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Am J Psychiatry. Author manuscript; available in PMC 2022 February 01.
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Published in final edited form as:

Am J Psychiatry. 2021 August 01; 178(8): 701–714. doi:10.1176/appi.ajp.2020.20081187.

Evolution, Emotion, & Episodic Engagement

Daniel S. Pine1, Steven P. Wise2, Elisabeth A. Murray3
1Section on Development and Affective Neuroscience, Emotion and Development Branch,
National Institute of Mental Health, Bethesda, MD 20892
2Olschefskie Institute for the Neurobiology of Knowledge, Bethesda, MD 20814
3Section on the Neurobiology of Learning and Memory, Laboratory of Neuropsychology, National
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Institute of Mental Health, Bethesda, MD 20892

Abstract
Rodent research provides important insights into neural correlates of human psychology, but
new cortical areas, connections, and cognitive abilities emerged during primate evolution,
including human evolution. Comparison of human brains with those of nonhuman primates
reveals two aspects of human brain evolution particularly relevant to emotional disorders:
expansion of homotypical association areas and expansion of the hippocampus. Two uniquely
human cognitive capacities link these phylogenetic developments with emotion: (i) a subjective
sense of participating in and re-experiencing remembered events; and (ii) a limitless capacity
to imagine details of future events. These abilities provided evolving humans with selective
advantages, but they also created proclivities for emotional problems. The first capacity evokes
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the “reliving” of past events in the “here-and-now”, accompanied by emotional responses that
occurred during memory encoding. It contributes to risk for stress-related syndromes, such as
post-traumatic stress disorder. The second capacity, an ability to imagine future events without
temporal limitations, facilitates flexible, goal-related behavior by drawing on and creating a
uniquely rich array of mental representations. It promotes goal achievement and reduces errors,
but the mental construction of future events also contributes to developmental aspects of anxiety
and mood disorders. With maturation of homotypical association areas, the concrete concerns
of childhood expand to encompass the abstract apprehensions of adolescence and adulthood.
These cognitive capacities and their dysfunction are amenable to a research agenda that melds
experimental therapeutic interventions, cognitive neuropsychology, and developmental psychology
in both humans and nonhuman primates.
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Keywords
Amygdala; Anxiety; Association area; Brain evolution; Episodic memory; Hippocampus; Mental
simulation; Prefrontal cortex; Primate research; Stress disorder

Address: Daniel S. Pine, M.D., Chief, Section on Development and Affective Neuroscience, Co-Chief, Emotion and Development
Branch, National Institute of Mental Health, National Institutes of Health, Building 15K, Room 110, MSC 2670, Bethesda, MD
20892-2670, Phone: 301 594-1318, Fax: 301 402-2010, [email protected].
Co-author academic degrees:
Steven P. Wise, Ph.D.
Elisabeth A. Murray, Ph.D.
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Introduction
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This Review and Overview explores two related topics. One is brain evolution and unique
aspects of human cognition that depend on recent changes in hominin brains (1–5). The
other concerns the role of primate research in understanding mental illness. To address these
topics, this article proceeds in three sections. The first introduces the idea that advantageous
evolutionary changes can create vulnerabilities; the second reviews research on social and
mnemonic capacities reflecting unique features of nonhuman-primate and human brains; and
the third describes a research agenda aimed at combining human and primate research to
improve treatment and outcome prediction.

Evolutionary Perspectives
Phylogenetic disease
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More than 30 years ago, Rapoport (6) introduced the concept of a phylogenetic disease,
in which cognitive and mnemonic vulnerabilities arise as by-products of evolutionary
innovation. He chose as his example Alzheimer’s dementia, and he postulated that genetic
factors underlying the evolution of large human brains introduced vulnerabilities along with
their more obvious benefits. Specifically, he proposed (p. 148) that:
neuropathological studies of Alzheimer patients demonstrate selective disease in
the frontal, parietal and temporal association neocortices, and in the posterior
hippocampus, entorhinal cortex, basocortical amygdaloid complex and nucleus
basalis of Meynert, all of which underwent recent “integrated phylogeny.”

By “integrated phylogeny,” Rapoport meant that the brain structures he listed had undergone
significant expansion and modification during human evolution and that these phylogenetic
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developments interacted with each other. Nonhuman primates, he concluded, could never
suffer from Alzheimer’s dementia because they lack the evolutionary innovations that
produce distinctively human forms of memory, which patients lose in this disease. More
recently, Konopka et al. (7) advanced a similar idea regarding speech and language, and
Pattabiraman et al. (8) have done so for other disorders.

The idea that vulnerabilities accompany advantageous evolutionary changes can be

counterintuitive, but increases in fitness often come with inherent disadvantages. For
example, during locomotion, homeothermic animals need to expend ~20-fold more energy
than poikilotherms matched for body size; even at rest they burn 5–10 times more calories
(9). So, compared to other vertebrates, homeotherms succumb to starvation much faster.
Their evolutionary success attests to the net benefit of this trade-off, but this fact provides
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cold comfort to individuals facing famine. Likewise, trade-offs between the large neonatal
head size of hominins and the pelvic architecture required for bipedal gait produced both
advantages in cognition and vulnerabilities in childbirth (10).

Here we propose that two evolutionary innovations, both involving episodic memory,
contribute to emotional disorders. One is a capacity for re-experiencing events (REE) with a
subjective sense of personal participation; another is flexible planning through constructive
episodic simulation (CES), which empowers a temporally limitless imagination of events.

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In The Evolution of Memory Systems (5), two of us linked these cognitive capacities to
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neural representations of the “self”, conspecifics, and rules governing social relationships.
We reviewed evidence that these forms of memory evolved in hominins, building on
anthropoid innovations. Cortical networks representing the “self” involve lasting memories
of an individual’s attributes, capacities, past experiences, and social relationships. We
proposed that: (i) species-specific representations of the “self” and “others” evolved in
tandem with new social systems during hominin evolution; and (ii) a sense of participation
in remembered and imagined events depends on these self-representations.

This Review and Overview discusses two aspects of hominin brain evolution that enabled
REE and CES: expansion of homotypical association areas, including granular prefrontal
cortex, and expansion of the hippocampus. We explore clinical implications of the
idea that prefrontal-cortex expansion generated human-specific self-representations, while
hippocampus expansion reflected the integration of these representations into episodic
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memories and mental simulations.

Cortical evolution
About 6.3 million years ago, hominins diverged from the chimpanzee–bonobo lineage
(Figure 1B). Until ~3 million years ago, hominin brains differed little from those of modern
chimpanzees in either relative size or sulcal pattern (11). Subsequently, hominin brains
expanded dramatically, but nonuniformly: granular prefrontal cortex came to dominate the
frontal lobe (12, 13), and similar expansions occurred in homotypical association areas of
the parietal and temporal lobes (13–15).

Recently, Donahue et al. (13) used structural magnetic-resonance imaging to measure the
density of cortical myelin in humans, chimpanzees, and macaque monkeys. Figure 1A
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shows that lightly myelinated areas (dark blue) occupy a much larger proportion of the
frontal, parietal, and temporal lobes in humans than in either chimpanzees or macaques.
Granular prefrontal cortex exemplifies these findings. Donahue et al. used cytoarchitectonic
analysis to confirm that homotypical association areas make up the vast majority of lightly
myelinated frontal cortex (12, 13), resolving a controversy on this point (16, 17). They
observed, for example, that granular prefrontal cortex is 9–10 times larger than primary
motor cortex in humans, but only 3 times larger in chimpanzees and macaques. Passingham
and Smaers (18) came to similar conclusions based on a different dataset.

Human brains show significant person-to-person differences in the volume of homotypical

association areas (19). This variation correlates with overall brain volume; and areas
that expanded more recently in evolution also develop later in ontogeny (15). The most
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dramatically expanded parts of the temporal, parietal, and frontal lobes have strong
interconnections with each other, as revealed by resting-state covariance in functional
magnetic-resonance imaging (fMRI) data (20). These areas also show selective fMRI
activations and coupling during tasks requiring individuals to draw on knowledge from
multiple cognitive domains (20), a hallmark of general intelligence (21).

Evolutionary change depends on modifications of genetic programs. Fiddes et al. (22)

concluded that ~14 million years ago a replication error inserted an incomplete and

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functionally defective copy of the ancestral NOTCH2 gene into the genome of an ancestor
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shared by humans, gorillas, and chimpanzees (Figure 1B). A subsequent replication error
inserted an additional nucleotide sequence from the same gene ~3 million years ago,
during human evolution, which restored the gene’s function. Later, that gene—NOTCH2NL
—duplicated again, eventually producing three active versions on human chromosome 1.
Suzuki et al. (23) showed that the NOTCH2NL protein blocks a signal that stops the division
of neural stem cells. This blockade leads to the production of many more neurons, which
augment the human neocortex.

The NOTCH2 gene is one of several that contribute to cortical development. Another gene
on chromosome 1, SRGAP2, duplicated ~2.4 million years ago (Figure 1B). Its paralog,
SRGAP2C, counteracts the effect of the original SRGAP2 gene, causing proliferation
of dendritic spines and branching (24, 25). Two additional human-specific segmental
duplications, HAR5 (26) and ARHGAP11B, made further contributions. Expression of the
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latter in mouse (27) or marmoset (28) embryos increases mitotic division in radial glial
cells, which causes the subventricular zone of the developing cortex to increase in thickness
by almost a third. This brief summary only scratches the surface of the specific genes and
genetic pathways involved in cerebral expansion, but it suffices to illustrate the principles at
work.

Taken together, these findings support the idea that homotypical association areas expanded
dramatically during human evolution, beginning ~3 million years ago. Additional evidence
from comparative neuroanatomy, reviewed by Murray et al. (5) and first recognized by
Preuss and Goldman-Rakic (29), shows that several new homotypical association areas
emerged during anthropoid primate evolution, including new parts of granular prefrontal
cortex. During hominin brain evolution, it was these areas that expanded preferentially.
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Another phylogenetic change occurred in the hippocampus. It decreased in relative size

during most of anthropoid evolution, but during hominin evolution this trend reversed (30,
31). These findings suggest that hippocampal functions became less important during most
of anthropoid evolution. Later, during hominin evolution, one or more of its functions
acquired new significance, and it is likely that this development provided novel selective
advantages based on innovative forms of memory (5, 31).

Primate-unique Neurocognitive Capacities

Social representations in medial prefrontal cortex
Converging evidence implicates a large-scale cortical network in the two cognitive processes
mentioned above: re-experiencing events (REE) and constructive episodic simulation
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(CES). This circuitry is variably described as the medial or default-mode network, which
includes medial prefrontal cortex, hippocampus, and cingulate cortex, among other areas.
Despite some method-based disagreements about its components, all methods place medial
prefrontal cortex in this network (32, 33).

In addition to a role in episodic memory, this area supports social cognition by storing a
unique form of memory: features of conspecifics and of one’s self. After reviewing the

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evolution of medial prefrontal cortex, Murray et al. (5) proposed that its self-representations
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endow the medial network with unique properties that characterize human episodic
memories, especially a vivid sense of participation in the “here and now”. This proposal
drew heavily on the work of Lau and colleagues (34, 35), who attributed human self­
representation to successive re-representation of personal actions, intentions, goals, and
states, which reside in medial prefrontal cortex. This region encompasses the cortex
extending from the medial frontal pole (area 10) to the caudal boundary of anterior cingulate
cortex (ACC, areas 24, 25, and 32). Comparative neuroanatomy suggests that its rostral,
granular component originally evolved in anthropoids and expanded during human evolution
(5). As such, rostral parts of the medial prefrontal cortex are well suited to establish re­
representations of the “self” by drawing on information encoded in phylogenetically older
areas. Re-representation involves the abstraction of information by higher-order prefrontal
areas from lower-order ones. Rostral, granular prefrontal areas draw on representations in
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areas situated more caudally, and higher levels of re-representation emerged as granular
prefrontal cortex expanded during human evolution. Murray et al. reasoned that if each
anthropoid species evolved a modified version of self-representation, suited to the social
system of that species, then modern humans also have a species-specific form of self­
representation.

Across anthropoids, including humans, ACC represents social value in addition to other
kinds of valuations (36). Single-neuron activity in ACC encodes a monkey’s social
preferences, acquired through vicarious reinforcement (37); and selective ACC lesions
prevent monkeys from acquiring prosocial preferences (38). Phylogenetic analysis shows
that social complexity increased during the evolution of anthropoids, which descended from
primates with solitary social systems (39). The same analysis reveals that complex social
systems evolved convergently in prosimians and anthropoids. So, notwithstanding social
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functions of ACC in other mammals (40), nonsocial functions of medial prefrontal cortex
were likely co-opted for social ones independently during anthropoid evolution (41).

In humans, meta-analysis shows that a large part of medial prefrontal cortex has significant
fMRI activations while people make judgements about themselves and others. There are
at least two clusters of self-related sites: one in pregenual cortex (area 32); the other
immediately rostral to the first in the medial frontal-pole cortex (area 10) (42). A meta­
analysis of fMRI covariance confirms that these rostral areas process social representations
(43), with three subdivisions: dorsomedial, ventromedial (including subgenual), and
pregenual cortex. Performance on both episodic-memory and social tasks significantly
predicts fMRI activations in all three subdivisions (43), which points to these areas as key
sites for combining the representations of one’s self and events.
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REE and CES: self-representation and shared neural substrates

From an origin in medial prefrontal cortex, corticocortical connections can distribute
conjunctive self–event representations to other components of the medial network, in which
they are thought to infuse episodic memories with a “here-and-now” quality. A subjective
sense of re-experiencing events (REE) results: “what it was like” when the event occurred
(5). Self-representations can also establish a sense of participation in events imagined via

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constructive episodic simulation (CES), which generally lacks “here-and-now” qualities.

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This distinction arises because reality monitoring allows people to differentiate imaginary
from actual events, although this function can fail in mental illness (44).

Episodic memories and imagined events might seem distantly related, but four lines of
evidence suggest that the neural networks supporting REE also underlie CES. First, when
people either remember events or imagine future ones, overlapping brain regions manifest
activations in fMRI studies, implicating a core network in REE and CES (45, 46). This
network includes medial prefrontal cortex and other medial-network areas, such as the
hippocampus and retrosplenial cortex (Figure 2A). Second, remembering and imagining
events share properties (47), such as a positivity bias, i.e., a preponderance of memories
and imagined events with a positive affective valence. The extent of this positivity bias
correlates significantly for re-experiencing past events and imagining future ones (48).
Third, patients with impairments in remembering events also have a poor capacity for
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imagining future events (49, 50). And fourth, individual differences in pre-commissural (but
not post-commissural) fornix microstructure correlate with the episodic richness of both past
and future autobiographical narratives (51).

An overlap in the neural circuitry for REE and CES probably reflects their common
dependence on mechanisms for mental construction of event sequences and boundaries (49,
52, 53). Furthermore, memories of past events populate imagined ones.

Medial prefrontal cortex, by re-representing one’s self and others at the highest hierarchical
level, enables the incorporation of self-representations into event memories, in part via
interaction with the hippocampus. Medial prefrontal cortex and the hippocampus play
related but specialized roles in this process. Damage to the hippocampus causes an
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impairmentin constructing detailed episodic simulations, but these patients incorporate

themselves normally. Patients with medial prefrontal damage show the opposite pattern;
they can construct detailed mental simulations but rarely incorporate themselves (54).

Emotion and amygdala

Emotional responses are prominent features of both REE and CES, an observation with
several clinical implications. Research on macaques reveals important circuitry underlying
emotional features of REE and CES in humans.

Specifically, this work shows that medial prefrontal cortex (Figure 3) and the hippocampus
have dense interconnections with the amygdala. According to Price and Drevets (55), the
amygdala and medial prefrontal cortex are reciprocally connected, especially the latter’s
caudal parts. The hippocampus and the amygdala also have dense interconnections with
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each other, mostly involving the temporal (anterior) hippocampus (56, 57), which underlies
mental scene construction (58). The hippocampus also sends dense inputs to medial
prefrontal cortex, which like amygdala inputs, concentrate in its caudal aspects (59). Thus,
inputs from the amygdala and hippocampus overlap in medial prefrontal cortex, though they
terminate mostly in different laminae (60). Through these inputs and local circuitry, medial
prefrontal cortex has the connections needed to integrate information from the amygdala and
hippocampus with representations of one’s self.

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The understanding of neuroanatomy in this rich detail depends on research in macaque

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monkeys. These species and other anthropoids can provide this information for a simple
reason: they have a homolog of granular prefrontal cortex, but other common laboratory
animals, such as rats and mice, do not (5, 29). For this reason, insights about brain structures
conserved among anthropoids can, by applying an evolutionary perspective, contribute to
understanding of human-specific cognitive functions and their relations with mental illness.

Several findings have implicated these connections in memories of emotional events,

whether imagined or re-experienced. For example, neuroimaging studies have identified
regions with greater activation for emotional events than for neutral events. Two meta­
analyses using this approach have implicated the amygdala and hippocampus, along
with entorhinal, perirhinal, and visual cortex, in the encoding and retrieval of emotional
episodic memories (61, 62). Another fMRI study found that functional connectivity between
the amygdala and hippocampus increased during the retrieval of emotional contextual
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information (63).

Figure 4 presents a conceptual model of the amygdala’s hippocampal and medial prefrontal
inputs, which contribute to emotional responses during REE and CES. These inputs
combine with those from sensory (and other) areas of the cortex to regulate the amygdala’s
net output. Reciprocal projections from the amygdala amplify these responses. Before
discussing this model, we highlight some current ideas about amygdala function.

It is generally accepted that the amygdala biases behavioral outputs to enhance Darwinian
fitness. This function involves exploiting resources (e.g., nutrients, fluids, warmth), avoiding
predators, producing progeny, and learning about sensory cues that signal resources, threats,
or safety (56). It is crucial that such biases adapt to an individual’s current state and
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motivations, and experiments on both macaque monkeys and rodents have shown that the
amygdala plays a necessary role in value-updating based on current biological needs (64).

Two widespread misunderstandings have hampered attempts to reach consensus concerning

amygdala function in this context. First, some authors have argued that the amygdala
functions primarily, if not exclusively, in threat processing and negative affect (65).
The vast literature on fear conditioning has contributed to this misconception, and
many discussions of amygdala function continue to focus exclusively on negative affect.
However, experimental evidence from both rodents and macaques has overturned this
idea conclusively. Holland and Gallagher (66) reviewed evidence from several laboratories
showing that the rat amygdala plays an important role in reward processing and positive
affect, and Janak and Tye (67) reached the same conclusion more recently. And in macaque
monkeys, the amygdala plays a necessary role in updating valuations that have a positive
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affective valence (68, 69).

Second, the idea that the prefrontal cortex predominantly “inhibits” amygdala output is
contradicted by neuroanatomical evidence from macaques. These studies show that cortical
projections to the amygdala, which are excitatory, terminate on both excitatory or inhibitory
interneurons (70–72). Thus, cortical influences on the amygdala can modulate its outputs
both positively and negatively, depending on the precise circuitry engaged. Figure 4 depicts

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this idea with green symbols for circuits contributing to positive-valence emotional read-outs
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and red symbols for negative-valence read-outs. In both cases, inputs from medial prefrontal
cortex and the hippocampus engage amygdala circuits that influence emotional responses
to both remembered and imagined events. Inputs from sensory areas of cortex, including
homotypical association areas such as inferior temporal cortex, provide current sensory
contexts.

In Figure 4A2, inputs to the amygdala from both the hippocampus and medial prefrontal
cortex convey threat-rich signals generated via retrieved episodic memories or by CES,
which strongly activates threat-avoidance circuits via the amygdala. According to this
model, when threat-rich signals from the medial network override signals reflecting a safe
sensory context, a negative affective state results. For traumatic REE, this means that after a
trigger prompts the recall of a harrowing event, a currently safe sensory context does little
to mitigate a patient’s emotional responses. For CES, a powerful emotional reaction occurs
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for imagined harmful events despite concurrent safety signals. Most research on CES stems
from studies of episodic memory, but CES also is highly relevant for studies of anxiety
because overactive CES represents a cardinal feature of generalized anxiety disorder (GAD),
an illness defined by excessive worry. In both GAD and worries that occur in other mental
disorders, maladaptive feedback loops (dashed red line in Figure 4A2) can arise, in which
rumination about future harms and failures generate persistent anxiety.

In Figure 4B2, a negative affective state prevails for a different reason. Mild threats should
cause little anxiety, if any, and in most people they do not. However, if reassuring REE or
CES have insufficient influence over the amygdala’s output, a negative affective state will
predominate despite a low or nonexistent risk.
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Note that Figure 4A1 and B1 do not necessarily reflect optimal emotional responses.
Some people respond inadequately to threats they have not experienced or are incapable
of imagining in rich, predictive detail (Figure 4A1). In contrast, individuals with a highly
cultivated capacity for CES (unusual foresight) can act in accordance with their imagination
rather than their experience, thereby avoiding danger (Figure 4A2). Of course, excessive
imagination of risks can create problems of its own.

REE, CES, & Emotional Vulnerabilities

The topics discussed thus far establish the foundation for a novel research agenda. This
agenda melds clinical and primate research to seek improved treatment and prediction of
anxiety and stress-related disorders. Creating such an agenda raises a question rarely posed
in discussions of primate research: If certain mental illnesses result from vulnerabilities
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that developed during human evolution, how can studying nonhuman primates help us
understand these illnesses? The answer is that monkeys have anthropoid-unique homologs
of the cortical areas that malfunction in mental illnesses (73, 74). Although the functions
of these areas may have changed during human evolution, nonhuman primate research
is necessary both for understanding these phylogenetic changes and for discovering the
fundamental neural functions that anthropoid-unique areas perform. Knowing how they

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might enhance evolutionary fitness in monkeys provides irreplaceable insight into their
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modified functions in humans.

While the proposed research agenda calls for studies of brain circuits and their functions,
research on the localization and timing of central nervous system gene expression
provides additional insight. Notable studies compare the transcriptional underpinnings of
brain development in rodents, nonhuman primates, and humans (75, 76). These reports
identify genetic pathways and developmental processes more strongly shared by humans
and macaques than by humans and rodents. Moreover, other gene-expression profiles
differentiating humans and nonhuman primates manifest in adolescence, a period where
humans also display unique mnemonic capacities relevant to emotional disorders. Thus,
much like data on cross-species comparisons of brain function, cross-species comparisons
of gene-expression profiles reveal novel brain mechanisms that correlate with evolutionary
changes in emotional processes.
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The research agenda we imagine draws on the evolutionary perspective outlined earlier and
targets new forms of memory that emerged during the evolution of anthropoids and humans
(5). Its goal is to inform clinical studies across two time scales: (i) for REE, ideas about
novel therapeutics relate to changes in brain circuitry that develop over days to weeks during
clinical trials; (ii) for CES, ideas about improving prediction of developmental change
involve cortical ontogeny, which unfolds over months to years. This research agenda could
help coordinate studies based on the Diagnostic Statistical Manual (DSM-5) with work
guided by Research Domains Criteria (RDoC). Our conceptual model is relevant to both
systems. For DSM, it defines phenomena using DSM criteria and seeks to improve outcomes
defined through available measures in clinical studies. For RDoC, it targets expressions of
clinically relevant phenomena across diagnostic boundaries. For both, the objective is to
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identify biological mediators and moderators of clinically defined outcomes.

Defensive behaviors provide an example to be targeted by this approach. Some functions,

such as those related to trauma, influence defensive behavior through effects on conserved,
homologous circuitry that operates similarly in rodents, nonhuman primates, and humans.
Other functions involve primate-unique circuitry and large-scale networks involving cortical
areas that emerged during anthropoid evolution and expanded dramatically in humans.
Thus, human defensive behavior and associated clinical problems reflect combinations
of perturbations in both primate-unique and circuitry more broadly conserved among
mammals. As stated previously (4, 5), our conceptual model presumes that humans
re-experience recollected events, construct episodic simulations, and experience their
associated emotional responses in a way that is fundamentally different from nonhuman
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primates. Nevertheless, these functions depend on cortical areas, circuits, and networks
that emerged during primate evolution and are homologous among anthropoids. Moreover,
cortical areas that are common to all mammals, such as ACC and the hippocampus,
are influenced by primate-specific circuitry in ways that also alter the functions of these
pan-mammalian structures. Note that none of this requires empirical knowledge about the
subjective, mental states of nonhuman anthropoids or other animals, let alone the dozen
or more hominin species of the past six million years. Instead, our model holds that each
species experiences events and plans future behavior in its own way. We do, however,

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reject the assumption that nonhuman animals have two cognitive traits characteristic of our
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species: a subjective experience of personal participation in events and a subjective sense of

owning one’s knowledge about the physical and social world. By rejecting this assumption,
a broad range of clinical and comparative data becomes both more comprehensible and more
translational.

Primate research also shapes clinical thinking by tying information-processing functions

and neural representations to tractable anatomical targets of clinical intervention.
Neuropsychological research in monkeys contributes to this knowledge via experiments
that identify neuroanatomical substrates of specific neural computations and representations.
Localization of function is essential because similar-appearing behaviors often arise from
distinct neural mechanisms, which are dissociable anatomically. Precision is needed because
diverse behavioral effects can arise from circuits and networks separated by millimeters
and with interweaving fibers-of-passage. Earlier, we discussed a core brain network
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supporting both REE and CES (Figure 2). However, subsystems within this network
have differential fMRI activations for remembering versus imagining events (77). These
anatomical distinctions may underlie the difference between REE and CES in terms of
the former’s “here-and-now” quality, as well as the different emotional responses that
re-experienced and imagined events evoke.

Accordingly, when seeking insights beyond the scope of currently available clinical tools,
linked studies in patients and monkeys would serve a unique and specific purpose. By
drawing on the concept of phylogenetic disease and the above-elucidated evolutionary
perspectives, cross-species studies can identify clinically useful, localizable targets. These
targets might be manipulated in an attempt to treat patients’ emotional or behavioral
problems, and they might be assessed through imaging in an attempt to predict anticipated
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developmental changes in symptoms. As just mentioned, neuroimaging research in humans

has identified neural targets for differential disruption of REE and CES (77). Consequently,
manipulations of their homologs in macaque monkeys can be performed experimentally
to generate mechanism-level insights into psychological processes. With this combined
knowledge, interventions aimed at mitigating overactive threat-related REE, while leaving
reassuring CES relatively intact, could be developed and tested. Concurrently, assessment
tools could be created to quantify CES in ways that predict children’s proclivities for
later-life emotional problems.

REE and traumatic-stress disorders

Not only do patients with post-traumatic stress disorder (PTSD) need therapeutic advances,
but so do other patient groups that experience emotionally distressing memories. For
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instance, among patients with major depressive disorder (MDD), those with traumatic
exposures present distinct therapeutic challenges compared to other depressed patients.
As one example, patients with MDD that occurs in the context of traumatic childhood
experiences exhibit poor responses to treatment with antidepressant medications (78, 79).

An RDoC approach to the traumatic re-experiencing of events (REE) could prove beneficial
for several mental disorders. DSM-5 classifies such memories as instances of intrusive
symptoms, one of four PTSD clinical domains. Yet, similar forms of intrusive recollection

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occur in MDD patients exposed to trauma (80, 81). Like in PTSD patients, when intrusive
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REE occurs in MDD patients, they report or act in ways that suggest a “here-and-now”
quality to the recollection. Patients in both diagnostic groups act and react emotionally as
if the event is actually occurring. Considerable research differentiates REE from the other
symptom domains in PTSD (81), so it makes sense to focus on the underlying information­
processing networks and the unique forms of memory that we described earlier: conjunctive
representations of events and one’s self. An understanding of how these networks and
their associated forms of memory evolved, based on comparative neuroscience, empowers
clinicians to develop concrete ideas about why similar phenomena occur across diagnostic
boundaries.

Combined human and monkey research could lead to specific therapies. For example,
an fMRI study probed two attributes of episodic memory relevant to REE and CES:
vividness and richness of detail (82). As participants engaged in CES, they rated vividness
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during scans and later conveyed richness of detail verbally. A core network for episodic
memory showed significant activation, including several medial areas—the hippocampus,
retrosplenial, and medial prefrontal cortex (Figure 2A)—along with lateral areas such as
the inferior temporal cortex and angular gyrus (Figure 2B). A contrast of high versus low
vividness identified the hippocampus as uniquely sensitive to this aspect of CES, whereas a
contrast of high versus low richness-of-detail yielded the angular gyrus.

These and related findings suggest targets for therapeutic interventions using transcranial-
or deep brain stimulation. In clinical studies, patients actively recall particular episodes
from their past, including instances involving traumatic exposures. It might be possible
to disrupt the vividness of REE while leaving the details of memory relatively intact.
Neuropsychological experiments in macaques can test this possibility on homologous
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cortical areas and pathways, based on behavioral designs tailored to the functions that
these homologs perform in macaques. Earlier, we mentioned a similar approach aimed
at disrupting threat-rich REE while leaving reassuring CES relatively unaffected. In both
examples, the evolutionary perspectives elucidated in the first parts of this Review and
Overview explain how research on monkeys can contribute to understanding human-specific
cognitive capacities and psychopathologies.

By understanding the functions of homologous structures in nonhuman primates, we can

gain insight into their specifically-human functions. As a relevant example, amygdala
lesions in macaques block the expression of defensive behaviors, and, at the same time,
heighten aspects of attentional processing for phobic stimuli, such as snakes and spiders
(83). This finding suggests that the intact amygdala mediates defensive behavior that also
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competes with attentional processing of threats. The article reporting this insight prompted
subsequent research on a patient with focal bilateral amygdala lesions. This patient lacked
defensive responses to snakes and other threats; although she reported a fear of snakes and
spiders, she displayed intense curiosity toward and tended to approach both stimuli (84).
Thus, in both macaques and humans, amygdala functions can compete with and lessen
certain aspects of sensory processing. In contrast, amygdala functions in other settings
might enhance reactions to threat stimuli (85, 86). Parallel studies in humans and nonhuman
primates could distinguish scenarios where threat-related processes are enhanced or reduced

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 Pine et al. Page 12

by amygdala function. Subsequent studies could then link anxiety symptoms in patients with
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amygdala-dependent attentional biases, which clinical trials could manipulate to determine

their causal role in the genesis or maintenance of anxiety.

To this end, three approaches leverage insights from primate research to improve clinical
targeting of neural circuits contributing to traumatic REE. Taken together, they provide
complementary advantages and disadvantages. One uses cognitive training to alter circuit
function through therapeutically-relevant exercises. Many such training approaches exist,
and they have the advantage of being noninvasive. Of most relevance to traumatic REE,
task-based procedures that engage homotypical association areas, including those connected
to medial prefrontal cortex, reduce the clinical impact of REE (87). Training approaches
have a clear weakness, however: an indirect relationship between training procedures and
levels of engagement of specific areas and pathways. This weakness might be addressed
by adapting biofeedback techniques used in PTSD (88). The second approach uses
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medications, either alone or with psychotherapy. Their utility in PTSD and MDD shows
that this approach is beneficial in many cases, as are emerging technical advances for
localizing pharmacological effects. Again, research on nonhuman primates will be crucial
for validating such advances. However, the lack of anatomical specificity is a weakness:
medications affect many neurochemical systems, and it is rarely clear which effect alters
symptoms. The third approach, brain stimulation, most directly links research in monkeys to
treatments in humans. Stimulation of hippocampal–neocortical networks has robust effects
on episodic memory in healthy adults (89), and recent findings in PTSD appear promising
(90). Published work in PTSD (90) and MDD (74, 91) typically emphasizes prefrontal
cortex, but such interventions could be adapted to focus on other parts of the core REE/CES
network. The potential for adverse effects is the technique’s major weakness.
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CES and development of emotional disorders

Like psychopathology involving REE, emotional problems related to CES reflect both
ongoing dysfunction of relevant cortical networks and aspects of individuals’ life histories.
Some individuals with excessive CES manifest symptoms at many points in life, with
clinical features that change with maturation and experience; other individuals acquire
capacities that might mitigate these tendencies, as reflected in only temporary symptoms
during childhood.

These patterns raise two questions on the developmental nature of emotional problems. First,
although most adult emotional problems begin as pediatric anxiety disorders, many children
with anxiety disorders mature to become psychiatrically healthy adults. Thus, we need to
know which aspects of brain development distinguish forms of pediatric anxiety leading
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to chronic problems from forms with minimal long-term impact. Second, among affected
patients, clinical expressions change during development, often beginning with separation­
related problems, followed by fear of particular objects or situations. With adolescence,
emotional problems change further to involve abstract concerns, such as consternation
about one’s competence or lasting feelings of profound sadness. These patterns parallel
broader normative changes seen across cultures in fears, anxieties, and moods (92, 93).

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 Pine et al. Page 13

Such observations raise questions about developmental trajectories that produce persistent
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psychopathology, expressed through changing emotional features in anxiety.

Like the trauma-related disorders mentioned above, studies in macaques provide avenues
for translational research on developmental features of anxiety. For CES, linked studies in
humans and monkeys promise to improve outcome prediction by clarifying the nature of
developmental processes contributing to chronic psychopathology in anxious children.

One notable set of findings concerns the stability of individual differences over the lifespan
(92, 93). Both acute response to experimental threats and variation in broadly-expressed
temperaments relate to individual differences in brain function, such as high levels of
activity in CES-related circuits. These individual differences generate ideas on predictive
biomarkers to be tested experimentally in monkeys. For example, there is continuity
between early-childhood anxious temperament and adult outcomes involving internalizing
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psychopathologies such as depression and anxiety (94). Understanding the underlying

biology improves outcome prediction in children with anxious temperament. For example,
among children with heightened levels of behavioral inhibition, the subset who also manifest
enhanced neural sensitivity to error commission in adolescence, compared to the subset with
low neural sensitivity, face higher risk for internalizing psychopathologies in adulthood (94).

Similar continuity of temperament occurs in macaque monkeys (95), which makes parallel
studies promising. Research on potential biomarkers that predict long-term stability of
temperament in monkeys can support applications useful for predicting clinical outcomes
in at-risk children. As explained later and as illustrated in Figure 5, this work could
utilize the human intruder paradigm in macaque monkeys, which evokes correlates of
pediatric anxiety disorders (96). Studies of choice behavior employing this paradigm in
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monkeys could include event-related potentials (ERPs) related to error monitoring and
their association with functions of medial prefrontal areas such as ACC. As noted above,
children with behavioral inhibition tend to have the linked traits of high error-sensitivity in
adolescence and internalizing disorders in adulthood. Thus, improvements in the ability
to assess functioning of relevant circuitry in adolescence might enhance prediction of
clinical outcomes in adulthood. To create such improvements, hypotheses on mechanisms
that connect early temperament, error-sensitivity, and stable levels of defensive behavior
could be tested in monkeys. This research program might involve manipulations of the
homologous ACC regions and associated circuitry in juvenile monkeys, using a broader and
more invasive array of methods than available for human research.

Other findings relevant to outcome prediction concern cortical development, especially

the neotenous character of homotypical association areas. Earlier, we cited evidence
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that anthropoid-unique cortical areas expanded dramatically during evolution (Figure

1A). In monkeys (97), as in humans (15), the most recently evolved and expanded
cortical regions are also the last to mature, along with the representations and information­
processing functions they support (5). Furthermore, these late-maturing regions exhibit
longer windows of plasticity than earlier-maturing regions. Some data suggest clinical
relevance. For example, selective serotonin reuptake inhibitor exposure in juvenile monkeys
produces particularly large effects in superior and inferior temporal cortex (98), which are

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 Pine et al. Page 14

homotypical association areas that expanded during human evolution and exhibit delayed
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maturation. Delayed and prolonged maturation of anthropoid-unique areas presumably

underlies the marked, gradually-unfolding adolescent changes in emotional processes.

Figure 5 depicts linked studies based on this idea: in patients with anxiety disorders (top)
and in monkeys (bottom). It exemplifies the kind of coordinated, iterative studies that
could improve outcome predictions in patients. For example, when pediatric emotional
problems persist into adulthood, their changing clinical features might reflect the maturation
of cortical areas. These areas could include regions shown in the figure as engaged during
learning, such as temporal areas and the amygdala, which link sensory representations
to emotional responses. Such changes might incorporate medial frontal areas also shown
in Figure 5, which shape such forms of learning through error-monitoring functions.
The bottom part of Figure 5 illustrates a study in monkeys aimed at examining these
developmental changes, which fMRI experiments can then apply to patients to identify
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neural correlates of long-term outcomes.

For anxiety disorders, future fMRI studies might target the role of homotypical association
areas in the memory of frightening events, which changes in adolescence. Past work
informing Figure 5 has established methods for localizing neural correlates of encoding
and recall for enduring fears (99). Future studies might employ these methods to
quantify individual differences in flexible episodic representations, as assessed with digital
techniques (e.g., ecological momentary assessment) over weeks-long time frames separating
encoding and recall and which populate imagined events (CES). Such work could test
hypotheses relevant to long-term outcomes, such as the idea that persistent (versus transient)
emotional problems involve enhanced CES and dysregulation of the association cortex–
amygdala circuitry highlighted in Figure 5 (top right).
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The parallel studies imagined for macaques could serve to focus this clinical research
constructively. For example, mature macaque monkeys can rapidly learn arbitrary
associations between abstract visual stimuli and emotional responses. As noted above,
embedding such learning with exposure to the human intruder paradigm leverages prior
findings. These findings delineate parallels between the neural correlates of anxious
temperament in monkeys and anxiety disorders in children (96). Future studies might
examine the associative memories linking abstract visual stimuli with exposures to human
intruders. As displayed in bottom half of Figure 5, mature macaques can learn to associate
each of three novel, abstract visual cues, such as fractal patterns, with an impending event:
entry of a human intruder; a control condition; or access to conspecifics. Studies in mature
and juvenile monkeys could delineate mechanisms linking age-related changes in inferior
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temporal and granular prefrontal cortex to age-related changes in the ability to establish
memories that evoke emotional responses. Similar mechanisms might underlie dynamic
features of persistent emotional problems in patients, including transitions from concrete
fears to generalized anxiety during maturation.

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 Pine et al. Page 15

Conclusions
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Although research on nonprimates, such as rodents, can broadly inform an understanding of

mental illness, nonhuman primate studies can uniquely target brain structures and functions
that distinguish primates from other species. Evolutionary innovations endowed humans
with advantageous information-processing functions and new forms of memory. Along
with their advantages, however, these phylogenetic developments produced vulnerabilities
to emotional problems. Both insufficiencies and excesses in specifically human cognitive
capacities can develop over the lifespan, as the underlying cortical networks mature
and adapt to modern life. Re-experiencing events (REE) and constructive episodic
simulation (CES) are two examples of such clinically-relevant capacities unique to humans.
Neuroimaging findings in illnesses with prominent emotional features encourage an agenda
of linked studies in nonhuman primates and patients to delineate mechanisms that generate
these capacities. For REE, these studies promise to generate novel treatments for illnesses
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that follow trauma. For CES, they could improve outcome prediction by illuminating
developmental processes underlying chronic illnesses that begin as early-life anxiety
disorders.

Acknowledgements:
D.S.P and E.A.M. are supported by the Intramural Research Program of the National Institute of Mental Health.

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Figure 1.
(A) Myeloarchitectonics based on structural MRI in humans, chimpanzees, and macaque
monkeys: plotted onto an inflated image of the cerebral cortex. White lines show the caudal
boundary of the granular prefrontal cortex (PFC) based on using an arbitrary criterion,
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the genu of the corpus callosum, as the boundary. This practice led to a substantial
underestimate of PFC’s size. Purple and blue lines show the caudal boundary of PFC based
on cytoarchitectonics. This analysis identified homotypical areas, which have a reasonable
proportion of the six major neocortical layers. (Note that, despite the term “granular”, this
part of PFC consists of homotypical cortex.) Purple lines provide a conservative estimate,
i.e., the least plausible amount of granular PFC; blue lines indicate the most likely boundary
between the granular PFC and other parts of the frontal lobe. Top row: rostral is to the

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left; dorsal is up. Bottom row: rostral is to the right; dorsal is up. Black bars indicate
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relative scale. Reproduced from Donahue et al. (13). (B) Cladogram of relationships among
anthropoids, with divergence and gene-duplication times in green type. Abbreviation: Ma,
million years ago. Adapted from Fiddes et al. (22).
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Figure 2.
Core network for REE and CES. (A) Medial areas. Rostral is to the right; dorsal is up. (B)
Lateral areas. Rostral is to the left; dorsal is up. Adapted from Schacter et al. (45).
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Figure 3.
Amygdala–cortical connectivity in macaque monkeys. Amygdala projections to the
neocortex are ranked according to the density of inputs: high (black), medium (dark gray), or
low (light gray). Abbreviations: EC, entorhinal cortex; Id, Ig, Iam, Iapm, Iai, parts of insular
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cortex; PrCO, frontal opercular cortex; TEO, TEp, TEa, and TG, parts of inferior temporal
cortex; STGr, rostral superior temporal cortex; V1, primary (striate) visual cortex. Rostral is
to the right in all parts. Top and bottom: dorsal is up; middle: lateral is up. Reproduced from
Price and Drevets (55).

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Figure 4.
Model of amygdala output regulation. Emotional responses evoked by threat and safety
signals can have either a positive (green) or negative (red) valence. Inputs to the amygdala
from the hippocampus and other parts of the medial network convey signals associated with
remembered or imagined events. (A) REE or CES convey threat-rich memories or mental
simulations to the amygdala, which contradict inputs from sensory areas signaling safety.
(B) REE or CES convey reassuring signals to the amygdala, which contradict sensory­
cortex inputs signaling mild threats. (1) Positive emotional responses dominate mood and
behavior. (2) Negative emotional responses dominate mood and behavior. Note that the
depiction of inputs from sensory areas omits the influence of top-down attention and other
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processes that affect the flow of sensory information to the amygdala. Abbreviations: CES,
constructive episodic simulation; GAD, generalized anxiety disorder; REE, re-experiencing
events retrieved from memory.

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Figure 5.
Schematic for parallel studies in humans and nonhuman primates. The study in humans
is adapted from prior research on pediatric anxiety disorders. It begins with a threat
conditioning exercise, which involves visually presented faces, some of which are associated
with an aversive scream (left), followed by a weeks-long period of ecological momentary
assessment quantifying emotional experiences and memory (middle). Finally (right),
memories linking visual stimuli with emotional responses are probed during fMRI using
stimuli adapted from the threat conditioning sessions (left). The study in nonhuman primates
is adapted from prior research on two homotypical association areas: granular prefrontal
and inferior temporal cortex, both of which are connected with the amygdala (Figure 3).
Macaque monkeys learn to associate each of three novel fractals (left) with one of three
events (middle), two of which induce emotional responses (top to bottom): an aversive
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exposure to a human intruder; a control condition (an innocuous sound, matched in duration
to the intruder’s time in the room); or a rewarding exposure to grooming with a socially
paired conspecific. With experience, mature macaques can learn a new set of three fractal–
event associations within a few minutes. Later (right), the monkey makes a choice among
fractals, presumably choosing the one associated with grooming. Parallel studies on juvenile
monkeys can reveal how cortical maturation enables adult monkeys to establish memories
linking abstract visual stimuli with predicted emotional responses. Such studies also might

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assess how anxious temperament, quantified using the human intruder paradigm, relates to
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cortical maturation.
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