ORIGINAL RESEARCH
published: 26 March 2018

doi: 10.3389/fnbeh.2018.00057

Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 March 2018 | Volume 12 | Article 57

Edited by:

Nelly Alia-Klein,

Icahn School of Medicine at Mount

Sinai, United States

Reviewed by:

Gianluca Serafini,

Ospedale San Martino (IRCCS), Italy

Etsuro Ito,

Waseda University, Japan

*Correspondence:

Katja Bertsch

[email protected]

Received: 14 December 2017

Accepted: 09 March 2018

Published: 26 March 2018

Citation:

Krauch M, Ueltzhöffer K, Brunner R,

Kaess M, Hensel S, Herpertz SC and

Bertsch K (2018) Heightened Salience

of Anger and Aggression in Female

Adolescents With Borderline

Personality Disorder—A Script-Based

fMRI Study.

Front. Behav. Neurosci. 12:57.

doi: 10.3389/fnbeh.2018.00057

Heightened Salience of Anger and
Aggression in Female Adolescents
With Borderline Personality
Disorder—A Script-Based fMRI Study
Marlene Krauch1, Kai Ueltzhöffer1,2,3, Romuald Brunner4, Michael Kaess4,5,

Saskia Hensel6, Sabine C. Herpertz1 and Katja Bertsch1*

1 Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany,
2 Department of Psychology, Goethe University Frankfurt, Frankfurt am Main, Germany, 3 Bernstein Center for Computational

Neuroscience, University of Heidelberg, Mannheim, Germany, 4 Department of Child and Adolescent Psychiatry, Center for

Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany, 5 University Hospital of Child and Adolescent

Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland, 6 Department of Psychosomatic Medicine, Central

Institute of Mental Health, Mannheim, Germany

Background: Anger and aggression belong to the core symptoms of borderline

personality disorder. Although an early and specific treatment of BPD is highly relevant

to prevent chronification, still little is known about anger and aggression and their neural

underpinnings in adolescents with BPD.

Method: Twenty female adolescents with BPD (age 15–17 years) and 20 female healthy

adolescents (age 15–17 years) took part in this functional magnetic resonance imaging

(fMRI) study. A script-driven imagery paradigm was used to induce rejection-based

feelings of anger, which was followed by descriptions of self-directed and other-directed

aggressive reactions. To investigate the specificity of the neural activation patterns for

adolescent patients, results were compared with data from 34 female adults with BPD

(age 18–50 years) and 32 female healthy adults (age 18–50 years).

Results: Adolescents with BPD showed increased activations in the left posterior insula

and left dorsal striatum as well as in the left inferior frontal cortex and parts of the

mentalizing network during the rejection-based anger induction and the imagination of

aggressive reactions compared to healthy adolescents. For the other-directed aggression

phase, a significant diagnosis by age interaction confirmed that these results were

specific for adolescents.

Discussion: The results of this very first fMRI study on anger and aggression in

adolescents with BPD suggest an enhanced emotional reactivity to and higher effort

in controlling anger and aggression evoked by social rejection at an early developmental

stage of the disorder. Since emotion dysregulation is a known mediator for aggression in

BPD, the results point to the need of appropriate early interventions for adolescents with

BPD.

Keywords: anger, aggression, emotion regulation, borderline personality disorder, adolescence, social threat

sensitivity, functional magnetic resonance imaging, group x age interaction

Krauch et al. Anger and Aggression in Female Adolescents With BPD

INTRODUCTION

Borderline Personality Disorder (BPD) is a life-span mental
disorder, which causes a high burden for the affected
individuals and their social environment. Patients with
BPD are characterized by instability in affect and interpersonal
relationships, identity disturbance, and heightened impulsivity.
Furthermore, deficits in emotion regulation as well as intense
feelings of anger and difficulties in anger control belong to

the core symptoms of BPD [American Psychiatric Association
(APA), 2013]. In an effort to cope with strong negative feelings,
such as anger, many BPD patients show self-destructive
behaviors such as self-injury that commonly begins already in
early adolescence (Zanarini et al., 2008). In addition, aggressive
outbursts against significant others are frequent reactions in
patients with BPD. These often result from intense feelings of
anger provoked by potential signals of interpersonal threat,
such as interpersonal provocation, rejection, or exclusion and
may therefore be described as predominantly reactive in nature
(Newhill et al., 2009, 2012; for review, also see Mancke et al.,
2015; Zanarini et al., 2017).

Previous cross-sectional and longitudinal studies have

revealed emotion dysregulation and high levels of trait anger
as important mediators of increased reactive aggression in
BPD (Newhill et al., 2012; Scott et al., 2014; Mancke et al.,
2017), thus supporting the theory of aggressive behavior in
BPD being a dysfunctional effort to control intense feelings
of anger. Typical situational triggers for feelings of anger are
interpersonal situations where the patients feel rejected or
excluded by others. Consistently it is assumed that patients with
BPD are hypersensitive for interpersonal rejection and threats
(Barnow et al., 2009; Bertsch et al., 2013, 2017; Veague and
Hooley, 2014) and it has been described that this heightened
interpersonal threat sensitivity is one of the core mechanisms
for reactive aggression in BPD (Mancke et al., 2015). The
deficit in coping with feelings of anger is supposed to be
due to the patients’ more general deficit in regulating intense
negative emotions. Several studies have investigated the neural
mechanisms that underlie these emotion regulation difficulties
in adult patients with BPD and revealed structural as well
as functional frontolimbic abnormalities. A meta-analysis of

Schulze et al. (2016) confirmed enhanced activation in the left
amygdala and the left hippocampus to emotionally negative
stimuli in medication-free adult patients with BPD compared
to healthy controls. Furthermore, enhanced activation in the
left posterior insula could be found in adult patients with
BPD (Schulze et al., 2016). While these findings on limbic
hyperactivation reflect a heightened emotional responding to
negative emotional stimuli, further findings on a hypoactivation
in the anterior cingulate cortex (ACC) and prefrontal regions,
such as the orbitofrontal cortex (OFC) (Silbersweig et al., 2007;
Koenigsberg et al., 2009; Krause-Utz et al., 2014) support the
assumption of deficits in regulating limbic activation. Using a
script-driven imagery paradigm to study the neural correlates
of imagined physical aggressive reactions to rejection-related
anger, we recently found elevated right lateral orbitofrontal
and right dorsolateral PFC activations in adult male BPD

patients compared to both adult female BPD patients and
healthy male controls (Herpertz et al., 2017). While female
groups did not differ in neural responses to anger induction
in this study, enhanced activations in the dorsal anterior
cingulate cortex (dACC), medial prefrontal cortex (mPFC),
precuneus, and insula were found in female adult BPD patients
compared to healthy controls when feelings of social exclusion
were induced with a cyberball paradigm (Domsalla et al.,
2013).

Although empirical research has confirmed the reliability and
validity of BPD among adolescents (Kaess et al., 2014; Winsper
et al., 2016), until now only few studies on emotion dysregulation
have focused on BPD in childhood and adolescence. However,
this group is of particular interest since the investigation of
deficits in emotion regulation in adolescents with BPD could give
essential insights in the etiology and the course of the disorder
and might hence minimize confounding influences in adult
samples, such as a long history of illness and comorbidities as
well as treatment exposure. It could therefore not only contribute
to a better understanding of BPD in general but also to an
improvement of early interventions that may attenuate the full
manifestation of the disorder.

Interestingly, Lawrence et al. (2011) found that being
excluded triggered the same negative emotions in adolescents
and young adults with BPD (15–24 years) as in healthy
controls, but that the subjective intensity of these negative
emotions (amongst others anger) was elevated in the BPD
group. Hence, although triggering negative emotions across
groups, already in adolescence experiences of social exclusion
are associated with stronger arousal and higher emotional
intensity in adolescents with BPD. Besides more intense
negative emotional reactions to experiences of social exclusion,
deficits in the regulation of emotions have been found in
adolescents with BPD compared to healthy controls but also
adolescents with other psychiatric disorders, using psychometric
(Ibraheim et al., 2017) as well as ambulatory assessment methods
(Santangelo et al., 2017). On a neural level, the few studies
that investigated structural differences in adolescents with BPD
point to volume reductions in the OFC (Chanen et al., 2008;
Brunner et al., 2010) and the ventral ACC (Whittle et al.,
2009; Goodman et al., 2011), but not in the amygdala or
hippocampus as reported for adult BPD patients (Schulze
et al., 2016). Interestingly, structural brain differences in partly
overlapping brain regions could also be revealed at a very early
stage of development in other psychiatric disorders related to
emotion dysregulation, such as unipolar and bipolar depressive
disorders (Serafini et al., 2014). Functional brain alterations
in adolescents with BPD have so far only been addressed in
one pilot study. Comparing neural responses to emotionally
negative pictures in six adolescent patients with BPD and
six healthy controls, this study revealed increased activations
in the amygdala, hippocampus, superior frontal gyrus, and
precentral gyrus in adolescents with BPD (LeBoeuf et al.,
2016).

Taken together, previous fMRI studies on emotion
dysregulation as well as anger and aggression in BPD have
by the majority focused on adult samples and only little is

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Krauch et al. Anger and Aggression in Female Adolescents With BPD

known about the neural correlates of these aspects of the
symptomatology in the early stage of the disorder. Considering
the formerly reported structural alterations as well as deficient
self-reported emotion regulation in adolescents with BPD, we
also assume functional abnormalities in brain circuits involved
in the regulation of emotions, such as anger, in this early stage of
BPD. In improving our understanding of the neural correlates
associated with the symptomatology, we hope to contribute to an
early implementation of appropriate therapeutic interventions
for adolescents with BPD.

The aim of the present study was to investigate neural
correlates of rejection-related feelings of anger and of subsequent
other-directed or self-directed aggressive reactions in female
adolescent BPD patients in order to contribute to a better
understanding of the etiology of disturbed emotion regulation
in BPD. Given the fact that most of the psychiatric in- and
out-patients with BPD is female and most of previous research
has focused on female adult and adolescent BPD patients, we
decided to focus on an all-female sample in this first fMRI
study on anger and aggression in adolescents with BPD knowing
the importance of investigating sex-dependent effects in further
studies.

We used a script-driven imagery paradigm with scripts
describing a social rejection/exclusion situation and the elicited
intense feelings of anger followed by descriptions of self-directed
aggressive reactions or aggressive reactions against the rejecting
person. Based on previous findings in adolescents with BPD
and similar to adult BPD patients, we expected a heightened
emotional responding in adolescents with BPD compared to an
age-matched healthy control group. We hypothesized that the
latter would be reflected in a hyperactivation in the amygdala
and the insula in adolescents with BPD compared to adolescent
healthy controls when listening to the scripts describing anger
inducing rejection situations as well as aggressive behavior.
Furthermore, we hypothesized to find reduced activations in
prefrontal regions, such as the OFC reflecting deficits in the
regulation of highly arousing states of negative emotion in
adolescents BPD compared to healthy adolescents. Consistently,
we expected adolescents with BPD to score higher on the ratings
for feelings of anger after listening to the scripts.

MATERIALS AND METHODS

Participants
Twenty female adolescents with BPD (Y-BPD; age 15–17 years)
and 20 female adolescent healthy controls (Y-HC; age 15–17
years) took part in the study. The study also comprised 34 female
adults with BPD (A-BPD; age 18–50 years) and 32 female adult
healthy controls (A-HC; age 18–50 years). The adult sample was
almost identical with the female sample reported by Herpertz
et al. (2017), therefore, the current analyses and results focus on
the adolescent sample and age-related differences.

All adolescent and adult BPD patients currently met at
least 5 out of 9 BPD criteria according to the Diagnostic and
Statistical Manual of Mental Disorders, 4th edition (DSM-IV,
American Psychiatric Association, 2013) and all adolescent and
adult healthy controls had never received a psychiatric diagnosis

or undergone a psychotherapeutic/psychopharmacological
treatment (see Table 1 for details regarding the sample
characteristics). For the two adolescent groups, participants were
included with at least 15 years and at most 17 years of age, for the
two adult groups participants had to be 18–50 years old. General
exclusion criteria comprised: Neurological disorders, current
alcohol/drug abuse (urine toxicology screening), alcohol/drug
abuse in the last 2 months (interview) or severe medical
illness. Additional exclusion criteria were lifetime diagnoses
of schizophrenia, schizoaffective or bipolar disorder, as well as
reported alcohol/drug dependence in the last 12 months. In the
adolescent group, N = 4 patients took antidepressant medication
(N = 3 SSRIs, N = 1 Agomelatin), while all adult patients had
been free from any psychotropic medication-use for at least 2
weeks prior to participation.

Recruitment was done by the central project of the KFO 256
(Schmahl et al., 2014), a Clinical Research Unit funded by the
German Research Foundation (DFG) dedicated to investigating
mechanisms of disturbed emotion processing in BPD. The study
was approved by the Ethics Committee of the Medical Faculty of
the University of Heidelberg. Participants and caregivers (in case
of minors) provided written informed consent.

Measures
All patients and healthy controls took part in an extensive on-site
diagnostic interview to assess BPD and other current and lifetime
psychiatric disorders. Interviews consisted of the Structured
Clinical Interview for DSM-IV disorders (SCID-I; Wittchen et al.,
1997) and the International Personality Disorder Examination
(IPDE; Loranger, 1999) for assessing the diagnosis of BPD
and axis I and II comorbidities. Interviews were performed
by experienced diagnosticians who held at least a Master’s
degree in Psychology or M.D. and underwent standardized
training resulting in high inter-rater reliabilities (ICC ≥ 0.91 for
both, the number of BPD criteria and the dimensional score
assessed by the ZAN-BPD scale). BPD symptom severity was
assessed with the Zanarini Rating Scale (ZAN-BPD; Zanarini
et al., 2003). Additionally the following trait measurements
were assessed: impulsivity with the Barratt Impulsiveness
Scale (BIS; Patton and Stanford, 1995), dissociation with the
“Fragebogen zu Dissoziativen Symptomen” (FDS; Freyberger
et al., 1999; German version of the Dissociative Experience
Scale by Bernstein and Putnam), and emotion dysregulation
with the Difficulties in Emotion Regulation Scale (DERS; Gratz
and Roemer, 2004), as well as intelligence based on Raven’s
progressive matrices (Raven et al., 2003). Moreover, trait anger
was assessed with the State-Trait Anger Expression Inventory
(STAXI; Spielberger, 1991), a factor derived instrument that
comprises 44 items measuring the experience as well as the
expression of anger. Discriminant and convergent validity have
been supported (Deffenbacher et al., 1996). Trait aggressiveness
was measured with the Aggression Questionnaire (AQ; Buss
and Warren, 2000), which comprises the four scales Anger,
Hostility, Verbal Aggression and Physical Aggression. It is a well-
established instrument for the assessment of aggression, the four
scales have been reported to have moderate to high internal

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Krauch et al. Anger and Aggression in Female Adolescents With BPD

TABLE 1 | Sample description and self-report data.

Y-BPD (N = 20) Y-HC (N = 20) A-BPD (N = 34) A-HC (N = 32) Y-BPD vs. Y-HC group × age

Mean Std. Mean Std. Mean Std. Mean Std. t p F p

Age (years) 16.35 0.88 15.85 0.81 25.69 5.08 27.33 6.37 t(38) = 1.87 P = 0.069 F(1, 101) = 1.36 P = 0.246

Raven 50.55 4.55 52.89 4.65 53.46 4.29 53.40 4.43 t(37) = −1.59 P = 0.120 F(1, 100) = 1.78 P = 0.185

ZAN-BPD

total score

17.40 5.86 0.00 0.00 11.76 4.86 0.39 0.80 t(19) = 13.28 P ≤ 0.001 F(1, 101) = 15.64 P ≤ 0.001

AQ total score 62.75 16.91 41.32 8.08 61.12 11.92 43.39 7.83 t(33) = 4.91 P ≤ 0.001 F(1, 96) = 0.63 P = 0.431

STAXI trait

anger

21.19 8.31 14.11 4.47 23.82 5.87 14.40 3.58 t(33) = 3.21 p = 0.003 F(1, 96) = 1.02 P = 0.315

DERS total

score

109.56 34.11 56.00 11.13 123.55 16.14 63.85 14.14 t(17.69) = 6.02 P ≤ 0.001 F(1, 96) = 0.60 P = 0.442

BIS total

score

75.81 14.32 57.22 8.52 77.17 12.09 60.49 10.46 t(23.84) = 4.53 P ≤ 0.001 F(1, 95) = 0.16 P = 0.694

FDS total

score

20.85 15.39 3.62 3.32 19.26 12.12 2.93 2.35 t(15.04) = 4.26 P = 0.001 F(1, 95) = 0.05 P = 0.824

Lifetime Current Lifetime Current Lifetime Current Lifetime Current

Affective

disorders

12

(60%)

10

(50%)

0 0 31

(91%)

11

(32%)

0 0

Substance

ass. disorders

1 (5%) 0 (0%) 0 0 6 (18%) 0 (0%) 0 0

Anxiety

disorders

4 (20%) 5 (25%) 0 0 20

(59%)

15

(44%)

0 0

PTSD 1 (5%) 1 (5%) 0 0 9 (27%) 8 (24%) 0 0

Somatoform

disorders

0 (0%) 0 (0%) 0 0 5 (15%) 5 (15%) 0 0

Eating

disorders

8 (40%) 4 (20%) 0 0 20

(59%)

13

(38%)

0 0

Antisocial PD 0 (0%) 0 (0%) 0 0 1 (3%) 1 (3%) 0 0

Avoidant PD 0 (0%) 0 (0%) 0 0 0 (0%) 0 (%) 0 0

Y-BPD, female adolescents with BPD; Y-HC, female adolescent healthy controls; A-BPD, female adults with BPD; A-HC, female adult healthy controls. ZAN-BPD, Zanarini Rating Scale

for Borderline Personality Disorder; AQ, Buss and Perry Aggression Questionnaire; STAXI trait anger, trait scale of the State-Trait Anger Expression Inventory; DERS, Difficulties in Emotion

Regulation Scale; BIS, Barratt Impulsiveness Scale; FDS, Fragebogen für dissoziative Symptome (FDS), which is the German version of the Dissociative Experiences Scale (DERS);

PTSD, Posttraumatic Stress Disorder; PD, personality disorder.

consistencies and to be stable over 7 months of testing (Harris,
1997).

Script-Driven Imagery Task
We used a script-driven imagery task with participants listening
to eight standardized scripts, each consisting of four separate
phases: baseline, anger induction, other-directed/self-directed
aggression, relaxation. The anger induction phase was based
on narratives of interpersonal rejection, the other-directed
aggression phase comprised narratives of directing physical
aggression toward another person, the self-directed aggression
phase narratives of self-harming behavior. Each participant
listened to four scripts containing narratives of aggressive
behavior against others and four scripts describing aggressive
behavior against oneself, with order of presentation of the two
script types being pseudo-randomized. Within each script, the
duration of each of the four phases was 25 s and the duration
of the inter-phase interval was 8 s. The scripts were lively
read by professional actors and participants were instructed
to imagine the described scenes as vividly as possible in

order to provoke intense emotional responses. Each of the
eight scripts was followed by self-ratings on 5-point Likert
scales asking for feelings of anger after the anger induction
phase, feelings of anger after the aggression phase as well
as for levels of dissociation, derealization, and vividness of
imagination. The self-ratings were followed by a 20 s inter-script
interval.

Data Acquisition
Data acquisition was performed in a 3T Tim Trio whole-
body scanner (Siemens, Erlangen, Germany) equipped with
a 32-channel head coil. Forty transverse slices were acquired
in each volume using a T2∗-sensitive gradient EPI sequence
(TR = 2.350 s, TE = 27 ms, voxel size 2.3 × 2.3 × 2.3 mm).
Additionally, isotropic high-resolution (1 × 1 × 1 mm) T1-
weighted coronal-oriented structural images were recorded. The
course of the experiment as well as acquisition of the data
during the experiment was controlled by Presentation 14.2
(Neurobehavioral Systems). Audio texts were presented using an
in-ear sound system (Sensimetrics).

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Krauch et al. Anger and Aggression in Female Adolescents With BPD

Data Analysis
Self-Report and Self-Rating Data
Self-report and self-rating data were analyzed using SPSS 20.0
using t-tests for independent groups (Y-BPD vs. Y-HC) with a
two-tailed p < 0.05. We additionally performed 2 × 2 analyses
of variance (ANOVAs) to analyze specific characteristics of the
adolescent BPD sample (group by age interactions). Please note
that varying degrees of freedom are due to missing data from one
A-HC for ZAN-BPD, from four Y-BPD, one Y-HC, and one A-
HC for all other questionnaire data, and from one Y-HC and one
A-HC for the self-ratings during the experiment.

FMRI Data
FMRI data were preprocessed and analyzed in SPM8 under
Matlab R2012b. Standard data preprocessing comprised
temporal adjustment for differences in slice time acquisition,
motion correction, co-registration of EPI images with T1-
weighted structural images, segmentation of structural images,
normalization into MNI space, and spatial smoothing with an
8-mm full-width-half-maximum (FWHM) kernel. On the first
level we set up a general linear model (GLM) for each participant
with baseline, anger, other-directed aggression, self-directed
aggression, relaxation and rating as regressors as well as 6
motion regressors; we defined the contrasts baseline, anger,
other-directed aggression and self-directed aggression for each
participant. On the second level, we entered these contrasts into
a group (BPD, HC) × age (adolescent, adult) × phase (baseline,
anger, other-directed aggression, self-directed aggression) full-
factorial model. Since we were primarily interested in neural
correlates of anger and aggression in adolescents with BPD and
differences between adults with and without BPD are reported
elsewhere (Herpertz et al., 2017), the reported analyses focus on
differential contrast between Y-BPD and Y-HC (i.e., Y-BPD vs.
Y-HC for anger>baseline, other directed aggression > baseline,
and self-directed aggression > baseline). The specificity of the
reported effects for the adolescent sample was addressed in
additional group (BPD vs. HC) by age (adolescent vs. adults)
interaction analyses. To protect against false positive activations,
we used a double-threshold approach in all of our fMRI analysis,
combining a voxel-based threshold (p < 0.001, uncorrected) with
a minimum cluster size of k ≥ 88 (Hayasaka and Nicols, 2004).
For this purpose we first used the AFNI program 3dFWHMx
to estimate the parameters of an extended, mixed model spatial
autocorrelation function (ACF) on the basis of our data. We
entered the resulting parameters (a, b, c) 0.313954, 5.59137,
10.2879 into 3dClustSim and obtained a minimum cluster size
of 87.7 voxels for our current data, given an uncorrected single
voxel threshold of p < 0.001 and a corrected cluster based
threshold of p < 0.05.

RESULTS

Self-Report Data
Adolescents with BPD reported significantly higher levels of BPD
symptoms, aggressiveness, trait anger, emotion dysregulation,
impulsivity, and dissociation than healthy adolescent controls
[all t(33) ≥ 3.21, p ≤ 0.003]. The group by age interaction

was significant for symptom severity [F(1, 101) = 15.64; p ≤
0.001; η2p = 0.13; higher symptom severity in Y-BPD vs. A-
BPD; t(52) = −3.81; p ≤ 0.001]. Further details on demographic,
diagnostic, and self-report data are provided in Table 1.

Self-Ratings
Adolescents with BPD did not differ significantly from healthy
adolescent controls in their subjective anger ratings after the
rejection-based anger induction phase or the aggression phase,
the vividness of imagination, or subjective derealization [t(39)
≤ 1.92, p ≥ 0.062], but Y-BPD reported significantly stronger
dissociation than Y-HC [t(39) ≤ 2.50, p ≥ 0.017]. There were no
significant group by age interactions except for subjective anger
after aggression [F(1, 114) = 4.26; p = 0.041] with significantly
higher anger ratings in healthy adolescents than healthy adults
[t(46) = −2.07; p = 0.045], but no significant difference between
adolescents and adults with BPD [t(40.87) = 0.11; p = 0.913].
Details about self-rating data are provided in Table 2.

fMRI Data
Anger-Induction Phase
Y-BPD showed higher activation in a large cluster comprising
parts of the left insula, putamen and claustrum (peak voxel [x,
y, z]: −32, −10, 10; T = 3.62, k = 394, p < 0.001) compared to
Y-HC. The reverse contrast (Y-HC>Y-BPD) did not result in any
significant effects (see Table 3 and Figure 1A). The group by age
interactions revealed a significant cluster in the left postcentral
gyrus and the left precuneus ((Y-BPD>Y-HC)>(A-BPD>A-HC)
peak voxel [x, y, z]: −30, −36, 68; T = 4.20, k = 102, p < 0.001).

Other-Directed Aggression Phase
Y-BPD showed higher activation in a large cluster including parts
of the left insula, putamen, opercular part of the inferior frontal
gyrus, middle and superior temporal gyri, pallidum, precuneus,
thalamus, and hippocampus (peak voxel [x, y, z]: −34, −48,
8; T = 5.03, k = 1963, p < 0.001; see Table 4 and Figure 1B)
compared to Y-HC. The group by age interaction revealed a
similar cluster ((Y-BPD>Y-HC)>(A-BPD>A-HC) peak voxel [x,
y, z]: −30, −12, 8; T = 4.11, k = 1050, p < 0.001). In addition,
Y-HC compared to Y-BPD showed higher activation in a cluster
that included the right caudate (peak voxel [x, y, z]: 22, 28, 0;
T = 4.04, k = 100, p < 0.001) as well as in a cluster which
comprised parts of the right middle and superior temporal gyri
(peak voxel [x, y, z]: 42, −48, 10; T = 4.48, k = 430, p < 0.001).
Similar to the latter finding, the group by age interaction revealed
higher activation in the right middle and superior temporal gyri
((Y-HC>Y-BPD)>(A-HC>A-BPD), peak voxel [x, y, z]: 52, −46,
8; T = 3.69, k = 126, p < 0.001).

Self-Directed Aggression Phase
When comparing Y-BPD to Y-HC, we found higher activation in
a cluster including the left putamen and insula (peak voxel [x, y,
z]: −32, −10, −2; T = 3.74, k = 178, p < 0.001) and, additionally,
in the left middle temporal gyrus (peak voxel [x, y, z]: −50, −28,
0; T = 3.68, k = 93; p < 0.001). The reverse contrast (Y-HC>Y-
BPD) as well as the group by age interactions did not reveal any
significant effects (Table 5 and Figure 1C).

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Krauch et al. Anger and Aggression in Female Adolescents With BPD

TABLE 2 | Self-rating data.

Y-BPD (N = 20) Y-HC (N = 19) A-BPD (N = 34) A-HC (N = 31) Y-BPD vs. Y-HC Group x Age

Mean Std. Mean Std. Mean Std. Mean Std. t p F p

Anger after

provocation

3.54 0.87 3.63 0.54 3.66 0.63 3.24 0.98 −0.58 0.564 1.29 0.259

Anger after

aggression

3.43 1.04 3.23 0.87 3.64 0.79 2.69 1.04 0.65 0.522 4.26 0.041

Derealisation 2.28 1.02 1.74 0.80 2.26 1.04 1.42 0.81 2.06 0.046 1.37 0.244

Dissociation 2.13 1.09 1.36 0.60 2.06 0.97 1.26 0.71 3.04 0.005 0.10 0.757

Vividness of

imagination

2.89 0.99 3.34 1.09 2.86 0.85 2.52 1.34 −1.51 0.139 3.04 0.084

Y-BPD, female adolescents with BPD; Y-HC, female adolescent healthy controls; A-BPD, female adults with BPD; A-HC, female adult healthy controls.

TABLE 3 | Full-Factorial Analysis, whole brain results during anger induction phase, p < 0.001 and cluster size k ≥ 88.

k p T Z MNI (peak voxel)

x y z

Y-BPD > Y-HC Left insula, left putamen, left rolandic operculum,

claustrum

394 <0.001 3.62 3.59 −32 −10 10

Y-HC > Y-BPD

(Y-BPD>Y-HC) > (A-BPD>A-HC)

No significant results

left postcentral gyrus, left precuneus

102 <0.001 4.20 4.15 −30 −36 68

(Y-HC>Y-BPD) > (A-HC>A-BPD) No significant results

Y-BPD, female adolescents with BPD; Y-HC, female adolescent healthy controls; A-BPD, female adults with BPD; A-HC, female adult healthy controls; k, cluster size; MNI, location of

the peak voxel according to the Montreal Neurological Institute brain atlas.

DISCUSSION

This is the first fMRI study investigating neural correlates of
rejection-related feelings of anger and reactive aggression in
adolescent BPD patients. Using a script-driven imagery setting

to induce feelings of anger, and descriptions of subsequent
aggressive reactions, we found increased activations in the left
posterior insula and left dorsal striatum as well as in the
inferior frontal gyrus and parts of the mentalizing network in
female adolescents with BPD compared to female age-matched
healthy controls. At least for the other-directed aggression
phase, this pattern of activation could only be found in the
adolescent sample suggesting specific alterations for adolescents
with BPD. Together with previous studies, these findings suggest
an enhanced emotional reactivity to interpersonal threat- or
rejection-related situations early in the development of BPD.
Since deficient emotion regulation has emerged an important
mediator for aggression in BPD, the current findings support the
need of early and specific interventions for affected adolescents.

Listening to anger-inducing descriptions of interpersonal
rejection resulted in stronger activations in large clusters
including the left posterior insula and the left dorsal striatum,
mainly the putamen, in adolescents with BPD compared to
healthy adolescents. Similar patterns of increased activations
in the left insula and putamen, but also the middle temporal
gyrus, were also found in adolescents with BPD during the
descriptions of self-directed aggressive behaviors. Furthermore,
the imagination of acting out aggressively against the rejecting

person also caused elevated activations in large clusters including
the left posterior insula and putamen, the middle temporal
gyrus reaching into the superior temporal gyrus, the pallidum,
precuneus, thalamus, hippocaumpus, and the inferior frontal
gyrus. Notably the results of the group by age interaction indicate
that the latter effect is characteristic for adolescents with BPD.

Increased left posterior insula activation indicates enhanced
emotional reactivity to anger-inducing descriptions of
interpersonal rejection and subsequent behavioral responses in
terms of aggression directed against the own or the rejecting
person in adolescents with BPD. The insula has been found to be
crucially involved in the detection and processing of emotionally
salient stimuli (Mühlberger et al., 2010). Therefore, it is not
surprising that elevated insular activations are commonly
reported in response to social exclusion or rejection in adults
(Peyron et al., 2000; Eisenberger et al., 2003; Lieberman and
Eisenberger, 2009) and adolescents (Masten et al., 2009). Since
the posterior insula is part of the affective pain network, it’s
activations in the context of social rejection may be regarded
as a neural correlate of social pain. Following this, the current
findings suggest that interpersonal rejection leads to higher
levels of social pain in adolescents with BPD than in healthy
adolescents. In adult patients with BPD similarly elevated
posterior insula activations in response to emotional stimuli
have been interpreted as a neural correlate of deficient emotion
regulation (Niedtfeld et al., 2010; Schulze et al., 2011). This is of
interest since adolescents with BPD did not only show rejection-
related increased, but also prolonged posterior insula responses

Frontiers in Behavioral Neuroscience | www.frontiersin.org 6 March 2018 | Volume 12 | Article 57

Krauch et al. Anger and Aggression in Female Adolescents With BPD

FIGURE 1 | fMRI results for anger, other-directed aggression and self-directed aggression phase. This figure displays whole brain results (p < 0.001 and cluster size k

≥ 88) for the contrast adolescents with BPD (Y-BPD) vs. healthy adolescents (Y-HC) for anger phase vs. baseline phase (A), other-directed aggression phase vs.

baseline phase (B) and for self-directed aggression phase vs. baseline phase (C).

TABLE 4 | Full-Factorial Analysis, whole brain results during other-directed aggression phase, p < 0.001 and cluster size k ≥ 88.

k p T Z MNI (peak voxel)

x y z

Y-BPD > Y-HC Left insula, left putamen, left rolandic operculum, left heschl

gyrus, left inferior frontal gyrus opercular part, left middle

temporal gyrus, left pallidum, left superior temporal gyrus, left

precuneus, left calcarine fissure, left thalamus, left

hippocampus

1,963 <0.001 5.03 4.95 −34 −48 8

Y-HC > Y-BPD Right middle temporal gyrus, right superior temporal gyrus 430 <0.001 4.48 4.42 42 −48 10

Right caudate 100 <0.001 4.04 4.00 22 28 0

(Y-BPD>Y-HC) > (A-BPD>A-HC) Left insula, left putamen, left rolandic operculum, left inferior

frontal gyrus opercular part, left inferior frontal gyrus triangular

part, left pallidum

1,050 <0.001 4.11 4.06 −30 −12 8

(Y-HC>Y-BPD) > (A-HC>A-BPD) Right middle temporal gyrus, right superior temporal gyrus 126 <0.001 3.69 3.66 52 −46 8

Y-BPD, female adolescents with BPD; Y-HC, female adolescent healthy controls; A-BPD, female adults with BPD; A-HC, female adult healthy controls; k, cluster size; MNI, location of

the peak voxel according to the Montreal Neurological Institute brain atlas.

that was also present during the description of subsequent
other-directed and self-directed aggressive reactions suggesting
deficits in emotion regulation capacities.

Support for the interpretation that interpersonal rejection
may be more painful and hence salient for adolescents with
BPD than healthy adolescents also comes from enhanced
activations in the left dorsal striatum (putamen) as this region
is involved in the coding of stimulus saliency (Zink et al.,
2003). In addition, elevated activations in the thalamus and

hippocampus in response to descriptions of other-directed
aggressive reactions speak for enhanced elevated bottom up
emotion generation (Reiman et al., 1997) and may indicate
deficits in the processing of contextual information (Holland
and Bouton, 1999; Liberzon and Abelson, 2016). Interestingly,
stress effects on the hippocampus and the dorsal striatum are
well documented and have been associated with alterations in
related contextual and habitual memory processes (for review see
de Quervain et al., 2017).

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Krauch et al. Anger and Aggression in Female Adolescents With BPD

TABLE 5 | Full-factorial analysis, whole brain results during self-directed

aggression phase, p < 0.001 and cluster size k ≥ 88.

k p T Z MNI (peak voxel)

x y z

Y-BPD > Y-HC Left putamen,

left insula

178 <.001 3.74 3.71 −32 −10 −2

Left middle

temporal

gyrus

93 <0.001 3.68 3.65 −50 −28 0

Y-HC > Y-BPD No significant

results

(Y-BPD>Y-HC) >

(A-BPD>A-HC)

No significant

results

(Y-HC>Y-BPD) >

(A-HC>A-BPD)

No significant

results

Y-BPD, female adolescents with BPD; Y-HC, female adolescent healthy controls; A-BPD,

female adults with BPD; A-HC, female adult healthy controls; k, cluster size; MNI, location

of the peak voxel according to the Montreal Neurological Institute brain atlas.

Contrary to our hypotheses and to previous studies in adults
with BPD (Schulze et al., 2016), we did not find increased
amygdala responses to the descriptions of interpersonal rejection,
other-directed aggression, or self-directed aggression in female
adolescents with BPD in the current study. As Herpertz et al.
(2017) indeed found a heightened amygdala activation in male
but not in female adults with BPD it remains unclear whether
the lack of increased amygdala activation in the female adolescent
sample in the present study is due to sex differences in amygdala
responsivity to the current experimental manipulation or due to
a lack in statistical power related to the rather small sample of
adolescents (see below). It should also be taken into consideration
that the lack of heightened amygdala activation in our paradigm
might be specific to the adolescent sample. Previous structural
MRI studies also could not find amygdala gray volume alterations
(Chanen et al., 2008; Brunner et al., 2010) that have commonly
been reported in samples of adult patients with BPD (see Schulze
et al., 2016). Additionally, the fact that we found higher anger
ratings not only in the adolescent patients, but also in the
adolescent healthy controls may indicate a likewise increased
emotional reaction—and amygdala activation—in the sample
of the healthy controls as a reason for the lack of significant
differences in this region between the two adolescent groups.

Interestingly, adolescents with BPD showed a heightened
activation in the inferior frontal gyrus in response to descriptions
of aggressive reactions against others. As the inferior frontal
gyrus has been associated with different forms of self-control and
self-regulation, including the regulation of emotion in general
(Lieberman, 2007; Tabibnia et al., 2011) and of anger in particular
(Fabiansson et al., 2012), this suggests strong efforts to control
intense feelings of anger as well as aggressive impulses in
adolescents with BPD. Furthermore, elevated activations in the
middle temporal gyrus, superior temporal gyrus, and precuneus,
regions that belong to the mentalizing network (Saxe and Powell,
2006), in adolescents with BPD could reflect a neural correlate of
the tendency to hypermentalize or over-attribute emotions and
intensions of others in adolescents with BPD (Sharp et al., 2011).

Heightened activation in the precuneus might additionally reflect
a stronger emotional reaction to interpersonal rejection in the
adolescents with BPD in the present study, as a hyperactivation
in the precuneus recently has been associated not only with
mentalizing but also with the experience of social exclusion in
adult healthy volunteers (Beyer et al., 2014) and with a heightened
interpersonal rejection sensitivity in healthy adolescents (Masten
et al., 2009).

On a behavioral level, the rating data did not reveal
significant differences for the anger ratings between adolescents
with BPD and healthy adolescents, which is contrary to our
hypothesis. Interestingly healthy adolescents compared to adult
healthy controls showed higher anger ratings when listening
to descriptions of aggressive behavior, indicating a heightened
emotional responding not only in adolescents with BPD but
also in healthy adolescents. This might explain why the two
adolescent groups did not differ in their anger ratings on the
behavioral level, although they showed significant differences in
neural activation.

Taken together, the fMRI data suggest a stronger salience
of interpersonal rejection in adolescents with BPD associated
with higher levels of social pain. Elevated activations in
the thalamus and hippocampus suggest an even stronger
activation of bottom-up emotion generation and memory
retrieval despite high effort to mentalize and control feelings
of anger. Considering heightened anger ratings also in healthy
adolescents, the fMRI results indicate a level of emotion
dysregulation in adolescents with BPD that goes beyond regular
emotion regulation difficulties in adolescence (Guyer et al., 2016)
suggesting deficits in the interplay of brain regions involved in
the generation and regulation of negative emotions, which has
been previously proposed as an important neural correlate of
emotion dysregulation in BPD. Importantly, this is the first time
that this has been shown in adolescents with BPD suggesting an
early onset of a failure in emotion regulation.

The experimental paradigm and the possibility to compare
the findings in adolescents to those of an adult sample are
major advantages of the current study. Nevertheless, several
shortcomings need to be mentioned. First, we were only able
to include N = 20 female adolescents with BPD aged 15–17
years and future studies with larger samples of (medication-
free) adolescents, a broader age spectrum and/or a longitudinal
design are needed before strong conclusions can be drawn.
Second, mainly for reasons of feasibility we only included
female adolescents in the present study and thus were not
able to investigate possible sex differences in neural correlates
of anger and aggression in adolescents. As we recently
reported distinct sex differences in the same task (Herpertz
et al., 2017), further studies with male and female adolescents
are needed.

Third, a clinical control group would be needed to address
the specificity of the current findings for adolescents with
BPD. Fourth, although the majority of our participants
were medication-free, we cannot rule out that antidepressant
medication in N = 4 adolescents with BPD may have affected
amygdala activation (see Schulze et al., 2016 for negative effects
of medication on amygdala activity in adult BPD patients). Fifthly

Frontiers in Behavioral Neuroscience | www.frontiersin.org 8 March 2018 | Volume 12 | Article 57

Krauch et al. Anger and Aggression in Female Adolescents With BPD

a longitudinal investigation of the adolescent sample would be
necessary to draw conclusions regarding the development of
BPD symptomatology. Finally, we do not have information on
feelings of loneliness, shame, guilt, or other negative emotions in
response to our rejection-based anger induction and description
of aggressive behaviors.

Our results suggest a stronger salience of interpersonal
rejection and subsequent aggressive reactions in female
adolescents with BPD compared to age-matched healthy female
controls. A heightened emotional reactivity to interpersonal
rejections might thus be already apparent at early developmental
stages of BPD. A question that arises from the current findings
is if the stronger emotional reaction to interpersonal rejection
in adolescents with BPD is related to real experiences of former
peer rejection. This aspect should be further addressed in
future studies. In a therapeutic context it could be helpful
for adolescents with BPD to develop functional strategies to
regulate negative emotions, such as intense feelings of anger.
So far, interventions from dialectical behavioral therapy for
adolescents (DBT-A; Rathus and Miller, 2002), such as reality
check or emotion regulation and stress tolerance skills, or
mentalization-based interventions (MBT-A; Bateman and
Fonagy, 2010; Rossouw and Fonagy, 2012) could be helpful
to down-regulate high levels of emotional arousal already at
a very early stage of BPD symptomatology. Learning adaptive
emotion regulation strategies at an early stage of the disorder
may reduce self-destructive and aggressive behaviors and thus
increase the likelihood for positive interpersonal relationships
and social functioning in general. Since interpersonal
dysfunctions belong to the most persistent symptoms of BPD

(Gunderson, 2007), specific and early treatments are of particular
importance.

AUTHOR CONTRIBUTIONS

MaK has contributed substantially to acquisition, analysis, and
interpretation of the data. She has drafted the article. KU
has contributed substantially to analysis and interpretation
of the data. RB and MiK have contributed to conception
and design as well as the interpretation of data. They have
revised the manuscript critically for important intellectual
content. SH has contributed substantially to acquisition of the
data. She has revised the manuscript critically for important
intellectual content. SCH and KB have contributed substantially
to conception and design as well as the interpretation of
data. They have revised the manuscript critically for important
intellectual content. All authors gave final approval of the version
to be published.

ACKNOWLEDGMENTS

The study was part of the Clinical Research Group KFO 256
supported by the German Research Foundation (Schmahl
et al., 2014; www.kfo256.de; HE2660/12-1,HE2660/12-2;
HE2660/7-2;HE2660/14-1;HE2660/16-2;BE5292/2-1;BE5292/
3-2). We acknowledge financial support by Deutsche
Forschungsgemeinschaft within the funding programme

Open Access Publishing, by the Baden-Württemberg
Ministry of Science, Research and the Arts and by
Ruprecht-Karls-Universität Heidelberg.

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Conflict of Interest Statement: The authors declare that the research was

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