neuronal oscillations. There is abundant evidence that oscillations, particularly those in
gamma (40–100 Hz) and theta (4–8 Hz) frequencies, control PSAs during episodic encoding
and retrieval (Nyhus & Curran 2010). During encoding, gamma phase synchronization helps
bind perceptual features into objects in posterior cortices (Engel et al. 1991), and gamma-
theta coupling helps integrate objects into events in the HPC and posterior cortices ( Jensen
& Lisman 2005). In animal studies, HPC theta has been linked to successful spatial learning
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(Ekstrom et al. 2001) and to long-term potentiation (Hyman et al. 2003). In human studies,
successful encoding has been associated with both gamma (Osipova et al. 2006) and theta
(Long et al. 2014) frequencies in the HPC and posterior cortices. The coupling is assumed to
be controlled by the PFC, and as WM load increases, theta power increases in frontal-
midline electroencephalography (EEG) electrodes (frontal-midline theta) ( Jensen & Tesche
2002). Moreover, an intracranial EEG study found phase-amplitude coupling between theta
and beta-gamma when faces were maintained in WM (Axmacher et al. 2010).

During retrieval, access to a fraction of the HPC representation of the original event is
assumed to cause reinstatement of the associated theta cycle, which triggers the
reinstatement of the nested gamma cycles and their associated cortical representations
( Jensen & Lisman 2005). In keeping with this hypothesis, human studies have found greater
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gamma and theta (Osipova et al. 2006) power in the HPC and posterior cortices for correct
old responses than for new ones. There is evidence of greater gamma power for remember
than for know responses in several scalp locations (Burgess & Ali 2002). One of these
locations is the parietal cortex, consistent with the aforementioned PSA between the pHPC
and the VPC.

In sum, the HPC can only support episodic memory if it interacts very closely with other
regions. Each episodic process is mediated by a transient collaboration between regions
mediating complementary operations, or PSA, consistent with our component process
model. PSAs require a mechanism that can rapidly turn on and off interactions among
distant regions, such as neural oscillations in gamma and theta frequencies ( Johnson &
Knight 2015), and our understanding of these PSAs may help distinguish between recurrent
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retrieval and re-encoding processes (Ben-Yakov et al. 2014).

CONCLUSION
Since its inception, the scientific study of memory has been influenced by the research
program of its pioneers. Ebbinghaus [1964 (1885)] wished to study memory’s essence,
isolated from the influence of any other mental function. Bartlett (1932), on the other hand,
saw memory as inextricably tied to other mental functions, and often operating in their

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 Moscovitch et al. Page 25

service. To accomplish his goals, Ebbinghaus used nonsense syllables as memoranda,

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whereas Bartlett used complex verbal and pictorial stimuli. Given Ebbinghaus’s memoranda,
memory could only be seen as strengthened or lost (forgotten). Memory for Bartlett’s
material, on the other hand, could also be transformed with time and experience to reflect
the cultural and personal schemas of the person. Memory is the only topic covered in
Ebbinghaus’s classical book, whereas Bartlett’s reads like a book in social psychology.
Indeed, Bartlett eschewed the word memory since it implied something static, preferring
instead to title his book Remembering to reflect an active, adaptive, and changing process
akin to other actions we perform. In this regard, his view was closer to that of James [1950
(1890)], who was concerned with the phenomenology of memory and had a functionalist
approach to psychology. Although this review has discussed elements of all three
perspectives, it has focused especially on Bartlett’s and James’s. At this time, it would be
surprising if it were otherwise, given how interactive brain regions are with one another and
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how new technological advances drive this point home. We should take care, however, not to
lose sight of the trees while our attention is directed toward the interactive forest.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
The writing of this article and some of the research reported herein were supported by grants to M.M. and G.W.
from the Canadian Institutes for Health Research (grant MGP 6694) and from the Natural Sciences and Engineering
Research Council of Canada; to L.N. from NIH, NSF, and the LuMind Foundation; and to R.C. from NIH-NIA
(AG19731). The authors gratefully acknowledge the support of the following people: Nick Hoang in preparing the
manuscript; Yadin Dudai, Jessica Robin, and Talya Sadeh for their helpful comments; and Dan Schacter for his
suggestions, encouragement, and patience.
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Annu Rev Psychol. Author manuscript; available in PMC 2017 January 01.