Substance Abuse and Posttraumatic Stress DisorderAuthor(s.docx

Substance Abuse and Posttraumatic Stress Disorder
Author(s): Kathleen T. Brady, Sudie E. Back and Scott F.
Coffey
Source: Current Directions in Psychological Science, Vol. 13,
No. 5 (Oct., 2004), pp. 206-209
Published by: Sage Publications, Inc. on behalf of Association
for Psychological Science
Stable URL: http://www.jstor.org/stable/20182954
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CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE
Substance Abuse and
Posttraumatic Stress Disorder
Kathleen T. Brady, Sudie E. Back, and Scott F. Coffey
Medical University of South Carolina and University at
Buffalo, State University of New York
ABSTRACT?Posttraumatic stress disorder (PTSD) and
substance
use disorders (SUDs) frequently co-occur. Among individuals
seeking treatment for SUDs, approximately 36% to 50% meet
criteria for lifetime PTSD. The self-medication and suscepti
bility hypotheses are two of the hypotheses that have been
proposed to help explain the etiological relationship between
PTSD and SUDs. It is also possible that common factors, such
as
genetic, neurobiological, or environmental factors, contribute
to
the high rate of PTSD-SUD co-occurrence. Preliminary results
from integrated psychotherapy approaches for the treatment of
patients with both disorders show promise. This article reviews
these and other advances in the study of comorbid PTSD and
SUDs, and suggests areas for future work.
KEYWORDS?posttraumatic stress disorder; trauma; substance
use disorders; addiction; comorbidity

Posttraumatic stress disorder (PTSD) is characterized by
symptoms
that persist for at least 1 month following exposure to a
traumatic
event. Interpersonal violence (e.g., physical and sexual abuse),
com
bat, and natural disasters are examples of traumas commonly
asso
ciated with PTSD. The characteristic symptoms of PTSD can be
divided into three clusters: avoidant, intrusive, and arousal
symptoms.
Examples of intrusive symptoms include unwanted thoughts or
flashbacks of the event. Avoidant symptoms include, for
example,
attempts to avoid any thoughts or stimuli that remind one of the
event.
These symptoms are particularly relevant to this review
because
substances of abuse are often used by individuals with PTSD in
an
attempt to avoid or escape memories. Arousal symptoms
generally
include exaggerated startle reflex, sleep disturbance, and
irritability,
and are generally associated with hyperactivity of the
autonomie
nervous system. These symptoms are also pertinent to our
discussion
here because the use and withdrawal of many substances of
abuse are
associated with autonomie nervous system hyperactivity.

A number of recent studies have emphasized the common co-oc
currence (i.e., comorbidity) of PTSD and substance use
disorders
(SUDs). The interaction between PTSD and SUDs is likely
multifac
eted and variable. Further exploration of the relationship
between
these two disorders may prove useful in explicating the
underlying
pathophysiological processes involved. In this article, we
explore the
relationship between PTSD and SUDs.
PREVALENCE
The prevalence of the co-occurrence of PTSD and SUDs has
been
examined in epidemiological studies in the general population,
as well
as in studies of individuals who seek treatment for one or both
of these
disorders.
Epidemiological Studies
Epidemiological investigations provide information about the
number
of individuals with a given disorder in the general population
or in
subgroups of the general population. Two large
epidemiological
studies focusing on psychiatric disorders have been conducted

fairly
recently in the United States: the Epidemiologie Catchment
Area
Study (ECA; Regier et al., 1990) and the National Comorbidity
Study
(NCS; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995).
The ECA data revealed that men with PTSD were 5 times as
likely
and women with PTSD were 1.4 times as likely to have drug
abuse or
dependence, compared with individuals without PTSD. Using
the
ECA data, Cottier, Compton, Mager, Spitznagel, and Janea
(1992)
found that cocaine and opiate users had the highest rate of
PTSD,
which was 10 times higher than the rate in other SUD groups.
In the NCS sample, approximately 7.8% of the participants
(5.0%
of men, 10.4% of women) met criteria for lifetime PTSD (i.e.,
were
diagnosed with PTSD at some point in their lifetime), and
35.4% of
men and 17.9% of women met criteria for an SUD. More than
half
(51.9%) of men and 27.9% of women with PTSD met criteria
for
lifetime alcohol abuse or dependence.
Studies of Individuals Seeking Treatment
Studies of individuals seeking treatment for SUDs indicate an
ex

traordinarily high prevalence of PTSD in this group. In a
number of
studies examining individuals with drug or alcohol use
disorders, the
lifetime prevalence of PTSD was found to be between 36% and
50%,
and the current prevalence of PTSD was between 25% and 42%
(Jacobsen, Southwick, & Kosten, 2001). The wide variability in
these
numbers reflects the differing populations and diagnostic
techniques
used in different studies. In general, PTSD is more common in
women
with SUDs than in men with SUDs.
Address correspondence to Kathleen T. Brady, Medical
University of
South Carolina, Division of Clinical Neuroscience, 67
President St.,
P.O. Box 250861, Charleston, SC 29425; e-mail:
[email protected]
206 Copyright ? 2004 American Psychological Society Volume
13?Number 5
2016 20:00:37 UTC
The most common types of traumas reported among individuals
with

PTSD and SUDs are interpersonal, usually involving sexual
abuse
among women and physical abuse or assault among men.
Patients in
treatment for PTSD and SUDs also frequently report childhood
his
tories of emotional and physical neglect or abuse, rape or
sexual as
sault, witnessing domestic violence, robbery, death of a loved
one due
to homicide, and unhealthy environments. It is important to
note that
most individuals with both PTSD and an SUD report
experiencing
multiple traumatic events during their lifetimes.
ETIOLOGICAL RELATIONSHIPS BETWEEN PTSD AND
SUDS
Although PTSD and SUDs appear to be strongly linked, little is
known
about the nature of their relationship. The most widely held
expla
nation of their frequent co-occurrence is the self-medication
hypoth
esis. This hypothesis is based primarily on clinical observation
and
posits that traumatized individuals attempt to use substances in
order
to dampen traumatic memories, or to avoid or "escape" from

other
painful symptoms of PTSD. A second hypothesis, the high-risk
hy
pothesis, posits that individuals with SUDs, because of high-
risk
lifestyles, are likely to experience a trauma and are, therefore,
more
likely than the general population to develop PTSD. Finally, a
third
hypothesis, known as the susceptibility hypothesis, states that
sub
stance use increases an individual's susceptibility to developing
PTSD
following a trauma.
Chilcoat and Breslau (1998) have tested these three hypotheses
using a large longitudinal data set drawn from a health
maintenance
organization. The authors found that having PTSD greatly
increased
the risk of developing a subsequent SUD, but exposure to a
traumatic
event that did not result in PTSD did not increase the risk of
devel
oping a subsequent SUD. Thus, it appears to be the
development of
PTSD, not exposure to trauma per se, that increases the risk of
de
veloping an SUD. In addition, the study found that drug abuse
or

dependence did not increase, or only slightly increased, an
individ
ual's risk of developing PTSD, and did not increase an
individual's
risk of trauma exposure. The findings from Chilcoat and
Breslau's
study provide strong support for the self-medication hypothesis
and
little support for the high-risk hypothesis.
Another possible explanation for the high comorbidity of PTSD
and
SUDs is that the disorders have common susceptibility factors.
These
might be genetic, neurobiological, or environmental. To date,
studies
that have examined family patterns of the two disorders do not
support
the hypothesis that there is a genetic vulnerability common to
PTSD
and SUDs (S.H. Stewart & Conrod, 2003).
Although a full description of the commonalities in
neurobiology
between PTSD and SUDs is beyond the scope of this report,
there is
growing evidence that shared neurobiological relationships may
play a
significant role in PTSD-SUD comorbidity. In a description of
fear
conditioning, Armony and LeDoux (1997) proposed that

information
about a traumatic event is sent to the amygdala via the sensory
thal
amus or indirectly via the cortex or the hippocampus (a
structure
important for memory and spatial perception). The activation
of the
central nucleus of the amygdala causes a fear response,
followed by
activation causing an anxiety response. Interestingly, a number
of
abused drugs exert their anxiety-reducing effects by inhibiting
activity
in the amygdala, and this inhibition leads to an attenuated
startle
response (recall that an exaggerated startle response is one of
the
symptoms of PTSD). Alcohol may also inhibit the startle
response by
acting on the amygdala and the cortex. The areas activated by
fear and
anxiety associated with PTSD may be inhibited by drugs of
abuse, so
neurobiological evidence supports the self-medication
hypothesis.
Other investigations have focused on the hypothalamic-
pituitary
adrenal (HPA) axis, the primary neuroendocrine system

involved in
the stress response (J. Stewart, 2003). Abnormalities in the
function of
the HPA axis have been implicated in both PTSD and SUDs.
Animal
studies have demonstrated that exposure to stress facilitates
both the
initiation of substance use and its reinstatement after a period
of
abstinence in previously dependent animals (Kreek & Koob,
1998).
This reinstatement can be blocked by drugs that interfere with
the
activity of the HPA axis (Kreek & Koob, 1998; J. Stewart,
2003). The
"fight or flight" (noradrenergic) system is also intimately
involved in
the stress response. Increased activity in the noradrenergic
system
leads to the increase in blood pressure, heart rate, and sweating
often
seen with the fear response. This system is activated during
with
drawal from many substances of abuse, providing another
potential
neurobiological link between PTSD and SUD.
TREATMENT
The treatment of individuals with co-occurring PTSD and
SUDs has

only recently been explored systematically. Therefore, most of
the data
in this area are preliminary, but there are a number of
promising
approaches under development.
Psychotherapy
The psychotherapeutic treatment of comorbid PTSD and
substance
use has received much recent attention. In the past, individuals
with
PTSD and SUDs received treatment for their substance use, and
treatment of PTSD was deferred. More recently, this approach
has
been considered problematic because the symptoms of PTSD
(i.e.,
sleep disturbance and intrusive thoughts) may drive relapse to
sub
stance use. In response to this concern, integrated therapies
targeting
both disorders have been developed and are under investigation
(Ouimette & Brown, 2003). Most of these therapies combine
suc
cessful elements of existing psychotherapeutic treatments for
sub
stance abuse and trauma. For both disorders, cognitive-
behavioral
strategies, in particular, have demonstrated success. Several
prelim
inary studies support the use of the Seeking Safety (SS)
program. This
is a manual-guided group therapy designed specifically for
women

with PTSD and substance dependence and consists of 25
sessions
equally aimed at modifying thoughts, behaviors, and
interpersonal
issues (Najavits, Weiss, Shaw, & Muenz, 1998). In one
controlled trial,
SS and relapse prevention therapy (another cognitive-
behavioral
therapy, in this case aimed at preventing return to substance
use) were
equally efficacious, and both were superior to treatment as
usual
The amygdala and thalamus are part of the limbic system,
which plays a
critical role in processing emotional information. The thalamus
computes both
nonemotional and emotional information and then sends this
information on to
the amygdala. The amygdala is central to the expression of
negative emotions
in humans and has been associated with anger, avoidance, and
fear.
The HPA axis helps to regulate the body's stress symptoms. It
controls the
release of stress hormones and aids in reestablishing a steady
state after a
disturbance or stressful event.
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2016 20:00:37 UTC

Substance Abuse and Posttraumatic Stress Disorder
(i.e., standard treatment they would receive in a clinic if they
were not
participating in a research study).
One controversy concerning integrated psychotherapy involves
the
use of exposure-based PTSD therapy in substance-dependent
indi
viduals. There is a great deal of empirical evidence supporting
ex
posure-based treatment for PTSD, which involves helping
patients
confront memories, places, or specific situations that remind
them of
the trauma, that they have avoided, and that now evoke
unrealistic and
intense fear (Friedman, Davidson, Mellman, & Southwick,
2000). This
therapy can cause distress and discomfort and was not
recommended
for individuals with SUDs because of the concern that exposure
might
precipitate relapse in this vulnerable population. However,
several
recent studies have demonstrated successful use of exposure-

based
therapy in some individuals with co-morbid PTSD and SUDs,
although
the sample sizes of these studies were small and dropout rates
high
(Back, Dansky, Carroll, Foa, & Brady, 2001; Coffey, Dansky,
& Brady,
2003; Triffleman, Carroll, & Kellogg, 1999).
Although the early results from integrated treatments suggest
that
they may be helpful for many individuals with PTSD and
SUDs, the
studies of these treatments have been limited by small sample
sizes,
lack of comparison groups, and high dropout rates. To date,
only one
controlled trial using integrated psychotherapies has been
conducted.
Thus, it is not yet known whether integrated treatments are
superior to
sequential therapies (i.e., treating one disorder and then the
other) or
single-model therapies (i.e., treating only one of the disorders),
how
the various integrated treatments compare with one another,
who
benefits most from integrated treatments, and for whom
integrated

treatments are contraindicated.
Pharmacotherapy
One important goal of pharmacotherapy for comorbid PTSD-
SUDs is
to reduce key symptoms of PTSD so that patients do not need
to use
substances of abuse to distance themselves from the traumatic
event.
In early double-blind, placebo-controlled studies, tricyclic and
monoamine-oxidase inhibitor antidepressants (e.g., Elavil,
Pamelor,
Nardil) were shown to improve intrusive and depressive
symptoms of
PTSD. There have also been uncontrolled trials suggesting
positive
effects of other medications, including carbamazepine, beta-
blockers,
clonidine, benzodiazepines, and lithium. More recently, a
number of
placebo-controlled trials with relatively large numbers of
subjects
have demonstrated that serotonin-reuptake inhibitors,
specifically,
sertraline (i.e., Zoloft), fluoxetine (i.e., Prozac), and paroxetine
(i.e.,
Paxil), are useful in treating PTSD (Friedman et al., 2000). In
addi
tion, pharmacotherapeutic treatments for SUDs may prove
useful
among individuals with comorbid PTSD. Although there have
been no
controlled trials of such approaches, recent advances in

psychother
apeutic treatment for alcohol, opiate, and nicotine dependence
suggest
new possibilities. This is clearly an area that warrants
investigation.
CONCLUSIONS AND FUTURE DIRECTIONS
Although there has been a great deal of recent study focused on
the
relationships among stress, PTSD, and SUDs, much work
remains.
Further investigation of the neurobiological interface between
PTSD
and SUDs is needed to provide more information about the
mecha
nisms underlying their causal connection. The noradrenergic
system
and HPA axis are two systems that are implicated in the
pathophys
iology of both SUDs and PTSD. Does chronic use of cocaine,
alcohol,
and other substances of abuse lead to changes in the
noradrenergic,
HPA, or other systems that make an individual more
susceptible to the
development of PTSD? Conversely, does a traumatic
experience,
particularly childhood trauma, lead to changes in
neurotransmitter
and neuroendocrine systems that make an individual more
vulnerable

to the development of an SUD?
Additional treatment studies are also critically important. The
commonalities in the pathophysiology of PTSD and SUDs
suggest that
pharmacotherapies targeting specific neurotransmitter or
neuroendo
crine systems might be particularly beneficial, yet there has
been little
exploration of agents that act on either the noradrenergic
system or the
HPA axis in individuals with both disorders.
Although there have been promising developments in
psychother
apeutic treatments, the question of the safety and efficacy of
exposure
based treatment for PTSD in substance-using populations still
remains
unanswered. It seems likely from the data obtained thus far that
ex
posure-based treatment may be beneficial for a subset of
patients.
Further exploration of different types and timing of
psychotherapeutic
interventions will be important. Finally, how to integrate
pharmaco
therapeutic and psychotherapeutic treatments to maximize

outcomes
is of critical importance. In particular, would medications be
useful in
early stages of recovery to help patients engage in and comply
with
psychotherapy, or are medications better utilized for patients
who do
not respond to psychotherapeutic interventions alone?
In conclusion, further exploration of PTSD, substance use, and
the
connections between these two disorders could provide
information
that will help not only in the treatment of these disorders, but
also in
the broader understanding of the complexity of the relationship
be
tween external Stressors and the development of
psychopathology.
Recommended Reading
Chilcoat, H.D., & Breslau, N. (1998). (See References)
Jacobsen, L.K., Southwick, S.M., & Kosten, T.R. (2001). (See
References)
Kreek, M., & Koob, G. (1998). (See References)
Ouimette, P., & Brown, P.J. (Eds.). (2003). (See References)
Stewart, J. (2003). (See References)

REFERENCES
Armony, J.L., & LeDoux, J.E. (1997). How the brain processes
emotional in
formation. In R. Yehuda & A.C. McFarlane (Eds.),
Psychobiology of
posttraumatic stress disorder (pp. 259-270). New York: New
York Acad
emy of Sciences.
Back, S.E., Dansky, B.S., Carroll, K.M., Foa, E.B., & Brady,
K.T. (2001). Ex
posure therapy in the treatment of PTSD among cocaine-
dependent in
dividuals: Description of procedures. Journal of Substance
Abuse
Treatment, 21, 35-45.
Chilcoat, H.D., & Breslau, N. (1998). Investigations of causal
pathways be
tween PTSD and drug use disorders. Addictive Behaviors, 23,
827-840.
Coffey, S.F., Dansky, B.S., & Brady, K.T. (2003). Exposure-
based trauma-fo
cused therapy for comorbid posttraumatic stress disorder-
substance use
disorder. In P. Ouimette & P.J. Brown (Eds.), Trauma and
substance abuse:
Causes, consequences, and treatment of comorbid disorders
(pp. 127-146).
Washington, DC: American Psychological Association.
Cottier, L., Compton, W., Mager, D., Spitznagel, E., & Janea,
A. (1992).

Posttraumatic stress disorder among substance users from the
general
population. American Journal of Psychiatry, 149, 664-670.
208 Volume 13?Number 5
2016 20:00:37 UTC
Friedman, M.J., Davidson, J.R.T., Mellman, T.A., &
Southwick, S.M. (2000).
Pharmacotherapy. In E.B. Foa, T.M. Keane, & MJ. Friedman
(Eds.),
Effective treatments for PTSD: Practice guidelines from the
International
Society for Traumatic Stress Studies (pp. 84-105). New York:
Guilford
Press.
Jacobsen, L.K., Southwick, S.M., & Kosten, T.R. (2001).
Substance use dis
orders in patients with posttraumatic stress disorder: A review
of the
literature. American Journal of Psychiatry, 158, 1184-1190.
Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M., & Nelson,
C.B. (1995).
Posttraumatic stress disorder in the National Comorbidity
Survey. Ar
chives of General Psychiatry, 52, 1048-1060.

Kreek, M., & Koob, G. (1998). Drug dependence: Stress and
dysregula
tion of brain reward pathways. Drug and Alcohol Dependence,
51,
23-47.
Najavits, L.M., Weiss, R.D., Shaw, S.R., & Muenz, L.R.
(1998). "Seeking
Safety": Outcome of a new cognitive-behavioral psychotherapy
for women
with posttraumatic stress disorder and substance dependence.
Journal of
Traumatic Stress, 11, 437-456.
Ouimette, P., & Brown, PJ. (Eds.). (2003). Trauma and
substance abuse: Causes,
consequences, and treatment of comorbid disorders.
Washington, DC:
American Psychological Association.
Regier, D.A., Farmer, M.E., Rae, D.S., Locke, B.Z., Keith,
S.J., & Judd, L.L.
(1990). Comorbidity of mental disorders with alcohol and other
drug
abuse: Results from the Epidemiologie Catchment Area (ECA)
Study.
Journal of the American Medical Association, 264, 2511-2518.
Stewart, J. (2003). Stress and relapse to drug seeking: Studies
in laboratory
animals shed light on mechanisms and sources of long-term
vulnerability.
American Journal on Addictions, 12, 1?17.
Stewart, S.H., & Conrod, PJ. (2003). Psychosocial models of
functional asso

ciations between posttraumatic stress disorder and substance
use disor
ders. In P. Ouimette & PJ. Brown (Eds.), Trauma and substance
abuse:
Causes, consequences, and treatment of comorbid disorders
(pp. 29-55).
Washington, DC: American Psychological Association.
Triffleman, E., Carroll, K, & Kellogg, S. (1999). Substance
dependence
posttraumatic stress disorder therapy: An integrated cognitive-
behavioral
approach. Journal of Substance Abuse Treatment, 17, 3-14.
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Contents206207208209Issue Table of ContentsCurrent
Directions in Psychological Science, Vol. 13, No. 5 (Oct.,
2004), pp. 173-214Front MatterNeurobiological Consequences
of Long-Term Estrogen Therapy [pp. 173-176]What Can
Neuroimaging Tell Us about the Mind? Insights from Prefrontal
Cortex [pp. 177-181]Neural Foundations of Emotional Speech
Processing [pp. 182-185]Saying What You Don't Mean: Social
Influences on Sarcastic Language Processing [pp. 186-189]What
the Social Brain Sciences Can Tell Us about the Self [pp. 190-
193]Violent Children in Developmental Perspective: Risk and
Protective Factors and the Mechanisms through Which They
(May) Operate [pp. 194-197]Seasonal Patterns of Stress,
Disease, and Sickness Responses [pp. 198-201]Do Psychiatric
Patients Do Better Clinically If They Live with Certain Kinds of
Families? [pp. 202-205]Substance Abuse and Posttraumatic
Stress Disorder [pp. 206-209]Beyond Quality: Parental and
Residential Stability and Children's Adjustment [pp. 210-

213]Back Matter
s anxiety sensitivity a predictor of PTSD in children and
adolescents?
· Emine Zinnur Kılıça, ,
· Cengiz Kılıçb,
· Savaş Yılmaza
Show more
http://dx.doi.org.ezproxy.fau.edu/10.1016/j.jpsychores.2008.02.
013
Get rights and content
Abstract
Objective
Anxiety sensitivity (AS) is the fear of the physical symptoms of
anxiety and related symptoms. Longitudinal studies support AS
as a vulnerability factor for development of anxiety disorders.
This study aimed to investigate AS as a vulnerability factor in
the development of childhood posttraumatic stress
disorder (PTSD) following traumatic experiences.
Methods
The study included 81 children 8–15 years of age who
experienced the 1999 earthquake in Bolu, Turkey. The
earthquake survivors were compared to a randomized group of
age- and sex-matched controls 5 years after the earthquake.
Both the subject and control groups were administered the
Childhood Anxiety Sensitivity Index (CASI), State and Trait
Anxiety Inventory for Children (STAI-C), and
Child Depression Inventory (CDI), while the PTSD symptoms of
the subjects were assessed using the Child Posttraumatic Stress
Reaction Index (CPTS-RI).
Results
Subjects and controls did not differ significantly in CASI,
STAI-C, or CDI scores. Multiple regression analysis showed
that both trait anxiety and CASI scores predicted CPTS-RI
scores of the subjects; the prediction by CASI scores was over

and above the effect of trait anxiety.
Conclusion
The results of this study support the hypothesis that AS may be
a constitutional factor, which might increase the risk of PTSD
following traumatic experiences.
Keywords
· Anxiety sensitivity;
· Child;
· Adolescent;
· PTSD
Introduction
Several factors are held responsible for the development and
chronicity of posttraumatic stress disorder (PTSD) in children
and adolescents exposed to traumas. These include within-
trauma factors such as trauma severity, and pretrauma factors
including gender and age [1]. Biological vulnerability factors,
such as anxiety sensitivity, have also been shown to play such a
role in adult samples. This study aims to show if the same
relationship holds for children and adolescents.
The concept of anxiety sensitivity
Anxiety sensitivity (AS) is a concept that was originally
developed by Reiss and McNally [2] to describe the degree of
discomfort and negative attributions to anxiety sensations
arising from the belief that these sensations are signs of
physical, psychological, or social harm. Rather than being a
sign of psychopathology itself, AS is seen as a constitutional
trait variable, acting as a risk factor for the development of
various anxiety disorders. The measurement of AS includes the
assessment of the consequences of physical, cognitive, and
social harm associated with anxiety symptoms, such as body
awareness and feared cognitions. The Anxiety Sensitivity Index
(ASI) [3] is the principal measure used to assess AS in adults.
Studies that have used ASI in adults have generally
examined panic disorder and most found a positive association
between the presence of panic disorder and high ASI

scores [4] and [5]. Subjects with high AS have higher rates
of comorbid anxiety disorders and tend to be susceptible to
marked anxiety reactions following biological challenge
tests [6] and [7]. Evidence from several longitudinal
investigations suggests that AS is a predictor of subsequent
panic attacks in nonclinical samples [8].
Several studies have attempted to show the mechanisms that
link AS to specific anxiety disorders. Avoidance has been
suggested to be a clinically significant mechanism that might
play a role in maintaining anxiety disorder and to be associated
with poorer diagnosis. Wilson and Hayward [9], in their
prospective study on adolescents with panic disorder, showed
that AS may precede and exacerbate avoidance, which, in turn,
increases anxiety. Isyanov and Calamari [10], on the other hand,
hypothesized that individuals with high levels of AS appraise
many life events as much more stressful due to their reactivity
to both the event and to the anxious arousal they experience.
They suggest that AS might lead to increased general stress
levels by altering stress appraisal. Since they appraise anxious
arousal as not just unpleasant, but as dangerous, life
experiences that lead only to a transitory increase in anxiety
will elicit greater distress in individuals with elevated AS.
While individuals with high trait anxiety will respond to
stressors with more fear and distress, individuals with high AS
may react to both the stressor and the associated anxiety
experience. Additional evidence exists that demonstrating AS is
not merely a reflection of trait anxiety, but it is shown to be
related to disorders other than anxiety, namely somatoform
disorders and substance use disorders[11], [12] and [13].
Anxiety sensitivity and childhood disorders
Children with anxiety disorders have been shown to have higher
levels of AS compared to normal controls in several
studies [14] and [15]. A number of studies have reported a
relationship between panic attacks in children and adolescents
and AS [16], [17] and [18]. Reiss et al. [5] suggested that the
level of AS at ages 7-14 years might predict the development of

panic disorder in adult life. According to their theory, the
development of AS is influenced by cognitive factors, in
addition to genetic ones. By the time children become 7-10
years old, they will have already developed beliefs about what
will happen to them when they become nervous or experience
stress. These beliefs are hypothesized to significantly modify
the child's inherited sensitivity to anxiety [5]. Likewise, Mattis
and Ollendick [19], in their investigation of the cognitive
responses of children to panic symptoms, concluded that AS in
children predicted catastrophic attributions, regardless of age,
and speculated that high levels of AS and elevated internal
attributions in response to negative outcomes could set the stage
for the development of panic attacks and subsequent panic
disorder.
AS has been investigated in various other problems of children
and adolescents. Although AS was found to be related
to depression[20] and worry [21], AS predicted panic attacks in
children and adolescents, even after controlling for general
negative affectivity [22]. The predictive value of high AS for
panic attacks was also shown in an adolescent African-
American sample [23]. Watt and Stewart [11] investigated this
concept further, positing that heightened AS in childhood may
lead children learn to catastrophize their bodily sensations,
leading to hypochondriacal symptoms in adolescence. The study
of Hayward et al. [18], which showed that AS develops before
panic symptoms first appear, supports the conceptualization of
AS as a risk factor for anxiety disorders, rather than being a
disorder itself. AS, therefore, seems to be a constitutional factor
creating the basis for the development of an anxiety disorder in
the presence of an external challenge.
AS and PTSD
Although AS has been widely studied in childhood anxiety
disorders, studies on AS in PTSD are scarce. In adults, the
relationship of AS and PTSD has been shown in various
studies [24]. After the Bam earthquake in Iran, Hagh-Shenas et
al. [25] found a relationship between high AS and PTSD among

a group of rescue workers. They reported that among the
untrained rescue workers, students with high AS scores
exhibited greater adverse psychological effects.
PTSD is common in children after disasters; many studies report
incidence rates ranging from 30–60% in children and
adolescents [26]. The notion that PTSD symptoms decrease with
time has been challenged by long-term studies. PTSD may
become chronic in a group of disaster survivors, which, in turn,
may significantly affect psychological
development [27] and [28]. In their study, after the 1999
earthquake in Turkey, Karakaya et al. [29] found very severe or
severe degrees of posttraumatic stresssymptoms in 22.2% of
adolescents 3.5 years after the disaster.
Risk factors for the occurrence and persistence of PTSD
symptoms in children after disasters are widely studied.
Proximity to the trauma scene and severity of exposure (loss of
house/relatives, injury, etc.) are commonly found to be risk
factors [30]. Research has shown that parental reactions to a
child's symptoms and parents' symptoms are also important
predictors of childhood
PTSD [31], [32], [33], [34], [35], [36] and [37]. The risk of
developing PTSD depends upon the severity of trauma,
preexisting vulnerability factors, and an interaction between the
two. The “stress vulnerability” hypothesis holds that pretrauma
characteristics make one more susceptible to the negative
effects of a traumatic experience. It is typically seen as an
interaction between the predisposing factor and the traumatic
stressor, so that the relationship between the predisposing factor
and PTSD depends on the level of trauma. In the context of
extreme trauma, host factors may diminish in importance,
whereas in milder trauma vulnerability factors may be of greater
importance. Foy et al. [38] and McCranie et
al. [39] demonstrated this form of interaction. Silva et
al. [40] have demonstrated that preexisting anxiety predicted
PTSD severity in children and adolescents, while higher IQ was
a protective factor. AS, which has been implicated as a

constitutional factor in the development of several other anxiety
disorders, may be the mediating factor that leads to the
development and persistence of posttraumatic stress symptoms
following psychological trauma. To our knowledge, the only
study to assess the relation of AS to PTSD symptoms in
children was conducted by Meiser-Stedman et al. In their study
on children who had had individual traumatic experiences,
although AS did not directly predict PTSD status, it mediated
the relationship between subjective distress during trauma and
the development of acute stress disorder[41]. It will be
interesting to see if a similar relationship exists between AS and
chronic PTSD. It may be hypothesized that since children with
high levels of AS are more sensitive to anxiety-related
sensations, they will have more difficulty in overcoming the
effects of traumatic experiences.
This study aimed to investigate the relationships between AS
and PTSD symptoms in a group of children that experienced a
major earthquake in Bolu, Turkey. Bolu is a small town that had
a pre-earthquake population of 87,000 and lies 30 km away
from the epicentre. The November 12, 1999 (magnitude 7.2),
earthquake killed 48 people and injured 343 in Bolu, while 2400
houses were damaged. Families had to live in tent cities for up
to 2 years after the earthquake and fear of future earthquakes
continued for several months. The rate of severe and very
severe degrees of posttraumatic stress symptoms in children
living in one tent city was 18.8%, 6 months after the
earthquake [37].
The present study was conducted 5 years after the 1999 Bolu
earthquake, at a time when life in the city had returned to
normal and issues about the earthquake were largely forgotten,
except perhaps for temporary anniversary reactions. We
hypothesized that the severity of PTSD symptoms in
earthquake-survivor children, 5 years after the earthquake,
would at least be partly explained by higher AS scores.
Methods
Subjects

A sample of 87 children (43 boys and 44 girls) aged between 8
and 15 years (mean: 11.2 S.D. 2.2) were recruited from the Bolu
city centre. One hundred ninety-one households were randomly
selected from a list of all households at the city centre. All
children living in those households between ages 8–15 were
invited to participate in the study. Children who did not
experience the earthquake or who were unable to complete the
study measures due to a physical or mental problem were
excluded from the study. Six children were excluded from the
study due to incomplete data on their questionnaires. The final
sample thus consisted of 81 children (40 boys and 41 girls).
Controls
The control group (n=87) was randomly selected from a larger
sample of age- and gender-matched children from Ankara
schools. This group contained 43 boys and 44 girls aged
between 8 and 15 years (mean: 11.1, S.D. 2.3) that had not
experienced the earthquake and did not report any traumatic
experience in their lifetime, nor did they report any psychiatric
problem.
Measures
Both the subject and control groups were administered the
Childhood Anxiety Sensitivity Index (CASI), State and Trait
Anxiety Inventory for Children (STAI-C),
Child DepressionInventory (CDI), and a sociodemographic
form, while the PTSD symptoms of the subjects were assessed
using the Child Posttraumatic Stress Reaction Reactions Index
(CPTS-RI).
CASI is a self-report tool developed by Silverman and
colleagues that assesses AS in children [42]; it is a modified
form of the Anxiety Sensitivity Index (ASI) [3]. CASI includes
18 items and a three-point Likert-type scale ranging from 1 (not
at all) to 3 (very much). The reliability study of the Turkish
version was conducted by Yılmaz and Kılıç with a group of
Turkish school children [43]. In that study, the scale
demonstrated reasonable reliability, with a Cronbach's alpha of
0.74 and a test–retest reliability of 0.77.

CPTS-RI is a 20-item self-report scale designed to assess
the posttraumatic stress reactions of school-age children and
adolescents [44]. Pynoos [27] used a revised method in
determining caseness, which we also adopted. They found that
the measure's severe and very severe categories correctly
identified 78% of subjects who met Diagnostic and Statistical
Manual of Mental Disorder (DSM), Revised Third
Editioncriteria for PTSD. The reliability and validity study of
the Turkish version was conducted with primary school children
that survived an explosion in Turkey [45]. Test–retest reliability
was .86 and internal consistency (alpha) was .75. The scale
captured 80% of DSM, Fourth Edition PTSD cases.
STAI-C is a 40-item self-report questionnaire that assesses
anxiety-related symptoms in children [46]. The scale computes
2 separate total scores: state anxiety and trait anxiety. The
validity and reliability study of the Turkish version was
conducted with a primary school sample by Özusta [47]. Test–
retest reliability of state anxiety scale was .60 and internal
consistency (alpha) was .82. Test–retest reliability of the trait
anxiety scale was .65 and, internal consistency, (alpha) .81.
STAI-C Turkish version significantly differed children with
anxiety disorders from normal controls.
CDI is a 21-item self-report questionnaire that assesses
depressive symptoms in children [48]. The validity and
reliability study of the Turkish version was carried out by Öy in
Turkish children [49]. The reliability of the scale (alpha) was
.77, and test–retest reliability was .80. The sensitivity of the
scale was 60%, whereas the specificity was 95%.
Data analysis
Statistical analyses were made using SPSS v.10.0. The two
study groups were compared using t tests. Pearson's correlation
coefficients and linear regression were used to examine the
relationship between PTSD scores and other demographic and
clinical variables. Ethical approval was obtained from Ankara
University Medical School Ethics Committee.
Results

No significant differences were found between the subjects and
controls in terms of age or gender. Comparing subjects to
controls, there were no significant differences in their mean
CASI, STAI-C, and CDI scores (Table 1).
Table 1.
Comparison of subjects and controls, in terms of mean CASI,
STAI-C, and CDI scores (t tests)
Subjects (Mean, S.D.)
Controls (Mean, S.D.)
t
CASI
32.4 (7.3)
31.1 (6.2)
1.68 (NS)
Trait anxiety
35.4 (7.3)
34.1 (6.4)
1.24 (NS)
State anxiety
32.7 (6.5)
31.9 (6.5)
0.8 (NS)
CDI
10.8 (7.2)
9.7 (3.9)
1.2 (NS)
NS, nonsignificant; CASI, Childhood anxiety sensitivity index;
STAI-C, State and trait anxiety inventory for children; CDI,
Child Depression Inventory.
Table options
When the subjects were grouped according to the level of
CPTS-RI PTSD symptoms as nonsymptomatic (<12 points),
mild PTSD (12–24 points), moderate PTSD (25–39 points),
severe PTSD (40–59 points), and very severe PTSD (>60 points)
in accord with the original form of the scale [44], 10% did not

have PTSD, 40% had mild PTSD, 33% had moderate PTSD,
16% had severe PTSD, and 2.5% had very severe PTSD. There
were 42 subjects with moderate to very severe PTSD (PTSD
subgroup), whereas nonsymptomatic subjects and subjects with
mild PTSD (non-PTSD subgroup) numbered 39. Table 2 shows
that the PTSD and non-PTSD subgroups differed significantly in
terms of depression, state and trait anxiety, and AS scores;
those with more severe PTSD symptoms had higher scores on
all measures than the non-PTSD subgroup.
Table 2.
Comparison of the PTSD and non-PTSD subgroups, in terms of
age, CDI, CASI, and trait and state anxiety mean scores (t tests)
Moderate-Very Severe PTSD (mean, S.D.) (n=42)
Non-PTSD (mean, S.D.) [n=39]
T
P
Age
11.0 (2.1)
11.4 (2.3)
1.0
.3
CDI
13.6 (8.6)
8.1 (3.7)
−3.7
.01
CASI
35.6 (7.7)
29.4 (5.6)
−4.1
.01
Trait anxiety
39.1 (7.5)
31.9 (4.6)
−5.3

.01
State anxiety
35.2 (6.7)
30.6 (5.8)
−3.3
.01
Table options
The correlations between CPTS-RI, CASI, STAI-C, and CDI
scores in the subject group are shown in Table 3, and Table
4 shows correlations between CASI, STAI-C, and CDI in the
control group. AS had significant positive correlations with
state and trait anxiety in both groups; correlations with trait
anxiety were higher. The correlations with CDI did not reach
significance. CPTS-RI scores had significant positive
correlations with all study measures in the subject group.
The correlations ranged between 0.38 and 0.71; the highest
correlation was with trait anxiety.
Table 3.
Correlations between CPTS-RI, CASI, state anxiety, trait
anxiety, and depression scores of the subject group (Pearson's
correlations)
CASI r(P)
State anxiety r(P)
Trait anxiety r(P)
CDI r(P)
CPTS-RI
0.38 (P<.01)
0.47 (P<.01)
0.71 (P<.01)
0. 51 (P<.01)
CASI
–
0.29 (P<.01)
0.32 (P<.01)
0.17 (P<.13)

State anxiety
–
–
0.58 (P<.01)
0.60 (P<.01)
Trait anxiety
–
–
–
0.65 (P<.01)
CPTS-RI, Child Post-traumatic stress reaction index; CASI,
Childhood anxiety sensitivity index; CDI, Child Depression
Inventory.
Table options
Table 4.
Correlations between the CASI, state anxiety, trait anxiety,
and depression scores of the control group (Pearson's
correlations)
State anxiety
Trait anxiety
CDI
CASI
0.22 (P<.05)
0.44 (P<.01)
0.18 (P<.10)
State anxiety
–
0.40 (P<.01)
0.38 (P<.01)
Trait anxiety
–
–
0.28 (P<.01)
Table options
Multiple regression analysis was performed within the subject

group in order to show if AS played a unique role in
determining CPTS-RI scores. The independent (explanatory)
variables were age, gender (1=male, 2=female), CASI score,
CDI score, state anxiety score, and trait anxiety score. The
dependent variable was CPTS-RI score. The explanatory
variables were simultaneously entered into the regression
equation (method=enter). The result of this analysis showed that
higher PTSD scores were predicted independently by both CASI
and trait anxiety scores, and the prediction by trait anxiety was
stronger (Table 5). This finding shows that the prediction of
PTSD scores by CASI scores was over and above the effect of
trait anxiety.
Table 5.
Predictors of PTDS scores (multiple linear regression)
CPTSD-RI scores
Full regression model (r=0.74; adjusted r2=0.52;
F(15,104)=15.1; P<.001)
Significant predictors
β
P
Trait anxiety
0.55
.001
Anxiety sensitivity
0.21
.05
Gender
−.011
.185
Age
−.03
.715
CDI
.09

.40
State anxiety
.07
.52
Entered variables: gender, age, state anxiety, trait anxiety,
depression, and AS.
Table options
Discussion
To the best of our knowledge, this is the first study to examine
the relationship of AS to chronic PTSD symptoms in children.
We compared a group of children and adolescents who had
experienced the 1999 Bolu earthquake to a control group with
no history of traumatic experiences, in terms of depression,
anxiety, and AS scores. These two groups did not differ in terms
of their mean AS, depression, or anxiety symptom scores.
Although we did not find any difference between the subject
and control groups in terms of AS scores, the subjects with
more severe PTSD symptoms had higher AS, depression, and
anxiety scores than the subjects with less severe PTSD
symptoms. Linear regression analyses, taking CDI, CASI, and
STAI-C as independent variables, showed that AS and trait
anxiety scores, but not state anxiety or depression scores,
predicted PTSD. These results support the hypothesis that AS
might be a constitutional trait with a normal distribution among
the general population (traumatized or not), which may act as a
vulnerability factor leading to psychopathology during times of
stress.
The strong correlation we found between trait anxiety and AS
has been reported in other studies, which led some researchers
to conclude that AS is, in fact, trait anxiety. This idea has been
questioned by McNally [50], who suggests that while trait
anxiety predicts a general propensity to respond anxiously to
threatening stimuli, AS predicts a propensity specific to the
symptoms of anxiety. Reiss [51] also argued that, in trait
anxiety, the feared stimulus is regarded as dangerous, while in
AS, an uncontrollable reaction is feared. Since various studies

have made this distinction, Reiss et al. [5] conclude that AS is
theoretically and empirically distinct from Spielberger's
measure of trait anxiety. The fact that the two variables
independently predicted PTSD symptoms supports the above
notion that AS and trait anxiety are actually distinct constructs.
Not all individuals develop PTSD after traumas. Various factors
lead to the development and persistence of PTSD symptoms.
Individuals with high levels of AS are shown to appraise many
life events as much more stressful due to their reactivity to both
the event and to the anxious arousal they experience. They are
therefore more vulnerable to the effects of stressful life events
and to trauma reminders. Life experiences that lead only to a
transitory increase in anxiety will elicit greater distress and
catastrophic attributions in such individuals, leading to the
persistence of trauma-related stress symptoms.
Many studies demonstrate that the most persistent symptoms of
PTSD belong to the group of avoidance [52] and [53].
Avoidance is also known to relate to higher decrease in quality
of life in trauma studies. Since individuals with high AS are
more likely to respond with greater distress to stressful to life
events, it is reasonable to assume that they will tend more to
avoid events or situations that provoke anxiety. Avoidance may
also prevent improvement by removing the chance of exposure.
This avoidant attitude in children with high AS, therefore, may
be responsible for the persistence of PTSD symptoms.
The findings of our study may have implications on both
detection and management of high-risk groups. Trauma
survivors with high AS may be less motivated to volunteer for
anxiety-provoking treatments such as cognitive behavior
therapy (CBT), and they may avoid coming into contact with
treatment services or drop out of treatment prematurely.
Clinicians with an awareness of the significance of AS will,
therefore, have an advantage in engaging high AS trauma
survivors into treatment.
Some limitations of our study should be mentioned. Although
our study sample was representative of a town at the epicentre

of the November 1999 Bolu earthquake, the small sample size
did not allow for factor analytic studies of CASI, which would
have provided additional information contributing to an
understanding of how AS is related to PTSD. Future studies
with larger samples could overcome this limitation. A second
limitation was the cross-sectional nature of data collection.
Even if it is possible to control for the contribution of other
variables on outcome, the link of causality cannot be drawn in
cross-sectional studies. It is, therefore, possible that higher AS
may be the result of long-lasting PTSD symptoms in the
affected individuals, instead of causing it. Longitudinal
studies are therefore needed to clarify the role of AS in the
development of PTSD following psychological trauma.
Abnormalities of white matter integrity in the corpus callosum
of adolescents with PTSD after childhood sexual abuse: a DTI
study
· Authors
· Authors and affiliations
· Mirjam A. W. Rinne-AlbersEmail author
· Steven J. A. van der Werff
· Marie-José van Hoof
· Natasja D. van Lang
· Francien Lamers-Winkelman
· Serge A. Rombouts
· Robert R. J. M. Vermeiren
· Nic J. A. van der Wee
23 December 2015
DOI: 10.1007/s00787-015-0805-2
Cite this article as:
Rinne-Albers, M.A.W., van der Werff, S.J.A., van Hoof, MJ. et
al. Eur Child Adolesc Psychiatry (2016) 25: 869.
doi:10.1007/s00787-015-0805-2
Abstract

This study seeks to determine whether white matter integrity in
the brain differs between adolescents with post-traumatic stress
disorder (PTSD) due to childhood sexual abuse (CSA) and
matched healthy adolescents and whether there is a relationship
between white matter integrity and symptom severity in the
patient group. Using 3T diffusion tensor imaging, we examined
fractional anisotropy (FA) in a group of adolescents with CSA-
related PTSD (n = 20) and matched healthy controls (n = 20), in
a region of interest consisting of the bilateral uncinate
fasciculus (UF), the genu, splenium and body of the corpus
callosum (CC), and the bilateral cingulum. In addition, we
performed an exploratory whole brain analysis. Trauma
symptomatology was measured with the Trauma Symptom
Checklist for Children (TSCC) to enable correlational analyses
between FA differences and trauma symptomatology. The PTSD
group had significantly lower FA values in the genu, midbody
and splenium of the CC in comparison with controls (p < 0.05,
tfce corrected). Post hoc analyses of the eigenvalues of the DTI
scan showed increased radial and mean diffusivity in the patient
group. In addition, we found a significant negative correlation
between scores on the anger subscale of the TSCC and FA
values in the left body of the CC in patients (p < 0.05).
Adolescents with CSA-related PTSD show decreased FA in the
CC, with abnormalities in the integrity of the left body of the
CC being related to anger symptoms. These findings suggest
that early trauma exposure affects the development of the CC,
which may play a role in the pathophysiology of PTSD in
adolescents.
Keywords
PTSDDiffusion tensor imagingAdolescentsSexual
abuseNeuroimaging
Mirjam A.W. Rinne-Albers and Steven J.A. van der Werff share
first authorship.
Introduction
Childhood psychotrauma is a prevalent and important predictor
of both child and adult psychopathology as well as a number of

somatic disorders [1, 26, 31, 45]. Preclinical research in rodents
and non-human primates has shown that structure and
functioning of the developing brain are highly vulnerable to the
effects of adversity, especially in certain critical time windows.
In animal studies, childhood adversity was found to be
associated with changes in brain circuitry involved in stress and
emotion regulation, such as the hippocampus and certain
prefrontal regions, possibly underlying vulnerability to the
impact of stressors later in life [12, 25, 32, 41]. In adult
humans, a history of chronic traumatization during childhood
and adolescence was found to be associated with structural and
functional damage in key elements of emotion and stress
regulating brain circuitry, for example in the hippocampus in
adults reporting childhood abuse or in the medial prefrontal
cortex in adults reporting childhood emotional maltreatment
[5, 56]. Bearing in mind the neuroplasticity of the maturing
human brain [8], a thorough understanding of the human
neurobiology underlying the psychological sequelae of
childhood and youth psychotrauma may hold promise for
developing appropriate interventions to alter adverse
neurodevelopmental trajectories [22]. Some recent reviews and
meta-analyses have addressed structural brain alterations
following childhood trauma in both adolescents and (young)
adults with and without psychopathology [11, 40, 60]. The
studies included in these reviews and meta-analyses often used
different approaches and varied in sample size. Nevertheless,
next to findings in the cerebellum and sensory cortex, most of
the results from reviews and meta-analyses point toward
involvement of the corpus callosum (CC) and corticolimbic
circuits in the pathophysiological sequelae of psychotrauma in
children and young adults.
Diminished white matter (WM) integrity can constitute one
element of abnormalities in corticolimbic and related circuitry.
Diminished structural integrity may impede adaptive emotional
and cognitive functioning, thereby rendering an individual
vulnerable to childhood and adult psychopathology.

A promising tool for examining the structural integrity of WM
in children and youth who experienced psychotrauma is
diffusion tensor imaging (DTI). Fractional anisotropy (FA) is
the most commonly used DTI parameter and reflects the degree
of diffusion directionality of water, which in white matter can
be influenced by structural properties such as axonal density,
organization and myelinization. Smaller FA values are
associated with decreased white matter integrity. To further
interpret differences in FA, additional parameters such as the
mean diffusivity (MD), axial diffusivity (AD), and radial
diffusivity (RD) can be assessed as well.
So far, four studies in children and youth have employed DTI to
examine the effects of psychotrauma on white matter integrity
in the developing brain and several reported abnormalities in
the CC, but also in other areas. The first small study, in
children who had been subjected to early socioemotional
deprivation (N = 7), found decreased FA in the left UF [14].
The second study, in a group of children (N = 17) with post-
traumatic stress disorder (PTSD) following varying forms of
maltreatment, found reduced FA in the medial and posterior
subregions of the CC [24]. The third study looked at the
influence of Early Life Stress (ELS) on FA of the genu of the
CC across the life span in healthy individuals. The results
showed a lower FA in the youngest (8–12 years) and oldest (51–
72 years) ELS age groups compared to non-exposed controls,
suggesting that the effect is independent from the presence of
psychopathology [44]. This was corroborated in the fourth study
by Huang and Rao, in adolescents exposed to childhood
maltreatment but without a history of psychiatric illness, who
showed decreased FA values compared to controls in the left
and right superior longitudinal fasciculi, right cingulum bundle,
left inferior fronto-occipital fasciculus and splenium of the CC
[21]. None of these studies investigated additional DTI
parameters and only a region-of-interest (ROI) approach was
used, which may have led important alterations in WM
microstructure outside the ROI to go unobserved. Furthermore,

study populations were heterogeneous for type of child
adversity, which might have resulted in heterogeneous
neuroimaging findings and differences in psychopathological
sequelae.
The aim of our study was to investigate white matter integrity in
a group of adolescents with psychopathology related to
childhood sexual abuse (CSA) and matched healthy controls.
We chose CSA as this is a prevalent form of child psychotrauma
and a frequent cause of PTSD [15, 27]. This study is the first to
focus on integrity of white matter tracts in a group of
adolescents who had all experienced CSA. Based on previous
neuroanatomical studies in children and youth as well as in
adults, we hypothesized a reduced FA in the CC, the UF and the
cingulum, although findings have not been unequivocal. We
also aimed to investigate the possible relationship between FA
and clinical symptoms in the patient group. Next, we also
planned an exploratory whole brain analysis to detect aberrant
FA values in areas outside our a priori defined ROIs.
Methods
Participants
We included N = 22 adolescents with a history of CSA and
related PTSD (further described as PTSD group) and N = 30
healthy controls. The current cross-sectional study is part of the
Emotional Pathways’ Imaging Study in Clinical Adolescents
(EPISCA), a longitudinal MRI study in which adolescents are
followed over a 6-month period.
Inclusion criteria for the patient group were having experienced
sexual abuse during their lifetime more than once by one or
more perpetrators in- or outside the family and being referred to
a mental health service. Most participants came from
specialized psychotrauma centers and had experienced severe
and frequent sexual abuse. Presence of PTSD was not an
inclusion criterion, but clinical assessments (see below) showed
that all patients but one were having PTSD related to the CSA.
Exclusion criteria were: (1) primary DSM-IV diagnosis of
ADHD, pervasive developmental disorders, Tourette’s

syndrome, obsessive–compulsive disorder, bipolar disorder, and
psychotic disorders, (2) current use of psychotropic medication
other than stable use of SSRI’s, or amphetamine medication on
the day of scanning, and (3) current substance abuse. The
healthy control adolescents were recruited through local
advertisement, with the following inclusion criteria: no clinical
scores on validated mood and behavioral questionnaires, no
history of traumatic experiences and no current
psychotherapeutic intervention of any kind. All participants met
the following inclusion criteria: aged between 12 and 21,
estimated full scale IQ (FIQ) ≥80 as measured by Dutch
versions of the Wechsler Intelligence Scales for Children
(WISC-III) [59] or adults (WAIS) [58], being right-handed,
normal or corrected-to-normal vision, sufficient understanding
of the Dutch language, no history of neurological impairments
and no contraindications for MRI testing (e.g. braces, metal
implants or possible pregnancy). More extensive description of
the clinical group can be found in an earlier report about the
EPISCA project [57].
The medical ethics committee of the Leiden University Medical
Centre approved the study. All anatomical scans were reviewed
and cleared by a radiologist. Written informed consent was
obtained from all adolescents and their parents. Participants
received a financial compensation including travel expenses.
Clinical assessments
A standardized set of instruments was used to assess
symptomatology in both groups of adolescents.
The Anxiety Disorders Interview Schedule Child and Parent
Versions (ADIS-C/P) [46] are semi-structured interviews for the
classification of DSM-IV anxiety and depressive disorders in
children. The adolescents and at least one of their parents were
interviewed. A minimal interference score of 4, obtained by
trained examiners based on the ADIS-C and ADIS-P, is
necessary for classification. The ADIS is known to have good
reliability and validity [47] with reported strong test–retest
reliability statistics for the ADIS-C/P for combined diagnoses

(0.80–0.92) and individual diagnoses (0.62–0.88).
As brain development is known to be influenced by sexual
development, physical sexual development was measured with
the self-report Puberty Development Scale (PDS) [38]. The PDS
consists of five items that are measured on a five-point scale by
the examiner: 1 = pre-pubertal, 2 = early pubertal, 3 = mid-
pubertal, 4 = late pubertal, 5 = post-pubertal. The PDS is
considered a valuable instrument determining pubertal stage
[4, 19].
The Trauma Symptom Checklist for Children (TSCC) [7] which
measures trauma-related symptoms is a 54-item self-report for
children and adolescents aged 8 through 18, but is often used up
to 21 years [3, 18]. On a four-point scale (never to almost all of
the time), the adolescent indicates how often a thought, a
feeling or a behavior occurs. The items are grouped into six
clinical scales. The clinical scales are Anxiety (Anx),
Depression (Dep), Post-traumatic Stress (Pts), Sexual Concerns
(Sc), Dissociation (Dis) and Anger (Ang). The TSCC total score
is used as the main measure on post-traumatic symptomatology.
Cronbach’s alpha coefficients reported range from 0.77 to 0.89
for subscales and 0.84 for the total scale. The questionnaire has
extensively been studied, which has confirmed its good
psychometric qualities [29, 36].The internal consistency of the
TSCC subscales varied between 0.85 and 0.94, except for the
Sexual Concerns subscale that measured 0.68.
Six subscales from the Wechsler Intelligence scales scores
(picture completion, similarities, picture concepts, arithmetic,
block design and comprehension) were converted into FIQ
estimates.
Data acquisition and preprocessing
DTI data were collected using a Philips 3.0T Achieva MRI
scanner (Philips Medical Systems, Best, The Netherlands) with
an eight-channel SENSE (Sensitivity Encoding) head coil. A
single-shot echo-planar imaging sequence was used with the
following scan parameters: repetition time = 11,000 ms, echo
time = 56 ms, flip angle = 90°, b-factor = 1000 s/mm2, voxel

dimensions = 2.3 mm isotropic, number of slices = 73, and no
slice gap. DTI data were acquired along 32 directions, together
with a baseline image having no diffusion weighting (b = 0).
Total scanning time was ~7.5 min. Collected DTI data were
preprocessed and analyzed, using the Oxford Centre for
Functional MRI of the Brain (FMRIB) software library
(FSL; http://fsl.fmrib.ox.ac.uk.ezproxy.fau.edu/fsl/fslwiki/) [49]
version 5.0.2. First, DTI data were corrected for distortion and
motion artifacts, induced by eddy currents or by simple head
motions, using affine registration of each diffusion weighted
image to the b = 0 reference image. Next, non-brain tissue was
removed, using the Brain Extraction Tool. Finally, to generate
individual FA maps for each participant, the diffusion tensor
model was fitted to each voxel, using FMRIB’s Diffusion
Toolbox. Total brain volume, normalized for subject head size,
was estimated using SIENAX [51], part of FSL.
Tract-based spatial statistics
Tract-based spatial statistics (TBSS) [48] version 1.2 was used
for voxelwise analysis of the preprocessed FA data. First,
individual FA images were aligned to the FMRIB58_FA
standard-space image, using nonlinear registration. Next, the
mean FA image was generated and thinned to create a mean FA
skeleton, which represents the centers of all tracts common to
the entire group. The mean FA skeleton was then thresholded at
a FA value of ≥0.4, to exclude peripheral tracts and minimize
partial voluming. Finally, each participant’s aligned FA images
were projected onto the mean FA skeleton and the resulting data
were fed into voxelwise permutation-based analysis.
Region-of-interest TBSS
To test for regional specific FA alterations, we implemented an
ROI-based TBSS. A binary mask, encompassing the bilateral
UF, the genu, splenium and body of the CC and the bilateral
cingulum, was created as region of interest using the Johns
Hopkins University (JHU) white matter atlas provided by FSL
[34]. The uncinate fasciculus connects subcortical subregions of
the limbic system, such as the hippocampus and the amygdala,

with the medial prefrontal cortex. The corpus callosum is the
largest white matter bundle in the brain and connects left and
right cerebral hemispheres. It consists of three subregions,
namely the splenium (posterior), the body (middle), and the
genu (anterior). The cingulum bundle is situated superior to the
corpus callosum, curving around the genu and splenium. It
connects prefrontal and subcortical areas, with additional
projections to the parietal lobe.
The mask was then applied to the mean FA skeleton, to include
only voxels comprised in the mean FA skeleton. This confines
the statistical analysis exclusively to voxels from the center of
the tract, thereby minimizing anatomic inter-subject variability,
registration errors, and partial voluming. The resulting study-
specific ROI mask was used for voxelwise permutation-based
ROI analysis.
Statistical analysis of demographic and clinical data
We used analysis of variance (ANOVA) to compare the two
groups on age, IQ and TSCC total score. Because not all TSCC
subscales showed normal distribution we used non-parametric
analysis (Mann–Whitney) for the comparison of the TSCC
subscales between the two groups.
MRI analysis
Using FSL’s Randomize tool, permutation-based inferences
with Threshold-Free Cluster Enhancement (TFCE) were carried
out for voxelwise analysis of FA data [50]. 5000 random
permutations were generated to build up the null distribution of
the cluster size statistic, while testing the following contrasts:
(1) controls > PTSD, (2) controls < PTSD. PDS score, total
brain volume, gender and FIQ (demeaned across groups) were
included in the analysis as nuisance regressors to correct for
between groups variances. The resulting statistical maps were
corrected for multiple comparisons across space (p < 0.05) and
the JHU White Matter and Juelich Histological atlases were
used to label clusters with significant FA alterations. This step
was first carried out using the ROI mask to test our specific
hypotheses. Next, we ran this step a second time using a whole

brain mask for our exploratory analysis.
Post hoc analyses
The association between FA and symptom severity in the PTSD
group was examined using a voxelwise correlation approach. A
mask was created of the voxels that were found to differ
significantly on FA based on the between-group ROI analysis.
The TSCC total and subscale scores of the PTSD group were fed
into FSL’s Randomize tool along with the mask, using
permutation-based inferences with TFCE.
Last, we examined how the between-group differences in FA
values related to the other DTI measures. Therefore,
information on each individuals’ AD (the 1st eigenvalue), RD
(the average of the 2nd and 3rd eigenvalues), and MD was fed
into FSL’s Randomize tool along with the mask based on our
ROI analysis.
Results
From the original total of 22 PTSD and 30 control adolescents,
three controls were excluded because of image artifacts in T1-
weighted anatomical scans. Further, two adolescents with PTSD
were excluded because of image artifacts in the DTI dataset,
resulting in a final sample of 20 adolescents with PTSD. From
the remaining 27 controls, 20 subjects were group-wise matched
on age and gender with the PTSD adolescents. Eventually, 40
participants (20 PTSD and 20 controls) were included. Of the 20
PTSD participants, 19 fulfilled all PTSD criteria on the ADIS,
while one had sufficient PTSD symptoms, but with limited
interference. Since earlier research showed that persons with
subthreshold PTSD in many aspects resemble PTSD patients, we
decided to include this patient [10].
The majority of participants was female (88 %, see Table 1). Of
the participants with PTSD, 15 had comorbid anxiety disorders,
most often more than one. Eight had a comorbid depressive
disorder and one an oppositional defiant disorder (ODD). All
controls and 16 adolescents with PTSD were drug and treatment
naïve. Two adolescents with PTSD were on stable SSRI
treatment and two used amphetamines (not on the day of

scanning).
Table 1
Demographic and clinical characteristics of participants
PTSD (N = 20)
CNTR (N = 20)
p
Mean
SD
Mean
SD
Gender (f : m)
17:3
18:2
Age (in months)
198
24
185
19
0.06
FIQ
99
9
107
9
<0.01
PDSa
Pre/mid-pubertal
1
4

Late pubertal
6
9
Post-pubertal
10
5
TSCCb
Anxiety
9.3
6.0
3.3
Depression
9.9
4.9
2.6
Anger
6.2
3.5
2.0
Post-traumatic stress
11.8

7.2
2.3
Dissociation
8.6
5.6
2.7
Sexual concerns
4.7
3.3
1.3
Because less than 20 % of the data in TSCC were missing,
expectation maximization as regression method was used to
calculate the scale scores
aMissing data: 2 in control group, 3 in PTSD group
bThree PTSD participants did not complete the questionnaire
The PTSD group had a significantly lower FIQ than controls
[F(1, 38) = 8,14, p < 0.01] and more subjects in the post-
pubertal phase (50 versus 25 %). As expected, there was a
significant main effect of group on the TSCC scale scores [with
and without controlling for age and
FIQ; F(7,28) = 6,48, p < 0.01]. The PTSD group had
significantly higher scores on all TSCC scales (all
with p < 0.01).
TBSS Analyses
ROI-based TBSS analysis showed that, in comparison with
controls, the PTSD group had lower FA values in the genu,
midbody and splenium of the CC (p < 0.05, TFCE corrected)
(Fig. 1). No FA differences were observed in the bilateral UF
and cingulum. The exploratory whole brain TBSS revealed no
significant lower FA values. When the threshold was lowered
we found lower FA values in the body of the CC in the left

hemisphere, adjacent to the splenium (p < 0.075, TFCE
corrected; Fig. 2). No white matter tracts with lower FA values
were found for controls versus PTSD.
Fig. 1
Region-of-interest analysis results. Coronal, sagittal and
transversal axial sections of the white matter skeleton (green)
superimposed on the FMRIB58_FA_1 mm standard brain (gray).
Depicted in yellow are the regions in which FA values are
significantly smaller in patients with PTSD compared to
matched healthy controls. For better visibility, the results are
thickened using the “tbss-fill” command (red). All TBSS results
are corrected for multiple comparisons (p < 0.05, TFCE
corrected), and the axial images are in radiological convention
(the right side of the image corresponds with the left
hemisphere of the brain and vice versa)
Fig. 2
Whole brain TBSS results. Coronal, sagittal and transversal
axial sections of the white matter skeleton (green) superimposed
on the FMRIB58_FA_1 mm standard brain (gray). Depicted
in yellow are the regions in which FA values are significantly
smaller in patients with PTSD compared to matched healthy
controls. For better visibility, the results are thickened using the
“tbss-fill” command (red) All TBSS results are corrected for
multiple comparisons (p < 0.075, TFCE corrected), and the
axial images are in radiological convention (the right side of the
image corresponds with the left hemisphere of the brain and
vice versa)
Using a voxelwise correlation approach, we examined the
association between the observed smaller FA values from the
ROI analysis, and the TSCC total and subscale scores in the
patients. We found a significant negative correlation between
scores on the anger subscale of the TSCC and FA values in the
left body of the CC (p < 0.05; uncorrected, Fig. 3.)

Fig. 3
Voxel-wise correlation between TSCC anger subscale scores
and FA values in adolescents with PTSD. Coronal, sagittal and
transversal axial sections of the white matter skeleton (green)
superimposed on the FMRIB58_FA_1 mm standard brain (gray).
FA values in the left CC correlated negatively with TSCC anger
subscale scores (p < 0.05) in the adolescents with PTSD
(yellow). For better visibility, the results are thickened using
the “tbss-fill” command (red). The axial images are in
radiological convention (the right sideof the image corresponds
with the left hemisphere of the brain and vice versa)
Post hoc analyses of the AD, RD and MD in the voxels that
showed FA differences between groups revealed a significant
increase (p < 0.05, TFCE corrected) of RD and MD in the PTSD
group compared to controls. No significant differences were
found between groups in AD. Omitting the one CSA participant
who met all PTSD criteria except for interference did not
change our findings. Excluding the two participants that were
using medication from the analyses did not change the results
either.
Discussion
We examined white matter integrity in a sample of adolescents
with CSA-related PTSD, using an ROI and an additional
exploratory whole brain approach. We hypothesized reduced FA
in a number of relevant white matter tracts: the CC, UF and
cingulum. Compared to the control group, our adolescent PTSD
group only showed decreased FA in areas of the CC, with
additional DTI parameters suggesting demyelinization and
dysmyelinization in these areas. We also found a significant
correlation (uncorrected) between FA in the CC and Anger
scores on the TSCC in the adolescents with CSA-related PTSD.
This study is the first to report on white matter integrity in a
group of adolescents with CSA-related PTSD. The results of our
study are in line with the findings of the recent DTI study by
Jackowski and colleagues, who examined the CC in a group of
children with PTSD following various forms of intrafamilial

maltreatment, and also found reduced FA in several subregions
of the CC [24]. Our findings are in line with recent reviews
indicating that the most consisting finding in youth with
psychotrauma is structural abnormalities of the CC, in contrast
to the reduction of hippocampal volume typically reported in
adults with PTSD [5, 40].
The CC is known to change throughout life, but most
dramatically during childhood and adolescence [2, 30]. These
developmental changes in the CC are the consequence of
varying degrees of axonal myelinization, redirection, and
pruning, reflecting a permanent adjustment and fine-tuning of
fibers connecting homologous cortical areas. The general trend
during adolescence is toward increasing FA and decreasing MD
[43]. This CC maturation parallels puberty development
suggesting gonadal hormonal influences [2]. For this reason, we
included PDS scores as regressor. However, we must
acknowledge that a simple linear regression of pubertal stage
and total brain volume may still not sufficiently account for the
results as they are known not to be linear across adolescence.
Early traumatization is likely to have a major influence on the
integrity of the CC, as the processes of myelinization and
selective pruning are typically influenced by stress hormones
[52, 54]. Of importance, the smaller FA values we found in the
CC of the PTSD group were due to increases in RD and MD,
known to reflect demyelinization (less development of the
myelin sheet) and dysmyelinization (aberrant development of
the myelin sheet), linking the abnormalities of the CC integrity
to the possible influence of stress hormones. Supporting this
possible association, a recent study found that in rhesus
monkeys exposed to early maternal abuse, cortisol levels at the
time of abuse correlated with abnormalities in white matter
connectivity in the CC, brain stem and other brain areas in
adolescence [20]. Our results are in line with the study of
Teicher et al. who, comparing abuse and neglect, found that
sexual abuse was the strongest factor influencing CC size in
girls [53].

Recent topographic research on the CC is beginning to map the
different regions of the CC and their connections. Apart from
frontal connections, the body of the CC also has connections
with subcortical nuclei [21]. Changes in the midbody of the CC
in children and adolescents who experienced psychological
trauma could be related to disturbances in connectivity with
limbic subcortical nuclei, resulting from or underlying the
disturbances in emotion regulation.
We found a negative association in the adolescent PTSD group
between FA in the CC and the TSCC Anger subscale. This in
contrast to the result of the small DTI study in socioemotional
deprived children with PTSD [14] in which correlations of FA
measures in the CC were found with total anxiety scores, panic
scores and separation anxiety scores. This may be due to
methodological differences as well as the populations studied. A
preclinical study in male non-human primates examined the
effects of early life stress on hippocampal volume and CC
development and found a significant inverse relationship
between CC mid-sagittal area in adult monkeys and the response
toward an intruder which typically consists of a mixture of
aggressive and anxious behavior [23]. In a recent DTI study in
male adolescents with conduct disorder, Zhang et al. report
increased structural connectivity in the genu and body of the CC
[61]. Impulsivity correlated positive with WM integrity, which
is the opposite pattern of what we found in our study. This
suggests that different pathophysiological mechanisms are
involved, which is in accordance with the putative mechanisms
described in the literature. For instance, Raine et al.
hypothesize that structural abnormalities in the CC are a
consequence of an early arrest of the normal
neurodevelopmental process of axonal pruning, while the
abnormalities in myelinization following CSA may be more
linked to detrimental stress hormone influences [39].
We believe the relatively homogeneous sample and the state-of-
the-art DTI approaches are strengths of our study, although
several potential limitations should be taken into account. While

we know that gender influences brain development and the
reaction to psychological trauma, we included gender as a
regressor, but could not further explore this issue because our
participants are mainly girls. Full scale IQ measures differed
significantly between the PTSD group and controls. Several
studies report a negative effect of ELS on cognitive function
[13, 37]. In this respect intellectual ability in the PTSD group
and the control group might originally have been more equal.
The New Zealand longitudinal birth cohort study [28] instead
points to IQ as a risk factor for the development of PTSD. In
the discussion about lower IQ being a consequence or a
predictor of PTSD, it is suggested that trauma severity overrules
IQ as a predictor [33] which could be the case in our study
where all included adolescents fulfilled symptom criteria for
PTSD diagnosis although this was not an inclusion criterion, but
here too results are inconclusive [6]. Navas-Sanchez et al. [35]
found a positive correlation between IQ and FA in the CC in
math gifted adolescents compared to controls matched for age
and academic level. Other studies report about correlations,
mostly positive, of cognitive function with FA in several WM
tracts [17, 42]. To decrease the potential influence of IQ on the
white matter integrity differences we included IQ as a covariate
in our analyses, but clearly further research is needed to unravel
the exact relationship between childhood adversity, IQ and WM
integrity in adolescence.
The normal increase of FA in the CC during adolescence is
related to pubertal development. Therefore, the PDS score is
chosen as nuisance regressor instead of age. The PTSD group
was older and more advanced in pubertal stage. Because of the
expected increase, the decrease in FA found in the PTSD group
cannot be a consequence of normal (pubertal) development.
Two adolescents with PTSD were on stable SSRI treatment.
Omitting these two participants from our analyses did not have
any effect on the results. To our knowledge no influence of
SSRIs on the CC is reported [9].
Patients were selected based on the presence of CSA and all

except one, who fulfilled PTSD criteria except interference,
showed CSA-related PTSD. Hence, we cannot differentiate
whether the neuroimaging results were a consequence of
exposure to trauma or the (development of) PTSD pathology or
reflect an underlying vulnerability. Previous research in twins
discordant for combat exposure suggests that anatomical
abnormalities may indeed represent pre-existing vulnerability
factors [16]. The ideal cross-sectional design to disentangle the
effects of exposure, psychopathology and resilience would have
incorporated a CSA group with psychopathology, a CSA group
without psychopathology and a non-exposed, healthy control
group [55]. Furthermore, we could not assess the influence of
timing and duration of the CSA in our study, which is thought
to be highly relevant in children and youth.
About one-third of the subjects also reported physical abuse,
but as we did not assess experiences of other forms of
psychotrauma we could have missed other prevalent traumatic
experiences, like emotional maltreatment, which might be
associated with the presence of DTI abnormalities in our
sample.
In conclusion, our DTI findings in this sample of adolescents
with CSA-related PTSD point at the involvement of the CC in
brain alterations associated with juvenile sexual psychotrauma,
and together with recent animal data can be taken to point at the
influence of stress hormone levels on CC integrity. Clearly,
longitudinal studies till mid-adulthood are needed to further
elucidate the role of altered CC white matter integrity in the
biopsychological consequences of early traumatization and to
examine its malleability.

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