ArticlePDF AvailableLiterature Review

A Review of the Neurobiological Basis of Trauma-Related Dissociation and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response: a Transdiagnostic, Translational Approach

Authors:

Abstract and Figures

Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb’s threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model.
Adapted with permission from Zeitschrift für Psychologie/Journal of Psychology 2010; Vol. 218(2):109–127., p. 111 ©2010 Hogrefe Publishing, www.hogrefe.com. The defense cascade model of dissociation posits that defensive responses occur on a continuum, mediated by pathways involving the periaqueductal gray (PAG), hypothalamus, and amygdala. Here, threat is met initially with an orienting freezing response via the superior colliculus and PAG, followed by fight or flight (blue shaded area; mirrored in symptoms of hyperarousal and hypervigilance) via activation of the sympathetic nervous system and the dorsolateral PAG (lPAG) involved in activating motor patterns of fight or flight, via the PAG, amygdala, and limbic forebrain. Fight or flight is accompanied by release of endocannabinoids, leading to analgesia. Fight or flight is followed by a stage of tonic immobility (tonic immobility), with co-activation of both the sympathetic and parasympathetic nervous systems. Critically, when escape and/or chance of survival is low, a dissociative state follows (yellow shaded area), referred to as unresponsive immobility/emotional shutdown, mediated by the ventrolateral PAG (brake to the lateral PAG). During unresponsive immobility (shutdown response), sensation, perception, and motor abilities are significantly altered (mirrored by symptoms of depersonalization and derealization) and vagal parasympathetic activity dominates. Opioid-mediated analgesia accompanies the shutdown response, and emerging work suggests that perceptual and mood alterations (e.g., dysphoria) may be carried out by the kappa-opioid (dynorphin) system (activated in response to chronic, inescapable stress) ([2, 18, 19••])
… 
Increased patterns of resting-state functional connectivity in the dissociative subtype as compared to PTSD without the subtype. Here, brain regions with an asterisk indicate seed regions from insula, amygdala, and periaqueductal gray functional connectivity studies comparing patients with the dissociative subtype of PTSD with PTSD patients [17, 18, 20••]. Regions in green correspond to brain areas implicated in emotion regulation, including the prefrontal cortex and lobule VI/crus I of the cerebellum. Areas in yellow correspond to areas implicated in emotion reactivity and response, including the amygdala complexes (bilateral basolateral amygdala and centromedial amygdala) and the ventrolateral periaqueductal gray. Critically, the left amygdala is associated with detailed and elaborate emotional response evaluation, while the right amygdala is more involved in rapid and automatic detection of emotional stimuli [21]. Brain areas in red correspond to subregions of the insula related to interoceptive awareness. Finally, brain areas in blue are related to the processing of awareness, consciousness, and proprioception, including the superior parietal lobe, dorsal posterior cingulate cortex, precuneus, and the temporoparietal junction. Importantly, among patients with the dissociative subtype of PTSD, increased connectivity between emotion regulation regions (regions in green) and emotion reactivity regions (regions in yellow) is thought to contribute to a characteristic pattern of emotion overmodulation associated with symptoms such as depersonalization and derealization and emotional detachment. Additionally, increased connectivity between emotion reactivity regions (regions in yellow) and regions relating to interoceptive awareness, perception of self, and bodily self-awareness (regions in blue) may provide an explanation for symptoms such as an altered sense of self and altered perception of the environment associated with symptoms of depersonalization and derealization. Abbreviations: PFC, prefrontal cortex; BLA, basolateral amygdala; CMA, centromedial amygdala; vlPAG, ventrolateral periaqueductal gray; post, posterior; ant, anterior
… 
This content is subject to copyright. Terms and conditions apply.
DISASTER PSYCHIATRY: TRAUMA, PTSD, AND RELATED DISORDERS (MJ FRIEDMAN, SECTION EDITOR)
A Review of the Neurobiological Basis of Trauma-Related Dissociation
and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response:
a Transdiagnostic, Translational Approach
Ruth A. Lanius
1,2,3,4
&Jenna E. Boyd
4,5,6
&Margaret C. McKinnon
4,5,7
&Andrew A. Nicholson
1,2,3
&Paul Frewen
8
&
Eric Vermetten
9,10
&Rakesh Jetly
11
&David Spiegel
12
Published online: 7 November 2018
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment
response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms
through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treat-
ment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other
trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense
cascade model of dissociation and Mobbs threat detection model. In particular, we review neuroimaging studies highlighting
alterations in functional connectivity of key brain regions associated with these models, including connectivity between the
prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid
and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms
by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment mo-
dalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor
antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion
overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the
endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components
of the defense cascade model.
Keywords PTSD .Dissociation .Stress response .Opioids .Endocannabinoids .Amygdala .Periaqueductal grey .Prefrontal
cortex
Ruth A. Lanius and Jenna E. Boyd contributed equally to this work.
This article is part of the Topical Collection on Disaster Psychiatry:
Trauma, PTSD, and Related Disorders
*Ruth A. Lanius
Ruth.lanius@lhsc.on.ca
1
Department of Neuroscience, Western University, London, ON,
Canada
2
Department of Psychiatry, Western University, London, ON, Canada
3
Lawson Health Research Institute, London, ON, Canada
4
Homewood Research Institute, Guelph, ON, Canada
5
Mood Disorders Program, St. Josephs Healthcare, Hamilton, ON,
Canada
6
Department of Psychology, Neuroscience, and Behaviour, McMaster
University, Hamilton, ON, Canada
7
Department of Psychiatry and Behavioural Neuroscience, McMaster
University, Hamilton, ON, Canada
8
Department of Psychology, Western University, London, ON,
Canada
9
Department of Psychiatry, Leiden University Medical Center,
Leiden, Netherlands
10
Military Mental Health Research, Ministry of Defense,
Utrecht, Netherlands
11
Canadian Forces, Health Services, Ottawa, ON, Canada
12
Stanford University School of Medicine, Stanford, CA, USA
Current Psychiatry Reports (2018) 20: 118
https://doi.org/10.1007/s11920-018-0983-y
Introduction
Dissociative phenomena involve alterations in conscious-
ness underlying normal integration of thought, memory,
emotions, sense of self, body awareness, and perception
of the external environment [1]. Commonly experienced
symptoms of dissociation include disengagement (spac-
ing out), emotional constriction (reduced ability to expe-
rience emotions), memory disturbance (e.g., blanksin
memory), depersonalization (feeling outside of or as if
you do not belong to your own body), derealization (feel-
ing as though things around you are strange or unfamiliar),
and identity dissociation (e.g., feeling as though there is
more than one person inside of you) [2]. Although disso-
ciative phenomena occur across a wide range of psycho-
logical disorders and in healthy individuals [3,4], patho-
logical dissociative symptoms typically develop following
chronic exposure to traumatic life events, particularly
those occurring early in development such as childhood
abuse and neglect [5]. Consistent with a traumatogenic
etiology, the neurobiological mechanisms of dissociation
have become increasingly understood through studies ex-
amining trauma-related disorders and the dissociative sub-
type of posttraumatic stress disorder (PTSD+DS). PTSD+
DS is a subtype diagnosed in approximately 1530% of
individuals with PTSD [6,7] and characterized by symp-
toms of depersonalization and derealization [1]. PTSD+DS
has been identified across individuals with differing trau-
ma etiologies, including military or combat trauma [6],
childhood abuse, and mixed civilian trauma [7].
Critically, however, dissociative symptoms are present
not only in PTSD but are also observed at clinically sig-
nificant levels in numerous other trauma-related disorders,
including borderline personality disorder (BPD) and dis-
sociative identity disorder (DID) [8], and in conditions less
classically associated with trauma exposure, such as major
depressive disorder (MDD) and depersonalization/
derealization disorder (DDD) [3]. Although DDD has not
been linked historically to traumatic experiences, some
evidence indicates that childhood interpersonal trauma is
predictive of a subsequent diagnosis of depersonalization
disorder [9]. Similarly, dissociative symptoms in MDD are
also linked to trauma exposure [10,11]. For example, a
study by Sar and colleagues identified a subgroup of
women with MDD and comorbid dissociative disorders
who had higher rates of childhood abuse than women
with MDD and no dissociative disorder [11]. Taken to-
gether, these findings suggest strongly that dissociative
symptoms experienced transdiagnostically are often of a
traumatogenic nature.
Notably, dissociative symptoms, including those seen
in PTSD+DS, are associated with a longer duration of
illness (e.g., onset of PTSD in childhood), severe role
impairment, and heightened suicidality [7]. Although
PTSD+DS has been identified across trauma types
(e.g., childhood abuse, military members, and veterans)
[6,7], dissociative symptoms are often linked to chron-
ic, inescapable stress occurring within the context of
prolonged, repeated traumatic experiences (e.g., child-
hood neglect or abuse), where dissociation may serve
as a means of psychological escape from intense trauma
or suffering [12]. This recent meta-analysis reported
higher levels of dissociation among samples exposed to
childhood abuse or neglect than among non-abused or
neglected samples [12]. Moreover, a younger age of on-
set, a longer duration of abuse, and parental abuse were
associated with higher levels of dissociative symptoms
[12]. Hence, increased understanding of not only the
mechanisms through which dissociative symptoms
emerge, but also are maintained in trauma-exposed clin-
ical populations is likely to have wide-reaching implica-
tions. Given the association between dissociative symp-
toms and increased disease severity and comorbidity, the
identification of novel treatment modalities is crucial.
Accordingly, we review emerging evidence suggesting
the potential role of opioid- and endocannabinoid-
mediated stress responses in dissociative phenomena,
highlighting the implications of this literature for treat-
ment and pharmacotherapy.
The Neurobiology of Dissociation
Neurobiological Models of Dissociation
as Fronto-Limbic Inhibition
Recent neurobiological investigations of dissociative symp-
tomatology stem largely from the PTSD literature as well as
from studies investigating DID, BPD, and depersonalization/
derealization disorder (DDD) [13,14]. Although dissociation
has been conceptualized broadly as including divisions within
ones sense of self and has been considered relevant to cultural
phenomena such as possession [15], the majority of neurobi-
ological work to date has focused largely on symptoms con-
sistent with the aforementioned definition of dissociation as a
disturbance in integration of thought, memory, emotional feel-
ings, sense of self, body awareness, and perception of the
external environment, including symptoms of depersonaliza-
tion and derealization. Flashbacks in PTSD, for example com-
bine dissociation of future orientation (memory of surviving
the trauma) with intense reliving of the trauma. Despite this
limitation of our model, we are focusing on the aspects of
dissociation involving emotion overmodulation and associat-
ed emotional detachment.
Neuroimaging studies in PTSD support the existence
of a distinct dissociative subtype. Early work identified
118 Page 2 of 14 Curr Psychiatry Rep (2018) 20: 118
a neurobiological model reflecting emotion dysregula-
tion among individuals with PTSD+DS due to excessive
prefrontal inhibition of limbic regions, including the
amygdala [16]. This dysregulation is referred to as emo-
tional overmodulation and involves depersonalization
and derealization and associated emotional detachment
characteristic of individuals with PTSD+DS. Emotional
overmodulation seen in PTSD+DS contrasts sharply
with the more common presentation of PTSD involving
hyperemotionality, characterized by reduced prefrontal
activity and limbic over-activity, and often referred to
as emotional undermodulation [16]. Notably, whereas
PTSD is associated predominantly with emotional
undermodulation, individuals with PTSD+DS may cycle
between these two presentations, even though symp-
toms of emotional overmodulation often predominate
[16].
Recent work has expanded significantly this conceptu-
alization in an effort to delineate further the subcortical
structures implicated in PTSD and PTSD+DS and to spec-
ify the directionality of connectivity between key regions
associated with emotional over- and undermodulation [17,
18,19••,20••]. In particular, subregions of the amygdala,
namely the centromedial amygdala (CMA) and basolateral
amygdala (BLA) complexes, and the periaqueductal gray
(PAG) have been tied uniquely to differential patterns of
brain connectivity among individuals with PTSD+DS
compared to PTSD [17,18,19••,20••]. The CMA,
BLA, and PAG contribute differentially to fear process-
ing. Specifically, whereas the BLA is moderated by top-
down inhibition from the mPFC and is responsible for the
evaluation of sensory information and its subsequent cor-
tical processing via projections to the thalamus, striatum,
and PFC, the CMA is responsible for activation of
nociception and execution of fear responses via projec-
tions to the PAG and other subcortical brain regions
[21]. By contrast, the PAG and its subregions contribute
to autonomic responses associated with fear. Here, the
dorsolateral and lateral PAG (dl-PAG and l-PAG) are im-
plicated in activation of the sympathetic nervous system
in response to threat and subsequent activation of active
defense responses associated with emotional
undermodulation [22]. Conversely, the ventrolateral PAG
(vl-PAG) is thought to serve as a brakefor the dl-PAG
and l-PAG, and is associated with passive defensive re-
sponses and activation of the parasympathetic nervous
system, thus its association in the literature is with emo-
tional overmodulation [22].
Dissociation and Response Inhibition
The connection between these brain regions and defensive
responding can be understood through a framework
introduced by Mobbs et al. [23,24] illustrating that threat
processing among healthy individuals is dependent on the
physical distance of the individual from an environmental
threat. Specifically, as threat approaches and is conse-
quently perceived as more imminent, defensive process-
ing at the neural level shifts from prefrontal brain regions
(e.g., orbitofrontal cortex, ventromedial PFC (vmPFC)) to
subcortical brain regions involved in primitive defensive
responses (e.g., amgydala and PAG) [23,24]. For exam-
ple, Mobbs [23] found that among healthy control sub-
jects, anticipation of threat following initial detection
was associated with increased activity in forebrain struc-
tures, (e.g., vmPFC and hippocampus) as well as subcor-
tical structures including the hypothalamus and amygdala.
By contrast, when subjects perceived threat to be immi-
nent, midbrain and subcortical regions, including the PAG
and dorsal anterior cingulate cortex (dACC), were most
active [23]. Thus, among individuals with PTSD, bottom-
up processing of threat, with subcortical regions including
the PAG and amygdala driving these responses, is mir-
roredbyimminentthreatdetectioninhealthycontrols
and may lead to chronic hyperarousal and defensive pos-
turing towards perception of imminent threat. In particu-
lar, as reviewed above, emotional undermodulation in
PTSD is associated with reduced modulation of the amyg-
dala and dl-PAG by the mPFC leading to chronic activa-
tion of these brain regions and persistent hyperemotional-
ity and hyperarousal. By contrast, among individuals with
PTSD+DS, dominant top-down processing may indicate
over-regulation of defensive processing by PFC regions,
as seen in healthy controls during early detection of threat
(e.g., during a freeze or orienting response). Here, in
PTSD+DS, increased modulation of the amygdala and
PAG regions by the mPFC may be associated with passive
defensive responding and chronic emotional detachment
associated with symptoms of depersonalization and
derealization.
Dissociation and Defense Cascade
Mobbs et al.swork[23,24] is complemented by the defense
cascade model of dissociation [25,26] (see Fig. 1), which
proposes that defensive responses to threat occur on a contin-
uum and are mediated by neural pathways involving the PAG,
hypothalamus, amygdala, and sympathetic and vagal nuclei.
While this model is based on the animal literature and has not
yet been explicitly examined in humans, several authors have
pointed to important relations between this established model
of defensive responding in animals and defensive responding
in humans [25,26].
In this model, threat is met initially with an orienting
freezeresponse (analogous to early detection of threat as
described above) with threatening stimuli first processed
Curr Psychiatry Rep (2018) 20: 118 Page 3 of 14 118
by the superior colliculus (SC), a brain region closely tied
to the PAG, allowing the organism to determine the pres-
ence and location of threat in the environment at a subcor-
tical level. This is followed by fight or flight, via the sym-
pathetic nervous system with release of catecholamines
(e.g., noradrenaline) and activation of the l-PAG (and thus
motor patterns associated with fight or flight). In situations
where the chance of survival is deemed low and the stress-
or is inescapable, a state of tonic immobility followed by
unresponsive immobility/emotional shutdown ensues, also
referred to as a dissociative shutdown response, mediated
by activation of the ventrolateral PAG (vl-PAG) serving as
a break to the l-PAG and inhibition of fight or flight motor
patterns. These responses are mediated by activation of
tactile, sensory, and proprioceptive afferent nerves, in com-
bination with fear, leading to activation of the vagal and
parabrachial sensory nuclei. This shutdown response is
thought to be associated with cortical-sensory deafferenta-
tion, where reduced integration of sensory stimuli via the
thalamus to the cortex allows the individual to reduce
responding to external stimuli [26]. During unresponsive
immobility, the individual exhibits reduced responsiveness
tosensorystimuliandpainacting as a means of shutting
down or modulating overwhelming sensory information.
Whereas in animals, tonic immobility (a form of death
feigning) may occur in order to prevent predation, in
humans a tonic immobility followed by unresponsive
immobility/emotional shutdown during inescapable stress
represents a psychological defense to trauma. Tonic immo-
bility and associated shutdown responses during inescap-
able stress can be considered analogous to dissociative
symptomatology, where reduced integration of environ-
mental sensory stimuli is associated with symptoms of dis-
engagement, depersonalization, and derealization, as well
as interrupted formation of memories and experiences of
emotion [26].
Although there is no direct evidence in humans that the
likelihood of survival increases in relation to the onset of
dissociative or shutdown responses, animal research indicates
that these responses are induced by cues that indicate immi-
nent threat, such as mechanical restraint, pointing towards
their role in enhancing survival [27]. Accordingly, future work
in humans should examine specifically whether chances of
survival increase and/or level of threat decreases in association
with tonic immobility or unresponsive immobility. Notably,
bodily reactions to threat consistent with tonic immobility
have been reported among healthy controls [28]. In particular,
when healthy individuals were shown a threatening
image indicating little chance of escape (gun pointing at
them), they exhibited reduced body sway and bradycardia
(indicative of tonic immobility). By contrast,
pictures consistent with an increased chance of escape (gun
pointing away from them) elicited increased body sway (e.g.,
preparation for active escape or flight) [28]. On balance, the
findings reviewed here suggest strongly that the defense cas-
cade model can be applied to humans.
The defense cascade model is complimented by Porges
polyvagal theory [29], positing that the vagal complex of
the parasympathetic nervous system can be divided into
two systems, the dorsal vagal complex (DVC) and the ven-
tral vagal complex (VVC). The VVC is associated with
bonding, communication with others, and self-soothing,
acting as a brake for the sympathetic nervous system,
which is released under situations of threat allowing fight
or flight responses to occur [29]. Under the polyvagal the-
ory, immobilization and death feigning are thought to oc-
cur due to activation of the DVC and its inhibitory inputs
Dissociative Status
Baseline Arousal
Depersonalization
& Derealization
Responses
Hyperarousal
& Hypervigilance
Responses
Defense Cascade Model
Fight or Flight
Response
Active Defense
Sympathetic Dominance
Unresponsive
Immobility
Passive Defense
Parasympathetic Dominance
Tonic
Immobility
Endocannabinoids Kappa & Mu Opioids
Dorsolateral PAG Mediated Ventrolateral PAG Mediated
Defense Reaction
Fig. 1 Adapted with permission from Zeitschrift für Psychologie/Journal
of Psychology 2010; Vol. 218(2):109127., p. 111 ©2010 Hogrefe
Publishing, www.hogrefe.com. The defense cascade model of
dissociation posits that defensive responses occur on a continuum,
mediated by pathways involving the periaqueductal gray (PAG),
hypothalamus, and amygdala. Here, threat is met initially with an
orienting freezing response via the superior colliculus and PAG,
followed by fight or flight (blue shaded area; mirrored in symptoms of
hyperarousal and hypervigilance) via activation of the sympathetic
nervous system and the dorsolateral PAG (lPAG) involved in activating
motor patterns of fight or flight, via the PAG, amygdala, and limbic
forebrain. Fight or flight is accompanied by release of
endocannabinoids, leading to analgesia. Fight or flight is followed by a
stage of tonic immobility (tonic immobility), with co-activation of both
the sympathetic and parasympathetic nervous systems. Critically, when
escape and/or chance of survival is low, a dissociative state follows
(yellow shaded area), referred to as unresponsive immobility/emotional
shutdown, mediated by the ventrolateral PAG (brake to the lateral PAG).
During unresponsive immobility (shutdown response), sensation,
perception, and motor abilities are significantly altered (mirrored by
symptoms of depersonalization and derealization) and vagal
parasympathetic activity dominates. Opioid-mediated analgesia
accompanies the shutdown response, and emerging work suggests that
perceptual and mood alterations (e.g., dysphoria) may be carried out by
the kappa-opioid (dynorphin) system (activated in response to chronic,
inescapable stress) ([2,18,19••])
118 Page 4 of 14 Curr Psychiatry Rep (2018) 20: 118
to the heart, associated with immobilization, bradycardia,
and apnoea [29].
As described above, the PAG plays an important role in
carrying out motor patterns of fight or flight and is impli-
cated in the defense cascade model [25,26]andin
Mobbs threat processing model [23,24]. Recent work
by Nicholson et al. identifies a pattern of predominant
top-down connectivity from the vmPFC to the amygdala
and PAG and from the amygdala to the PAG among indi-
viduals with PTSD+DS, consistent with overmodulation
of fear processing [19••]. Moreover, as compared to
PTSD, individuals with PTSD+DS exhibit greater func-
tional connectivity of both the CMA and the BLA with
frontal regions, supporting previous findings of increased
top-down inhibition and thus reduced defensive
responding via the CMA [17](seeFig.2).
Increased connectivity between the BLA and CMA has
also been found with regions involved in consciousness,
awareness, and proprioception, (e.g., superior parietal
lobe, precuneus, and cerebellar culmen) among individ-
uals with PTSD+DS [17], where this increased connectiv-
ity may be directly related to experiences of depersonali-
zation and derealization involving altered spatial percep-
tion, perspective taking, and understanding of oneself as a
part of ones environment, particularly when confronted
with threat [17].
In a related pattern of contrast, among individuals with
PTSD and PTSD+DS, the amygdala shows differential
connectivity with insula subregions, a structure key to
monitoring of internal states and arousal [18]. Insular sub-
regions are thought to serve differential functions, with the
anterior, mid, and posterior insula associated with arousal
and interoceptive awareness, with awareness of body
movement and body ownership, and with processing and
perception of pain and sensorimotor function, respectively
[30]. Among individuals with PTSD+DS, increased insula-
BLA connectivity across insula subregions was reported in
a recent study when compared to patients with PTSD or
with controls [18]. In addition, dissociative symptoms of
depersonalization and derealization and PTSD symptom
severity predicted anterior insula-BLA connectivity among
PTSD+DS and PTSD patients [18]. These findings may be
related to altered arousal monitoring (e.g., due to the role
of the BLA in the evaluation of sensory information) [18].
Mid-insula-BLA and posterior insula-BLA connectivity,
respectively, may also be related to altered body perception
and reduced sensory integration seen in PTSD+DS [18].
Critically, the insula has been implicated in the defense
cascade model of dissociation, where it may partly mediate
tonic immobility experienced by individuals with PTSD,
leading to reduced responding to internal and external
cues, as well as reduced proprioceptive awareness [25]
(see Fig. 3and Box 1).
Box 1 Functional glossary: anatomical areas implicated in
PTSD, its dissociative subtype (PTSD+DS), dissociative dis-
orders, and borderline personality disorder
Fight or flight is associated with endocannabinoid-
mediated analgesia via the l-PAG [25], while tonic and un-
responsive immobility are associated with activation of the
parasympathetic nervous system and opioid-mediated anal-
gesia, leading to reduced awareness by the organism of
Emotion regulation
The Prefrontal Cortex (PFC) comprises distinct areas related to emotion
regulation, emotional processing, and executive functioning. Whereas
PTSD+DS is associated with excessive medial prefrontal inhibition
(mPFC) of limbic regions including the amygdala [16], the classical
presentation of PTSD is characterized by reduced prefrontal activity
and limbic over-activity, representing emotional undermodulation.
Lobule VI and crus I of the cerebellum are also involved in executive
functioning and in the regulation of emotional responses, further
supporting exacerbated top-down inhibition in the dissociative subtype
[31]. Finally, the hippocampus is associated with contextual responses
to traumatic memories [32••].
Emotion reactivity and response
The basolateral amygdala (BLA) aids in the evaluation of sensory infor-
mation and its subsequent cortical processing via projections to the
thalamus, striatum, and PFC. This subregion of the amygdala is mod-
erated by top-down inhibition from the mPFC [21]. By contrast, the
centromedial amygdala (CMA) is responsible for activation of
nociception and for the execution of fear responses via projections to
the PAG and other subcortical brain regions [21].
The periaqueductal gray (PAG) and its subregions contribute to auto-
nomic responses associated with fear. Here, the dorsolateral and lateral
PAG (dl-PAG and l-PAG) are implicated in activation of the sympa-
thetic nervous system in response to threat and active defense
responses, associated with emotional undermodulation [22].
Conversely, the ventrolateral PAG (vl-PAG) promotes emotional
overmodulation, serving as the brakefor the dl-PAG and l-PAG, and
is associated with passive defensive responses and activation of the
parasympathetic nervous system [22]. The superior colliculus (SC) is
functionally tied to the PAG, allowing the organism to determine the
presence and location of threat in the environment at a subcortical
level. Finally, the hypothalamus is a key structure involved in regu-
lating stress hormones and the HPA axis [33].
Interoceptive awareness
The insular subregions have differential functions; the anterior insula is
associated with arousal and interoceptive awareness; the mid-insula is
related to awareness of body movement and body ownership; and the
posterior insula is associated with processing and perception of pain
and sensorimotor function.
Consciousness, awareness, and proprioception
The precuneus is involved in first-person perspective taking,
consciousness, and self-related mental representations during rest [34].
The superior parietal lobe has a wide range of functions, including
spatial orientation, motor imagery, monitoring of imagined limb
configuration, and proprioception [35]. Both the temporoparietal
junction (TPJ) and rolandic operculum (RO) have been previously
shown to be implicated in depersonalization responses [3638]. The
dorsal posterior cingulate cortex (dPCC) is involved in consciousness,
awareness, and attention [39].
Curr Psychiatry Rep (2018) 20: 118 Page 5 of 14 118
sensory stimuli, including pain, and an effective temporary
shut-downof central nervous system activity hypothe-
sized to occur through functional cortical deafferentation
at the level of the thalamus [25,26].
Importantly, Mobbs threat detection model and the de-
fense cascade model complement one another, providing a
framework for understanding threat responding in the context
of key dimensions, including perceived imminence,
escapability, and proximity. In particular, both models posit
that when threat is perceived to be imminent, active defensive
responses are employed (e.g., fight or flight), which are driven
by subcortical brain structures (e.g., dACC, PAG) and associ-
ated with decreased prefrontal cortex activation.
Alternatively, increased prefrontal cortex activation is associ-
ated with reduced responding in subcortical regions (e.g.,
PAG and amygdala), driving passive defensive responses
when threat is deemed inescapable, characterized by tonic
immobility and increasing emotional detachment and emo-
tional shutdown if the stressor remains inescapable [2325].
Taken together, the available evidence suggests that disso-
ciative responses in PTSD+DS are carried out bybrain regions
involved in the defense cascade model of dissociation and also
mirror responses seen in Mobbs threat detection model dur-
ing anticipation of threat. Subcortical regions, including the
amygdala, hypothalamus, and PAG are implicated, with the
PAG emerging as a key subcortical structure involved in mod-
ulation of both fight or flight and dissociative shut-down
responses via the dl-PAG/l-PAG and vl-PAG, respectively.
In particular, dissociative responses are thought to occur via
the vl-PAG indicating that the threat is too great for fight or
flight responses to be effective, leading to release of endoge-
nous opioids and a shutdown of sympathetic signaling and
increase in parasympathetic signaling, resulting in reduced
awareness of the environment and sensory integration.
Critically, the amygdala complexes also play important and
differential roles among individuals with PTSD+DS, with re-
duced activation of threat responses via the CMA and reduced
awareness of the external environment via the BLA due to
increased top-down inhibition [17,19••] (also see Box 1).
Transdiagnostic Evidence for the Neurobiological
Model of Dissociation as Defensive Overmodulation
of Affective Arousal
The existing evidence among dissociative disorders, in-
cluding DID and depersonalization disorder also points
to aberrant reactivity and functional connectivity of key
regions associated with the defense cascade model of dis-
sociation and Mobbs threat processing model and mirrors
findings of emotional overmodulation as seen in PTSD+
DS. Specifically, aberrant cortico-limbic functioning
among individuals with depersonalization disorder has
been reported, where increased activation in prefrontal
regions [e.g., mPFC, dlPFC and reduced activation of
limbic regions (e.g., the amygdala)] is seen in conjunction
with attenuated responding of the autonomic system [13].
Moreover, reduced responsivity of the insula has been
noted among individuals with depersonalization disorder
in response to aversive or sad images [13,14], a finding
that may be related to experiences of tonic immobility and
Directionality of Connectivity
vmPFC
PAG
Bilateral
BLA
Bilateral
CMA
vmPFC
PAG
Bilateral
BLA
Bilateral
CMA
PTSD Dissociative Subtype
Fig. 2 Based on work by Nicholson and colleagues, the directionality of
connectivity of key brain regions implicated in emotional responding
among individuals with PTSD and PTSD+DS is elucidated. PTSD (left
side of image) is characterized by predominant bottom-up connectivity
from the peraqueductal gray (PAG) to the bilateral centromedial
amygdala (CMA) and from the BLA to the vmPFC suggesting
defensive responding driven by mibrain and limbic regions and chronic
fear responses. In contrast, PTSD+DS (right side of image) is
characterized by predominant top-down connectivity between the
bilateral CMA and PAG and vmPFC with the BLA, consistent with
chronic emotional overmodulation and detachment from emotional
responses associated with symptoms of depersonalization and
derealization
118 Page 6 of 14 Curr Psychiatry Rep (2018) 20: 118
reduced responding to internal and external cues [25]and
that is consistent with findings of reduced insula-BLA
connectivity in PTSD+DS [18].
In addition to findings in depersonalization disorder, indi-
viduals with DID also demonstrate aberrant neural reactivity
consistent with excessive top-down inhibition of limbic re-
gions, depending on their identity state [13,14]. In particular,
when individuals with DID were in a traumatic identity state
(a state with access to trauma memories), these patients
showed increased activity in limbic regions, as well as de-
creased activity in prefrontal regions, and increased perfusion
in the thalamus in comparison to when they were in their
normal functioning identity state(a state where dissociative
amnesia is present) [13,14]. Findings of increased thalamic
perfusion in the trauma vs. dissociative identity state are crit-
ical given the role of the thalamus in sensory integration and in
the defense cascade model of dissociation [3,25]. Moreover,
Sar and colleagues reported reduced perfusion in the
orbitofrontal cortex of individuals with DID while in their
normal identity state[40], suggesting that during the normal
identity state individuals with DID may experience emotional
undermodulation. Importantly, in Mobbs threat processing
model, the OFC is activated as threat becomes more distant,
suggesting it is involved in signaling safety [24].
Finally, among BPD samples, whereas trait dissociation
was associated with increased amygdala-dlPFC connectivity,
acute dissociative experiences correlated to reduced amygdala
reactivity to negative stimuli [13], again mimicking findings
among individuals with PTSD+DS [41]. Furthermore, among
individuals with BPD, increased prefrontal activity and re-
duced amygdala responding in response to painful stimuli
has been reported in conjunction with reduced pain sensitivity
[13,14].
In sum, the available literature investigating dissociation
transdiagnostically among PTSD+DS, depersonalization dis-
order, DID, and BPD supports a model of emotional
overmodulation underlying dissociative experiences.
Moreover, these findings converge with the defense cascade
Cerebellum
Superior Parieta l Lobe,
Dorsal Posterior
Cingulate Cortex,
Precuneus
Le
BLA
Right
CMA
Le
CMA Right
BLA
Emoon Reacvity & Response
Le Basolateral Amygdala*
Right Basolateral Amygdala*
Le Centromedial Amygdala*
Right Centromedial Amygdala*
Ventrolateral Periaqueductal Gray*
Emoon Regulaon
PFC
Cerebellum (Lobule VI/Crus I)
Ant.
Insula
Mid
Insula
Post.
Insula
PFC
Consciousness, Awareness
of Bodily Self &
Propriocepon
Superior Parietal Lobe
Dorsal Posterior Cingulate
Cortex
Precuneus
Temporoparietal Juncon
Interocepve Awareness
Anterior Insula*
Mid Insula*
Posterior Insula*
Paerns of Increased Connecvity
in the Dissociave Subtype versus PTSD
Temporoparietal Juncon
vlPAG
Fig. 3 Increased patterns of resting-state functional connectivity in the
dissociative subtype as compared to PTSD without the subtype. Here,
brain regions with an asterisk indicate seed regions from insula,
amygdala, and periaqueductal gray functional connectivity studies
comparing patients with the dissociative subtype of PTSD with PTSD
patients [17,18,20••]. Regions in green correspond to brain areas
implicated in emotion regulation, including the prefrontal cortex and
lobule VI/crus I of the cerebellum. Areas in yellow correspond to areas
implicated in emotion reactivity and response, including the amygdala
complexes (bilateral basolateral amygdala and centromedial amygdala)
and the ventrolateral periaqueductal gray. Critically, the left amygdala is
associated with detailed and elaborate emotional response evaluation,
while the right amygdala is more involved in rapid and automatic
detection of emotional stimuli [21]. Brain areas in red correspond to
subregions of the insula related to interoceptive awareness. Finally,
brain areas in blue are related to the processing of awareness,
consciousness, and proprioception, including the superior parietal lobe,
dorsal posterior cingulate cortex, precuneus, and the temporoparietal
junction. Importantly, among patients with the dissociative subtype of
PTSD, increased connectivity between emotion regulation regions
(regions in green) and emotion reactivity regions (regions in yellow) is
thought to contribute to a characteristic pattern of emotion
overmodulation associated with symptoms such as depersonalization
and derealization and emotional detachment. Additionally, increased
connectivity between emotion reactivity regions (regions in yellow) and
regions relating to interoceptive awareness, perception of self, and bodily
self-awareness (regions in blue) may provide an explanation for
symptoms such as an altered sense of self and altered perception of the
environment associated with symptoms of depersonalization and
derealization. Abbreviations: PFC, prefrontal cortex; BLA, basolateral
amygdala; CMA, centromedial amygdala; vlPAG, ventrolateral
periaqueductal gray; post, posterior; ant, anterior
Curr Psychiatry Rep (2018) 20: 118 Page 7 of 14 118
model of dissociation highlighting aberrant reactivity of lim-
bic regions, including the amygdala and insula [25]seenin
dissociative disorders and BPD [13,14].
Opioid- and Endocannabinoid-Mediated
Contributions to Dissociation and Stress
Responses
Opioid-Mediated Contributions
Recent work elucidating the neurochemical components of the
defense cascade model of dissociation provides opportunities
for the identification of specific, targeted treatment approaches
for dissociative symptoms transdiagnostically. As mentioned
briefly above, opioid-mediated contributions play a critical role
in defensive responding. Moreover, not only are opioids in-
volved in the analgesic aspects of defensive responses, but they
also play important roles in their enactment. Specifically, opi-
oids are implicated in immobility, suppressed vocal responses,
and downregulation of the sympathetic nervous system [3].
Furthermore, opioid receptors are found in high volumes in
the thalamus and claustrum and may be related to reduced
somatosensory integration and disruptions in consciousness as-
sociated with shutdown defensive responses [3,42].
The endogenous opioid system has long been associated
with combine paragraphs PTSD. Here, seminal work by van
der Kolk utilizing an animal model of PTSD, inescapable
shock, provided a key demonstration of the relation between
endogenous opioids and stress-induced analgesia [43], with
later work identifying further an association between chronic
PTSD symptomatology and heroin abuse in Vietnam veterans
[44]. The inescapable shock model has been suggested to
mimic closely chronic, inescapable trauma experienced by
victims of childhood abuse. Inescapable shock is also associ-
ated with altered responding of the endogenous opioid system,
particularly, initial upregulation followed by chronic down-
regulation of opioid signaling [43]. It was hypothesized that
these processes become conditioned responses, replicable at
thetimeofexposuretotraumacuesorsubsequentstress[43].
This hypothesis was supported in work identifying secretion
of endogenous opioids following exposure to trauma-related
stimuli [45] and increased β-endorphin levels in the cerebro-
spinal fluid of veterans with PTSD compared to those without
PTSD, as well as correlations between PTSD intrusion and
avoidant symptoms and β-endorphin levels [46].
Notably, it has been further suggested that this chronic
downregulation of the endogenous opioid system and upreg-
ulation of opioid release in response to stress may lead trau-
matized individuals to engage in subsequent self-destructive
behavior (e.g., self-harm, involvement in future abusive rela-
tionships) [47]. Additional research suggests that the release
of opioids at the time of trauma may be protective, where
among juvenile burn victims, levels of PTSD symptomatolo-
gy were correlated with the dose of morphine received
posttrauma, such that those who received higher doses of
morphine reported fewer PTSD symptoms 6 months
posttrauma [48]. Similarly, individuals given morphine during
initial treatment of physical trauma were less likely to develop
PTSD (OR 0.47, p<.001)[49]. Taken together, these findings
suggest that mu-opioid receptors play an important role in
posttrauma reactions and increased opioid signaling following
trauma may be protective.
Indeed, upregulation of opioid responding appears to per-
sist among individuals with PTSD. For example, Pitman and
colleagues reported findings of naloxone (opioid receptor an-
tagonist) reversible stress-induced analgesia among veterans
with PTSD in comparison to those without PTSD, suggesting
upregulation of the opioid response following exposure to
trauma cues [50]. In addition,altered mu-opioid receptor bind-
ing has been reported among combat-exposed individuals
with PTSD and those without PTSD in comparison to non-
trauma-exposed controls, where reduced binding was reported
in subcortical regions, including the amygdala and thalamus,
and cortical regions, including the insula, mPFC, and dorsal
ACC [51]. By contrast, increased binding was reported in the
orbitofrontal cortex among the PTSD group compared with
the trauma-exposed controls and healthy controls [51]. Here,
the authors posit that inhibitory action of mu-opioid receptors
in the OFC may lead to impaired regulation of subcortical
structures involved in emotional responding [51], i.e., emotion
undermodulation.
Opioids also play a central role in attachment processes,
where social isolation is associated with reduced opioid levels
and reduced availability of endogenous opioids leads to in-
creased motivation to seek social contact [52]. Here, van der
Kolk linked profound disruptions in attachment that occur as a
result of prolonged childhood abuse with alterations in the en-
dogenous opioid system [43], as mirrored in findings of altered
endogenous opioid levels and receptor availability among indi-
viduals with PTSD [45,46,51]. The relation between attach-
ment processes and alterations in the endogenous opioid system
are of particular importance given the strong relation between
attachment trauma and dissociative symptomatology [53,54].
This may explain why betrayal trauma, assault by one expected
to love and protect, is particularly likely to trigger immobiliza-
tion, since it imposes not only the current assault but diminishes
theprospectoffutureescape[55].
Whereas most studies have investigated the mu-opioid sys-
tem (activated by neurochemical endorphins) in trauma-
exposed persons, the kappa-opioid system is also a candidate
mechanism for mediating negative emotional experiences
such as depression and dysphoria to chronic inescapable stress
[56]. Recent evidence for the dysphoric components of the
kappa-opioid system comes from a study demonstrating that
the dissociogenic drug ketamines antidepressant effect is
118 Page 8 of 14 Curr Psychiatry Rep (2018) 20: 118
completely blocked by the opiate antagonist naloxone [57].
Furthermore, recent work has tied the kappa-opioid system
(dynorphins) to disruptions in consciousness [42,58]. Here,
studies reveal that individuals who ingested Salvia divinorum
(SD), a kappa-opioid receptor agonist, described alterations in
consciousness, including abrupt shifts in normal waking con-
sciousness and disorientation, marked changes in sensory pro-
cessing and perceptual integration (including auditory, visual,
and interoceptive perception), visual distortions, tactile, or
kinaesthetic hallucinations, change in affect (both negative
and positive), and altered reality monitoring [42,58].
Notably, these individuals also reported experiences of deper-
sonalization, or a feeling as though they do not belong to their
own body, similar to those described as altered states of con-
sciousness associated with PTSD+DS [59]. Although these
experiences may not be precisely equivalent to dissociative
experiences of individuals with PTSD+DS or other trauma-
related disorders, we hypothesize that the kappa-opioid sys-
tem may play a contributing role in experiences of dissocia-
tion in trauma-related disorders (see Fig. 2). In particular,
opioid-mediated analgesia is thought to be a key component
of defensive shut-down,and may also play a critical role in
the experience of disrupted consciousness, as seen during dis-
sociative states [25].
The claustrum has been implicated as a key structure in-
volved in kappa-opioid mediated disruptions in conscious-
ness, and potentially, dissociative experiences [42,60]. In par-
ticular, the claustrum is thought to be in part responsible for
consciousness given its anatomical location and reciprocal
connections with multiple cortical regions [60]. More recently,
it has been suggested that the endogenous kappa-opioid sys-
tem may play a key role in this function, given high volumes
of kappa-opioid receptors (KOR) in the claustrum and afore-
mentioned alterations in experiences of consciousness de-
scribed by subjects who have ingested SD [42]. Importantly,
the claustrum has also been implicated in defensive
responding among individuals with PTSD [61]. Along with
the insula, the claustrum is considered a component of the
salience network (SN), a brain network integral in orienting
individuals to salient internal and external stimuli. Recent in-
vestigations have revealed decreased integration of the claus-
trum with the SN during subliminal threat processing among
individuals with PTSD [61]. Although not investigated in
PTSD+DS specifically, this finding may indicate a reduced
ability to integrate conscious experience during salience de-
tection (in this case, threat detection) among individuals with
PTSD. Critically, given the claustrums role in the integration
of perceptual stimuli into consciousness, aberrant functioning
of the claustrum could lead to disrupted threat processing ob-
served in both PTSD and its dissociative subtype.
In line with these findings, emerging work using positron
emission tomography (PET) neuroimaging has identified al-
terations in KOR receptor availability among trauma-exposed
individuals in relation to trauma-related symptomatology.
Specifically, lower levels of KOR availability in the
amygdala-anterior cingulate cortex-ventral striatal neural cir-
cuit, and in the insula, caudate, and frontal cortex were asso-
ciated with increased severity of a composite symptom score,
including symptoms of emotional numbing, anhedonia, de-
tachment, and reduced range of affect [62]. Here, reduced
availability of KORs may be related to increased circulating
opioids following trauma. The aforementioned symptoms
converge with symptoms such as emotional numbing and de-
tachment. Furthermore, these regions are implicated in both
Mobbs threat processing model and the defense cascade
models of dissociation.
Finally, emerging work has identified increased functional
connectivity of the claustrum with the bed nucleus of the stria
terminalis (BNST) among individuals with PTSD+DS as
compared to those with PTSD and to healthy controls [63].
The BNST is a subcortical brain structure considered an ex-
tension of the amygdala that has been implicated consistently
in the anticipation of threat and worry about the future (as
compared to the amygdala, involved in evaluation and re-
sponse to immediate threat) [63]. Critically, as the BNST also
contains KORs, the authors posit that increased connectivity
between the BNST and the claustrum in PTSD+DS may be
related to increased activation of the kappa-opioid system in
response to chronic inescapable stress, leading to dissociative
symptoms and secondary dysphoria.
Thus, while alterations in the mu-opioid system first
emerged in the PTSD literature, in association with symptoms
including intrusions and avoidance and increased analgesia [3,
45,46], the kappa-opioid system has emerged as a candidate
neurochemical system mediating alterations in consciousness.
In particular, while both the mu- and kappa-opioid system
may be involved in dissociative reactions and the defense
cascade, the mu-opioid system may be related to analgesic
effects, while the kappa-opioid system is responsible for alter-
ations in consciousness and dysphoria. Here, we posit that the
kappa-opioid system and claustrum play key roles in dissocia-
tive symptoms and dysphoria. In particular, this hypothesis is
supported by findings of increased endogenous opioids
among individuals with PTSD [45,46] and evidence of aber-
rant functional connectivity of the claustrum in PTSD+DS
[63], coupled with the role of the claustrum in experiences
of consciousness as mediated by the kappa-opioid system
[42]. Furthermore, when considering the role of opioid during
defensive shutdown under conditions of inescapable stress (as
in defense cascade model of dissociation), it is likely that the
release of opioids during this shift in defensive responding
plays a role in experiences of disrupted consciousness. In par-
ticular, given findings reviewed above indicating an associa-
tion between the kappa-opioid system and experiences of al-
tered consciousness in healthy individuals [42,58] and the
dissociative quality of defensive shutdown responses, it is
Curr Psychiatry Rep (2018) 20: 118 Page 9 of 14 118
possible that the release of endogenous opioids during this
phase of the defense cascade underlies experiences of
disrupted consciousness.
Endocannabinoid-Mediated Contributions
The endogenous cannabinoid (endocannabinoid) system has
also been characterized as a key component of the defense
cascade model (see Fig. 1). In particular, endocannabinoid
signaling, emanating from the lateral PAG [2], is responsible
for analgesia during the fight or flight response [25]. In addi-
tion, endocannabinoids are important regulators of the stress
response and are involved in adaption of the neuroendocrine
system following repeated stress [64]. Endocannabinoids play
a neuromodulatory role associated with inhibition of neuro-
transmitter release from both excitatory and inhibitory neu-
rons and have been shown to influence the behavioral com-
ponents of the fight or flight stage of the defense cascade [64].
For example, cannabis use has been associated with reduced
neuronal firing in the amygdala and increased reactivity of the
vmPFC of humans in response to emotional stimuli [64].
Importantly, among individuals with PTSD, increased avail-
ability of cannabinoid receptor type 1 (CB1 receptors) in the
amygdala (associated with reduced bioavailability of
endocannabinoids) was associated with increased attentional
bias to threat, which mediated the relation between CB1 re-
ceptor availability and threat-related symptomatology (e.g.,
re-experiencing, hyperarousal) [65]. These data suggest that
reduced levels of endocannabinoids may be related to in-
creased threat sensitivity and related symptoms in individuals
with PTSD.
Given these findings, among others, Hill et al. [64]sug-
gest an endocannabinoid deficiency hypothesis of PTSD,
where exposure to stress reduces endocannabinoid signal-
ing, resulting in hyperactivity of the amygdala, hypoactivity
of the mPFC, and impaired regulation of the stress response.
This may be particularly relevant for individuals who expe-
rience predominantly emotion undermodulation. By con-
trast, the effects of cannabinoids on other brain structures
implicated in Mobbs fear processing model and the defense
cascade model may diverge from these findings.
Specifically, injection of cannabinoid receptor agonists into
the dl-PAG of rats was associated with increased sympathet-
ic activity, blood pressure, and limb movements [66], sug-
gesting that they may be important in carrying out motor
and sympathetic responses of fight or flight. Paradoxically,
exposure to stressful stimuli has been associated with in-
creased levels of endocannabinoids in the PAG of rats and
injection of CB1 agonists into the PAG has also been asso-
ciated with anxiolytic effects in rats [67]. Importantly, these
aberrant findings may be understood through findings of a
bell-shaped dose response curve, whereby low doses of
cannabinoids are associated with anxiolytic effects and high
doses are associated with anxiogenic effects [68].
Given the role of endocannabinoids in mediating fight or
flight in the defense cascade, their neuromodulatory role and
impact on emotional responses via signaling in the amygdala
and vmPFC, and their role in modulating activity of the PAG,
modulation of the endocannabinoid system may provide an
opportunity to treat emotion undermodulation, including
hyperarousal/fight or flight symptoms associated with the de-
fense cascade. Importantly, however, cannabinoids are known
to have paradoxical effects at high doses, where increased
fight or flight and panic-like symptoms are observed.
Implications for Treatment and Future Pharmacotherapies
Increased identification of the roles of the kappa-opioid and
endocannabinoid systems in the defense cascade model pro-
vides a unique opportunity for identification of targeted novel
pharmacotherapeutic interventions for individuals with PTSD
and PTSD+DS, and for those experiencing clinically signifi-
cant dissociative symptoms more broadly (see Table 1). This
is particularly critical given the only modest efficacy of cur-
rent pharmacotherapy approaches for individuals with PTSD
[69] and findings that individuals with PTSD often retain their
diagnosis or continue to experience clinically significant
symptoms following treatment with first-line psychotherapies
[70,71]. Furthermore, pharmacological and non-
pharmacological treatment approaches to dissociative symp-
toms in PTSD+DS and transdiagnostically have not been ad-
equately explored.
Both endocannabinoids and opioids are released in re-
sponse to stress and play differential and important roles in
the defensive cascade model, modulating fight or flight and
dissociative shutdown responses, respectively. Thus, modula-
tion of these neurochemicals provides the opportunity to in-
tervene differentially for patients exhibiting predominantly
emotion undermodulation/fight or flight symptomatology
(PTSD) and those who present with emotion
overmodulation/passive defensive responses associated with
dissociative symptoms (PTSD+DS). Pharmacological inter-
ventions that target these neurochemical systems may be of
significant benefit as these patterns of defensive responding
are re-enacted among individuals with trauma-related pathol-
ogy. Evidence of disrupted endocannabinoid and opioid sig-
naling among individuals with PTSD and other trauma-related
pathology provides further evidence for their potential utility.
Indeed, emerging evidence points to the use of naloxone and
naltrexone, nonspecific opioid receptor antagonists targeting
both mu- and kappa-opioid receptors, in the treatment of dis-
sociative symptoms among individuals with depersonaliza-
tion disorder [72]andBPD[51; but see 52].
The kappa-opioid system has been linked further to dys-
phoric components of the opioid response, including reduced
118 Page 10 of 14 Curr Psychiatry Rep (2018) 20: 118
motivation, and has been associated with depressive states
[73]. KOR antagonists have also been found to have antide-
pressant effects among rodents [74]. Furthermore, recent work
highlights that among trauma-exposed individuals, KOR
availability in several key regions associated with Mobbs
defense model and the defense cascade model, including the
amygdala and anterior cingulate cortex, are associated with
dysphoric symptoms [62]. Thus, these findings provide pro-
vocative evidence that opioid receptor antagonists, and in par-
ticular KOR antagonists, may be effective both in disrupting
re-enactment of emotional shutdown and in reducing
dissociative symptoms of depersonalization and derealiza-
tion and negative mood states associated with PTSD+DS.
Importantly, given the transdiagnostic nature of dissocia-
tive symptoms [8], KOR antagonists may prove to be
useful in their treatment across disorders where dissocia-
tive symptoms predominate.
Whereas the kappa-opioid system exerts its influence dur-
ing the unresponsive immobility/emotional shutdown phase
of the defense cascade model, endocannabinoids have
emerged as important regulators of fight or flight responses.
Emerging work also highlights the potential utility of canna-
binoid receptor agonists in the treatment of PTSD. In particu-
lar, uncontrolled trials of nabilone, a synthetic form of Δ
9
-
tetrahydocannbinol (THC, the psychoactive component of
cannabis), have reported reductions in nightmares and re-
duced PTSD symptom severity among individuals with
PTSD [75,76]. In addition, a recent randomized-controlled
trial reported a reduction in distressing nightmares in a small
sample of individuals with PTSD [77]. Specifically, a sample
of 10 males with PTSD stemming from operational trauma
(i.e., combat) who reported distressing dreams at baseline ex-
perienced a significant reduction on the Clinician
Administered PTSD Scale (CAPS) recurrent and distressing
dreams item (3.6 points, where the maximum score is 8 and
higher scores indicate greater frequency and intensity of
symptoms) after receiving treatment with nabilone for a peri-
od of 7 weeks [77]. Similarly, the addition of THC to the drug
regimen of individuals with PTSD was associated with re-
duced nightmares and hyperarsoual [78]. Thus, there is emerg-
ing evidence that treatment with THC or nabilone reduces
nightmares among individuals with PTSD and may be asso-
ciated with reduced hyperarousal.
Although treatment with both kappa-opioid antagonists
and cannabinoids appears to hold promise for the treatment
of dysregulation in the dissociative and fight or flight compo-
nents of the defense cascade among individuals with PTSD
and PTSD+DS, respectively, a lack of rigorous randomized-
controlled trials precludes definitive conclusions about their
efficacy. Furthermore, given findings of bell-shaped dose re-
sponse curve for the use of cannabis [68], careful dosing and
investigation of the therapeutic effects of different doses will
be important. Similarly, KOR antagonists have been found to
have long durations of action [74], and thus careful investiga-
tion of dosing and effects of the drug over the period that it is
active will be necessary. Moreover, the utility of these inter-
ventions may differ for individuals with PTSD+DS and those
with PTSD. Specifically, individuals with PTSD+DS do not
experience only static symptoms of depersonalization and de-
realization, but rather vacillate between symptoms of emotion
under- and overmodulation (although emotion overmodulation
predominates). By contrast, individuals with PTSD without the
dissociative subtype do not usually experience symptoms of
depersonalization and derealization [16]. It is therefore
Table 1 Hypothesized mechanisms and target symptoms of proposed
pharmacological interventions
Proposed
pharmacological
treatment
Symptom targeted Hypothesized
mechanism
and evidence
Opioid-receptor
antagonists
Dissociative symptoms,
including
depersonalization,
derealization,
emotional numbing,
and dysphoria
Reduced signaling at
KORs
KORs linked to
dysphoric components
of opioid response
Reduced KOR
availability in amygdala
and anterior cingulate
cortex associated with
dysphoric symptoms
among trauma-exposed
individuals
Use of KOR agonists
associated with
experiences of altered
consciousness,
disorientation, and
perceptual disturbances,
including
depersonalization and
derealization
Cannabinoid
receptor
agonists
Hyperarousal,
re-experiencing
symptoms
Increased activation of
CB1 receptors
Increased availability of
CB1 receptors (due to
reduced bioavailability
of endocannabinoids) in
amygdala of individuals
with PTSD associated
with increased
attentional bias to threat
and hyperarousal
Treatment with nabilone
(synthetic cannabinoid)
or THC associated with
reduced nightmares and
hyperarousal in
individuals with PTSD
(small uncontrolled
trial)
KOR, kappa-opioid receptor; CB1, cannabinoid receptor type 1
Curr Psychiatry Rep (2018) 20: 118 Page 11 of 14 118
important to treat both symptoms of emotion under- and
overmodulation experienced in PTSD+DS, and thus treatment
with endocannabinoids may be appropriate not only for indi-
viduals with PTSD but may also be potentially combinable with
KOR antagonists in those with PTSD+DS. Importantly, the
longitudinal course of PTSD and PTSD+DS remain unknown
(e.g., an individual may meet criteria for PTSD and PTSD+DS
at different times), rendering it necessary for clinicians to close-
ly monitor patients symptoms in order to ensure appropriate
treatment.
Conclusions
We have reviewed emerging neurobiological models of disso-
ciative symptomatology often experienced by individuals
with trauma-related disorders, including the dissociative sub-
type of PTSD, BPD, and DID as well as other psychiatric
disorders. In particular, the defense cascade model of dissoci-
ation and Mobbs threat processing model complement one
another to provide an elegant description of neurobiological
responses to threat and, consequently, dissociative symptom-
atology [2325]. These models describe differential responses
to threat depending on perceived imminence, escapability, and
proximity. Here, individuals utilize active defensive responses
(e.g., fight or flight) driven by subcortical brain structures
(e.g., PAG, amygdala) and associated decreased prefrontal
cortex activation when threat is perceived to be imminent
(e.g., fight or flight). By contrast, when threat is deemed ines-
capable, reduced activation of subcortical regions (e.g., PAG
and amygdala) associated with increased prefrontal cortex
activation drive passive defensive responses characterized by
emotional detachment and dissociative shutdown, including
reduced responding to environmental stimuli, a response char-
acteristic of dissociative symptoms, including depersonaliza-
tion and derealization [2325]. A growing body of evidence
reviewed here suggests key alterations in structures implicated
in these models among individuals with PTSD+DS, BPD and
DID, including most notably, the amygdala, PAG, claustrum,
andprefrontalcorticalregions[13,14,17,18,19••,20••,63].
Indeed, emerging work has identified aberrant reactivity and
connectivity of subcortical regions involved in the defense
cascade, including the PAG, amygdala, and claustrum among
individuals with PTSD+DS, as well as findings of predomi-
nant top-down connectivity between forebrain and subcortical
regions consistent with early findings of emotional
overmodulation [17,18,19••,20••,63].
Our understanding of these neurobiological mechanisms
allows for the opportunity to discover novel pharmacological
interventions. We reviewed an emerging body of evidence
implicating the kappa-opioid system in experiences of altered
consciousness, carried out by regions implicated in PTSD+
DS, including the BNST and claustrum [42,56,58,60,63].
Thus, we suggest that treatment with kappa-opioid antagonists
may be a promising approach to the treatment of emotion
overmodulation, including symptoms of depersonalization
and derealization [79]. In contrast, the endocannabinoid sys-
tem has been implicated in downregulation of fight or flight
responses of the defense cascade, suggesting that treatment
with cannabinoids may target emotion undermodulation,
which importantly, is experienced by individuals with
PTSD+DS and often precede symptoms of emotion
overmodulation, including symptoms of depersonalization
and derealization. Future work will be critical to understand
the efficacy of these putative pharmacological interventions,
particularly in order to determine when and at what doses
therapeutic effectiveness can be achieved.
References
Papers of particular interest, published recently, have been
highlighted as:
Of importance
•• Of major importance
1. American Psychiatric Association. Diagnostic and statistical man-
ual of mental disorders. 5th ed. Arlington: American Psychiatric
Publishing; 2013.
2. Briere J, Weathers FW, Runtz M. Is dissociation a multidimensional
construct? Data from the multiscale dissociation inventory. J
Trauma Stress. 2005;18(3):22131.
3. McKinnon MC, Boyd JE, Frewen PA, Lanius UF, Jetly R,
Richardson JD, et al. A review of the relation between dissociation,
memory, executive functioning and social cognition in military
members and civilians with neuropsychiatric conditions.
Neuropsychologia. 2016;90:21034.
4. Spiegel D, Lewis-Fernández R, Lanius R, Vermetten E, Simeon D,
Friedman M. Dissociative disorders in DSM-5. Annu Rev Clin
Psychol. 2013;9:299326.
5. Dalenberg CJ, Brand BL, Gleaves DH, Dorahy MJ, Loewenstein
RJ, Cardeña E, et al. Evaluation of the evidence for the trauma and
fantasy models of dissociation. Psychol Bull. 2012;138(3):55088.
6. Wolf EJ, Lunney CA, Miller MW, Resick PA, Friedman MJ,
Schnurr PP. The dissociative subtype of PTSD: a replication and
extension. Depress Anxiety. 2012;29:67988.
7. Stein DJ, Koenen KC, Friedman MJ, Hill E, McLaughlin KA,
Petukhova M, et al. Dissociation in posttraumatic stress disorder:
evidence from the world mental health surveys. Biol Psychiatry.
2013;73(4):30212.
8. Lyssenko L, Schmahl C, Bockhacker L, Vonderlin R, Bohus M,
Kleindienst N. Dissociation in psychiatric disorders: a meta-
analysis of studies using the dissociative experiences scale. Am J
Psychiatry. 2017;175:3746.
9. Simeon D, Guralnik O, Schmeidler J, Sirof B, Knutelska M. The
role of childhood interpersonal trauma in depersonalisation disor-
der. Am J Psychiatry. 2001;158(9):102733.
10. Parlar M, Frewen PA, Oremus C, Lanius RA, Mckinnon MC.
Dissociative symptoms are associated with reduced neuropsycho-
logical performance in patients with recurrent depression and a
history of trauma exposure. Eur J Psychotraumatol. 2016;7:29061.
118 Page 12 of 14 Curr Psychiatry Rep (2018) 20: 118
11. Sar V, Akyüz G, Oztürk E, Alioğlu F. Dissociative depression
among women in the community. J Trauma Dissociation.
2013;14:42338.
12. Vonderlin R, Kleindienst N, Alpers GW, Bohus M, Lyssenko L,
Schmahl C. Dissociation in victims of childhood abuse or neglect:
a meta-analytic review. Psychol Med. 2018.
13. Krause-Utz A, Frost R, Winter D, Elzinga BM. Dissociation and
alterations in brain function and structure: implications for border-
line personality disorder. Curr Psychiatry Rep. 2017;19:6.
14. Brand BL, Lanius R, Vermetten E, Loewenstein RJ, Spiegel D.
Where are we going? An update on assessment, treatment, and
neurobiological research in dissociative disorders as we move to-
ward the DSM-5. J Trauma Dissociation. 2012;13:931.
15. Sar V, Alioǧlu F, Akyüz G. Experiences of possession and paranor-
mal phenomena among women in the general population: are they
related to traumatic stress and dissociation? J Trauma Dissociation.
2014;15(3):30318.
16. Lanius RA, Vermetten E, Loewenstein RJ, Brand B, Christian S,
Bremner JD, et al. Emotion modulation in PTSD: clinical and neu-
robiological evidence for a dissociative subtype. Am J Psychiatry.
2010;167(6):6407.
17. Nicholson AA, Densmore M, Frewen PA, Théberge J, Neufeld RW,
McKinnon MC, et al. The dissociative subtype of posttraumatic
stress disorder: unique resting-state functional connectivity of
basolateral and centromedial amygdala complexes.
Neuropsychopharmacology. 2015;40(10):231726.
18. Nicholson AA, Sapru I, Densmore M, Frewen PA, Neufeld RWJ,
Theberge J, et al. Unique insula subregion resting-state functional
connectivity with amygdala complexes in posttraumatic stress dis-
order and its dissociative subtype. Psychiatry Res Neuroimaging.
2016;250:6172.
19.•• Nicholson AA, Friston KJ, Zeidman P, Harricharan S, McKinnon MC,
Densmore M, et al. Dynamic causal modeling in PTSD and its disso-
ciative subtype: bottom-up versus top-down processing within fear and
emotion regulation circuitry. Hum Brain Mapp. 2017;38(11):555161.
This recent study utilizes dynamic causal modeling to elucidate the
directionality of connectivity between key brain regions implicated
in PTSD and its dissociative subtype.
20.•• Harricharan S, Rabellino D, Frewen P, Densmore M, Theberge J,
McKinnon M, et al. fMRI functional connectivity of the
periaqueductal gray in PTSD and its dissociative subtype. Brain
Behav. 2016;6:e00579. This study highlights novel work indicat-
ing an important role of the periaqueductal gray in the neuro-
biology of PTSD and its dissociative subtype.
21. Duvarci S, Pare D. Amygdala microcircuits controlling learned fear.
Neuron. 2014;82:96680.
22. Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating
patterned autonomic activity during active vs. passive emotional
coping. Brain Res Bull. 2000;53(1):95104.
23. Mobbs D, Marchant JL, Hassabis D, Seymour B, Tan G, Gray M,
et al. From threat to fear: the neural organization of defensive fear
systems in humans. J Neurosci. 2009;29(39):1223643.
24. Mobbs D, Yu R, Rowe JB, Eich H, FeldmanHall O, Dalgleish T.
Neural activity associated with monitoring the oscillating threat
value of a tarantula. Proc Natl Acad Sci U S A. 2010;107(47):
205826.
25. Kozlowska K, Walker P, McLean L, Carrive P. Fear and the defense
cascade. Harv Rev Psychiatry. 2015;23(4):26387.
26. Schauer M, Elbert T. Dissociation following traumatic stress.
Zeitschrift Psychol / J Psychol. 2010;218(2):10927.
27. Gallup GG, Rager DR. Tonic immobility as a model of extreme
states of behavioural inhibition. In: Sanberg PR, Ossenkopp KP,
Kavaliers M, editors. Motor activity and movement disorders.
New York: Springer Science+Business Media; 1996.
28. Volchan E, Rocha-Rego V, Bastos AF, Oliveira JM, Franklin C,
Gleiser S, et al. Immobility reactions under threat: a contribution
to human defensive cascade and PTSD. Neurosci Biobehav Rev.
2017;76:2938.
29. Porges SW. The polyvagal theory: neurophysiological foundations
of emotions, attachment, communication, and self-regulation. New
York: Norton; 2011.
30. Craig AD. How do you feelnow? The anterior insula and human
awareness. Nat Rev Neurosci. 2009;10(1):5970.
31. Stoodley C, Schmahmann J. Evidence for a topographic organiza-
tion in the cerebellum of motor control versus cognitive and affec-
tive processing. Cortex. 2010;46:83144.
32.•• Fenster RJ, Lebois LAM, Ressler KJ, Suh J. Brain circuit dysfunc-
tion in post-traumatic stress disorder: from mouse to man. Nat Rev
Neurosci. 2018;19:53551. A recent review describing alter-
ations in brain function and connectivity and symptom do-
mains of PTSD.
33. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and
autonomic stress responses. Nat Rev Neurosci. 2009;10:397409.
34. Cavanna AE, Trimble MR. The precuneus: a review of its function-
al anatomy and behavioural correlates. Brain. 2006;129:56483.
35. Wolbers T, Weiller C, Büchel C. Contralateral coding of imagined
body parts in the superior parietal lobe. Cereb Cortex. 2003;13:
3929.
36. Zaytseva Y, Szymanski C, Gutyrchik E, Pechenkova E, Vlasova R,
Wittmann M. A disembodied man: a case of somatopsychic deper-
sonalization in schizotypal disorder. Psych J. 2015;4:18698.
37. Murray RJ, Debbané M, Fox PT, Bzdok D, Eickhoff SB. Functional
connectivity mapping of regions associated with self- and other-
processing. Hum Brain Mapp. 2015;36:130424.
38. Blanke O, Arzy S. The out-of-body experience: disturbed self-
processing at the temporo-parietal junction. Neuroscientist.
2005;11:1624.
39. Leech R, Sharp DJ. The role of the posterior cingulate cortex in
cognition and disease. Brain. 2014;137:1232.
40. Sar V, Unal SN, Ozturk E. Frontal and occipital perfusion changes
in dissociative identity disorder. Psychiatry Res Neuroimaging.
2007;156(3):21723.
41. Lanius RA, Brand B, Vermetten E, Frewen PA, Spiegel D. The
dissociative subtype ofposttraumatic stress disorder: rationale, clin-
ical and neurobiological evidence, and implications. Depress
Anxiety. 2012;29(8):7018.
42. Stiefel KM, Merrifield A, Holcombe AO. The claustrums pro-
posed role in consciousness is supported by the effect and target
localization of Salvia divinorum. Front Integr Neurosci. 2014;8:20.
43. van der Kolk BA. The trauma spectrum: the interaction of biolog-
ical and social events in the genesis of the trauma response. J
Trauma Stress. 1988;1(3):27390.
44. Bremner JD, Southwick SM, Darnell A, Charney DS. Chronic
course ptsd in Vietnam combat veterans: course of illness and sub-
stance abuse. Am J Psychiatry. 1996;153(3):36975.
45. Van der Kolk BA. The psychobiology and psychopharmacology of
PTSD. Hum Psychopharmacol. 2001;16:S4964.
46. Baker DG, West SA, Orth DN, Hill KK, Nicholson WE, Ekhator NN,
et al. Cerebrospinal fluid and plasma β-endorphin in combat veterans
with post-traumatic stress disorder. Psychoneuroendocrinology.
1997;22(7):51729.
47. van der Kolk BA. The compulsion to repeat the trauma: re-enact-
ment, revictimization, and masochism. Psychiatr Clin N Am.
1989;12:389411.
48. Saxe G, Stoddard F, Courtney D, Cunningham K, Chawla N,
Sheridan R, et al. Relationship between acute morphine and the
course of PTSD in children with burns. J Am Acad Child
Adolesc Psychiatry. 2001;40(8):91521.
49. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL.
Morphine use after combat injury in Iraq and post-traumatic stress
disorder. N Engl J Med. 2010;362(2):1107.
Curr Psychiatry Rep (2018) 20: 118 Page 13 of 14 118
50. Pitman RK, van der Kolk BA, Orr SP, Greenberg MS. Naloxone-
reversible analgesic response to combat-related stimuli in posttraumatic
stress disorder: a pilot study. Arch Gen Psychiatry. 1990;47:5414.
51. Liberzon I, Taylor SF, Phan KL, Britton JC, Fig LM, Bueller JA,
et al. Altered central μ-opioid receptor binding after psychological
trauma. Biol Psychiatry. 2007;61(9):10308.
52. Panksepp J. Affective neuroscience: the foundation of human and
animal emotions. New York: Oxford University Press; 1998.
53. Schore AN. Dysregulation of the right brain: a fundamental mech-
anism of traumatic attachment and the psychopathogenesis of post-
traumatic stress disorder. Aust N Z J Psychiatry. 2002;36:930.
54. Schore AN. Attachment trauma and the developing right brain:
origins of pathological dissociation. In: Dell PF, ONeil JA, editors.
Dissociation and the dissociative disorders: DSM-V and beyond.
New York: Routledge; 2011.
55. Gobin RL, Freyd J. Do participants detect sexual abuse depicted in
a drawing? Investigating the impact of betrayal trauma exposure on
state dissociation and betrayal awareness. J Child Sex Abus.
2017;26(3):23345.
56. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C.
The dysphoric component of stress is encoded by activation of the
dynorphin-opioid system. J Neurosci. 2008;28(2):40714.
57. Williams NR, Heifets B, Sudheimer K, Pannu J, Pankow H,
Hawkins J, et al. Opioid receptor antagonism attenuates antidepres-
sant effects of ketamine. Am J Psychiatry.
58.Addy PH, Garcia-Romeu A, Metzger M, Wade J. The subjective
experience of acute, experimentally-induced Salvia divinorum in-
ebriation. J Psychopharmacol. 2015;29(4):42635. This study
highlights the role of the kappa-opioid receptor agonist, Salvia
divinorum, in experiences of altered consciousness consistent
with depersonalization and derealisation experiences.
59. Frewen PA, Lanius RA. Trauma-related altered states of conscious-
ness: exploring the 4-d model. J Trauma Dissociation. 2014;15(4):
43656.
60. Crick FC, Koch C. What is the function of the claustrum? Philos
Trans R Soc Lond Ser B Biol Sci. 2005;360:12719.
61. Rabellino D, Tursich M, Frewen PA, Daniels JK, Densmore M,
Theberge J, et al. Intrinsic connectivity networks in post-traumatic
stress disorder during sub- and supraliminal processing of threat-
related stimuli. Acta Psychiatr Scand. 2015;132(5):36578.
62. Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng M-Q,
Stein MB, et al. Association of in vivo κ-opioid receptor availability
and the transdiagnostic dimensional expression of trauma-related
psychopathology. JAMA Psychiatry. 2014;71(11):126270.
63. Rabellino D, Densmore M, Harricharan S, Jean T, McKinnon MC,
Lanius RA. Resting-state functional connectivity of the bed nucleus
of the stria terminalis in post-traumatic stress disorder and its dis-
sociative subtype. Hum Brain Mapp. 2017;39:136779.
64. Hill MN, Campolongo P, Yehuda R, Patel S. Integrating
endocannabinoid signaling and cannabinoids into the biology and
treatment of posttraumatic stress disorder.
Neuropsychopharmacology. 2018;43(1):80102.
65. Pietrzak RH, Huang Y, Corsi-Travali S, Zheng M-Q, Lin S, Henry
S, et al. Cannabinoid type 1 receptor availability in the amygdala
mediates threat processing in trauma survivors.
Neuropsychopharmacology. 2014;39(11):251928.
66. Dean C. Endocannabinoid modulation of sympathetic and cardio-
vascular responses to acute stress in the periaqueductal gray of the
rat. Am J Phys Regul Integr Comp Phys. 2011;300(3):R7719.
67. Moreira FA, Aguiar AC, Campos AC, Lisboa SF, Terzian AL,
Resstel LB, et al. Antiaversive effects of cannabinoids: is the
periaqueductal gray involved? Neural Plast. 2009;625469.
68. Moreira FA, Wotjak CT. Cannabinoids and anxiety. Curr Top
Behav Neurosci. 2010;2:42950.
69. Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA,
et al. Pharmacotherapy for post-traumatic stress disorder: systemat-
ic review and meta-analysis. Brit J Psychiatry. 2015;206:93100.
70. Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy
for military-related PTSD. JAMA. 2015;314(5):489500.
71. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimen-
sional meta-analysis of psychotherapy for PTSD. Am J Psychiatry.
2005;162(2):21427.
72. Simeon D, Knutelska M. An open trial of naltrexone in the treat-
ment of depersonalization disorder. J Clin Psychopharmacol.
2005;25(3):26770.
73. Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid
receptor: from addiction to depression, and back. Front
Psychiatry. 2014;5:170.
74. Chavkin C. The therapeutic potential of κ-opioids for treatment of
pain and addiction. Neuropsychopharmacology. 2011;36(1):36970.
75. Fraser GA. The use of a synthetic cannabinoid in the management
of treatment-resistant nightmares in posttraumatic stress disorder.
CNS Neurosci Ther. 2009;15(1):848.
76. Cameron C, Watson D, Robinson J. Use of a synthetic cannabinoid
in a correctional population for posttraumatic stress disorderrelat-
ed insomnia and nightmares, chronic pain, harm reduction, and
other indications. J Clin Psychopharmacol. 2014;34(5):55964.
77. Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a
synthetic cannabinoid, in the treatment of PTSD-associated night-
mares: a preliminary randomized, double-blind, placebo-controlled
cross-over design study. Psychoneuroendocrinology. 2015;51:5858.
78. Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A. Preliminary,
open-label, pilot study of add-on oral Delta9-tetrahydrocannabinol
in chronic post-traumatic stress disorder. Clin Drug Investig.
2014;34(8):58791.
79. Lanius, UF, Paulsen, SL, Corrigan, FM, Neurobiology and
Treatment of Traumatic Dissociation: Toward an Embodied Self,
Springer Piblishing Company, 2014.
118 Page 14 of 14 Curr Psychiatry Rep (2018) 20: 118
... Arousal is critical to the conceptualization of posttraumatic stress disorder (PTSD) since it is a dynamic disorder that includes arousal states ranging from hyperarousal (e.g., hypervigilance, altered startle threshold) to more blunted arousal patterns associated with emotional detachment, depersonalization, and derealization. These latter states are more frequently associated with the dissociative subtype of PTSD (PTSD + DS) (Wolf et al., 2012a,b;APA, 2013;Seligowski et al., 2019; for review see Hansen et al., 2017;Fenster et al., 2018;Lanius et al., 2018;van Huijstee and Vermetten, 2018). ...
... On a neural level, hyperarousal states have been found to be associated with reduced activation of brain regions underlying cognitive control (e.g., ventromedial prefrontal cortex) and enhanced activation of brain regions underlying emotion generation (e.g., amygdala, periaqueductal gray), while the reverse pattern has been implicated in more blunted arousal states (e.g., Fenster et al., 2018;Lanius et al., 2018; see also Lebois et al., 2021). Critically, the aforementioned interaction profile between subcortical and cortical brain regions has recently been extended to include deep-layer brain regions involved in arousal and innate reflexive function (Harricharan et al., 2016; see also Holmes et al., 2018;Olive et al., 2018;Rabellino et al., 2018aRabellino et al., , 2019Brandão and Lovick, 2019;Terpou et al., 2019bTerpou et al., , 2020Terpou et al., , 2022Thome et al., 2019;Haubrich et al., 2020;Lanius et al., 2020;Webb et al., 2020). ...
... Indeed, prior investigations have demonstrated a positive relationship between parasympathetic nervous system (PNS) activity and dissociation in response to threatening cues in other clinical populations, thus pointing to a close relationship between sympathoinhibition and dissociative symptomatology (Farina et al., 2015;Fitzpatrick and Kuo, 2015;Chou et al., 2018;Schäflein et al., 2018;Krause-Utz et al., 2019). Specifically, dissociation has been associated with parasympathetic overactivation, which has been thought to be linked to emotional detachment as expressed by symptoms of emotional numbing, depersonalization, and derealization (for an overview see Schauer and Elbert, 2015;Lanius et al., 2018Lanius et al., , 2020Terpou et al., 2019b). ...
Article
Full-text available
Background Increasing evidence points toward the need to extend the neurobiological conceptualization of posttraumatic stress disorder (PTSD) to include evolutionarily conserved neurocircuitries centered on the brainstem and the midbrain. The reticular activating system (RAS) helps to shape the arousal state of the brain, acting as a bridge between brain and body. To modulate arousal, the RAS is closely tied to the autonomic nervous system (ANS). Individuals with PTSD often reveal altered arousal patterns, ranging from hyper- to blunted arousal states, as well as altered functional connectivity profiles of key arousal-related brain structures that receive direct projections from the RAS. Accordingly, the present study aims to explore resting state functional connectivity of the RAS and its interaction with the ANS in participants with PTSD and its dissociative subtype. Methods Individuals with PTSD ( n = 57), its dissociative subtype (PTSD + DS, n = 32) and healthy controls ( n = 40) underwent a 6-min resting functional magnetic resonance imaging and pulse data recording. Resting state functional connectivity (rsFC) of a central node of the RAS – the pedunculopontine nuclei (PPN) – was investigated along with its relation to ANS functioning as indexed by heart rate variability (HRV). HRV is a prominent marker indexing the flexibility of an organism to react adaptively to environmental needs, with higher HRV representing greater effective adaptation. Results Both PTSD and PTSD + DS demonstrated reduced HRV as compared to controls. HRV measures were then correlated with rsFC of the PPN. Critically, participants with PTSD and participants with PTSD + DS displayed inverse correlations between HRV and rsFC between the PPN and key limbic structures, including the amygdala. Whereas participants with PTSD displayed a positive relationship between HRV and PPN rsFC with the amygdala, participants with PTSD + DS demonstrated a negative relationship between HRV and PPN rsFC with the amygdala. Conclusion The present exploratory investigation reveals contrasting patterns of arousal-related circuitry among participants with PTSD and PTSD + DS, providing a neurobiological lens to interpret hyper- and more blunted arousal states in PTSD and PTSD + DS, respectively.
... Brain imaging studies on dissociative disorders have focused on two issues: the brain imaging correlates of dissociation per se , and the brain imaging diff erences between dissociative patients and normal controls (or other psychiatric patients). Signifi cant brain-imaging diff erences have been found between (a) diff erent types of dissociative parts of the patient's personality in DID patients (Reinders, Nijenhuis, Paans, Korf, Willemsen, & Den Boer, 2006 ; see Nijenhuis,Chapter 38 ,and Lebois et al.,Chapter 24 ,this volume), (b) dissociative responses and nondissociative responses to trauma-related scripts as elements of PTSD patients' responses to triggers (Lanius, Williamson, Boksman, Densmore, Gupta, Neufeld, Gati, & Menon, 2002 ;see Schiavone & Lanius, Chapter 39 , this volume) including comparisons of the dissociative subtype to other types of PTSD (Lanius et al., 2018 ); (c) perfusion before versus perfusion during switching in DID patients ( Tsai, Condie, Wu, & Chang, 1999 ;Savoy et al., 2012 ); and (d) the cerebral perfusion of dissociative patients versus that of normal controls ( Ş ar, Ü nal, K ı z ı ltan, Kundak çı , & Ö zt ü rk, 2001 ; Ş ar, Ü nal, & Ö zt ü rk, 2007 ). ...
... Despite its potential implications, this perspective has not been specifi cally addressed in subsequent neurobiological studies on DID. Lanius et al. (2018) hypothesized that kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotional overmodulation in the dissociative subtype of PTSD. Conversely, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fi ght or fl ight components of the defense cascade. ...
Chapter
This chapter explores the most pertinent research questions to understand and advance the study of dissociation. Drawing on specifi c themes, recommendations for future work are outlined at the end of each section. Our chapter in the fi rst edition of this book still contains questions empirically unanswered (e.g., genetics and neurobiology of dissociative disorders, dissociation in other psychiatric disorders). We will focus in this chapter on the most pressing questions that currently need to inform the scientifi c understanding of dissociation.
... As such, multiple investigations have found that symptoms of dissociation are frequently reported, and even distinctly elevated among those who have experienced betrayal trauma, as opposed to other types of trauma (Goldsmith et al., 2012;Hulette et al., 2011;Tang & Freyd, 2012). Dissociation is part of the freeze response to danger, marked by physiological hypoarousal and emotional overmodulation (Lanius et al., 2018). Dissociation is thought to serve a uniquely protective function in the context of betrayal trauma, as it allows a young victim to maintain an attachment relationship with a caregiver upon whom they are dependent by attenuating the youth's awareness of caregiver threat (Freyd, 1994(Freyd, , 1996Gagnon et al., 2017). ...
... Dissociative symptoms are "characterized by a disruption of and/or discontinuity in the normal integration of consciousness, memory, identity, emotional, perception, body representation, motor control, and behavior" (American Psychiatric Association, 2013, p. 291). Dissociation can contribute to a state of emotional overmodulation/inhibition, which can alter threat detection, thereby increasing one's own vulnerability for subsequent revictimization, as well as their vulnerability of their child (Lanius et al., 2018;Tschoeke et al., 2019).Studies by Chu and DePrince (2006) and Hulette et al. (2011) have both found statistically significant associations between histories of maternal betrayal trauma and maternal dissociation, which is known to negatively impact parenting behaviors, potentially resulting in overall reduced maternal availability, specifically in the areas of maternal sensitivity and non-intrusiveness (Williams et al., 2021). Additionally, Hulette et al. (2011) reported unique links between maternal exposure to betrayal trauma during childhood and subsequent interpersonal revictimization among the mothers during adulthood, which also amplified dissociative symptoms. ...
Article
Full-text available
Betrayal trauma is associated with dissociative symptoms, which can increase the risk of suicidal thoughts and behaviors. Previous research demonstrates associations between a mother’s history of betrayal trauma and intergenerational patterns of maltreatment and dissociation among their children. However, maternal betrayal trauma history remains unexplored in the etiology of youth suicidality. This study was conducted to investigate pathways between maternal betrayal trauma and youth suicidality, while considering the influences of youth maltreatment exposure and symptoms of dissociation. We implemented conditional growth curve modeling in a structural equation modeling framework to analyze secondary data from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN; N = 1,354; 51.48% female, 53.29% Black). Predictors included mothers’ betrayal trauma history, youth maltreatment exposure, and youth dissociative symptoms at ages 8, 12, and 16. The slope and intercept of dissociative symptoms at the age-8, age-12, and age-16 visit were modeled as latent factors. A robust weighted least squares estimator accounted for categorical outcomes. Indirect effects were assessed via the delta method. We found a significant indirect effect from maternal betrayal trauma to adolescent suicidal ideation through children’s maltreatment exposure and the growth in children’s dissociative symptoms from ages 8 through 16. Maternal betrayal trauma may play a unique role in perpetuating intergenerational patterns of trauma that contribute to subsequent trajectories of youth suicidality among their offspring. Practice implications for screening, prevention, and early intervention strategies are described, along with directions for further study.
... Les maltraitances ou négligences subies durant l'enfance peuvent être à l'origine d'un manque de connectivité entre les réseaux neuronaux isolés qui représentent des Modes ou parties de personnalité fixées au temps du traumatisme ou encore d'une intégration sous-optimale entre différentes régions et couches du cerveau (Lanius et al., 2010(Lanius et al., , 2018Reinders et al., 2014). Les répétitions sont très importantes pour ancrer de nouveaux apprentissages mais aussi pour développer des connections neuronales plus robustes dans le cerveau qui contribuent à ce que la personne puisse s'orienter de mieux en mieux dans le temps et l'espace et parvienne à un sentiment d'unité du Soi. ...
Thesis
Full-text available
Ce projet de thèse vise à étudier la pertinence d’utiliser la médiation équine en thérapie, auprès de personnes ayant des troubles addictifs. Dans un premier temps, il s’agira d’étudier l’influence du style d’attachement des patients sur leur niveau d’autonomie ; en s’appuyant sur des modèles théoriques tels que la théorie de l’attachement (Bowlby, 1969-82 ; Hazan, 1987) et la théorie de la motivation autonome (Decy et Ryan, 2000). Dans un deuxième temps, l’objectif sera d’explorer, de décrire et d’évaluer les processus à l’œuvre durant l’intervention à visée thérapeutique avec le cheval. Cette recherche s’inscrit dans le cadre de la compréhension et de l’évaluation des interventions complexes, axe fort de recherche du laboratoire APEMAC. Le questionnement principal de ce projet de thèse est d'interroger la place de la théorie de l’attachement dans les interventions en psychologie de la santé, notamment dans les programmes de prévention de la reconsommation et de la rechute. Quels liens la motivation et l’attachement entretiennent-ils ? En quoi les troubles de l’attachement peuvent-ils entraver le processus de guérison et la tenue de l’abstinence chez ces patients ? L’utilisation du cheval en thérapie peut-elle permettre d’augmenter le sentiment de sécurité interne des personnes et favoriser le développement de leurs compétences d’auto-régulation et de la motivation autonome ? En somme, peut-on augmenter l’autonomie des patients en leur proposant une intervention qui cible les troubles de l’attachement ? Le recueil des données sera réalisé au Centre de Soins de Suite et de Réadaptation en Addictologie « la Fontenelle ». Tout au long de cette recherche, nous prévoyons d’effectuer différentes évaluations quantitatives à l’aide d’outils psychométriques. Nous utiliserons également des méthodes qualitatives en réalisant des entretiens cliniques.
Article
A PTSD subtype with dissociative symptoms (D-PTSD) was included in the DSM-5 recognizing the existence of a more severe form of PTSD, associated to past trauma, high comorbidity, and complex clinical management. As research is rapidly growing and results are inconsistent, a better investigation of this subtype is of primary importance. We conducted a systematic review of studies using Latent Profile Analysis to investigate the existence of a D-PTSD subtype. Covariates of D-PTSD were included, to understand additional symptoms, risk factors and comorbidities. The search was performed on PubMed, EBSCOHost, and PTSDPubs according to 2020 PRISMA guidelines. Eligible articles assessed trauma exposure, PTSD symptoms and diagnosis, and dissociation, in adult samples. 13 of 165 articles met the inclusion criteria. All identified a dissociative subtype of PTSD, mainly characterized by higher levels of depersonalization and derealization. D-PTSD profile sometimes presented other dissociative symptoms, such as gaps in awareness and memory, other comorbid disorders, and a history of abuse. Despite some limitations, this review supports the existence of a dissociative subgroup of individuals among those with PTSD. More rigorous studies are needed to clarify these findings and their clinical implications.
Chapter
Anxiety is a common experience, a physiologic mechanism that lets us cope with a stressor, but if it occurs without a stimulus or it is exaggerated and general functioning is impaired, it becomes pathological. Treating anxiety disorders requires pharmacotherapy to lower anxiety levels and psychological therapies to learn to cope with stressors adaptively.Obsessive-compulsive disorder (OCD) has been considered as part of the Anxiety Disorders chapter up to the fourth edition of the DSM (DSM IV-TR), while from the fifth edition (DSM-5) it is placed in a separate chapter. The nosographic autonomy of this disorder depends on the fact that the anxious manifestations, even if present, would be secondary and dependent on the obsessive contents. A group of conditions related to OCD from a clinical, epidemiological, and sometimes aetiopathological perspective is included in the DSM chapter about “obsessive-compulsive and related disorders”.After a traumatic experience, one person physiologically develops a limited-in-time reaction. In some cases, more pronounced depressive, anxious, intrusive, and/or dissociative symptoms occur. The biological basis for trauma-related disorders is not fully understood, but insights so far have let us choose pharmacological treatments alongside with psychotherapy in order to control symptoms and elaborate the traumatic experience.KeywordsAnxietyAvoidanceStressTraumaOCDObsessionCompulsion
Article
Individuals who experience burns are at higher risk of developing post-traumatic stress disorder and chronic pain. A synergistic relationship exists between post-traumatic stress disorder and chronic pain. We sought to examine the role of individual post-traumatic stress disorder symptom clusters as predictors of pain interference. We hypothesized that the hyperarousal and emotional numbing symptom clusters would be predictive of pain interference, even when accounting for the other two post-traumatic stress disorder symptom clusters, pain intensity, and other covariates. Multivariate linear regression analyses were completed using data from the Burn Model System National Database. A total of 439 adult participants had complete responses on self-report measures assessing posttraumatic stress disorder symptoms, pain intensity, and pain interference at 6-months after discharge and were included in analyses. Results indicate hyperarousal (B = .10, p = .03) and emotional numbing (B = .13, p = .01) post-traumatic stress disorder symptom clusters were each significantly associated with pain interference, even when accounting for pain intensity (B = .64, p < .001). Results highlight the importance of the emotional numbing and hyperarousal post-traumatic stress disorder symptom clusters in explaining pain interference. Findings suggest that when post-traumatic stress disorder symptoms or chronic pain are present, screening for and treating either condition may be warranted to reduce pain interference. Further, psychological interventions that target emotional numbing and hyperarousal post-traumatic stress disorder symptoms may be fruitful for promoting better coping with chronic pain and reducing pain interference.
Article
Background High betrayal trauma (HBT), or interpersonal trauma perpetrated by someone close, is linked to dissociation and shame, while trauma perpetrated by someone less close, low betrayal trauma (LBT) is associated with post-traumatic stress disorder (PTSD). Objective Child interpersonal trauma is common among women with chronic pelvic pain (CPP) and can negatively impact physical and mental health-related quality of life (HRQOL). Our study investigates unexplored connections between these variables. Participants & setting Survey data were analyzed from 96 English-speaking female patients with CPP at a women's health clinic (mean age = 33, 59 % White non-Hispanic, 62 % married or cohabitating, 61.5 % completed post-high school degree); prevalence of HBT and LBT were 65.2 % and 45.6 %, respectively. Methods Multiple regression analyzed relationships between mental and physical HRQOL and dissociation, shame, and PTSD. Parallel mediation analyses examined indirect relationships between mental and physical HRQOL and exposure to childhood HBT and LBT. Results Dissociation was related to worse physical HRQOL, while shame was related to worse physical and mental HRQOL. Dissociation and shame mediated relationships between childhood HBT and current mental (R² = 0.08, p = .01) and physical (R² = 0.11, p = .002) HRQOL. Shame, but not PTSD, mediated relationships between childhood LBT and current mental (R² = 0.14, p < .001) and physical (R² = 0.16, p < .001) HRQOL. Conclusions Our study provides preliminary evidence that dissociation and shame negatively impact HRQOL among individuals with CPP in the context of exposure to different types of childhood betrayal trauma. Replication studies to validate our results with larger samples and longitudinal designs are encouraged.
Chapter
Full-text available
Lapsiin ja nuoriin kohdistuvan seksuaaliväkivallan ennaltaehkäisyssä on perinteisesti panostettu erityisesti lasten suojelemiseen ja heidän turvataitojensa parantamiseen. Myös seksuaalirikokseen syyllistyneiden kuntoutuksessa on painotus ollut pitkään uusintarikollisuuden ehkäisemisessä. Tehokkainta lastensuojelua ja lapsiin kohdistuvien seksuaalirikosten ennaltaehkäisyä on painopisteen siirtäminen suojelukeskeisyydestä ja korjaavasta toiminnasta preventiivisen tuen tarjoamiseen henkilöille, joiden seksuaalinen kiinnostus kohdistuu lapsiin ja/tai joilla on riski syyllistyä lapseen kohdistuvaan seksuaalirikokseen. Artikkelissa esitellään suunnitelma näille henkilöille suunnatuista primaari-, ja sekundaaritasojen ehkäisevistä hoitopoluista sekä ehdotus hoitopolkujen intergroimisesta osaksi julkista sosiaali- ja terveydenhuollon palvelujärjestelmää.
Article
Full-text available
Objective: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects. Method: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1. Results: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis. Conclusions: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.
Article
Full-text available
Post-traumatic stress disorder (PTSD) is a prevalent, debilitating and sometimes deadly consequence of exposure to severe psychological trauma. Although effective treatments exist for some individuals, they are limited. New approaches to intervention, treatment and prevention are therefore much needed. In the past few years, the field has rapidly developed a greater understanding of the dysfunctional brain circuits underlying PTSD, a shift in understanding that has been made possible by technological revolutions that have allowed the observation and perturbation of the macrocircuits and microcircuits thought to underlie PTSD-related symptoms. These advances have allowed us to gain a more translational knowledge of PTSD, have provided further insights into the mechanisms of risk and resilience and offer promising avenues for therapeutic discovery.
Article
Full-text available
The bed nucleus of the stria terminals (BNST) is a subcortical structure involved in anticipatory and sustained reactivity to threat and is thus essential to the understanding of anxiety and stress responses. Although chronic stress and anxiety represent a hallmark of post-traumatic stress disorder (PTSD), to date, few studies have examined the functional connectivity of the BNST in PTSD. Here, we used resting state functional Magnetic Resonance Imaging (fMRI) to investigate the functional connectivity of the BNST in PTSD (n = 70), its dissociative subtype (PTSD + DS) (n = 41), and healthy controls (n = 50). In comparison to controls, PTSD showed increased functional connectivity of the BNST with regions of the reward system (ventral and dorsal striatum), possibly underlying stress-induced reward-seeking behaviors in PTSD. By contrast, comparing PTSD + DS to controls, we observed increased functional connectivity of the BNST with the claustrum, a brain region implicated in consciousness and a primary site of kappa-opioid receptors, which are critical to the dynorphin-mediated dysphoric stress response. Moreover, PTSD + DS showed increased functional connectivity of the BNST with brain regions involved in attention and salience detection (anterior insula and caudate nucleus) as compared to PTSD and controls. Finally, BNST functional connectivity positively correlated with default-mode network regions as a function of state identity dissociation, suggesting a role of BNST networks in the disruption of self-relevant processing characterizing the dissociative subtype. These findings represent an important first step in elucidating the role of the BNST in aberrant functional networks underlying PTSD and its dissociative subtype.
Article
Full-text available
Dissociation involves disruptions of usually integrated functions of consciousness, perception, memory, identity, and affect (e.g., depersonalization, derealization, numbing, amnesia, and analgesia). While the precise neurobiological underpinnings of dissociation remain elusive, neuroimaging studies in disorders, characterized by high dissociation (e.g., depersonalization/derealization disorder (DDD), dissociative identity disorder (DID), dissociative subtype of posttraumatic stress disorder (D-PTSD)), have provided valuable insight into brain alterations possibly underlying dissociation. Neuroimaging studies in borderline personality disorder (BPD), investigating links between altered brain function/structure and dissociation, are still relatively rare. In this article, we provide an overview of neurobiological models of dissociation, primarily based on research in DDD, DID, and D-PTSD. Based on this background, we review recent neuroimaging studies on associations between dissociation and altered brain function and structure in BPD. These studies are discussed in the context of earlier findings regarding methodological differences and limitations and concerning possible implications for future research and the clinical setting.
Article
Two well-established first-line cognitive-behavioral psychotherapies for posttraumatic stress disorder (PTSD), prolonged exposure therapy (PE) and cognitive processing therapy (CPT), are used in the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) based chiefly on good outcomes in randomized clinical trials (RCTs) with civilians. PE and CPT are manualized (ie, protocolized in a session-by-session manner) trauma-focused therapies that are based on processing the emotional and cognitive aspects of the traumatic event. Consequently, these treatments are emotionally demanding for patients because PTSD is characterized by a strong motivation to avoid talking about the trauma and rekindling negative emotions associated with it. The prominence of PE and CPT in treating individuals with military-related PTSD has been increasingly challenged in recent years because RCTs of veterans and military personnel have yielded mixed results, with patients often not obtaining clinically meaningful symptom improvement. These findings have led to questions about the extent to which these therapies should be prioritized and how military-related PTSD is best conceptualized, namely as a disorder that can be reliably managed by brief (approximately 12 session) monotherapies or as a highly complex and multiform condition requiring more individualized and comprehensive intervention.
Article
Childhood abuse and neglect are associated with dissociative symptoms in adulthood. However, empirical studies show heterogeneous results depending on the type of childhood abuse or neglect and other maltreatment characteristics. In this meta-analysis, we systematically investigated the relationship between childhood interpersonal maltreatment and dissociation in 65 studies with 7352 abused or neglected individuals using the Dissociative Experience Scale (DES). We extracted DES-scores for abused and non-abused populations as well as information about type of abuse/neglect, age of onset, duration of abuse, and relationship to the perpetrator. Random-effects models were used for data synthesis, and meta-regression was used to predict DES-scores in abused populations from maltreatment characteristics. The results revealed higher dissociation in victims of childhood abuse and neglect compared with non-abused or neglected subsamples sharing relevant population features ( MAbuse = 23.5, MNeglect = 18.8, MControl = 13.8) with highest scores for sexual and physical abuse. An earlier age of onset, a longer duration of abuse, and parental abuse significantly predicted higher dissociation scores. This meta-analysis underlines the importance of childhood abuse/neglect in the etiology of dissociation. The identified moderators may inform risk assessment and early intervention to prevent the development of dissociative symptoms.
Article
Objective: Dissociation is a complex, ubiquitous construct in psychopathology. Symptoms of dissociation are present in a variety of mental disorders and have been connected to higher burden of illness and poorer treatment response, and not only in disorders with high levels of dissociation. This meta-analysis offers a systematic and evidence-based study of the prevalence and distribution of dissociation, as assessed by the Dissociative Experiences Scale, within different categories of mental disorders, and it updates an earlier meta-analysis. Method: More than 1,900 original publications were screened, and 216 were included in the meta-analysis, comprising 15,219 individuals in 19 diagnostic categories. Results: The largest mean dissociation scores were found in dissociative disorders (mean scores >35), followed by posttraumatic stress disorder, borderline personality disorder, and conversion disorder (mean scores >25). Somatic symptom disorder, substance-related and addictive disorders, feeding and eating disorders, schizophrenia, anxiety disorder, OCD, and most affective disorders also showed mean dissociation scores >15. Bipolar disorders yielded the lowest dissociation scores (mean score, 14.8). Conclusions: The findings underline the importance of careful psychopathological assessment of dissociative symptoms in the entire range of mental disorders.
Article
Objective: Posttraumatic stress disorder (PTSD) is associated with decreased top-down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top-down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. Methods: To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting-state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age-matched healthy trauma-unexposed controls [n = 52]). Results: PTSD was characterized by a pattern of predominant bottom-up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top-down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. Conclusions: These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper- vs. hypo-emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom-up defensive fear processing versus enhanced top-down regulation. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.
Article
Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the United States, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Lastly, we propose that a state of endocannabinoid deficiency could represent a stress-susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.
Article
An inability to identify betrayal may increase risk for victimization. Harm perpetrated by close others early in life may impair the ability to identify betrayal and develop trust. Dissociation may facilitate impaired betrayal awareness. The present study examined the impact of high betrayal trauma on state dissociation and betrayal awareness in a college sample (N = 216). Self-report measures were used to assess trauma history and state dissociation. Awareness for betrayal was measured using a drawing depicting an ambiguous interpersonal interaction between an adult and a child. We hypothesized that high betrayal trauma would be associated with both more state dissociation and lower awareness for betrayal. Participants with histories of high betrayal trauma reported high levels of state dissociation. Contrary to our second hypothesis, high betrayal trauma did not directly predict impaired betrayal awareness. State dissociation contributed significantly to betrayal awareness. Implications of findings for theory and practice are discussed.