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Sleep and REM sleep disturbance in the
pathophysiology of PTSD: the role of extinction
memory
Edward F. Pace-Schott
1*
, Anne Germain
2
and Mohammed R. Milad
1
Abstract
Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and
remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms
typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and
fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals
exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma,
or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over
time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may
result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive
mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are
neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance
potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence
that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction
memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically
timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow
sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders.
Keywords: Extinction, Sleep, REM sleep, PTSD, Anxiety, Insomnia, Stress
Review
Introduction
This review explores the possibility that disruption of
sleep by acute or chronic stress may lead to alterations
in emotional memory processing and, thereby, contrib-
ute to psychiatric illnesses such as post-traumatic stress
disorder (PTSD) [1]. Here, one particular form of emo-
tional memory, extinction of a conditioned fear response
(i.e., learning that something that once signaled danger
no longer does so) is emphasized. Extinction is a form of
emotional memory that is important to normal emotion
regulation [2], influenced by normal sleep and its dis-
turbance [3–5], impaired in anxiety disorders [6], and
exploited in their treatment [7]. Recent experimental
findings, which are reviewed in reference [8], suggest
that sleep may play key roles in the consolidation, inte-
gration, and balance of fear and extinction memory. The
current review focuses on clinical issues and puts for-
ward the hypothesis that one mechanism leading from
psychological trauma to PTSD is stress-related sleep dis-
turbances that interfere with sleep-dependent consolida-
tion of emotion-regulatory neuroplasticity such as fear
extinction and habituation.
Disturbances of sleep and of emotions are reciprocally
related
Healthy sleep is associated with normal emotion regulation
[9, 10]. Conversely, sleep disturbance is both a common
behavioral sequela of acute and chronic stress [11, 12]
and a prominent symptom of anxiety and mood disorders
[13, 14]. Specifically, sleep disturbance is a characteristic
* Correspondence: epace-schott@mgh.harvard.edu
1
Department of Psychiatry, Harvard Medical School, Massachusetts General
Hospital—East, CNY 149 13th Street Room 2624, Charlestown, MA 02129,
USA
Full list of author information is available at the end of the article
Biology of
Mood & Anxiety Disorders
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Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3
DOI 10.1186/s13587-015-0018-9
sequela of psychological trauma although subjective re-
ports often indicate far greater severity than objective
measurements in the immediately post-trauma period
[15, 16]. While daytime affective symptoms and associ-
ated neural, physiological, and endocrine disturbances
can adversely affect sleep, there is growing evidence
that sleep disturbances (e.g., insomnia) can reciprocally
impact daytime symptoms. For instance, epidemiological
and prospective studies show that sleep disturbances that
are present prior to trauma exposure, or that occur soon
after trauma exposure, are a robust risk factor of poor psy-
chiatric outcomes including PTSD, anxiety disorders,
mood disorders, suicidality, and alcohol/substance use dis-
orders [17–20]. Similarly, pre-existing insomnia has been
shown to be a risk factor for incident depression [21–23].
The presence of untreated sleep disturbances comorbid
with psychiatric disorders tends to attenuate treatment
response and increase the risk of relapse [24–27]. Con-
versely, the persistence of consolidated sleep following
stress or trauma exposure, as well as sleep improvements
over the course of treatment for affective disorders, are as-
sociated with better mental health outcomes [28, 17].
As a result of such observations, it has been widely hy-
pothesized that sleep disturbance is crucially involved in
the etiology of PTSD rather than being solely a symptom
arising secondarily from this disorder [16, 29–36]. In a
comprehensive review on the temporal sequence of sleep
disruption following traumatic events and the subsequent
emergence of PTSD, Babson and Feldner [16] have shown
that, in many cases following psychological trauma, sub-
jective and, to a lesser extent, objective sleep disturbances
can precede PTSD diagnosis thus providing clear evidence
that such an etiological role of sleep is a distinct possibil-
ity. They note, however, the study of potential mechanisms
for such a role is only in its infancy. The current review
begins to explore evidence of one such factor, impaired
fear extinction.
Involvement of sleep disturbance in the pathophysi-
ology of PTSD does not, of course, exclude the more
traditional view that psychiatric illness produces unique
sleep disturbances or exacerbates pre-existing ones.
Moreover, it is likely that a third vulnerability factor,
such as individual variability in the degree to which psy-
chological stress provokes enduring arousal in central
limbic and autonomic circuits, can contribute to both
poor sleep and increased risk of psychopathology. For
example, waking hypervigilance and sleep disturbance
could both arise from excess sympathetic activation
without a direct interaction between the waking and
sleep effects of such hyperarousal. As discussed below,
chronic hyperarousal is increasingly implicated in the
development of insomnia [37–42]. Similarly, repetitive
nightmares and daytime traumatic memory intrusions
may reflect a similar priming or disinhibition of retrieval
for stored representations of the traumatic event, again
without direct interaction between these two phenom-
ena. Moreover, it has been suggested that sleep loss may
secondarily diminish daytime coping strategies increas-
ing the likelihood of developing psychopathology. Simi-
larly, nightmares may sensitize individuals to waking
trauma cues, or sleep disruption may directly exacerbate
anxiety (reviewed in [16]). As in other disorders of bio-
logical systems, it is likely that pathogenic factors inter-
act and that impaired negative feedback, escalating
positive feedback, or compensatory allostatic mecha-
nisms allow abnormalities in one domain to exacerbate
those in others [43]. Therefore, we suggest that sleep
disturbance and its negative effect on extinction memory
is one of a number of neurocognitive and physiological
pathways that could exacerbate risk of developing PTSD
following a traumatic experience. For example, other
neurocognitive factors potentially escalating risk of
PTSD following initial trauma might include persistent
threat of re-traumatization (enhanced conditioning),
whereas physiological factors might include poor nutri-
tional status (impairment of memory processing).
The temporal development of PTSD following
psychological trauma
Before proceeding to consider how sleep disturbance fol-
lowing trauma could contribute to the development of
PTSD, it must first be established that PTSD is a disorder
that can, in fact, develop over time following trauma
rather than simply being an acute stress disorder (ASD)
[1] that persists beyond an arbitrary 1-month threshold
[1, 44]. What is the evidence that this is the case?
First, in a systematic review of prospective studies,
among 19 studies of adults, following a median 6-month
follow-up, a median of only 50 % of those with ASD
subsequently met criteria for PTSD, whereas a median
of only 47 % of those with PTSD previously met criteria
for ASD [45]. Second, in a study of over 1000 traumatic
injury survivors, only about a third of persons who devel-
oped PTSD by 1 year following a traumatic event showed
ASD immediately following the trauma [46]. Importantly,
this percentage increased by only about 9 % when a more
liberal (subsyndromal) definition of ASD, not requiring
dissociative symptoms, was used [46]. A similar percent-
age of persons with ASD (36 %) or subsyndromal ASD
(30 %) went on to develop PTSD, although 65 % did even-
tually develop some psychiatric disorder.
Third, among post-combat military populations, it is not
uncommon for diagnosed PTSD to emerge only after a
delay of several months post-deployment [47]. For ex-
ample, 88,235 Army soldiers were evaluated immediately
upon returning from the Iraq war with a self-administered
Post-Deployment Health Assessment that included spe-
cific screening questions for PTSD [48]. These same
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 2 of 19
individuals were then re-evaluated with an assessment that
contained the same PTSD screening questions at a median
of 6 months after finishing the first evaluation [47]. In this
re-assessment, report of psychological distress was mark-
edly higher and reports of PTSD symptoms increased
from 11.8 to 16.7 % in active-service Army and from 12.7
to 24.5 % in Reserve and National Guard [47]. Notably,
among those who had reported PTSD symptoms on the
immediately post-deployment assessment, approximately
half reported improvement of these symptoms at re-
assessment [47]. Therefore, the increased proportion of
individuals reporting PTSD symptoms at re-assessment
must have included individuals in whom symptoms ap-
peared following their first assessment.
Fourth, although delayed-onset PTSD, defined most
strictly as onset of any PTSD symptoms only after
6 months or more following trauma, is controversial and
rare [49, 50], exacerbation of existing symptoms is com-
mon [49]. For example, a comprehensive review re-
ported that, over the 6 months following a traumatic
experience, worsening of existing PTSD symptoms or
re-emergence of previously experienced symptoms was
reported by 15.3 % of civilians and 38.2 % of military
personnel [49]. Therefore, sleep disturbance may directly
worsen existing symptoms, or, as here suggested, result
in a failure to ameliorate such symptoms through con-
solidation of naturalistic or therapeutic extinction learn-
ing. In either case, the characteristic PTSD symptoms of
intrusions (including nightmares), avoidance, negative
affect, and hyperarousal [1] clearly may emerge or
worsen over the initial months following a traumatic
event.
Fear conditioning and extinction
Fear conditioning occurs when an emotionally neutral
stimulus is associated with an inherently aversive experi-
ence (unconditioned stimulus or US). The neutral stimu-
lus thereby becomes a conditioned stimulus (CS) with
the capability, on its own, to evoke a fearful conditioned
response (CR). When the CS is subsequently presented
repeatedly without the US, extinction (reduction) of the
CR typically takes place. However, rather than erasing
the CS-US association, extinction represents formation
of a new memory, an “extinction memory,”signifying
“CS-no US,”that competitively inhibits the memory of
the CS-US contingency and expression of its associated
CR when the CS is again encountered [51–59]. Neuro-
imaging research using de novo fear-conditioning and
extinction paradigms has revealed areas in the brain
associated with experiencing conditioned fear (a “fear
expression network”) in the amygdala and dorsal anterior
cingulate cortex (dACC) and other areas associated with
memory for the extinction (inhibition) of this fear (an “ex-
tinction memory network”) that includes the hippocampus
and ventromedial prefrontal cortex (vmPFC) [8, 59–61]
(Fig. 1).
Extinction learning, viz. learning the “CS-no US”con-
tingency, is the neurobehavioral basis for the efficacy of
exposure therapy [7, 62]. Means by which memory for
this therapeutic learning may be strengthened, and re-
lapse to dominance of the fear (CS-US) memory pre-
vented, are currently the subject of extensive clinical
research [62–64]. It is also, however, important to
recognize that extinction is a process that is ongoing in
the course of everyday life. For example, individuals who
display resilience and recovery, without any therapeutic
intervention, following a psychologically traumatic event,
presumably acquire extinction memories based upon
spontaneous encounters with reminders of the trauma.
And these extinction memories, in turn, prevent subse-
quent trauma cues from triggering fearful responses.
And, as is the case for other forms of emotional memory
[10], healthy sleep may be of ongoing, and cumulative
importance in the consolidation of memory for both
therapeutically induced and naturally learned extinction.
Sleep-dependent memory consolidation
Extinction memory must be encoded, consolidated, and
then retrieved in order to oppose conditioned fear. For
declarative and procedural forms of memory, sleep has
Fig. 1 The “anterior paralimbic REM activation area”overlaps with
fear and extinction circuits.
18
Fluoro-deoxyglucose PET image of
areas that reactivate during REM sleep following relative quiescence
during NREM sleep. Dashed lines surround approximate cortical regions
commonly activated in experimental protocols during fear conditioning
(yellow lines) and during recall of extinguished conditioned fear (white)
based upon Milad and Rauch [61], Fig. 3. Solid lines encircle approximate
anatomic loci of subcortical structures similarly activated during fear
conditioning (yellow) and extinction recall (white). The anterior
paralimbic REM activation area includes the amygdala (A), and regions
of dorsal anterior cingulate (dACC) and insular (not shown) cortices
linked to a putative fear expression network. Additionally, this region
includes the ventromedial prefrontal (vmPFC) and hippocampal (H)
areas [127–129] linked to a putative extinction memory network
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 3 of 19
been widely demonstrated to promote the consolidation
stage of memory formation [65–68], including processes
related to prioritization and integration of newly ac-
quired memories with existing stores [69–72]. Moreover,
prior sleep can facilitate memory retrieval via such func-
tions as protection from retroactive interference [73]
and enhanced updating during reconsolidation [74].
Rapid eye movement (REM) sleep is associated with con-
solidation of emotional memory (reviewed in [8–10]), and
REM sleep has been suggested to be the stage of sleep dur-
ing which emotion is regulated [75]. For example, in the
“Sleep to Remember, Sleep to Forget”model, Walker and
colleagues suggest that REM sleep serves the dual purpose
of consolidating the content of emotional memory and
diminishing the memory’s emotional charge [75, 10]. Simi-
larly, regulation of mood and working through of emo-
tional responses to intra- and interpersonal stressors have
been linked with REM sleep and associated dreaming [76–
78]. Significantly, a broad anterior midline area of cortex
and subcortex (the “anterior paramedian REM sleep activa-
tion area”detailed below) selectively activates during REM
sleep following relative deactivation during non-REM
(NREM) sleep [79], and this region encompasses both the
fear expression and extinction memory networks (Fig. 1).
Physiological processes underlying sleep’s effects on
memory consolidation have been demonstrated in animals
and include replay, during sleep, of patterns of hippocam-
pal place-cell firing that accompanied learning [80, 81].
Similar encoding-induced changes in subsequent sleep
physiology are reported human polysomnographic and
neuroimaging studies (reviewed in [67]). Post-learning
sleep may facilitate synaptic, second messenger, gene tran-
scription, and protein synthesis steps required for memory
consolidation [82] such as N-methyl-D-aspartate (NMDA)
receptor-dependent hippocampal long-term potentiation
[83, 84]. Critical periods requiring sleep, including specif-
ically REM sleep, for memory consolidation following en-
coding have been demonstrated in animals and humans
[85], and such a period for extinction memory has recently
been demonstrated for REM sleep [86].
Extinction and disorders with abnormal levels of anxiety
Abnormal levels of anxiety seen in Diagnostic and Statis-
tical Manual of Mental Disorders—5th ed. (DSM-5)
Anxiety Disorders and Trauma- and Stressor-Related
Disorders suggest a deficiency in emotion-regulatory
mechanisms. A deficit in the ability to encode, consoli-
date, or retrieve extinction memory is believed to play a
role in the development and perpetuation of such disor-
ders [6, 59, 61, 87].
Having hypothesized deficient extinction in PTSD, at
what point in the processes of fear acquisition, extinc-
tion learning, and extinction memory does this problem
arise? Deficient memory for extinction has been shown
to differentiate individuals with PTSD from trauma-
exposed controls at both the behavioral and neural levels
[88–90]. Notably, in these particular studies, acquisition
of fear conditioning and extinction learning did not dif-
fer between these groups [88–90]. Other studies have
specifically implicated a deficiency in PTSD to use con-
textual information to disambiguate danger versus safety
[91]. Such findings would suggest that a deficiency in
emotional memory systems might be of primary etio-
logical importance in PTSD as might be expected given
the above-cited abundant evidence for sleep effects on
memory consolidation. Nonetheless, other studies do sug-
gest greater de novo fear conditioning in PTSD [92] and
deficient acquisition of extinction [93–95]. In addition, the
degree of recall of de novo fear conditioning may predict
later development of PTSD symptoms [96, 97]. Moreover,
enhanced physiological reactivity to acoustic startle stimuli
compared to controls is also commonly noted in this dis-
order [98–100]. Therefore, lesser capacity to acquire ex-
tinction, possibly due, in part, to enhanced ability to
acquire a conditioned fear that is itself related to aug-
mented autonomic and limbic reactivity may also play a
role, particularly in the hyperarousal symptoms of PTSD.
Interestingly, such hyperarousal also produces sleep
disturbance that, in turn, may further disrupt sleep-
dependent memory processes as detailed below.
The gold standard treatment for certain disorders with
abnormal levels of anxiety involves formation of thera-
peutic extinction using exposure therapy [7, 62]. In such
treatment, the patient is exposed to imaginal, pictorial,
video, virtual reality, or in vivo representations of feared
stimuli for a sufficient duration that anxiety is experienced
and withstood and the patient thereby develops a new,
inhibitory memory that opposes subsequent fear re-
sponses [7, 62, 101, 102]. Exposure is especially effective
when fearful symptoms are associated with specific stimuli
as in the case of PTSD [103], social anxiety disorder
[104], obsessive-compulsive disorder [105], and specific
phobia [106]. It is especially important to promote the
generalization of extinction memories acquired during
exposure sessions to prevent the return of fear outside
of the safe, therapeutic context [3, 62, 64, 107–110].
An important distinction made during exposure therapy
is between within-session learning by which extinction/
habituation is initially acquired and between-session ex-
tinction/habituation, or the persistence of such learning
across time from one exposure session to another [62].
(The combined term “extinction/habituation”is used
because habituation is difficult to differentiate from ex-
tinction in clinical practice [111].) Note, however, that
typically in exposure therapy, within-session extinction/
habituation is continued following each session in the
form of exposure homework (e.g., [103, 112]); therefore,
the encoding and consolidation of extinction/habituation
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 4 of 19
is, in reality, an iterative process. Between-session extinc-
tion/habituation corresponds to memory for what was
learned within session and thus requires consolidation to
persist over time. In the case of between-session extinc-
tion, this involves consolidation of an associative memory
(e.g., of the CS-no US contingency) and, in the case of
between-session habituation, the consolidation is of neural
changes corresponding to a non-associative learning
process [8]. Current animal research suggests that within-
session and between-session extinction are dissociable
processes [113], and studies of exposure therapy also show
that the degree of within-session extinction does not
predict the extent of the between-session extinction
that, cumulatively, leads to clinical improvement [62].
Consequently, much research has gone into ways to
strengthen this new learning via the timing, spacing,
and gradation of intensity of exposures, manipulations
of aspects of the environments or stimuli in which it is
carried out, pharmacological interventions to potentiate
the encoding and consolidation of inhibitory memory,
and prevention of spontaneous recovery, renewal, or
reinstatement of fear responses [62–64, 101, 114]. Sleep
strategically timed so as to promote consolidation of
extinction memory constitutes a potential new technique
directed toward this same goal [3, 115]. Memory consolida-
tion processes also provide opportunity for extinction/
habituation to generalize, and sleep appears to augment
this process as well [3, 107]. Specific clinical implications re-
garding the use of sleep as a means to enhance extinction/
habituation are discussed in the “Sleep and exposure
therapy”section below.
Brain bases of deficient extinction in PTSD
PTSD patients show structural abnormalities in limbic
regions associated with extinction recall including the
perigenual anterior cingulate, amygdala, and hippocampus
[6, 116, 117]. These are accompanied by greater functional
activation of the fear expression network (amygdala
and dACC) and lesser activation of the extinction net-
work (hippocampus and vmPFC) during de novo fear-
conditioning and extinction experiments [59, 60, 118–120].
Compared with trauma-exposed controls, those with
PTSD show greater amygdala activation during extinction
learning, and, during extinction recall, lesser activation
of the vmPFC and hippocampus but greater activation
of the dACC [88]. Therefore, in PTSD, there is both hy-
peractivation of the fear expression and hypoactivation of
the extinction memory networks [59, 60]. However, not all
neuroimaging studies show functional differences between
PTSD and trauma-exposed controls in all of these loci or
at the same anatomic coordinates within them. While
a complete review of this diverse literature is beyond
the scope of this article, excellent reviews can be found
in [116, 119–126].
Importantly, the midline limbic and paralimbic areas
that selectively activate during REM sleep (Fig. 1) encom-
pass these same networks that show structural and func-
tional abnormalities in PTSD. For example, this “anterior
paralimbic REM sleep activation area”[79] includes the
amygdala, and regions of anterior cingulate and insular
cortex [127–129] that are linked to a putative fear expres-
sion network [61]. Similarly, this region includes the
ventromedial prefrontal and hippocampal areas [127–129]
linked to a putative extinction memory network [61]. As
noted, these fear-related structures are hyperactive and
extinction-related areas hypoactive in PTSD [88, 130].
Sleep and the anxiety-related disorders
These common mechanisms in etiology, perpetuation,
and treatment suggest that factors that strengthen or
weaken extinction, such as good and poor sleep, respect-
ively, may apply similarly across anxiety, traumatic stress,
and obsessive-compulsive disorders. Sleep disruption is a
DSM-5 [1] diagnostic criterion for generalized anxiety dis-
order and PTSD, is common in panic disorder [131, 132],
and appears, more subtly, in obsessive-compulsive dis-
order [133]. Because both sleep and extinction appear to
be degraded in PTSD, their interaction represents one
putative mechanism contributing to the development
and persistence of PTSD symptoms. And because treat-
ment of PTSD with exposure-based therapies relies
upon formation and strengthening of extinction memory,
the memory-enhancing function of healthy sleep may
play a role in recovery and disturbed sleep in treatment
resistance.
Sleep disruption in PTSD
Degradation of subjective and/or objective sleep quality is
commonly reported in studies of individuals with PTSD
[13, 16, 31, 134–136]. Sleep disruption and repetitive
nightmares meet DSM-5 PTSD criteria for “alterations in
arousal and reactivity”and “intrusion symptoms,”respect-
ively [1]. For example, in a self-report study, the severity
of PTSD symptoms predicted sleep problems to a much
greater degree than age, gender, psychiatric comorbidity,
type of trauma, or chronicity of PTSD [137]. Persistent
trauma-related nightmares of a replicative nature are a
near-universal symptom of PTSD [29, 138].
For objective sleep measures, a recent meta-analysis
[134] found that, among the highly variable alterations of
sleep in PTSD compared to control groups, increased
stage 1 NREM sleep, decreased slow wave sleep (SWS)
(see also [139]), and increased average number of rapid
eye movements per minute in REM sleep (REM sleep
density) were the most consistent abnormalities across
studies. Additional abnormalities expressed by subgroups
of PTSD patients included shorter total sleep time (TST),
increased sleep onset latency, reduced stage 2 NREM
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 5 of 19
sleep, and increased REM sleep as percent of TST
[134, 140]. Polysomnographic studies have also shown
that EEG spectral power at delta frequencies is signifi-
cantly decreased in PTSD patients [139, 141, 142].
These abnormalities are consistent with an underlying
hyperarousal in PTSD that lightens sleep, prevents
deeper, more restorative sleep stages, and alters the
distinct physiology of REM sleep [20, 29, 36, 134, 143].
Evidence that PTSD may influence the quality versus
absolute quantity of REM includes not only greater
REM density [134], but the fact that some studies have
shown greater percent REM in PTSD [140, 139].
Therefore, both objective and subjective sleep distur-
bances represent core features of PTSD [36, 134, 136].
As noted, however, specific polysomnographic sleep
abnormalities reported in different studies of PTSD are
highly variable in type and severity [134] and can vary
with age, sex, comorbidities, and other factors (for reviews,
see [13, 134, 139, 144, 145]).
Sleep abnormalities predict PTSD
Objective and subjective sleep abnormalities, including
insomnia complaints, that either precede or follow trau-
matic experiences, predict later development of PTSD
(reviewed in [16, 33]). For example, motor vehicle accident
survivors who later developed PTSD, unlike survivors who
did not, had more severe immediately post-trauma sleep
disturbances that failed to normalize over time [146].
Similarly, Mellman and colleagues showed that subjective
insomnia, nightmare severity, and abnormalities of REM
sleep, especially its fragmentation in the early aftermath of
a traumatic injury, predicted later development of PTSD
[20, 147–149]. In addition, higher sympathetic drive dur-
ing REM sleep within 1 month of trauma was associated
with development of PTSD symptoms at 2 months post-
trauma [149]. Such sleep disruption might impede normal
processing of emotional memories following trauma [20]
including the ability to consolidate memory for the extinc-
tion of fear associated with traumatic memories (Fig. 2).
It is noteworthy that only a minority of individuals
who have experienced a traumatic event develop PTSD.
For example, among 99 studies on diverse disasters, the
prevalence of PTSD at first assessment averaged 27 %
[150]. Similarly, prevalence of PTSD in combat-exposed
infantry is only around 20 % [151]. And, as noted above,
only around 30 % of individuals with ASD go on to de-
velop PTSD [46]. Therefore, factors other than trauma
exposure alone or the acute reaction to trauma must
contribute to the development of PTSD. In light of the
preceding findings, we suggest that alterations in the
emotion regulatory functions of sleep might be one such
factor.
Extinction and sleep in PTSD
Because sleep deprivation reduces amygdala-vmPFC
functional connectivity [152] as well as task-related acti-
vation of the ventral anterior cingulate cortex (part of
the vmPFC) in a positron emission tomography (PET)
Fig. 2 Possible pathway whereby sleep disruption accompanying acute response to trauma can lead to PTSD. In vulnerable individuals, acute
post-traumatic insomnia can become chronic and disrupt processes of sleep-dependent emotional memory consolidation, thereby contributing
to the etiology of PTSD. Chronic sleep disruption can subsequently perpetuate PTSD symptoms by continued interference with normal processing
of emotional memories as well as impaired consolidation of therapeutic extinction memories if exposure therapy has been initiated. Stars indicate
possible strategic points for sleep interventions to prevent PTSD onset or enhance exposure-based treatment
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 6 of 19
study [153], trauma-induced sleep loss might specifically
impair consolidation of extinction memory via interfer-
ence with vmPFC-amygdala circuitry. A finding that lon-
ger sleep on the night preceding functional magnetic
resonance imaging (fMRI) scans was positively associ-
ated with both resting-state amygdala-vmPFC functional
connectivity and higher self-report indices of mental
health indicates that even mild restriction of sleep can
diminish vmPFC-amygdala connectivity [154]. Animal
studies show that stress-associated cues continue to
interfere with REM sleep long after the original stressful
experience [155–157], raising the possibility that REM
sleep alterations in humans may play a role in both the
acquisition and perpetuation of PTSD (Fig. 2). Although,
there are not yet published studies on both sleep and ex-
tinction in PTSD patients, circuits involved in fear and
extinction learning and memory are implicated in sleep-
related symptoms of PTSD such as nightmares [138].
For example, in combat-exposed veterans with versus
without PTSD, REM sleep is characterized by increased
metabolic activity in the amygdala and anterior para-
limbic regions, and reduced metabolism in hippocampal
regions [158]. It is important to note that, in addition to
effects of sleep on amygdala-vmPFC connectivity, trauma
itself may affect such circuits, as is suggested by reports of
structural abnormalities in these areas in PTSD [116, 120].
Sleep-related neuroendocrine abnormalities in
PTSD—relationship to emotional memory consolidation?
By what mechanisms might both sleep and extinction
memory become progressively degraded following trau-
matic stress? One possibility is that physiological stress
responses produce sleep disruption that, via positive
feedback, perpetuates these stress responses. In the rat,
following experimental stress induction paradigms, sleep
shows a number of compelling parallels to changes in
human sleep following traumatic stress and in PTSD.
For example, in the rat, fear conditioning and other
forms of inescapable stress lead to disruption of sleep
and fragmentation of REM sleep, conditioned reminders
produce similar sleep-disruptive effects for several weeks
post conditioning, and extinction training reverses these
sleep effects (reviewed in ref. [157]). Such sleep distur-
bances in the rat have been linked with the actions of
central stress systems including the sympathetic re-
sponse, the hypothalamic-pituitary-adrenal (HPA) axis,
and the central extra-hypothalamic stress system (reviewed
in refs. [155, 157]). Within and between these stress sys-
tems, there are positive feedback mechanisms whereby
neuroendocrine responses lead to elevated arousal and
sleep disturbance that can, in turn, further activate stress
responses. Abnormal activation of these stress systems has
also been reported in PTSD, and these systems may inter-
act following traumatic stress in a manner analogous to
findings in animal models of stress. As depicted in Fig. 3,
following a traumatic stressor, such interactions may
disrupt sleep as well as sleep-mediated processing of
extinction memory producing an escalating abnormality
potentially leading to PTSD. The following section first
describes neuroendocrine abnormalities in these three
stress systems reported in PTSD. We then examine their
potential impact on fear and extinction memory and inter-
actions with sleep.
Noradrenergic abnormalities [“Sympathetic activation (NE)”]
PTSD is associated with elevated levels of central [159,
160] and urinary [161] norepinephrine, including mea-
surements taken during sleep [161]. Normal NREM
sleep is associated with a marked decrease in sympa-
thetic and increase in parasympathetic drive [162–164].
Central secretion of norepinephrine (NE), the catechol-
amine responsible for the acute sympathetic stress re-
sponse, acts to oppose REM sleep [165], and NE normally
declines with sleep onset and deepening NREM sleep to
reach its nadir in REM sleep [165]. Because nocturnal se-
cretion of NE may remain relatively elevated in PTSD
[159–161], this may be one factor serving to fragment
REM sleep [29]. The success of the alpha-adrenergic an-
tagonist prazosin in treating PTSD nightmares is strong
evidence of NE involvement in the pathophysiology of this
disorder [166, 167].
HPA-axis abnormalities [“HPA axis (cortisol)”]
Persons with PTSD frequently show abnormalities of the
HPA axis [168]. The initiating factor of the HPA response
is corticotropin-releasing factor (CRF), a polypeptide
neurohormone whose secretion by the paraventricular
nucleus (PVN) of the hypothalamus triggers release of
adrenocorticotropic hormone (ACTH) from the anterior
pituitary leading to the secretion of adrenal glucocorti-
coids [169]. Paradoxically, although CRF is elevated in
the cerebrospinal fluid (CSF) of patients with PTSD
[170–172], abnormally low baseline levels of plasma
cortisol are typically observed in this disorder [173],
possibly due to downregulation of pituitary CRF receptors
resulting from elevated CRF [174, 175].
Central actions of CRF [“Central stress response (CRF)”]
Although CRF triggers release of cortisol via ACTH and
PTSD may be characterized by low peripheral (plasma)
levels of cortisol, variations in levels of central CRF and
plasma cortisol are dissociable. This is illustrated, for ex-
ample, by their circadian rhythms [164]. CRF sampled
hourly in the cerebrospinal fluid of healthy volunteers
showed an evening acrophase and morning nadir
[176]—directly opposite to the pattern of plasma cortisol
[177]. In addition to its effect on the HPA axis, CRF
from the PVN as well as from the central nucleus of the
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 7 of 19
amygdala (CeA) is a key neuromodulator activating the
central extrahypothalamic stress system via CRF1 recep-
tors in the CeA, basolateral nucleus of the amygdala
(BLA), bed nucleus of the stria terminalis (BNST), and
locus coerulus (LC) [178, 179]. Activation of CRF recep-
tors in the BNST is associated with persistent (versus
acute) threat responses in the rat [180, 181]. BNST acti-
vation also tracks sustained anxiety in humans [182],
and sustained anxiety may better predict symptoms of
PTSD than acute fear responses [183].
Positive feedback between central stress systems, disrupted
sleep and REM sleep, and impaired extinction memory as a
putative pathway for the escalation of post-traumatic
psychopathology
Figure 3 suggests that activation of central stress systems
not only mutually elevates activity among these systems
themselves but also produces sleep disruption—itself a
stressor that can further activate stress systems. Here,
we present evidence for mutual activation between stress
systems, followed by evidence for their reciprocal rela-
tionship with disrupted sleep and, finally, by suggestion
of how impairment of extinction by poor sleep can fur-
ther exacerbate stress responses.
CRF-ergic activation promotes secretion of NE by the
LC [184, 185]. In turn, increased NE can stimulate the
PVN resulting in further CRF release and activation of
the HPA and central stress responses [184, 186].
Therefore, NE and CRF can reciprocally stimulate re-
lease of the other to escalate central stress responses
[178] (Fig. 3).
Exogenous CRF disrupts sleep [187], endogenous CRF
promotes waking [188], and sleep deprivation elevates
endogenous CRF [189]. Recent studies in rodents sug-
gest that the stress-induced reduction in REM sleep is
attributable to the actions of CRF [190–192] as is the
more general post-stress sleep fragmentation [193].
Chronically disturbed sleep can produce a persistent ele-
vation of sympathetic activity and central NE [164, 194,
195]. Increased NE, in turn, activates other stress sys-
tems via its action on subcortical limbic structures such
as the amygdala [178]. For example, based upon studies
using a single-prolonged stress model of PTSD in the rat
[196], a specific noradrenergic mechanism during sleep
has been recently proposed to act on hippocampal-
prefrontal systems and impair processing of traumatic
memories in PTSD [197]. Therefore, sleep deprivation
or restriction can generate a positive feedback cascade
whereby central stress responses and sleep disruption
mutually reinforce one another (Fig. 3). Thus, trauma
exposure may precipitate a failure of sleep-dependent
neuroendocrine processes that normally promote return
Fig. 3 Hypothetical interactions among activated stress systems and disrupted sleep in PTSD. Note that multiple positive feedback loops result in
depicted effects at any one node further driving effects at other nodes. Experimental evidence for many specific interactions depicted is provided
in text. For clarity, the following mechanisms mentioned in the text are not depicted: 1) interaction between sympathetic activation and the HPA
axis, 2) possible negative feedback mechanisms involving hypothalamic corticotropin releasing factor (CRF) that may explain hypocortisolemia in
PTSD, and 3) direct effects of stress systems on extinction memory and habituation. The dashed line depicts an additional positive feedback mechanism
whereby poor extinction memory promotes continued activation of neuroendocrine stress systems by failing to inhibit expression of conditioned fears.
HPA hypothalamic-pituitary-adrenal, CRF corticotropin releasing factor, NE norepinephrine
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 8 of 19
to emotional homeostasis via nocturnal reductions in
catecholamine levels, sympathetic drive, as well as HPA
axis, and central CRF-ergic activity. Such changes may
contribute to the development of PTSD in vulnerable
individuals.
However, in addition to interactions taking place en-
tirely within the interacting physiology of stress and
sleep, failure to extinguish fear may also exacerbate
stress and further drive the potentially pathogenic
physiological interactions described above. Deprivation,
curtailment, and fragmentation of sleep, and specifically
REM sleep, can affect the processing of emotional mem-
ory including the consolidation and generalization of ex-
tinction (reviewed in [8]). Moreover, the direct effects of
stress and stress hormones on memory are multifold
(reviewed in [198]), and memory for extinction of fear
conditioning may be especially susceptible to stress ef-
fects [199]. Therefore, the persistence of conditioned
fear, in the face of its failed extinction (dashed line in
Fig. 3), may continue to activate stress systems and
further exacerbate positive feedback mechanisms that
lead to further impairment of extinction and the per-
sistence of pathological fear.
The exact ways in which REM sleep is altered in the
period following a traumatic event, as well as after PTSD
symptoms have developed, are not yet fully understood,
and as noted above, a simple consistent quantitative
change is not observed. Nonetheless, there is suggestive
evidence in the fragmentation of REM following trauma
[147, 148] or following inescapable stress in the rat [157]
as well as in the increased REM density once PTSD has
developed [134] that hyperarousal of limbic structures
during REM may be one characteristic abnormality. The
neurochemical changes in arousal systems observed in
PTSD detailed above may underlie or contribute to such
limbic hyperarousal during REM sleep, and recurrent
REM sleep nightmares may be a subjective manifest-
ation. The effects of limbic hyperarousal in REM sleep
on consolidation of conditioned fear and its extinction
may be to bias consolidation processes taking place via
neuronal replay and other mechanisms during sleep
(reviewed in reference [8]) toward the fear expression
and away from the fear extinction networks described
above. The underlying changes in REM sleep in PTSD
thus remain areas in need of additional study.
Insomnia, emotional dysregulation, and PTSD
The preceding discussion reviewed evidence that sleep
disturbance is a cardinal symptom of PTSD that can
appear prior to and predict PTSD symptoms. We
reviewed evidence that stress responses and sleep disturb-
ance can mutually exacerbate each other via neuroendo-
crine systems that also show abnormalities in PTSD, and
that such abnormalities could potentially interfere with
extinction learning and memory. Evidence that experi-
mental sleep manipulations can influence fear condition-
ing and extinction is reviewed separately in [8]. However,
to what extent can sleep disturbance predating or acutely
following trauma itself initiate these pathogenic events?
Examining psychopathological correlates and conse-
quences of insomnia may begin to address this question.
The ubiquity of chronic insomnia both as a primary
disorder and comorbid with psychiatric [200, 201] and
non-psychiatric[202]conditionssuggeststhatitre-
flects a trait vulnerability that can be triggered by a var-
iety of stressors. Stressful events are a significant
predictor of insomnia with odds of incident insomnia
increasing in a dose-response manner for each such
event [203]. The following section considers insomnia
as a potential contributor to PTSD.
Emotional dysregulation and hyperarousal in insomnia
Insomnia is associated with dysregulation of emotions
pertaining to sleep itself [204, 205]. However, a more
general emotional dysregulation is a characteristic of
many individuals with insomnia [206] that can be
reflected in personality variables [207] such as a ten-
dency to internalize conflict [208] as well as by the
high comorbidity of insomnia with mood and anxiety
disorders [22, 32, 200, 209]. Such findings have led to
the suggestion that emotional reactivity is both a risk
and perpetuating factor for the development of chronic
insomnia [206, 210].
Contributing to this emotional dysregulation is the
now well-replicated evidence for chronic hyperarousal in
insomnia [37–39]. Such hyperarousal is manifested in
both peripheral [37] and central [38] physiology as well
as in pre- and post-morbid cognitive style [40, 41] and
sensitivity of sleep quality to acute stress [42]. Acute in-
somnia is ubiquitous following a wide variety of stressors
[211], and insomnia following traumatic events [146] in-
cluding combat [33] is predictive of later development of
PTSD [16].
REM sleep disruption in insomnia
As noted above, there is strong evidence that REM
sleep is important in the emotion-regulatory function
of sleep. For example, REM sleep fragmentation follow-
ing a traumatic event is predictive of later development
of PTSD [147, 148].
Although early polysomnographic studies of insomnia
reported little change or small reductions in REM sleep
compared to good sleepers [212], there is now increasing
evidence for both percentage reductions [204] and frag-
mentation [213–215] of REM sleep in insomnia. Being
the stage of sleep with the highest level of forebrain
arousal [38], REM sleep may also be the most vulnerable
stage to disruption by awakenings due to chronic
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 9 of 19
physiological and cognitive arousal. This is because, in
this activated behavioral state, the brain is closer to its
threshold for awakening [213, 214].
Neuroimaging studies of Insomnia
Evidence is accumulating that functional abnormalities
in emotional regulatory networks that overlap with the
fear expression and fear extinction networks also occur
in insomnia. Patients with insomnia showed higher
levels of arousal (greater glucose metabolism) during
NREM sleep compared with good sleepers, and object-
ive and subjective increases in sleep disruption were
positively associated with metabolic activity in the an-
terior cingulate cortex [38, 216]. Poor quality of sleep
may negatively impact the ability of the vmPFC to con-
solidate and later express extinction memory. During
resting-state fMRI, functional connectivity between the
amygdala and other brain areas was reduced in persons
with insomnia compared with healthy controls [217].
Specifically, amygdala connectivity with the insula, striatum,
and thalamus was reduced, again suggesting dysfunction in
emotion regulatory circuits.
Our studies suggest that insomnia patients show hy-
peractivation of the dACC and hypoactivation of the
vmPFC during REM sleep. Using
18
FDG-PET, insom-
nia patients showed a greater increase in cerebral glu-
cose metabolism from wakefulness to REM sleep
compared to good sleepers in an anterior midline re-
gion (Fig. 4a) in close proximity to the region of the dACC
that has been associated with fear expression (Fig. 1).
In addition, insomnia patients showed a smaller in-
crease in cerebral glucose metabolism in the vmPFC
from wakefulness to REM sleep (Fig. 4b). As noted, this
latter area is associated with the memory and expression
of fear extinction (Fig. 1). Thus, a closer investigation
of the effects of chronic insomnia on fear learning and
memory may provide novel insights into psychophysio-
logical and neural mechanisms underlying anxiety and
mood disorders.
Insomnia and PTSD
The normal, sleep-disrupting after-effects of a traumatic
experience may develop into diagnosed chronic insom-
nia disorder¹ or may be expressed as a more short-term,
reactive sleep disturbance that does not meet the dur-
ation criteria of a chronic disorder.² In either case, the
likelihood that PTSD will later develop may increase due
to the neurohormonal and mnemonic processes detailed
above. Similarly, if an individual has poor sleep quality
due to a pre-existing sleep disorder (such as obstructive
sleep apnea) or is experiencing poor sleep due to limited
sleep opportunity or sleep during an unfavorable circa-
dian phase (as is common in the military), these same
factors may increase vulnerability to PTSD irrespective
of formal insomnia diagnoses. Indeed, among military
service members, pre-deployment symptoms of insom-
nia have been shown to confer increased risk of post-
deployment PTSD symptoms [17] and individuals with
self-reported, pre-existing sleep problems had increased
likelihood of developing PTSD following Hurricane
Andrew [218]. Poor extinction memory may impair the
ability to modulate arousal that results from stressors and
thus could synergize with the physiological and cognitive
hyperarousal of insomnia [37–40] to further elevate the
risk of developing PTSD. Further evidence that insomnia
can be primary is the fact that, whereas insomnia comorbid
with anxiety disorders responds well to cognitive behav-
ioral therapies developed for primary insomnia [209, 219],
sleep disturbance often persists following successful treat-
ment of PTSD [31]. Moreover, sleep-focused treatments
can significantly improve both sleep and daytime symp-
toms of PTSD [220–222]. Therefore, insomnia may repre-
sent an emotionally dysregulated state that can contribute
to the development of PTSD as well as exacerbate its
symptoms and impede its treatment.
Sex differences in extinction memory, insomnia and PTSD
Prevalence is greater in females than in males for both in-
somnia [223] and PTSD [224]. Translational studies with
Fig. 4 Comparison of REM activations in individuals with insomnia versus without insomnia. When comparing REM to wake, there is a greater
increase in regional cerebral glucose metabolism (
18
fluoro-deoxyglucose PET) in an anterior midline region in close proximity to the region of the
dACC that has been associated with fear expression (a). However, in a comparison of two different groups, the insomnia group showed lesser
increase in the vmPFC, an area associated with the memory and expression of fear extinction (b)
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 10 of 19
both humans [225–229] and rodents [230, 227, 228]
have shown that extinction memory is sexually dimorphic
(better in males) and that it varies across the menstrual
cycle in females [225, 226]. Gender differences in the
relationship between PTSD and sleep are also now being
reported [144, 231]. For example, following a traumatic
event, females who progressed to PTSD showed greater
wake time after sleep onset than males who similarly
developed PTSD [231]. Sex differences in the sleep
symptoms of existing PTSD are also noted. For ex-
ample, a study comparing sleep in PTSD and healthy
controls in both sexes reported a gender × diagnosis
interaction whereby, among females, those with PTSD
showed greater REM duration and percent than controls
whereas, among males, this difference appeared (non-
significantly) in the opposite direction [139]. Additionally,
as in the case of extinction memory in the experimental
setting [232], it has been suggested that sleep symptoms in
women may vary with hormonal levels and phase of the
menstrual cycle [144].
Sleep and exposure therapy
The ability to remember fear extinction is a key element
of both normal recovery from trauma [118] and of psy-
chotherapeutic treatment of PTSD using exposure therapy
[7, 62, 101]. One mechanism by which sleep disturbance
might precipitate or perpetuate PTSD is by preventing
the consolidation and generalization of naturally occur-
ring or therapeutically induced extinction memories
during sleep [29]. The degree to which extinction learning
can generalize from the specific stimuli extinguished in
therapy to similar stimuli encountered outside the
treatment setting will strongly impact the efficacy of
such therapy [3, 62, 64, 108–110]. For example, fearful
responding may re-emerge when the patient encounters
an exemplar of a feared category of objects (e.g., spiders)
that differs from the specific exemplar (e.g., species of
spider) for which fear was extinguished in therapy
[110, 233]. Similarly, gains achieved in exposure therapy
may be compromised by fear renewal when the patient
encounters a feared stimulus (e.g., a trauma reminder)
outside of the therapeutic context in which it was extin-
guished [101, 108]. Such “return of fear”phenomena [234]
may be conceptualized as re-emergence of conditioned
fear due to failure of extinction memory to generalize
from the treatment setting to diverse stimuli and settings
that evoke such fears in the real world [63].
Extinction generalization may be particularly relevant
to the treatment of PTSD, a disorder in which the op-
posing effect, generalization of fear responses, is ubiqui-
tous [235]. Moreover, in PTSD, the same traumatic
event can produce conditioned fear to multiple stimuli
in multiple perceptual modalities each of which then be-
comes a warning signal of impending danger [236].
Generalization and multiplication of fear responses in
PTSD may occur via processes such as second-order fear
conditioning to primary trauma reminder cues [237].
Improved therapeutic extinction generalization thus
might mitigate mechanisms by which fear generalization
exacerbates the number and fear relevance of trauma
reminders.
Clinical strategies to maximize extinction generalization
include exposing patients to a variety of exemplars in a
class of feared objects [101, 110], exposure of patients to
feared stimuli in a variety of different contexts [101, 109]
and in vivo exposure sessions [103]. A promising pharma-
cological approach for enhancing exposure therapy involves
using D-cycloserine, an NMDA receptor partial agonist,
that promotes NMDA-dependent memory consolidation of
therapeutic extinction memory [238–240]. Some studies
have suggested that outcomes from exposure therapy for
PTSD can benefit from administration of D-cycloserine in
temporal proximity to exposure sessions [241, 242]. Since,
sleep [83] and, specifically, REM sleep [84] have also been
shown to be important for NMDA-dependent long-term
potentiation, sleep itself might be employed to help
strengthen and generalize extinction [107].
In a preliminary application of this hypothesis to anx-
iety disorders [3], highly spider-fearful, young adult
women were repeatedly exposed to a spider video after
which half, who were exposed in the evening, had a nor-
mal night’s sleep and other half, exposed in the morning,
had an equal (12-h) duration of continuous wakefulness.
Following the delay, all groups viewed the same video
and then videos of a new spider. Only in the wake group
was there loss of psychophysiological and self-reported
extinction and evidence of sensitization between ses-
sions. Only the sleep group was there psychophysio-
logical evidence of enhanced extinction retention and
generalization between sessions. Because these effects
did not differentiate control groups exposed and tested
entirely in the morning or evening, a time-of-day ex-
planation was ruled out. Thus, following exposure ther-
apy, sleep may promote retention and generalization of
extinction and prevent sensitization. These findings have
been replicated in a recent study that used virtual-reality
exposure therapy for DSM-IV diagnosed spider phobia
[115]. Yet more recently, a large study of cognitive be-
havioral therapy in social anxiety disorder has shown
that better self-reported baseline sleep was associated
with better post-exposure treatment outcome on mea-
sures of anxiety [243].
Important caveats
Impaired consolidation of extinction is unlikely to be the
only sleep-related factor contributing to PTSD. Sleep dis-
ruption may lead to fatigue [244, 245], executive deficits
[246, 247], mood dysregulation [10], and psychosocial
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 11 of 19
impairments [248], all of which may degrade psychological
resilience and exacerbate symptoms. Moreover, post-
trauma disturbed sleep is unlikely, by itself, sufficient to
produce PTSD—a disorder that also shows the above neu-
roendocrine abnormalities [161, 172, 173] as well as neu-
rocognitive changes [249, 250], emergent psychosocial
stressors [251], and genetic predispositions [252].
Caveats to animal models of physiological sleep dis-
turbance and PTSD need also be emphasized. First, the
sleep- and REM sleep-disruptive effects of experimental
stressors appear with inescapable forms of stress, of
which Pavlovian cued and contextual fear conditioning
are canonical examples [157, 253] as, of course, are most
traumatic events that precipitate PTSD in the human. In
contrast, escapable shock, such as occurs in active avoid-
ance learning paradigms, can instead lead to enhanced
total and REM sleep with robust rebound of any loss
resulting from the stress manipulation [156, 157, 253].
Therefore, aspects of the stressor such as controllability,
predictability, and even the specific form of stress (e.g.,
restraint versus footshock) may produce different and
even opposing effects on sleep and sleep-dependent
mnemonic processes [156, 157]
Therefore, although putative pathways from traumatic
stress to sleep disturbance and thence to poor extinction
memory are compelling, the current state of knowledge
cannot attribute development of PTSD solely or in part
to disturbed sleep-dependent extinction, nor, indeed,
to disturbed sleep alone. Nonetheless, among sleep-
mediated sources of waking symptoms in PTSD, impaired
consolidation and/or generalization of extinction memory
during sleep remains a hypothetical mechanism highly
suited to future investigation.
Essential directions for future research
Despite the growing number of studies investigating
sleep in PTSD, sleep and extinction memory, as well as
extinction memory in PTSD and in anxiety disorders,
there have been, to date, no studies specifically address-
ing sleep and extinction memory in patients with PTSD.
Such studies, therefore, will be essential to test whether
sleep-mediated effects on extinction memory seen in
healthy subjects are altered in PTSD. Similarly, the interac-
tions of extinction learning and memory with time-of-day
[254] as well as sleep quality and chronotype [255, 256]
described in healthy subjects (reviewed in ref. [8]) should
also be examined in PTSD. Especially informative would
be prospective longitudinal studies initiated following
a traumatic event to monitor sleep physiology, circadian
patterns of sleep-waking, HPA-axis function, mood, and
nightmare frequency/content in order to examine potential
linkages between these measures and emergent symptom-
atology in those individuals who progress to PTSD com-
pared to those who prove resilient.
There have been some early attempts to examine sleep
augmentation of pharmacological interventions that may
be used to enhance exposure therapy. For example, in
healthy volunteers following conditioning and extinction
learning, valproic acid, a histone deacetylase inhibitor,
enhanced delayed resistance to reinstatement following
sleep but D-cycloserine enhanced such resistance follow-
ing an awake delay [257]. Therefore, combining pharma-
cotherapy with strategically timed post-exposure sleep
may further enhance exposure therapy [258].
Finally, future studies might also examine the effects of
sleep on the newly described phenomenon of fear erasure
using reconsolidation blockade following retrieval of trau-
matic memory [2, 57, 259–261]. Given findings that bidi-
rectional plasticity, that includes depotentiation as well as
long-term potentiation (LTP), may require REM sleep
[197], it is possible that sleep following such reactivation
would allow depotentiation to better compete with recon-
solidation processes that require LTP. As in the pursuit of
enhanced extinction, a sleep component might be added
to pharmacological interventions designed to impede
reconsolidation of aversive memory such as blockade of
noradrenergic transmission [262, 263].
Conclusions
Sleep, acting as a modulator of physiological stress and
emotional memory, is of crucial importance in maintain-
ing day-to-day emotional homeostasis and long-term
mental health. Sleep disturbance predating or acutely
resulting from a traumatic event, particularly if it de-
velops into chronic insomnia, may initiate positive feed-
back and allostatic mechanisms that impair emotional
regulation and promote the pathophysiology of PTSD.
The findings reviewed herein have compelling research
and clinical implications. First, the effects of sleep
deprivation and restriction on extinction learning and
recall as well as their neural bases in healthy individuals
(reviewed in ref. [8]) should be further investigated. Sec-
ond, the interaction of sleep deficit, extinction recall,
and clinical diagnosis will require studies in which ex-
tinction learning and recall are visualized in the brains
of PTSD patients with greater and lesser sleep disturb-
ance and these findings compared to trauma-exposed
controls as well as patients with non-PTSD-related in-
somnia. Importantly, however, clinical applications of ac-
cruing knowledge need not await definitive findings but
can be concurrently investigated to help address the ur-
gent need for innovation in treatments for PTSD. For
example, just as disrupted sleep may impair emotional
recovery during the critical period following traumatic
stress, healthy sleep may be protective at this same point
in time. As has often been suggested, proactive treat-
ment of any acute sleep disruption may be a crucial first
intervention in the prevention or early treatment of
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 12 of 19
PTSD symptoms [20, 29, 31, 36]. Although the evidence
here reviewed indicates the specific importance of REM
sleep, behavioral techniques to selectively enhance this
sleep stage (e.g., prior REM sleep deprivation) involve
further sleep disruption. Therefore, to preserve REM
sleep following a trauma, optimizing overall sleep quality
by treating comorbid insomnia or other sleep disorders
and improving sleep hygiene is important. Another consid-
eration that requires more research is whether REM-sleep
suppressive agents, such as many aminergic antidepres-
sants, should be avoided in the early aftermath of trauma.
There is also preliminary evidence that the alpha-1 adre-
noreceptor antagonist, prazosin, which is effective in reliev-
ing nightmares in PTSD, may also serve to normalize REM
sleep [264]. Additionally, evaluation of pre-existing sleep
disorders may serve as a screening criterion to identify
individuals entering high-stress professions such as the
military or first responders who are at greatest risk of de-
veloping PTSD [17, 265]. Lastly, the memory-enhancing
function of sleep might be exploited to strengthen thera-
peutic extinction learned in exposure-based therapy using
strategically timed sleep bouts [3, 115].
Endnotes
1
In various studies, diagnosed insomnia is typically
DSM-IV [266] Primary Insomnia, DSM-5 [44] Insomnia
Disorder, International Classification of Sleep Disorders
Second Edition (ICSD-2) [267] Psychophysiological
Insomnia, or ICSD-3 Chronic Insomnia Disorder [268]
all of which have similar criteria including difficulty initi-
ating or maintaining sleep, daytime fatigue, malaise or
dissatisfaction with sleep, duration of at least 3 months
(1 month in DSM-IV) and symptom occurrence on 3 or
more days per week. Insomnia is frequently comorbid
with mood or anxiety disorders in which case it is vari-
ously classified as Insomnia Due to Mental Disorder
(ICSD-2, ICSD-3) Insomnia Related to another Mental
Disorder (DSM-IV) or Insomnia Disorder with Non
Sleep-Disorder Mental Comorbidity (DSM-5).
2
When sleep disturbance does not meet the duration
criteria for the above definitions, it is variously classified
as Situational/acute Insomnia (DSM-5), Adjustment In-
somnia (ICSD-2), or Short-Term Insomnia Disorder
(ICSD-3).
Abbreviations
1: BLA: basolateral nuclei (amygdala); BNST: bed nucleus of the stria
terminalis; CeA: central nucleus (amygdala); CRF: corticotropin-releasing
factor; CS: conditioned stimulus; CSF: cerebrospinal fluid; dACC: dorsal
anterior cingulate cortex; DSM-5: Diagnostic and Statistical Manual of Mental
Disorders—5th ed.; EEG: electroencephalography; fMRI: functional magnetic
resonance imaging; HPA axis: hypothalamic-pituitary-adrenal axis; LC: locus
coeruleus; LTP: long-term potentiation; NE: norepinephrine; NMDA: N-methyl-
D-aspartate receptor; NREM: non-REM sleep; PSQI: Pittsburgh Sleep Quality
Index; PTSD: post-traumatic stress disorder; PVN: paraventricular nucleus
(hypothalamus); REM: rapid eye movement; TST: total sleep time;
US: unconditioned stimulus; vmPFC: ventromedial prefrontal cortex.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
EFP-S was the lead writer of this review. AG and MRM were involved in
critically revising the manuscript for important intellectual content. All
authors read and approved the final manuscript.
Authors’information
Edward F. Pace-Schott, Ph.D., is Assistant Professor of Psychiatry at
Massachusetts General Hospital and Harvard Medical School. Anne Germain,
Ph.D., is Associate Professor of Psychiatry and Psychology at the University of
Pittsburgh School of Medicine and is Director of the Veterans Sleep and PTSD
Research Program. Mohammed R. Milad, Ph.D., is Associate Professor of
Psychiatry at Massachusetts General Hospital and Harvard Medical School
and Director of the Massachusetts General Hospital Behavioral Neuroscience
Program.
Acknowledgements
The research was supported by MH101567, MH090357, USAMRAA
Log11293006, and MH097965. The authors would like to thank Marie-France
Marin, Ph.D., Lisa Maeng, Ph.D., and Kara Cover for helpful comments.
Author details
1
Department of Psychiatry, Harvard Medical School, Massachusetts General
Hospital—East, CNY 149 13th Street Room 2624, Charlestown, MA 02129,
USA.
2
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Received: 14 January 2015 Accepted: 12 May 2015
References
1. American_Psychiatric_Association. Diagnostic and statistical manual of
mental disorders (Fifth ed.). Arlington, VA: American Psychiatric
Publishing; 2013.
2. Schiller D, Delgado MR. Overlapping neural systems mediating extinction,
reversal and regulation of fear. Trends Cogn Sci. 2010;14(6):268–76.
3. Pace-Schott EF, Verga PW, Bennett TS, Spencer RM. Sleep promotes
consolidation and generalization of extinction learning in simulated
exposure therapy for spider fear. J Psychiatr Res. 2012;46:1036–44.
doi:10.1016/j.jpsychires.2012.04.015.
4. Spoormaker VI, Schroter MS, Andrade KC, Dresler M, Kiem SA, Goya-Maldonado
R, et al. Effects of rapid eye movement sleep deprivation on fear
extinction recall and prediction error signaling. Hum Brain Mapp.
2012;33(10):2362–76. doi:10.1002/hbm.21369.
5. Spoormaker VI, Sturm A, Andrade KC, Schroter MS, Goya-Maldonado R, et al.
The neural correlates and temporal sequence of the relationship between
shock exposure, disturbed sleep and impaired consolidation of fear extinction.
J Psychiatr Res. 2010;44:1121–8.
6. Milad MR, Rauch SL, Pitman RK, Quirk GJ. Fear extinction in rats:
implications for human brain imaging and anxiety disorders. Biol Psychol.
2006;73(1):61–71.
7. McNally RJ. Mechanisms of exposure therapy: how neuroscience can
improve psychological treatments for anxiety disorders. Clin Psychol Rev.
2007;27(6):750–9.
8. Pace-Schott EF, Germain A, Milad MR. Effects of sleep on memory for
conditioned fear and fear extinction. Psychol Bull. 2015;Apr 20. [Epub ahead
of print].
9. Deliens G, Gilson M, Peigneux P. Sleep and the processing of emotions.
Exp Brain Res. 2014;232(5):1403–14. doi:10.1007/s00221-014-3832-1.
10. Goldstein AN, Walker MP. The role of sleep in emotional brain function.
Annual Reviews of Clinical Psychology. 2014;10:679–708.
11. Kim EJ, Dimsdale JE. The effect of psychosocial stress on sleep: a review of
polysomnographic evidence. Behav Sleep Med. 2007;5(4):256–78.
12. Vandekerckhove M, Cluydts R. The emotional brain and sleep: an
intimate relationship. Sleep Med Rev. 2010;14(4):219–26.
doi:10.1016/j.smrv.2010.01.002.
13. Mellman TA. Sleep and anxiety disorders. Sleep Med Clinics. 2008;3:261–8.
14. Peterson MJ, Benca RM. Sleep in mood disorders. Psychiatr Clin North Am.
2006;29(4):1009–32. abstract ix.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 13 of 19
15. Lavie P. Sleep disturbances in the wake of traumatic events. N Engl J Med.
2001;345(25):1825–32. doi:10.1056/NEJMra012893.
16. Babson KA, Feldner MT. Temporal relations between sleep problems and
both traumatic event exposure and PTSD: a critical review of the empirical
literature. J Anxiety Disord. 2010;24(1):1–15. doi:10.1016/j.janxdis.2009.08.002.
17. Gehrman P, Seelig AD, Jacobson IG, Boyko EJ, Hooper TI, Gackstetter GD,
et al. Predeployment sleep duration and insomnia symptoms as risk factors
for new-onset mental health disorders following military deployment. Sleep.
2013;36(7):1009–18.
18. Bryant RA, Creamer M, O’Donnell M, Silove D, McFarlane AC. Sleep
disturbance immediately prior to trauma predicts subsequent psychiatric
disorder. Sleep. 2010;33(1):69–74.
19. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric
disorders: a longitudinal epidemiological study of young adults. Biol
Psychiatry. 1996;39(6):411–8.
20. Mellman TA, Hipolito MM. Sleep disturbances in the aftermath of trauma
and posttraumatic stress disorder. CNS Spectr. 2006;11(8):611–5.
21. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and
psychiatric disorders. An opportunity for prevention? JAMA.
1989;262(11):1479–84.
22. Baglioni C, Battagliese G, Feige B, Spiegelhalder K, Nissen C, Voderholzer U,
et al. Insomnia as a predictor of depression: a meta-analytic evaluation of
longitudinal epidemiological studies. J Affect Disord. 2011;135(1-3):10–9.
doi:10.1016/j.jad.2011.01.011.
23. Ford DE, Cooper-Patrick L. Sleep disturbances and mood disorders:
an epidemiologic perspective. Depress Anxiety. 2001;14(1):3–6.
24. Marcks BA, Weisberg RB, Edelen MO, Keller MB. The relationship
between sleep disturbance and thecourseofanxietydisorders
in primary care patients. Psychiatry Res. 2010;178(3):487–92.
doi:10.1016/j.psychres.2009.07.004.
25. Hasler BP, Germain A, Nofzinger EA, Kupfer DJ, Krafty RT, Rothenberger
SD, et al. Chronotype and diurnal patterns of positive affect and
affective neural circuitry in primary insomnia. J Sleep Res. 2012.
doi:10.1111/j.1365-2869.2012.01002.x.
26. Buysse DJ, Hall M, Begley A, Cherry CR, Houck PR, Land S, et al. Sleep and
treatment response in depression: new findings using power spectral
analysis. Psychiatry Res. 2001;103(1):51–67.
27. Buysse DJ, Tu XM, Cherry CR, Begley AE, Kowalski J, Kupfer DJ, et al.
Pretreatment REM sleep and subjective sleep quality distinguish depressed
psychotherapy remitters and nonremitters. Biol Psychiatry. 1999;45(2):205–13.
28. Harvey AG, Talbot LS, Gershon A. Sleep disturbance in bipolar disorder
across the lifespan. Clin Psychol Publication Division Clinical Psychol Am
Psychol Assoc. 2009;16(2):256–77. doi:10.1111/j.1468-2850.2009.01164.x.
29. Germain A, Buysse DJ, Nofzinger E. Sleep-specific mechanisms underlying
posttraumatic stress disorder: integrative review and neurobiological
hypotheses. Sleep Med Rev. 2008;12(3):185–95.
30. Mellman TA. Sleep and post-traumatic stress disorder: a roadmap for
clinicians and researchers. Sleep Med Rev. 2008;12(3):165–7.
31. Spoormaker VI, Montgomery P. Disturbed sleep in post-traumatic stress disorder:
secondary symptom or core feature? Sleep Med Rev. 2008;12(3):169–84.
32. Alvaro PK, Roberts RM, Harris JK. A systematic review assessing
bidirectionality between sleep disturbances, anxiety, and depression. Sleep.
2013;36(7):1059–68. doi:10.5665/sleep.2810.
33. Wright KM, Britt TW, Bliese PD, Adler AB, Picchioni D, Moore D. Insomnia as
predictor versus outcome of PTSD and depression among Iraq combat
veterans. J Clin Psychol. 2011;67(12):1240–58. doi:10.1002/jclp.20845.
34. Babson KA, Badour CL, Feldner MT, Bunaciu L. The relationship of sleep
quality and PTSD to anxious reactivity from idiographic traumatic
event script-driven imagery. J Trauma Stress. 2012;25(5):503–10.
doi:10.1002/jts.21739.
35. Babson KA, Blonigen DM, Boden MT, Drescher KD, Bonn-Miller MO. Sleep
quality among U.S. military veterans with PTSD: a factor analysis and
structural model of symptoms. J Trauma Stress. 2012;25(6):665–74.
doi:10.1002/jts.21757.
36. Germain A. Sleep disturbances as the hallmark of PTSD: where are we now?
Am J Psychiatry. 2013;170(4):372–82. doi:10.1176/appi.ajp.2012.12040432.
37. Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science.
Sleep Med Rev. 2010;14(1):9–15.
38. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ.
Functional neuroimaging evidence for hyperarousal in insomnia. Am J
Psychiatry. 2004;161(11):2126–8.
39. Riemann D, Spiegelhalder K, Feige B, Voderholzer U, Berger M, Perlis M,
et al. The hyperarousal model of insomnia: a review of the concept and its
evidence. Sleep Med Rev. 2010;14(1):19–31. doi:10.1016/j.smrv.2009.04.002.
40. Fernandez-Mendoza J, Vela-Bueno A, Vgontzas AN, Ramos-Platon MJ,
Olavarrieta-Bernardino S, Bixler EO, et al. Cognitive-emotional hyperarousal
as a premorbid characteristic of individuals vulnerable to insomnia. Psychosom
Med. 2010;72(4):397–403. doi:10.1097/PSY.0b013e3181d75319.
41. Harvey AG. A cognitive model of insomnia. Behav Res Ther. 2002;40(8):869–93.
42. Drake CL, Friedman NP, Wright Jr KP, Roth T. Sleep reactivity and
insomnia: genetic and environmental influences. Sleep. 2011;34(9):1179–88.
doi:10.5665/SLEEP.1234.
43. McEwen BS. Physiology and neurobiology of stress and adaptation:
central role of the brain. Physiol Rev. 2007;87(3):873–904. doi:10.1152/
physrev.00041.2006.
44. Harvey AG, Bryant RA. Acute stress disorder: a synthesis and critique.
Psychol Bull. 2002;128:886–902.
45. Bryant RA. Acute stress disorder as a predictor of posttraumatic stress
disorder: a systematic review. J Clin Psychiatry. 2011;72(2):233–9.
doi:10.4088/JCP.09r05072blu.
46. Bryant RA, Creamer M, O’Donnell M, Silove D, McFarlane AC. The capacity
of acute stress disorder to predict posttraumatic psychiatric disorders.
J Psychiatr Res. 2012;46(2):168–73. doi:10.1016/j.jpsychires.2011.10.007.
47. Milliken CS, Auchterlonie JL, Hoge CW. Longitudinal assessment of mental
health problems among active and reserve component soldiers returning
from the Iraq war. JAMA. 2007;298(18):2141–8. doi:10.1001/jama.298.18.2141.
48. Hoge CW, Auchterlonie JL, Milliken CS. Mental health problems, use of
mental health services, and attrition from military service after returning
from deployment to Iraq or Afghanistan. JAMA. 2006;295(9):1023–32.
doi:10.1001/jama.295.9.1023.
49. Andrews B, Brewin CR, Philpott R, Stewart L. Delayed-onset posttraumatic
stress disorder: a systematic review of the evidence. Am J Psychiatry.
2007;164(9):1319–26. doi:10.1176/appi.ajp.2007.06091491.
50. FikretogluD,LiuA.Prevalence,correlates, and clinical features of
delayed-onset posttraumatic stress disorder in a nationally representative
military sample. Soc Psychiatry Psychiatr Epidemiol. 2012;47(8):1359–66.
doi:10.1007/s00127-011-0444-y.
51. Myers KM, Davis M. Behavioral and neural analysis of extinction. Neuron.
2002;36(4):567–84.
52. Bouton ME, Westbrook RF, Corcoran KA, Maren S. Contextual and temporal
modulation of extinction: behavioral and biological mechanisms. Biol
Psychiatry. 2006;60(4):352–60.
53. Konorski J. Integrative activity of the brain. Chicago: University of Chicago
Press; 1967.
54. Pavlov I. Conditioned reflexes. London: Oxford University Press; 1927.
55. Ji J, Maren S. Hippocampal involvement in contextual modulation of fear
extinction. Hippocampus. 2007;17(9):749–58.
56. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval.
Neuropsychopharmacology. 2008;33(1):56–72.
57. Maren S. Seeking a spotless mind: extinction, deconsolidation, and
erasure of fear memory. Neuron. 2011;70(5):830–45. doi:10.1016/
j.neuron.2011.04.023.
58. Herry C, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Luthi A. Neuronal
circuits of fear extinction. Eur J Neurosci. 2010;31(4):599–612.
59. Milad MR, Quirk GJ. Fear extinction as a model for translational
neuroscience: ten years of progress. Annu Rev Psychol. 2012;63:129–51.
doi:10.1146/annurev.psych.121208.131631.
60. Graham BM, Milad MR. The study of fear extinction: implications for
anxiety disorders. Am J Psychiatry. 2011;168(12):1255–65. doi:10.1176/
appi.ajp.2011.11040557.
61. Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond
segregated cortico-striatal pathways. Trends Cogn Sci. 2012;16(1):43–51.
doi:10.1016/j.tics.2011.11.003.
62. Craske MG, Kircanski K, Zelikowsky M, Mystkowski J, Chowdhury N, Baker A.
Optimizing inhibitory learning during exposure therapy. Behav Res Ther.
2008;46(1):5–27.
63. Vervliet B, Baeyens F, Van den Bergh O, Hermans D. Extinction,
generalization, and return of fear: a critical review of renewal research in
humans. Biol Psychol. 2013;92(1):51–8. doi:10.1016/j.biopsycho.2012.01.006.
64. Vervliet B, Craske MG, Hermans D. Fear extinction and relapse: state of
the art. Annu Rev Clin Psychol. 2013;9:215–48. doi:10.1146/annurev-
clinpsy-050212-185542.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 14 of 19
65. Diekelmann S, Wilhelm I, Born J. The whats and whens of sleep-
dependent memory consolidation. Sleep Med Rev. 2009;13(5):309–21.
doi:10.1016/j.smrv.2008.08.002.
66. Diekelmann S, Born J. The memory function of sleep. Nature Rev.
2010;11(2):114–26.
67. Rasch B, Born J. About sleep’s role in memory. Physiol Rev. 2013;93(2):681–766.
doi:10.1152/physrev.00032.2012.
68. Stickgold R. Sleep-dependent memory consolidation. Nature.
2005;437(7063):1272–8.
69. Landmann N, Kuhn M, Piosczyk H, Feige B, Baglioni C, Spiegelhalder K, et al.
The reorganisation of memory during sleep. Sleep Med Rev. 2014.
doi:10.1016/j.smrv.2014.03.005.
70. Payne JD, Chambers AM, Kensinger EA. Sleep promotes lasting changes in
selective memory for emotional scenes. Front Integrative Neurosci.
2012;6:108. doi:10.3389/fnint.2012.00108.
71. Pace-Schott EF, Nave G, Morgan A, Spencer RM. Sleep-dependent modulation
of affectively guided decision-making. J Sleep Res. 2012;21(1):30–9.
doi:10.1111/j.1365-2869.2011.00921.x.
72. Stickgold R, Walker MP. Sleep-dependent memory triage: evolving
generalization through selective processing. Nat Neurosci. 2013;16(2):139–45.
doi:10.1038/nn.3303.
73. Ellenbogen JM, Hulbert JC, Stickgold R, Dinges DF, Thompson-Schill SL.
Interfering with theories of sleep and memory: sleep, declarative memory,
and associative interference. Curr Biol. 2006;16(13):1290–4.
74. Deliens G, Schmitz R, Caudron I, Mary A, Leproult R, Peigneux P. Does
recall after sleep-dependent memory consolidation reinstate sensitivity
to retroactive interference? PLoS One. 2013;8(7):e68727. doi:10.1371/
journal.pone.0068727.
75. Walker MP, van der Helm E. Overnight therapy? The role of sleep in
emotional brain processing. Psychol Bull. 2009;135(5):731–48.
76. Cartwright R, Luten A, Young M, Mercer P, Bears M. Role of REM sleep and
dream affect in overnight mood regulation: a study of normal volunteers.
Psychiatry Res. 1998;81(1):1–8.
77. Cartwright R, Young MA, Mercer P, Bears M. Role of REM sleep and dream
variables in the prediction of remission from depression. Psychiatry Res.
1998;80(3):249–55.
78. Cartwright RD, Kravitz HM, Eastman CI, Wood E. REM latency and the
recovery from depression: getting over divorce. Am J Psychiatry.
1991;148(11):1530–5.
79. Nofzinger EA, Buysse DJ, Germain A, Carter C, Luna B, Price JC, et al.
Increased activation of anterior paralimbic and executive cortex from
waking to rapid eye movement sleep in depression. Arch Gen Psychiatry.
2004;61(7):695–702.
80. Skaggs WE, McNaughton BL. Replay of neuronal firing sequences in rat
hippocampus during sleep following spatial experience. Science.
1996;271(5257):1870–3.
81. Louie K, Wilson MA. Temporally structured replay of awake hippocampal
ensemble activity during rapid eye movement sleep. Neuron.
2001;29(1):145–56.
82. Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective.
Trends Neurosci. 2001;24(4):237–43.
83. Kopp C, Longordo F, Nicholson JR, Luthi A. Insufficient sleep reversibly alters
bidirectional synaptic plasticity and NMDA receptor function. J Neurosci.
2006;26(48):12456–65.
84. Ishikawa A, Kanayama Y, Matsumura H, Tsuchimochi H, Ishida Y, Nakamura
S. Selective rapid eye movement sleep deprivation impairs the maintenance
of long-term potentiation in the rat hippocampus. Eur J Neurosci.
2006;24(1):243–8.
85. Smith C. Sleep states and memory processes in humans: procedural versus
declarative memory systems. Sleep Med Rev. 2001;5(6):491–506.
86. Fu J, Li P, Ouyang X, Gu C, Song Z, Gao J, et al. Rapid eye movement sleep
deprivation selectively impairs recall of fear extinction in hippocampus-
independent tasks in rats. Neuroscience. 2007;144(4):1186–92.
87. Milad MR, Furtak SC, Greenberg JL, Keshaviah A, Im JJ, Falkenstein MJ, et al.
Deficits in conditioned fear extinction in obsessive-compulsive disorder and
neurobiological changes in the fear circuit. JAMA Psychiatry. 2013;70(6):608–18.
doi:10.1001/jamapsychiatry.2013.914. quiz 554.
88. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, et al.
Neurobiological basis of failure to recall extinction memory in
posttraumatic stress disorder. Biol Psychiatry. 2009;66(12):1075–82.
doi:10.1016/j.biopsych.2009.06.026.
89. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and
acquired origin of reduced recall for fear extinction in PTSD: results of a
twin study. J Psychiatr Res. 2008;42(7):515–20.
90. Shvil E, Sullivan GM, Schafer S, Markowitz JC, Campeas M, Wager TD,
et al. Sex differences in extinction recall in posttraumatic stress
disorder: a pilot fMRI study. Neurobiol Learn Mem. 2014;113:101–8.
doi:10.1016/j.nlm.2014.02.003.
91. Garfinkel SN, Abelson JL, King AP, Sripada RK, Wang X, Gaines LM,
et al. Impaired contextual modulationofmemoriesinPTSD:an
fMRI and psychophysiological study of extinction retention and
fear renewal. J Neurosci. 2014;34(40):13435–43. doi:10.1523/
JNEUROSCI.4287-13.2014.
92. Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK. De novo
conditioning in trauma-exposed individuals with and without posttraumatic
stress disorder. J Abnorm Psychol. 2000;109(2):290–8.
93. Blechert J, Michael T, Vriends N, Margraf J, Wilhelm FH. Fear conditioning in
posttraumatic stress disorder: evidence for delayed extinction of autonomic,
experiential, and behavioural responses. Behav Res Ther. 2007;45(9):2019–33.
doi:10.1016/j.brat.2007.02.012.
94. Lommen MJ, Engelhard IM, Sijbrandij M, van den Hout MA, Hermans D.
Pre-trauma individual differences in extinction learning predict posttraumatic
stress. Behav Res Ther. 2013;51(2):63–7. doi:10.1016/j.brat.2012.11.004.
95. Jovanovic T, Norrholm SD, Fennell JE, Keyes M, Fiallos AM, Myers KM, et al.
Posttraumatic stress disorder may be associated with impaired fear
inhibition: relation to symptom severity. Psychiatry Res. 2009;167(1-2):151–60.
doi:10.1016/j.ps ychres.2007.12. 014.
96. Guthrie RM, Bryant RA. Extinction learning before trauma and subsequent
posttraumatic stress. Psychosom Med. 2006;68(2):307–11.
97. Orr SP, Lasko NB, Macklin ML, Pineles SL, Chang Y, Pitman RK. Predicting
post-trauma stress symptoms from pre-trauma psychophysiologic reactivity,
personality traits and measures of psychopathology. Biology Mood Anxiety
Disorders. 2012;2(1):8. doi:10.1186/2045-5380-2-8.
98. Glover EM, Phifer JE, Crain DF, Norrholm SD, Davis M, Bradley B, et al. Tools
for translational neuroscience: PTSD is associated with heightened fear
responses using acoustic startle but not skin conductance measures.
Depress Anxiety. 2011;28(12):1058–66. doi:10.1002/da.20880.
99. Fani N, Tone EB, Phifer J, Norrholm SD, Bradley B, et al. Attention bias
toward threat is associated with exaggerated fear expression and impaired
extinction in PTSD. Psychol Med. 2012;42:533–43.
100. Carson MA, Paulus LA, Lasko NB, Metzger LJ, Wolfe J, Orr SP, et al.
Psychophysiologic assessment of posttraumatic stress disorder in Vietnam
nurse veterans who witnessed injury or death. J Consult Clin Psychol.
2000;68(5):890–7.
101. Hermans D, Craske MG, Mineka S, Lovibond PF. Extinction in human fear
conditioning. Biol Psychiatry. 2006;60(4):361–8.
102. Hofmann SG. Enhancing exposure-based therapy from a translational
research perspective. Behav Res Ther. 2007;45(9):1987–2001.
103. Foa E, Hembree E, Rothbaum B. Prolonged exposure therapy for PTSD.
Emotional processing of traumatic experiences. Therapist Guide: Oxford
University Press; 2007.
104. Hofmann SG. Exposure therapy for social anxiety disorder. (unpublished
treatment manual). 2004.
105. Williams MT, Mugno B, Franklin M, Faber S. Symptom dimensions in
obsessive-compulsive disorder: phenomenology and treatment outcomes
with exposure and ritual prevention. Psychopathology. 2013;46(6):365–76.
doi:10.1159/000348582.
106. Choy Y, Fyer AJ, Lipsitz JD. Treatment of specific phobia in adults. Clin
Psychol Rev. 2007;27(3):266–86. doi:10.1016/j.cpr.2006.10.002.
107. Pace-Schott EF, Milad MR, Orr SP, Rauch SL, Stickgold R, Pitman RK. Sleep
promotes generalization of extinction of conditioned fear. Sleep.
2009;32(1):19–26.
108. Vansteenwegen D, Hermans D, Vervliet B, Francken G, Beckers T, Baeyens F,
et al. Return of fear in a human differential conditioning paradigm caused
by a return to the original acquisition context. Behav Res Ther.
2005;43(3):323–36.
109. Vansteenwegen D, Vervliet B, Iberico C, Baeyens F, Van den Bergh O,
Hermans D. The repeated confrontation with videotapes of spiders in
multiple contexts attenuates renewal of fear in spider-anxious students.
Behav Res Ther. 2007;45(6):1169–79.
110. Rowe MK, Craske MG. Effects of varied-stimulus exposure training on fear
reduction and return of fear. Behav Res Ther. 1998;36(7-8):719–34.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 15 of 19
111. McSweeney FK, Swindell S. Common processes may contribute to
extinction and habituation. J Gen Psychol. 2002;129(4):364–400.
doi:10.1080/00221300209602103.
112. Hofmann SG, Otto MW. Cognitive behavioral therapy for social anxiety
disorder: evidence-based and disorder-specific treatment techniques.
New York, NY: Routledge; 2008.
113. Plendl W, Wotjak CT. Dissociation of within- and between-session
extinction of conditioned fear. J Neurosci. 2010;30(14):4990–8.
doi:10.1523/JNEUROSCI.6038-09.2010.
114. Norberg MM, Krystal JH, Tolin DF. A meta-analysis of D-cycloserine and the
facilitation of fear extinction and exposure therapy. Biol Psychiatry.
2008;63(12):1118–26. doi:10.1016/j.biopsych.2008.01.012.
115. Kleim B, Wilhelm FH, Temp L, Marg raf J, W iede rhold BK, Rasch B.
Sleep enhances exposure therapy. Psychol Med. 2013:1-9.
doi:10.1017/S0033291713001748.
116. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress
disorder and extinction: human neuroimaging research—past, present, and
future. Biol Psychiatry. 2006;60(4):376–82.
117. Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and
hippocampal function in PTSD. Ann N Y Acad Sci. 2006;1071:67–79.
118. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW,
et al. Biological studies of post-traumatic stress disorder. Nature Rev.
2012;13(11):769–87. doi:10.1038/nrn3339.
119. Liberzon I, Sripada CS. The functional neuroanatomy of PTSD: a critical
review. Prog Brain Res. 2008;167:151–69. doi:10.1016/S0079-6123(07)67011-3.
120. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders.
Neuropsychopharmacology. 2010;35(1):169–91. doi:10.1038/npp.2009.83.
121. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of
emotional processing in PTSD, social anxiety disorder, and specific phobia.
Am J Psychiatry. 2007;164(10):1476–88. doi:10.1176/appi.ajp.2007.07030504.
122. Liberzon I, Martis B. Neuroimaging studies of emotional responses in PTSD.
Ann N Y Acad Sci. 2006;1071:87–109. doi:10.1196/annals.1364.009.
123. Sartory G, Cwik J, Knuppertz H, Schurholt B, Lebens M, Seitz RJ, et al. In
search of the trauma memory: a meta-analysis of functional neuroimaging
studies of symptom provocation in posttraumatic stress disorder (PTSD).
PLoS One. 2013;8(3), e58150. doi:10.1371/journal.pone.0058150.
124. Daniels JK, Lamke JP, Gaebler M, Walter H, Scheel M. White matter integrity
and its relationship to PTSD and childhood trauma—a systematic review
and meta-analysis. Depress Anxiety. 2013;30(3):207–16. doi:10.1002/da.22044.
125. Simmons AN, Matthews SC. Neural circuitry of PTSD with or without mild
traumatic brain injury: a meta-analysis. Neuropharmacology. 2012;62(2):598–606.
doi:10.1016/j.neuropharm.2011.03.016.
126. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A. A meta-analysis
of structural brain abnormalities in PTSD. Neurosci Biobe hav Rev.
2006;30(7):1004–31. doi:10.1016/j.neubiorev.2006.03.004.
127. Nofzinger EA, Mintun MA, Wiseman M, Kupfer DJ, Moore RY. Forebrain
activation in REM sleep: an FDG PET study. Brain Res. 1997;770(1-2):192–201.
128. Braun AR, Balkin TJ, Wesenten NJ, Carson RE, Varga M, Baldwin P, et al.
Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O
PET study. Brain. 1997;120(Pt 7):1173–97.
129. Maquet P, Ruby P, Maudoux A, Albouy G, Sterpenich V, Dang-Vu T, et al.
Human cognition during REM sleep and the activity profile within frontal
and parietal cortices: a reappraisal of functional neuroimaging data. Prog
Brain Res. 2005;150:219–27.
130. Bremner JD, Elzinga B, Schmahl C, Vermetten E. Structural and functional
plasticity of the human brain in posttraumatic stress disorder. Prog Brain
Res. 2008;167:171–86.
131. Sheikh JI, Woodward SH, Leskin GA. Sleep in post-traumatic stress disorder
and panic: convergence and divergence. Depress Anxiety. 2003;18(4):187–97.
132. Lepola U, Koponen H, Leinonen E. Sleep in panic disorders. J Psychosom
Res. 1994;38 Suppl 1:105–11.
133. Paterson JL, Reynolds AC, Ferguso n SA, Dawson D. Sleep and
obsessive-compulsive disorder (OCD). Sleep Med Rev. 2013.
doi:10.1016/j.smrv.2012.12.002.
134. Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured
sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology.
2007;44(4):660–9.
135. Mellman TA. Sleep and anxiety disorders. Psychiatr Clin North Am.
2006;29(4):1047–58.
136. Ross RJ, Ball WA, Sullivan KA, Caroff SN. Sleep disturbance as the hallmark of
posttraumatic stress disorder. Am J Psychiatry. 1989;146(6):697–707.
137. Germain A, Buysse DJ, Shear MK, Fayyad R, Austin C. Clinical correlates of
poor sleep quality in posttraumatic stress disorder. J Trauma Stress.
2004;17(6):477–84.
138. Levin R, Nielsen TA. Disturbed dreaming, posttraumatic stress disorder, and affect
distress: a review and neurocognitive model. Psychol Bull. 2007;133(3):482–528.
139. Richards A, Metzler TJ, Ruoff LM, Inslicht SS, Rao M, Talbot LS, et al. Sex
differences in objective measures of sleep in post-traumatic stress
disorder and healthy control subjects. J Sleep Res. 2013;22(6):679–87.
doi:10.1111/jsr.12064.
140. Engdahl BE, Eberly RE, Hurwitz TD, Mahowald MW, Blake J. Sleep in a
community sample of elderly war veterans with and without posttraumatic
stress disorder. Biol Psychiatry. 2000;47(6):520–5.
141. Neylan TC, Lenoci M, Maglione ML, Rosenlicht NZ, Metzler TJ, Otte C, et al.
Delta sleep response to metyrapone in post-traumatic stress disorder.
Neuropsychopharmacology. 2003;28(9):1666–76.
142. Woodward SH, Murburg MM, Bliwise DL. PTSD-related hyperarousal assessed
during sleep. Physiol Behav. 2000;70(1-2):197–203.
143. Ebdlahad S, Nofzinger EA, James JA, Buysse DJ, Price JC, Germain A.
Comparing neural correlates of REM sleep in posttraumatic stress disorder
and depression: a neuroimaging study. Psychiatry Res. 2013;214(3):422–8.
doi:10.1016/j.pscychresns.2013.09.007.
144. Kobayashi I, Cowdin N, Mellman TA. One’s sex, sleep, and posttraumatic stress
disorder. Biology Sex Differences. 2012;3(1):29. doi:10.1186/2042-6410-3-29.
145. Harvey AG, Jones C, Schmidt DA. Sleep and posttraumatic stress disorder:
a review. Clin Psychol Rev. 2003;23(3):377–407.
146. Koren D, Arnon I, Lavie P, Klein E. Sleep complaints as early predictors of
posttraumatic stress disorder: a 1-year prospective study of injured survivors
of motor vehicle accidents. Am J Psychiatry. 2002;159(5):855–7.
147. Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B. REM sleep and the
early development of posttraumatic stress disorder. Am J Psychiatry.
2002;159(10):1696–701.
148. Mellman TA, Pigeon WR, Nowell PD, Nolan B. Relationships between REM
sleep findings and PTSD symptoms during the early aftermath of trauma.
J Trauma Stress. 2007;20(5):893–901.
149. Mellman TA, Knorr BR, Pigeon WR, Leiter JC, Akay M. Heart rate variability
during sleep and the early development of posttraumatic stress disorder.
Biol Psychiatry. 2004;55(9):953–6.
150. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress
disorder after disasters. Epidemiol Rev. 2005;27:78–91. doi:10.1093/epirev/mxi003.
151. Kok BC, Herrell RK, Thomas JL, Hoge CW. Posttraumatic stress disorder
associated with combat service in Iraq or Afghanistan: reconciling
prevalence differences between studies. J Nerv Ment Dis. 2012;200(5):444–50.
doi:10.1097/NMD.0b013e3182532312.
152. Yoo SS, Gujar N, Hu P, Jolesz FA, Walker MP. The human emotional brain
without sleep—a prefrontal amygdala disconnect. Curr Biol.
2007;17(20):R877–8.
153. Thomas M, Sing H, Belenky G, Holcomb H, Mayberg H, Dannals R, et al.
Neural basis of alertness and cognitive performance impairments during
sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional
brain activity. J Sleep Res. 2000;9(4):335–52.
154. Killgore WD. Self-reported sleep correlates with prefrontal-amygdala functional
connectivity and emotional functioning. Sleep. 2013;36(11):1597–608.
doi:10.5665/sleep.3106.
155. Pawlyk AC, Morrison AR, Ross RJ, Brennan FX. Stress-induced changes in
sleep in rodents: models and mechanisms. Neurosci Biobehav Rev.
2008;32(1):99–117.
156. Such ec ki D, Tib a PA, Mac hado RB . REM sle ep rebo und as an a dapti ve
response to stressful situations. Frontiers Neurol. 2012;3:41.
doi:10.3389/fneur.2012.00041.
157. Sanford LD, Suchecki D, Meerlo P. Stress, arousal, and sleep. Curr Top Behav
Neurosci. 2014. doi:10.1007/7854_2014_314.
158. Germain A, James J, Insana S, Herringa RJ, Mammen O, Price J, et al. A
window into the invisible wound of war: functional neuroimaging of REM
sleep in returning combat veterans with PTSD. Psychiatry Res.
2013;211(2):176–9. doi:10.1016/j.pscychresns.2012.05.007.
159. Southwick SM, Bremner JD, Rasmusson A, Morgan 3rd CA, Arnsten A,
Charney DS. Role of norepinephrine in the pathophysiology and treatment
of posttraumatic stress disorder. Biol Psychiatry. 1999;46(9):1192–204.
160. Geracioti Jr TD, Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, et al. CSF
norepinephrine concentrations in posttraumatic stress disorder. Am J
Psychiatry. 2001;158(8):1227–30.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 16 of 19
161. Mellman TA, Kumar A, Kulick-Bell R, Kumar M, Nolan B. Nocturnal/daytime
urine noradrenergic measures and sleep in combat-related PTSD. Biol
Psychiatry. 1995;38(3):174–9. doi:10.1016/0006-3223(94)00238-X.
162. Trinder J, Kleiman J, Carrington M, Smith S, Breen S, Tan N, et al. Autonomic
activity during human sleep as a function of time and sleep stage. J Sleep
Res. 2001;10(4):253–64.
163. Brandenberger G, Ehrhart J, Piquard F, Simon C. Inverse coupling between
ultradian oscillations in delta wave activity and heart rate variability during
sleep. Clin Neurophysiol. 2001;112(6):992–6.
164. Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted sleep: effects on
autonomic function, neuroendocrine stress systems and stress responsivity.
Sleep Med Rev. 2008;12(3):197–210.
165. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular
physiology and subcortical networks. Nature Rev. 2002;3(8):591–605.
166. Kung S, Espinel Z, Lapid MI. Treatment of nightmares with prazosin: a systematic
review. Mayo Clin Proc. 2012;87(9):890–900. doi:10.1016/j.mayocp.2012.05.015.
167. Raskind MA, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, et al. A trial
of prazosin for combat trauma PTSD with nightmares in active-duty
soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013.
doi:10.1176/appi.ajp.2013.12081133.
168. Yehuda R. Status of glucocorticoid alterations in post-traumatic stress
disorder. Ann N Y Acad Sci. 2009;1179:56–69. doi:10.1111/j.1749-
6632.2009.04979.x.
169. Aguilera G. HPA axis responsiveness to stress: implications for healthy aging.
Exp Gerontol. 2011;46(2-3):90–5. doi:10.1016/j.exger.2010.08.023.
170. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al.
Elevated CSF corticotropin-releasing factor concentrations in posttraumatic
stress disorder. Am J Psychiatry. 1997;154(5):624–9.
171. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, et al.
Serial CSF corticotropin-releasing hormone levels and adrenocortical activity
in combat veterans with posttraumatic stress disorder. Am J Psychiatry.
1999;156(4):585–8.
172. Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L,
et al. Corticotropin-releasing factor in posttraumatic stress disorder (PTSD)
with secondary psychotic symptoms, nonpsychotic PTSD, and healthy
control subjects. Biol Psychiatry. 2003;54(12):1382–8.
173. Morris MC, Compas BE, Garber J. Relations among posttraumatic stress
disorder, comorbid major depression, and HPA function: a systematic
review and meta-analysis. Clin Psychol Rev. 2012;32(4):301–15.
doi:10.1016/j.cpr.2012.02.002.
174. Heim C, Nemeroff CB. Neurobiology of posttraumatic stress disorder. CNS
Spectr. 2009;14(1 Suppl 1):13–24.
175. Yehuda R. Advances in understanding neuroendocrine alterations in PTSD
and their therapeutic implications. Ann N Y Acad Sci. 2006;1071:137–66.
doi:10.1196/annals.1364.012.
176. Kling MA, DeBellis MD, O’Rourke DK, Listwak SJ, Geracioti Jr TD, McCutcheon IE,
et al. Diurnal variation of cerebrospinal fluid immunoreactive corticotropin-
releasing hormone levels in healthy volunteers. J Clin Endocrinol Metab.
1994;79(1):233–9. doi:10.1210/jcem.79.1.8027234.
177. Kalsbeek A, van der Spek R, Lei J, Endert E, Buijs RM, Fliers E. Circadian
rhythms in the hypothalamo-pituitary-adrenal (HPA) axis. Mol Cell Endocrinol.
2012;349(1):20–9. doi:10.1016/j.mce.2011.06.042.
178. Koob GF. Corticotropin-releasing factor, norepinephrine, and stress. Biol
Psychiatry. 1999;46(9):1167–80.
179. Heinrichs SC, Koob GF. Corticotropin-releasing factor in brain: a role in
activation, arousal, and affect regulation. J Pharmacol Exp Ther.
2004;311(2):427–40.
180. Davis M, Walker DL, Miles L, Grillon C. Phasic vs sustained fear in rats and
humans: role of the extended amygdala in fear vs anxiety.
Neuropsychopharmacology. 2010;35(1):105–35. doi:10.1038/npp.2009.109.
181. Walker DL, Miles LA, Davis M. Selective participation of the bed nucleus of
the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like
responses. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(8):1291–308.
doi:10.1016/j.pnpbp.2009.06.022.
182. Somerville LH, Whalen PJ, Kelley WM. Human bed nucleus of the stria
terminalis indexes hypervigilant threat monitoring. Biol Psychiatry.
2010;68(5):416–24. doi:10.1016/j.biopsych.2010.04.002.
183. Pole N, Neylan TC, Otte C, Henn-Hasse C, Metzler TJ, Marmar CR. Prospective
prediction of posttraumatic stress disorder symptoms using fear
potentiated auditory startle responses. Biol Psychiatry. 2009;65(3):235–40.
doi:10.1016/j.biopsych.2008.07.015.
184. Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of
mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry.
2001;49(12):1023–39.
185. Krohg K, Hageman I, Jorgensen MB. Corticotropin-releasing factor (CRF) in
stress and disease: a review of literature and treatment perspectives with
special emphasis on psychiatric disorders. Nord J Psychiatry. 2008;62(1):8–16.
doi:10.1080/08039480801983588.
186. Dunn AJ, Swiergiel AH, Palamarchouk V. Brain circuits involved in
corticotropin-releasing factor-norepinephrine interactions during stress.
Ann N Y Acad Sci. 2004;1018:25–34. doi:10.1196/annals.1296.003.
187. Sanford LD, Yang L, Wellman LL, Dong E, Tang X. Mouse strain differences
in the effects of corticotropin releasing hormone (CRH) on sleep and
wakefulness. Brain Res. 2008;1190:94–104.
188. Chang FC, Opp MR. Corticotropin-releasing hormone (CRH) as a regulator of
waking. Neurosci Biobehav Rev. 2001;25(5):445–53.
189. Fadda P, Fratta W. Stress-induced sleep deprivation modifies corticotropin
releasing factor (CRF) levels and CRF binding in rat brain and pituitary.
Pharmacol Res. 1997;35(5):443–6.
190. Yang L, Tang X, Wellman LL, Liu X, Sanford LD. Corticotropin releasing
factor (CRF) modulates fear-induced alterations in sleep in mice. Brain Res.
2009;1276:112–22.
191. Wellman LL, Yang L, Ambrozewicz MA, Machida M, Sanford LD. Basolateral
amygdala and the regulation of fear-conditioned changes in sleep: role of
corticotropin-releasing factor. Sleep. 2013;36(4):471–80. doi:10.5665/sleep.2526.
192. Liu X, Wellman LL, Yang L, Ambrozewicz MA, Tang X, Sanford LD.
Antagonizing corticotropin-releasing factor in the central nucleus of the
amygdala attenuates fear-induced reductions in sleep but not freezing.
Sleep. 2011;34(11):1539–49. doi:10.5665/sleep.1394.
193. Philbert J, Beeske S, Belzung C, Griebel G. The CRF1 receptor antagonist
SSR125543 prevents stress-induced long-lasting sleep disturbances in a
mouse model of PTSD: comparison with paroxetine and d-cycloserine.
Behav Brain Res. 2015;279:41–6. doi:10.1016/j.bbr.2014.11.006.
194. Kim Y, Chen L, McCarley RW, Strecker RE. Sleep allostasis in chronic sleep
restriction: the role of the norepinephrine system. Brain Res. 2013;1531:9–16.
doi:10.1016/j.brainres.2013.07.048.
195. McEwen BS. Sleep deprivation as a neurobiologic and physiologic stressor:
allostasis and allostatic load. Metabolism. 2006;55 Suppl 2:S20–3.
196. Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast
feedback. Psychoneuroendocrinology. 1997;22(6):443–53.
197. Vanderheyden WM, Poe GR, Liberzon I. Trauma exposure and sleep: using a
rodent model to understand sleep function in PTSD. Exp Brain Res.
2014;232(5):1575–84. doi:10.1007/s00221-014-3890-4.
198. Schwabe L, Wolf OT. Stress and multiple memory systems: from ‘thinking’
to ‘doing’. Trends Cogn Sci. 2013;17(2):60–8. doi:10.1016/j.tics.2012.12.001.
199. Parsons RG, Ressler KJ. Implications of memory modulation for post-
traumatic stress and fear disorders. Nat Neurosci. 2013;16(2):146–53.
doi:10.1038/nn.3296.
200. Riemann D. Insomnia and comorbid psychiatric disorders. Sleep Med.
2007;8(4):S15–20. doi:10.1016/S1389-9457(08)70004-2.
201. Papadimitriou GN, Lin kows ki P. Sl eep di sturbance in anxiety
disorders. Int Rev Psychiatry (Abingdon, England). 2005;17(4):229–36.
doi:10.1080/09540260500104524.
202. Budhiraja R, Roth T, Hudgel DW, Budhiraja P, Drake CL. Prevalence and
polysomnographic correlates of insomnia comorbid with medical disorders.
Sleep. 2011;34(7):859–67. doi:10.5665/SLEEP.1114.
203. Pillai V, Steenburg LA, Ciesla JA, Roth T, Drake CL. A seven day actigraphy-
based study of rumination and sleep disturbance among young adults
with depressive symptoms. J Psychosom Res. 2014;77(1):70–5.
doi:10.1016/j.jpsychores.2014.05.004.
204. Baglioni C, Regen W, Teghen A, Spiegelhalder K, Feige B, Nissen C, et al.
Sleep changes in the disorder of insomnia: a meta-analysis of polysomnographic
studies. Sleep Med Rev. 2013. doi:10.1016/j.smrv.2013.04.001.
205. Baglioni C, Lombardo C, Bux E, Hansen S, Salveta C, Biello S, et al.
Psychophysiological reactivity to sleep-related emotional stimuli in primary
insomnia. Behav Res Ther. 2010;48(6):467–75. doi:10.1016/j.brat.2010.01.008.
206. Baglioni C, Spiegelhalder K, Lomba rdo C, Riemann D. Sleep and
emotions: a focus on insomnia. Sleep Med Rev. 2010;14(4):227–38.
doi:10.1016/j.smrv.2009.10.007.
207. van de Laar M, Verbeek I, Pevernagie D, Aldenkamp A, Overeem S. The
role of personality traits in insomnia. Sleep Med Rev. 2010;14(1):61–8.
doi:10.1016/j.smrv.2009.07.007.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 17 of 19
208. Kales A, Caldwell AB, Soldatos CR, Bixler EO, Kales JD. Biopsychobehavioral
correlates of insomnia. II. Pattern specificity and consistency with the Minnesota
Multiphasic Personality Inventory. Psychosom Med. 1983;45(4):341–56.
209. Stepanski EJ, Rybarczyk B. Emerging research on the treatment and etiology
of secondary or comorbid insomnia. Sleep Med Rev. 2006;10(1):7–18.
doi:10.1016/j.smrv.2005.08.002.
210. Espie CA. Insomnia: conceptual issues in the development, persistence, and
treatment of sleep disorder in adults. Annu Rev Psychol. 2002;53:215–43.
doi:10.1146/annurev.psych.53.100901.135243.
211. Ellis JG, Gehrman P, Espie CA, Riemann D, Perlis ML. Acute insomnia: current
conceptualizations and future directions. Sleep Med Rev. 2012;16(1):5–14.
doi:10.1016/j.smrv.2011.02.002.
212. Reite M, Buysse D, Reynolds C, Mendelson W. The use of polysomnography
in the evaluation of insomnia. Sleep. 1995;18(1):58–70.
213. Riemann D, Spiegelhalder K, Nissen C, Hirscher V, Baglioni C, Feige B. REM
sleep instability—a new pathway for insomnia? Pharmacopsychiatry.
2012;45(5):167–76. doi:10.1055/s-0031-1299721.
214. Feige B, Al-Shajlawi A, Nissen C, Voderholzer U, Hornyak M, Spiegelhalder K,
et al. Does REM sleep contribute to subjective wake time in primary insomnia?
A comparison of polysomnographic and subjective sleep in 100 patients.
J Sleep Res. 2008;17(2):180–90.
215. Perusse AD, Pedneault-Drolet M, Rancourt C, Turcotte I, St-Jean G, Bastien
CH. REM sleep as a potential indicator of hyperarousal in psychophysiological
and paradoxical insomnia sufferers. Int J Psychophysiol. 2015;95(3):372–8.
doi:10.1016/j.ijpsycho.2015.01.005.
216. Nofzinger EA, Nissen C, Germain A, Moul D, Hall M, Price JC, et al. Regional
cerebral metabolic correlates of WASO during NREM sleep in insomnia.
J Clin Sleep Med. 2006;2(3):316–22.
217. Huang Z, Liang P, Jia X, Zhan S, Li N, Ding Y, et al. Abnormal amygdala
connectivity in patients with primary insomnia: evidence from resting state
fMRI. Eur J Radiol. 2012;81(6):1288–95. doi:10.1016/j.ejrad.2011.03.029.
218. Mellman TA, David D, Kulick-Bell R, Hebding J, Nolan B. Sleep disturbance
and its relationship to psychiatric morbidity after Hurricane Andrew. Am J
Psychiatry. 1995;152(11):1659–63.
219. Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129–41.
doi:10.1016/S0140-6736(11)60750-2.
220. Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM. Multicenter,
double-blind comparison of sertraline and placebo in the treatment of
posttraumatic stress disorder. Arch Gen Psychiatry. 2001;58(5):485–92.
221. Galovski TE, Monson C, Bruce SE, Resick PA. Does cognitive-behavioral
therapy for PTSD improve perceived health and sleep impairment? J Trauma
Stress. 2009;22(3):197–204. doi:10.1002/jts.20418.
222. Talbot LS, Maguen S, Metzler TJ, Schmitz M, McCaslin SE, Richards A, et al.
Cognitive behavioral therapy for insomnia in posttraumatic stress disorder:
a randomized controlled trial. Sleep. 2014;37(2):327–41.
223. Zhang B, Wing YK. Sex differences in insomnia: a meta-analysis. Sleep.
2006;29(1):85–93.
224. Ditlevsen DN, Elklit A. Gender, trauma type, and PTSD prevalence: a re-analysis
of 18 nordic convenience samples. Annals General Psychiatry. 2012;11(1):26.
doi:10.1186/1744-859X-11-26.
225. Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK, et al.
Fear conditioning and extinction: influence of sex and menstrual cycle in
healthy humans. Behav Neurosci. 2006;120(6):1196–203.
226. Milad MR, Zeidan MA, Contero A, Pitman RK, Klibanski A, Rauch SL, et al.
The influence of gonadal hormones on conditioned fear extinction in
healthy humans. Neuroscience. 2010;168(3):652–8.
227. Graham BM, Milad MR. Blockade of estrogen by hormonal contraceptives
impairs fear extinction in female rats and women. Biol Psychiatry.
2013;73(4):371–8. doi:10.1016/j.biopsych.2012.09.018.
228. Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al.
Estradiol modulates medial prefrontal cortex and amygdala activity during
fear extinction in women and female rats. Biol Psychiatry. 2011;70(10):920–7.
doi:10.1016/j.biopsych.2011.05.016.
229. Lebron-Milad K, Abbs B, Milad MR, Linnman C, Rougemount-Bucking A,
Zeidan MA, et al. Sex differences in the neurobiology of fear conditioning
and extinction: a preliminary fMRI study of shared sex differences with
stress-arousal circuitry. Biology Mood Anxiety Disorders. 2012;2(1):7.
doi:10.1186/2045-5380-2-7.
230. Milad MR, Igoe SA, Lebron-Milad K, Novales JE. Estrous cycle phase and
gonadal hormones influence conditioned fear extinction. Neuroscience.
2009;164(3):887–95.
231. Kobayashi I, Mellman TA . Gend er dif fere nces i n sleep during the
aftermath of trauma and the development of posttraumatic stress
disorder. Behav Sleep Med. 2012;10(3):180–90. doi:10.1080/
15402002.2011.654296.
232. Lebron-Milad K, Milad MR. Sex differences, gonadal hormones and the fear
extinction network: implications for anxiety disorders. Biology Mood Anxiety
Disorders. 2012;2(1):3. doi:10.1186/2045-5380-2-3.
233. Vervliet B, Vansteenwegen D, Baeyens F, Hermans D, Eelen P. Return of fear
in a human differential conditioning paradigm caused by a stimulus change
after extinction. Behav Res Ther. 2005;43(3):357–71.
234. Rachman S. The return of fear: review and prospect. Clin Psychol Rev.
1989;9:147–68.
235. Sauerhofer E, Pamplona FA, Bedenk B, Moll GH, Dawirs RR, von Horsten S,
et al. Generalization of contextual fear depends on associative rather than
non-associative memory components. Behav Brain Res. 2012;233(2):483–93.
doi:10.1016/j.bbr.2012.05.016.
236. Ehlers A, Hackmann A, Steil R, Clohessy S, Wenninger K, Winter H. The
nature of intrusive memories after trauma: the warning signal hypothesis.
Behav Res Ther. 2002;40(9):995–1002.
237. Wessa M, Flor H. Failure of extinction of fear responses in posttraumatic
stress disorder: evidence from second-order conditioning. Am J Psychiatry.
2007;164(11):1684–92.
238. Hofmann SG. D-cyclose rine f or tre ating anxiety disorders: making
good exposures better and bad exposures worse. Depress Anxiety.
2014;31:175–7.
239. Bontempo A, Panza KE, Bloch MH. D-cycloserine augmentation of behavioral
therapy for the treatment of anxiety disorders: a meta-analysis. J Clin Psychiatry.
2012;73(4):533–7. doi:10.4088/JCP.11r07356.
240. Grillon C. D-cycloserine facilitation of fear extinction and exposure-based
therapy might rely on lower-level, automatic mechanisms. Biol Psychiatry.
2009;66(7):636–41.
241. Litz BT, Salters-Pedneault K, Steenkamp MM, Hermos JA, Bryant RA, Otto
MW, et al. A randomized placebo-controlled trial of D-cycloserine and ex-
posure therapy for posttraumatic stress disorder. J Psychiatr Res.
2012;46(9):1184–90. doi:10.1016/j.jpsychires.2012.05.006.
242. de Kleine RA, Hendriks GJ, Kusters WJ, Broekman TG, van Minnen A. A
randomized placebo-controlled trial of D-cycloserine to enhance exposure
therapy for posttraumatic stress disorder. Biol Psychiatry. 2012;71(11):962–8.
doi:10.1016/j.biopsych.2012.02.033.
243. Zalta AK, Dowd S, Rosenfield D, Smits JA, Otto MW, Simon NM et al. Sleep
quality predicts treatment outcome in CBT for social anxiety disorder.
Depress Anxiety. 2013. doi:10.1002/da.22170.
244. Eglinton R, Chung MC. The relationship between posttraumatic stress
disorder, illness cognitions, defence styles, fatigue severity and
psychological well-being in chronic fatigue syndrome. Psychiatry Res.
2011;188(2):245–52. doi:10.1016/j.psychres.2011.04.012.
245. Lerdal A, Lee KA, Rokne B, Knudsen Jr O, Wahl AK, Dahl AA. A population-
based study of associations between current posttraumatic stress
symptoms and current fatigue. J Trauma Stress. 2010;23(5):606–14.
doi:10.1002/jts.20562.
246. Jones K, Harrison Y. Frontal lobe function, sleep loss and fragmented sleep.
Sleep Med Rev. 2001;5(6):463–75.
247. McKenna BS, Eyler LT. Overlapping prefrontal systems involved in cognitive
and emotional processing in euthymic bipolar disorder and following sleep
deprivation: a review of functional neuroimaging studies. Clin Psychol Rev.
2012;32(7):650–63. doi:10.1016/j.cpr.2012.07.003.
248. Tavernier R, Willoughby T. Bidirectional associations between sleep (quality
and duration) and psychosocial functioning across the university years.
Dev Psychol. 2014;50(3):674–82. doi:10.1037/a0034258.
249. Dolan S, Martindale S, Robinson J, Kimbrel NA, Meyer EC, Kruse MI, et al.
Neuropsychological sequelae of PTSD and TBI following war deployment
among OEF/OIF veterans. Neuropsychol Rev. 2012;22(1):21–34.
doi:10.1007/s11065-012-9190-5.
250. Qureshi SU, Long ME, Bradshaw M R, Pyn e JM, Magruder KM,
Kimbrell T, et al. Does PTSD impair cognition beyond the effect of
trauma? J Neuropsychiatry Clin Neurosci. 2011;23(1):16–28.
doi:10.1176/appi.neuropsych.23.1.16.
251. Charuvastra A, Cloitre M. Social bonds and posttraumatic stress disorder. Annu
Rev Psychol. 2008;59:301–28. doi:10.1146/annurev.psych.58.110405.085650.
252. Broekman BF, Olff M, Boer F. The genetic background to PTSD. Neurosci
Biobehav Rev. 2007;31(3):348–62. doi:10.1016/j.neubiorev.2006.10.001.
Pace-Schott et al. Biology of Mood & Anxiety Disorders (2015) 5:3 Page 18 of 19
253. Sanford LD, Yang L, Wellman LL, Liu X, Tang X. Differential effects of
controllable and uncontrollable footshock stress on sleep in mice. Sleep.
2010;33(5):621–30.
254. Pace-Schott EF, Spencer RM, Vijayakumar S, Ahmed NA, Verga PW, Orr SP,
et al. Extinction of conditioned fear is better learned and recalled in the
morning than in the evening. J Psychiatr Res. 2013;47(11):1776–84.
doi:10.1016/j.jpsychires.2013.07.027.
255. Pace-Schott EF, Rubin Z, Verga PW, Spencer RMC, Orr SP, Milad MR.
Chronotype, sleep quality and extinction memory, an actigraphic study.
Sleep 37. 2014;(Abstract Supplement)(in press).
256. Pace-Schott EF, Rubin Z, Tracy LE, Spencer RMC, Orr SP, Verga PW.
Emotional trait and memory associates of sleep timing and quality.
Psychiatry Res. 2015. (in press).
257. Kuriyama K, Honma M, Soshi T, Fujii T, Kim Y. Effect of D-cycloserine and
valproic acid on the extinction of reinstated fear-conditioned responses
and habituation of fear conditioning in healthy humans: a randomized
controlled trial. Psychopharmacology (Berl). 2011;218(3):589–97.
doi:10.1007/s00213-011-2353-x.
258. Kuriyama K, Honma M, Yoshiike T, Kim Y. Valproic acid but not D-cycloserine
facilitates sleep-dependent offline learning of extinction and habituation of
conditioned fear in humans. Neuropharmacology. 2013;64:424–31.
doi:10.1016/j.neuropharm.2012.07.045.
259. Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, Phelps EA.
Preventing the return of fear in humans using reconsolidation update
mechanisms. Nature. 2010;463(7277):49–53. doi:10.1038/nature08637.
260. Monfils MH, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation
boundaries: key to persistent attenuation of fear memories. Science.
2009;324(5929):951–5. doi:10.1126/science.1167975.
261. Quirk GJ, Pare D, Richardson R, Herry C, Monfils MH, Schiller D, et al. Erasing
fear memories with extinction training. J Neurosci. 2010;30(45):14993–7.
262. Hoge EA, Worthington JJ, Nagurney JT, Chang Y, Kay EB, Feterowski CM,
et al. Effect of acute posttrauma propranolol on PTSD outcome and
physiological responses during script-driven imagery. CNS Neurosci Ther.
2012;18(1):21–7. doi:10.1111/j.1755-5949.2010.00227.x.
263. Brunet A, Poundja J, Tremblay J, Bui E, Thomas E, Orr SP, et al. Trauma
reactivation under the influence of propranolol decreases posttraumatic
stress symptoms and disorder: 3 open-label trials. J Clin Psychopharmacol.
2011;31(4):547–50. doi:10.1097/JCP.0b013e318222f360.
264. Taylor FB, Martin P, Thompson C, Williams J, Mellman TA, Gross C, et al.
Prazosin effects on objective sleep measures and clinical symptoms in
civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol
Psychiatry. 2008;63(6):629–32. doi:10.1016/j.biopsych.2007.07.001.
265. van Liempt S, van Zuiden M, Westenberg H, Super A, Vermetten E. Impact
of impaired sleep on the development of PTSD symptoms in combat
veterans: a prospective longitudinal cohort study. Depress Anxiety. 2013.
doi:10.1002/da.22054.
266. APA. Diagnostic and statistical manual of mental disorders DSM-IV-TR Fourth
Edition (Text Revision). Washington, DC: American Psychiatric Association; 2000.
267. AASM. International classification of sleep disorders—second edition (ICSD-2).
American Academy of Sleep Medicine: Darien, IL; 2005.
268. AASM. International classification of sleep disorders—third edition (ICSD-3).
American Academy of Sleep Medicine: Darien, IL; 2013.
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