Cattane et al. BMC Psychiatry (2017) 17:221
DOI 10.1186/s12888-017-1383-2
DEBATE
Open Access
Borderline personality disorder and
childhood trauma: exploring the affected
biological systems and mechanisms
Nadia Cattane1, Roberta Rossi2, Mariangela Lanfredi2 and Annamaria Cattaneo1,3,4*
Abstract
Background: According to several studies, the onset of the Borderline Personality Disorder (BPD) depends on the
combination between genetic and environmental factors (GxE), in particular between biological vulnerabilities and
the exposure to traumatic experiences during childhood. We have searched for studies reporting possible
alterations in several biological processes and brain morphological features in relation to childhood trauma
experiences and to BPD. We have also looked for epigenetic mechanisms as they could be mediators of the effects
of childhood trauma in BPD vulnerability.
Discussion: We prove the role of alterations in Hypothalamic-Pituitary-Adrenal (HPA) axis, in neurotrasmission, in
the endogenous opioid system and in neuroplasticity in the childhood trauma-associated vulnerability to develop
BPD; we also confirm the presence of morphological changes in several BPD brain areas and in particular in those
involved in stress response.
Summary: Not so many studies are available on epigenetic changes in BPD patients, although these mechanisms
are widely investigated in relation to stress-related disorders. A better comprehension of the biological and
epigenetic mechanisms, affected by childhood trauma and altered in BPD patients, could allow to identify “at high
risk” subjects and to prevent or minimize the development of the disease later in life.
Keywords: Borderline personality disorder, Childhood trauma, HPA axis, Endogenous opioid system,
Neurotransmission, Neuroplasticity, Neuroimaging studies, Epigenetic mechanisms
Background
Borderline Personality Disorder (BPD) is a pervasive pattern of emotional dysregulation, impulsiveness, unstable
sense of identity and difficult interpersonal relationships
[1]. The prevalence rates of BPD are between 0.2–1.8%
in the general community, 15–25% among psychiatric
inpatients and 10% of all psychiatric outpatients [2, 3].
Among the different aetiopathological theories that have
been proposed over years, the most supported is the one
proposed by Linehan in 1993 [4], which suggests that
BPD can be the result of the interactions between
* Correspondence: annamaria.cattaneo@kcl.ac.uk;
acattaneo@fatebenefratelli.eu
1
Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, via Pilastroni 4, Brescia, Italy
3
Stress, Psychiatry and Immunology Laboratory, Department of Psychological
Medicine, Institute of Psychiatry, King’s College London, 125 Coldharbour
Lane, London SE5 9NU, UK
Full list of author information is available at the end of the article
biological and psychosocial factors [2], in particular between biologically based temperamental vulnerabilities
and adverse and traumatic experiences during childhood.
BPD is a disorder primarily characterized by emotion
dysregulation and indeed, patients with BPD show
heightened emotional sensitivity, inability to regulate intense emotional responses, and a slow return to emotional baseline. Linehan proposed also that the
development of BPD occurs within an invalidating developmental context characterized by intolerance toward
the expression of private emotional experiences during
childhood [4]. As a consequence, children exposed to
this adverse environment show inability to learn how to
understand, label, regulate, or tolerate emotional
responses and, conversely, they vacillate between emotional inhibition and extreme emotional lability.
Recently, Hughes and colleagues [5] have proposed an
integration to the aethiopathogenetic model of BPD,
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Cattane et al. BMC Psychiatry (2017) 17:221
emphasizing the role played by a lack of social proximity
or responsiveness from relevant caregivers in the
development of BPD symptoms, which in turn impairs
the individual’s emotion regulation. Affect regulation difficulties have been also proposed as key mediators in the
relationship between childhood trauma and BPD [6].
Several studies have shown that a diagnosis of BPD is
associated with child abuse and neglect more than any
other personality disorders [7, 8], with a range between
30 and 90% in BPD patients [7, 9].
Adverse childhood experiences are also related to BPD
symptom severity [9–11]. In support to this, Widom and
collaborators [12] followed 500 children who had suffered physical and sexual abuse and neglect and 396
matched controls, and they observed that significantly
more abused/neglected children met criteria for BPD in
adulthood in comparison to controls. However, the presence of a risk factor, such as adverse childhood events,
was not necessary or sufficient to explain the reason
why some individuals developed BPD symptoms in
adulthood, whereas others did not.
In a recent study, Martin-Blanco and collaborators
[10] have hypothesized that the interaction of childhood
trauma and temperamental traits could be associated
with the severity of BPD. In this regard, they have evaluated the self-reported history of trauma, the psychobiological temperamental traits and the severity of the BPD
symptoms in a cohort of 130 BPD patients. Data showed
a correlation only between childhood maltreatment and
sociability and no other correlation was observed. Moreover, the interaction between high neuroticism-anxiety
traits and the presence of severe emotional abuse was
associated with the severity of the disorder.
Symptom overlap has been reported between BPD
diagnosis and other disorders including Post-Traumatic
Stress Disorder (PTSD) and other axis I disorders [13].
Moreover, in recent decades, different nosographic descriptions have been suggested to characterize the different symptoms associated with trauma, like complex
Post-Traumatic Stress Disorder (cPTSD) [14], also
known as Disorders of Extreme Stress Not Otherwise
Specified (DESNOS) [15], which describes a clinical syndrome following an experience of interpersonal traumatic victimization and shares many similarities with
BPD, including pathological dissociation, somatizations,
dysregulation of emotions, altered central self and relational schemas. The definition of cPTSD therefore refers
to the experience of severe and/or prolonged traumatic
situations, and does not merely identify the effects of
devastating traumatic events (like violence or chronic
maltreatment), which fall under the category of PTSD or
Acute Stress Disorder. Indeed, exposure to particular
types of traumatic experiences may result in far more insidious and crippling psychopathogenic disorders than
Page 2 of 14
PTSD, compromising the sound development of attachment behavior related systems and of the ability to
modulate emotions [16]. Recent research is currently trying to determine whether cPTSD and BPD diagnosis in
comorbidity with PTSD are distinct or should both be
considered and named as trauma-related disorders [17]. A
recent review [18] has explored the mechanisms through
which childhood trauma is related to the development of
BPD in adulthood, and has discussed how interrelated factors (such as heritable personality traits, affect regulation
and dissociation, trauma symptoms) could be mediators
in the relationship between childhood trauma and BPD.
Based on all these findings, in the following paragraphs we will discuss alterations in several neurobiological systems and in brain morphology that can be
induced by exposure to early life adverse experiences
and that are also associated with BPD (see Table 1). We
will examine the impact of early stressful events on different biological systems and mechanisms, possibly identifying biomarkers that could be involved in BPD
vulnerability. This might allow to identify at high risk
BPD subjects earlier, and to develop intervention strategies and programs.
Discussion
Neurobiological mechanisms involved in BPD
BPD and the hypothalamic-pituitary-adrenal axis
The Hypothalamic-Pituitary-Adrenal (HPA) axis is one
of the neuroendocrine systems which mediate the
response of the body to stress. Although the stress response mechanism is meant to maintain stability or
homeostasis, its long-term activation, as consequence of
chronic stress exposure, may have deleterious effects on
the body, increasing the risk for developing different
kinds of illnesses, including stress-related psychiatric
disorders.
In stress conditions, corticotropin-releasing factor
(CRF) and arginine vasopressin (AVP) are released from
the paraventricular nucleus (PVN) located in the hypothalamus. These peptides travel through the pituitary
portal system and act synergistically to stimulate the release of the adrenocorticotropic hormone (ACTH) from
the corticotroph cells. Then, ACTH is transported
throughout the systemic circulation and binds to receptors in the adrenal cortex of the adrenal gland, resulting
in the biosynthesis and release of cortisol [19]. Cortisol
can affect multiple organs and biological processes, such
as metabolism, growth, inflammation, cardiovascular
function, cognition, and behavior [20, 21], by binding to
specific receptors in the body and in several brain regions, as the hypothalamus, anterior pituitary and medial
prefrontal cortex. The central and peripheral effects of
cortisol are mediated by two intracellular glucocorticoid
receptor subtypes: the high-affinity type I receptor or
Cattane et al. BMC Psychiatry (2017) 17:221
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Table 1 Summary of the papers cited in the review and showing alterations in different biological systems in BPD
Biological systems
Authors
Sample size
Date of study Main Results
HPA axis
Southwick et al. [26]
37 subjects with PTSD comorbid
with BPD; 18 subjects only with
PTSD
2003
Higher 24 h urinary cortisol levels in
patients with PTSD compared to
patients with PTSD and comorbid BPD.
Wingenfeld et al. [27]
21 female patients with BPD; 24
healthy female controls.
2007
Higher overnight urinary cortisol levels
in BPD patients compared to controls.
Very high cortisol levels were found
only in BPD patients with a low number
of PTSD symptoms.
Rinne et al. [28]
39 BPD patients (24 with and 15
without sustained childhood
abuse and comorbid PTSD
(n = 12) or MDD (n = 11));
11 control subjects
2002
Higher ACTH and cortisol levels in the
blood of BPD females who had
experienced childhood abuse during
the DEX/CRH test.
Carvalho Fernando et al. [29] 32 female BPD patients; 32
healthy female
2013
Acute cortisol levels decreased the
reaction time to target stimuli in both
BPD patients and controls.
Martin-Blanco et al. [30]
481 subjects with BPD; 442
controls
2016
Case-control study focusing on 47 SNPs
in 10 HPA axis genes. An association
between polymorphic variants within
the FKPB5 and the CRHR genes with
the diagnosis of BPD was shown. Two
FKBP5 SNPs were more frequently
represented in patients with a history
of childhood trauma.
Wagner et al. [42]
159 BPD patients
2009
Association between stressful events
and low impulsivity in BPD patients.
5-HTTLPR S-allele carriers showed
higher impulsivity scores when exposed
to stressful events than LL omozygotes.
Wagner et al. [47]
112 female BPD patients
2010
COMT Val158Met SNP was associated
with early life stressful events and
impulsive aggression in female BPD
patients
Wagner et al. [48]
159 BPD patients
2010
The effect of COMT Val158Met SNP on
the association between stressful life
events and impulsivity was not confirmed.
Tadic et al. [49]
161 Caucasian BPD patients;
156 healthy controls.
2009
The COMT Met158Met SNP was
over-represented in BPD patients compared
to controls. No differences in 5-HTTLPR
genotype were found. An interaction
between the COMT Met158 and the
5-HTTLPR s-allele was observed.
Martin-Blanco et al. [50]
481 BPD subjects; 442 controls
2015
Genetic variants within COMT, DBH and
SLC6A2 genes were associated with an
enhanced risk to develop BPD
8 infant rhesus monkeys
(4 males and 4 females)
1988
The endogenous opioid system mediates
separate-induced vocalizations and
influences the HPA axis activation in
rhesus monkeys using the mother-infant
separation paradigm.
Prossin et al. [61]
18 un-medicated female BPD
patients; 14 female controls
2010
BPD patients had greater regional μ-opioid
availability at baseline in the left necleus
accumbens, the hypothalamus and the
right hippocampus/parahippocampus
relative to controls, showing an
endogenous opioid system activation.
Driessen et al. [36]
21 female BPD patients;
21 female controls
2000
Volume reduction in the hippocampus
and in the amygdala in BPD patients
compared to controls.
Schmahl et al. [38]
25 unmedicated female patients
2009
with BPD (10 with and 15 without
comorbid PTSD);
25 female controls
Hippocampal volume reduction in
patients with BPD and comorbid PTSD
as compared to controls.
Neurotransmission
Endogenous Opioid Kalin et al. [57]
System
Neuroimaging
studies
Cattane et al. BMC Psychiatry (2017) 17:221
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Table 1 Summary of the papers cited in the review and showing alterations in different biological systems in BPD (Continued)
Epigenetics
Neuroplasticity
Kreisel et al. [70]
39 BPD patients; 39 controls
2014
Smaller hippocampal volume in BPD
patients with a lifetime history than
those without comorbid PTSD.
Boen et al. [71]
18 women with BPD; 21 controls
2014
Two hippocampal structures (DG-CA4
and CA2–3 subfields) were significantly
smaller in patients with BPD than controls.
Kuhlmann et al. [73]
30 BPD patients; 33 controls
2013
Patients with BPD showed lower
hippocampal volumes than controls, but
higher volumes in the hypothalamus.
Rodrigues et al. [63]
124 BPD patients; 147 controls
2011
Both the left and the right sides of the
hippocampus were reduced in BPD patients
with PTSD when compared to controls.
Ruocco et al. [37]
205 BPD patients; 222 controls
2012
Bilateral volume reductions of the amygdala
and hippocampus were not related to
comorbid MDD, PTSD or substance use
disorders.
Martin-Blanco et al. [88]
281 subjects with BPD
2014
An association between NR3C1 methylation
levels and childhood trauma was found in
blood samples of BPD patients.
Dammann et al. [89]
26 BPD patients; 11 controls
2011
An increase in the methylation levels of
HTR2A,NR3C1,MAOA,MAOB and COMT
was found in BPD patients as compared
to controls.
Perroud et al. [91]
346 BD, BPD, and ADHD patients
2016
Differential 5-HT3AR methylation levels
were associated with the severity of
childhood trauma, mainly found in BPD
patients.
Teschler et al. [93]
24 female BPD patients;
11 female controls
2013
Genome-wide methylation analyses revealed
increased methylation levels of several genes
(APBA2,APBA3,GATA4,KCNQ1,MCF2,NINJ2,
TAAR5) in blood of BPD female patients
and controls.
Prados et al. [94]
96 BPD subjects suffering from a
high level of child adversity; 93
subjects suffering from MDD and
reporting a low rate of child
maltreatment
2015
Several CpGs within or near genes involved
in inflammation and in neuronal excitability
were differentially methylated in BPD patients
compared to MDD patients or in relation to
the severity of childhood trauma.
Teschler et al. [95]
24 female BPD patients;
11 female controls
2016
A significant aberrant methylation of rDNA and
PRIMA1 was revealed for BPD patients using
pyrosequencing. For the promoter of PRIMA1, the
average methylation of six CpG sites was higher in
BPD patients compared to controls. In contrast, the
methylation levels of the rDNA promoter region and
the 5′ETS were significantly lower in patients with BPD
compared to controls.
Koenigsberg et al. [109]
24 medication-free BPD patients;
18 healthy control subjects
2012
Decrease of PKC and BDNF protein levels in the blood
of BPD patients.
Tadic et al. [49]
161 Caucasian BPD patients;
156 healthy controls.
2009
Association between HTR1B A-161 variant and the
functional BDNF 196A allele in BPD patients.
Perroud et al. [90]
115 subjects with BPD;
52 controls
2013
Higher methylation levels in BDNF CpG exons I and IV
in BPD patients than in controls. Higher BDNF protein
levels in plasma of BPD patients than in controls.
Thaler et al. [92]
64 women with bulimia nervosa
and comorbid BPD; 32 controls
2014
Hypermethylation within BDNF promoter region sites
in women with bulimia nervosa and with a history of
BPD and/or trauma events.
mineralcorticoid receptor (MR) and the low-affinity type
receptor or glucocorticoid receptor (GR). It has been
suggested that MRs have a high affinity for both cortisol
and aldosterone; they bind cortisol when it is detectable
at low concentrations. The GRs have a relatively low affinity for cortisol, but high affinity for dexamethasone
(DEX) [22]; moreover, they bind cortisol at high concentration, reflecting what occurs in stress conditions.
The HPA axis is regulated by an auto-regulatory
mechanism mediated by cortisol itself, that is crucial in
the maintenance of the homeostatic functions of the
HPA axis. Indeed, when cortisol levels rise, as in
Cattane et al. BMC Psychiatry (2017) 17:221
response to stress, the MRs are saturated and, consequently, cortisol binds the GRs, promoting a cascades of
events that represent the main transduction signals of
glucocorticoids in stress conditions.
So far, the HPA axis activity has been widely investigated in the context of childhood trauma experiences
and findings support alterations in HPA axis in subjects
exposed to stress early in life. Indeed, several studies
have reported alterations in the cortisol circadian
rhythm and levels, indicating a deregulation of the HPA
axis responsiveness, due to childhood trauma experiences, upon stress conditions [23–25].
Despite the large amount of data on the HPA axis
functionality as consequence of exposure to stress early
in life, only a few studies have investigated possible alterations of this axis in BPD patients. For example, higher
urinary cortisol levels have been found in BPD patients
compared to controls [26, 27].
Southwick and colleagues [26] found higher 24 h urinary
cortisol levels in patients with PTSD compared to patients
with PTSD and comorbid BPD, suggesting that these alterations might reflect differences in the severity of PTSD
symptoms rather than factors related to BPD per se.
Another study [27] explored overnight urinary free
cortisol levels showing higher cortisol levels in BPD patients than in controls. A negative association between
cortisol and PTSD symptoms was also observed. Moreover, when BPD patients were divided according to the
presence of high or low number of PTSD symptoms,
very high cortisol levels were found only in BPD patients
with a low number of PTSD symptoms. Rinne and collaborators [28] found an exaggerated ACTH and cortisol
response during the DEX/CRH test in the blood of BPD
female subjects who had experienced childhood abuse.
Carvalho Fernando and colleagues [29] investigated the
effects of cortisol administration on response inhibition
of emotional stimuli in patients with BPD compared to
controls. They found that acute cortisol elevations
decreased the reaction time to target stimuli in both
BPD patients and controls, but they did not differ in task
performance.
Also genetic association studies support alterations in
HPA axis functionality in association with childhood
trauma exposure. Martin-Blanco and collaborators [30]
have investigated the contribution of genetic variants
within genes in the HPA axis, also in the context of childhood trauma exposures, in a sample of BPD patients and
controls. The authors performed a case-control study focusing on 47 SNPs in 10 HPA axis genes. Data showed an
association between polymorphic variants within the
FK506 Binding Protein 5 (FKBP5) and Corticotropin Releasing Hormone Receptor (CRHR) genes with the diagnosis of BPD. In particular, two FKBP5 polymorphisms,
rs4713902 and rs9470079, showed significant association
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with BPD. Stronger associations were found in patients
exposed to childhood trauma where the risk alleles of
other two FKBP5 polymorphisms, rs3798347-T and
rs10947563-A, were more frequently represented in
patients with a history of childhood physical abuse and
emotional neglect than in patients who had never experienced these trauma and controls.
All these findings suggest an association between a
deregulated functionality of the HPA axis and childhood
trauma and highlight the involvement of this biological
system in the development of BPD.
BPD and neurotransmission
In addition to the presence of HPA axis dysfunction,
several studies have also proposed that childhood
trauma can affect glutamatergic, serotonergic, dopaminergic and noradrenergic transmission, suggesting that
BPD is the result of alterations in several interacting
neurotransmitter systems [31, 32].
Glutamatergic and N-methyl-D-aspartate (NMDA)
neurotransmissions play a critical role in neurodevelopment, synaptic plasticity, learning and memory [33, 34]
and alterations in all these processes have been involved
also in the vulnerability and pathophysiology of BPD
[35]. For example, neuroimaging studies in BPD patients
as compared to controls have consistently demonstrated
the presence of decreased synaptic density and volume
in several brain regions involved in spatial or autobiographical memory and in the modulation of vigilance
and negative emotional states, such as hippocampus and
amygdala, which are also enriched in NMDA receptors
[36] (see also paragraph “BPD and neuroimaging studies”). Moreover, early chronic stress and mistreatments
experienced during life by BPD patients have been found
able to impact dendritic arborization, thus contributing
to the development of morphological alterations associated with BPD symptoms [37, 38].
The serotonin transporter gene (5-HTTLPR) and its
related signaling in neurotransmission represent another
system involved in the pathogenesis of BPD [39–42]. In
particular, a functional single nucleotide polymorphism
(SNP) within this gene (the 5-HTTLPR S/L SNP) has
been widely reported to be a modulator of early life
stressful events by several studies [43–45]; interestingly,
it has been also associated with BPD symptoms [42, 46].
For example, Wagner and collaborators [42] investigated
the effects of 5-HTTLPR S/L SNP and of early life
stressful events on impulsivity, assessed by the Barratt
Impulsiveness Scale (BIS), in BPD patients. The authors
reported an association between the presence of stressful
events with lower BIS impulsivity scores, suggesting that
subjects who have experienced trauma, in particular sexual abuse, may show a reduced impulsivity as a consequence of the activation of coping mechanisms that
Cattane et al. BMC Psychiatry (2017) 17:221
control behavior and social interaction. Further analyses
conducted by the same authors indicated that S-allele
carriers showed higher impulsivity scores when exposed
to early life stressful events as compared to LL omozygotes, suggesting that patients with 5-HTTLPR S-allele
are more vulnerable to early life stress. These data highlight the contribution of the serotonergic system on impulsivity in BPD [42].
Another gene suggested to be a genetic risk factor for
BPD is represented by Catechol-O-methyltransferase
(COMT), an enzyme catalyzing the degradation of catecholamines, including the neurotransmitters dopamine,
epinephrine, and norepinephrine; however, literature
data on the role of this gene are contrasting. In a first
study conducted by Wagner and collaborators [47], the
COMT Val158Met SNP has been found associated with
early life stressful events and impulsive aggression,
assessed by the Buss-Durkee-Hostility Inventory (BDHI)
sum score, in female BPD patients. In particular, the authors identified that in COMT Val158Val carriers, but
not in Val/Met and Met/Met carriers, childhood sexual
abuse and the cumulative number of stressful events
were associated with lower BDHI impulsive aggression
scores. However, in another study conducted by the
same authors, the effect of the COMT Val158Met SNP
on the association between stressful life events and impulsivity was not confirmed [48], probably due to the
small sample size. The same authors [49] also investigated, in a group of BPD patients and controls, the role
of (i) the COMT Val158Met SNP, (ii) the 5-HTTLPR S/L
variant and (iii) their interaction as genetic vulnerability
factors for BPD. Data showed that the genotype COMT
Met158Met was over-represented in BPD patients than
in controls, whereas no differences in 5-HTTLPR genotype between BPD and controls were reported. In
addition, the COMT Met158Met genotype was significantly over-represented in BPD patients carrying at least
one 5-HTTLPR S-allele and, interestingly, an interaction
between the COMT Met158 and the 5-HTTLPR S-allele
was also observed. These results suggest an interactive
effect of COMT and 5-HTTLPR gene variants on the
vulnerability to develop BPD and, according to the authors, highlight again the key role of the serotonergic
and dopaminergic system in the pathogenesis of BPD.
Martin-Blanco and collaborators [50] investigated the
possible involvement of the noradrenergic system in BDP
pathogenesis, by evaluating genetic variants within 4 noradrenergic genes. In addition to COMT, the authors selected Dopamine Beta-Hydroxylase (DBH), that acts
transforming dopamine into noradrenaline, Solute Carrier
Family 6 Member 2 (SLC6A2), a transporter responsible
for the reuptake of extracellular neurotransmitters, and
Adrenoceptor Beta 2 (ADRB2), that mediates the
catecholamine-induced activation of adenylate cyclase
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through the action of G proteins. The authors’ findings indicated that only genetic variants within 3 genes (COMT,
DBH and SLC6A2) were associated with an enhanced risk
to develop BPD.
These studies, taken together, show that alterations in
several neurotransmitter systems could be involved in
BPD pathogenesis; however, due to the small number of
available studies, further investigations are needed.
BPD and the endogenous opioid system
According to Bandelow and Schmahl’s theory, a reduction in the sensitivity of the opioid receptors or in the
availability of endogenous opioids might constitute part
of the underlying pathophysiology of BPD [51].
Endogenous opioids mainly include three classes (endorphins, enkephalins and dynorphins), which activate
three types of G protein-coupled receptors (μ, δ, and κ
opioid receptors [52]). One of the most important endogenous opioid is β-endorphin which is synthesized in
part in the arcuate nucleus of the hypothalamus and is
released into the blood, the spinal cord and in various
brain regions, including reward-related areas [53]. βendorphin is activated by a variety of stressors [54] and
induce euphoria and analgesic effects (for example during childbirth and during positive experiences [55]).
The μ-opioid receptors appear to be more relevant for
the social and affective regulation associated with BPD,
suggesting that this system can contribute to the interpersonal vulnerabilities and intrapersonal pain of BPD. These
receptors are widely distributed throughout the human
Central Nervous System (CNS), with a particular density
in the basal ganglia, cortical structures, thalamic nuclei,
spinal cord, and specific nuclei in the brainstem [56].
The endogenous opioid system modulates responses
to acute and chronic stressful and noxious stimuli that
induce physical, emotional, or social pain. In animal
models, the endogenous opioid system has been
implicated in affiliative responses, emotion and stress
regulation, including stress-induced analgesia and
impulsive-like behavior [57]. Using the mother-infant
separation paradigm in rhesus monkeys, Kalin and collaborators [57] studied for the first time the role of the
opioid system in modulating the behavioural and neuroendocrine consequences of a brief occurring stressor.
The authors conducted several experiments where animals received morphine, an opioid agonist, naloxone, an
opioid antagonist or both to test the increase in
vocalization and the activation of the HPA axis in infant
primates separated or not from their mothers. The results showed that morphine significantly decreased
separation-induced vocalizations and locomotion without affecting activity levels, whereas naloxone increased
separation-induced vocalizations and environmental exploration. When the two drugs were co-administered,
Cattane et al. BMC Psychiatry (2017) 17:221
the effect of morphine was reversed only with the
0.1 mg/kg dose of naloxone. The authors also assessed
the effects of separation on neuroendocrine function
and tested whether activation of the opioid system may
attenuate these effects by measuring plasma concentrations of ACTH and cortisol in infant rhesus monkeys
separated or not separated from their mothers, treated
with morphine or naloxone or co-treated with the two
drugs. Plasma ACTH and cortisol levels were higher in
infant rhesus monkeys separated from their mothers
compared to not separated ones, confirming the involvement of the HPA axis during stress exposure. However,
only ACTH plasma levels were modulated by morphine
and by naloxone and by their interaction in the group of
infant separated by their mothers. These findings suggest
that the endogenous opioid system is involved in mediating separation-induced vocalizations and influences
the HPA axis activation following a stress condition.
In humans, regional endogenous opioid system activation has been associated with suppression of both sensory and affective qualities of stressors and with trait
impulsivity [58–60] whereas its regional deactivation has
been related to hyperalgesic responses and increases in
negative affect during stress [61]. The hypothesis is that
the activation of the μ-opioid receptors could have a
suppressive effect during emotional or physical challenges that threaten organism homeostasis.
Research has described regional alterations in the
function of the endogenous opioid system and μ-opioid
receptors in brain regions involved in emotion and stress
processing, decision making, and pain and neuroendocrine regulation. However, to date, there is only limited
evidence of alterations of endogenous opioid levels in
BPD patients. In an interesting study Prossin and collaborators [61] investigated the role of the endogenous opioid system and μ-opioid receptors in emotion regulation
in un-medicated female BPD patients compared to female controls by using positron emission tomography
(PET) (see paragraph “BPD and neuroimaging studies”
for details).
Comparing BPD patients to their matched controls,
the authors found significant differences in baseline regional μ-opioid receptor concentrations in vivo, as well
as in this neurotransmitter system’s response to a negative emotional challenge that can be related to some of
the clinical characteristics of BPD.
BPD and neuroimaging studies
Volumetric alterations in brain areas involved in stress
response
To date, several functional and structural in vivo neuroimaging studies have been performed in BPD patients,
detecting alterations mainly localized in the limbic circuit and in frontal cortex. These regions are related to
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the distinctive clinical features of the disorder (i.e impulsivity, aggression, and emotional reactivity). The most
replicated result, confirmed in recent meta-analyses [37,
62, 63], is represented by the reduction in the volumes
of the hippocampus and the amygdala of BPD patients
compared to controls [36, 64–69]. The robustness of this
finding seems to suggest that volumetric decreases in
these two brain areas could be specific for BPD and thus
useful as possible endophenotypes of illness. In 2000
Driessen and collaborators [36] performed the first magnetic resonance imaging volumetric measurement of the
hippocampus, amygdala, temporal lobes, and prosencephalon in 21 female BPD patients and female controls,
reporting in BPD patients a volume reduction of the
16% in the hippocampus and of the 8% in the amygdala.
Moreover, hippocampal volumes were negatively correlated with the extent and the duration of self-reported
early trauma, but only in the entire sample of BPD patients and controls.
The role of PTSD and trauma as comorbidity with BPD
on hippocampus and amygdala volumes has been object
of investigation but the results are still controversial.
Schmahl and colleagues [38] compared two groups of unmedicated BPD female patients with and without comorbid PTSD and 25 female controls. They found reduced
hippocampal volumes only in patients with BPD and comorbid PTSD but not in BPD patients without a history
of PTSD as compared to controls. Similarly, Kreisel and
collaborators [70] investigated in details the hippocampal
structural volumes comparing 39 BPD patients with 39
matched controls, and, although no volume differences
were found between the two groups, patients with a lifetime history of PTSD had a smaller hippocampal volume
(−10,5%) than those without comorbid PTSD. Boen and
collaborators [71] investigated the volumes of the Cornu
Ammonis (CA) and the Dentate Gyrus (DG), two hippocampal structures prone to morphological changes [72] in
response to adverse environmental changes in a group of
18 women with BPD and 21 controls. The authors found
that the stress-vulnerable DG-CA4 and CA2–3 subfields
were significantly smaller in patients with BPD than in
controls. However, they did not identify any significant
association between subfield volumes and reported childhood trauma.
In another interesting study, Kuhlmann and collaborators [73] investigated alterations in the grey matter of
central stress-regulating structures, including hippocampus, amygdala, anterior cingulate cortex and hypothalamus, in female patients with BPD and controls. The
authors also explored whether grey matter volume of
these four brain structures was associated with childhood trauma, reporting that patients with BPD showed
lower hippocampal volumes than healthy controls, but
higher volumes in the hypothalamus. Interestingly,
Cattane et al. BMC Psychiatry (2017) 17:221
hypothalamic volume correlated positively with a history
of trauma in patients with BPD.
Two recent meta-analyses [37, 63] evaluated whether
the magnitude of hippocampus and amygdala volume
reductions may be associated with state-of-illness factors
and psychiatric disorders (i.e. PTSD) which often cooccured with BPD. In the Rodrigues’ meta-analysis, the
authors included 7 articles with a total number of 124
patients and 147 controls. They showed that both the
left and the right sides of hippocampal volumes were reduced in BPD patients with PTSD when compared to
controls. The left hippocampal volume was not significantly smaller in BPD patients without PTSD relative to
healthy controls and the right hippocampal volume was
reduced in patients with BPD without comorbid PTSD,
but to a lesser degree than in BPD patients with PTSD.
In contrast, the results reported by Ruocco’s metaanalysis [37] which included 11 studies with a total number of 205 BPD patients and 222 controls, revealed that
bilateral volume reductions of the amygdala and hippocampus were unrelated to comorbid Major Depressive
Disorder (MDD), PTSD, or substance use disorders.
Taken together, all these studies show that the main
brain regions involved in BPD are those associated to
stress and highlight the importance of classifying subgroups of patients with BPD, especially taking into account the presence of comorbidity with PTSD or of a
history of childhood trauma. Notwithstanding, the association between the volume reduction and the degree to
which childhood trauma could be responsible for these
changes remains unclear.
Endogenous opiod system alterations in brain regions
involved in stress response
Despite a large amount of data referred to volumetric
and morphological alterations in brain regions associated
to specific clinical features of BPD, not many neuroimaging studies have been conducted to investigate the role
of the endogenous opioid system in BPD. As previously
mentioned, Prossin and collaborators [61] measured the
in vivo availability of the μ-opioid receptors (non-displaceable binding potential (BPND)) in a group of unmedicated female BPD patients compared to female controls by using PET and the selective radiotracer [11C]
carfentanil at baseline and during sustained sadness
states. Patients had greater regional μ-opioid BPND than
controls at baseline (neutral state) in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects,
showing an endogenous opioid system activation. As
suggested by the authors, differences between BPD patients and controls in baseline in vivo μ-opioid receptor
concentrations and in the endogenous opioid system response to a negative emotional challenge can be related
Page 8 of 14
to some of the clinical characteristics of BPD patients.
These findings show alterations in the function of the
endogenous opioid system and μ-opioid receptors in
brain regions involved in emotion and stress processing,
decision making, and pain and neuroendocrine regulation, features also associated with BPD.
BPD and epigenetic mechanisms
The influence of environmental factors, such as childhood trauma, has been suggested to occur through
epigenetic mechanisms, which may underlie geneenvironment associated vulnerability to develop stressrelated disorders [74] including BPD where childhood
trauma history occurs in most of the patients (with a
range between 30 and 90%) [7, 9].
Among the most investigated epigenetic mechanisms
there are: (i) DNA methylation, which occurs at CG
dinucleotides (CpG) and can influence the spatial structure of the DNA and the binding or the repression of
specific DNA-binding proteins to the DNA [75], (ii) histone modifications, which influence the condensation of
the DNA around histone proteins and regulate the accessibility of functional regions to transcriptional factors
[76] and (iii) post-transcriptional regulation by noncoding RNAs such as microRNAs (miRNAs) [77].
All these epigenetic processes and, in particular,
changes in DNA methylation have been widely investigated in the context of long-term negative effects of
early life stressful events. In non-human primates and in
rodents, several paradigms of stress early in life, including maternal separation or prenatal stress have been associated with epigenetic alterations via DNA
methylation [78, 79]. For example, non-stressed dams
during pregnancy showed increased frequency of licking
and grooming in the first week of the puppies’ life that
were associated with changes in DNA methylation
within the promoter of genes, such as glucocorticoid receptor gene (NR3C1), known to be involved in behavior
and neurodevelopment.
The hypothesis is that the quality of maternal care, affected by stress or depression in pregnancy and postpartum [80, 81] could impact, through epigenetic mechanisms, on gene expression and behavioral traits that are
maintained throughout life [78].
Recently, McGowan and colleagues [79] examined
DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18
containing the NR3C1 gene in the hippocampus of adult
rat offspring, whose mothers differed in the frequency of
maternal care. The authors found that the adult offspring of high compared to low maternal care showed a
pattern of regions spanning the NR3C1 gene which were
differentially methylated and acetylated, highlighting the
idea that epigenetic changes, in the context of early life
Cattane et al. BMC Psychiatry (2017) 17:221
stress, involve alterations in gene-networks rather than
in a single or few genes.
Similarly, studies in humans reported similar results as
those found in rodents, including the increased methylation levels within the NR3C1 promoter region in subjects who reported a history of early life adverse events
[82–84]. For example, in another interesting study,
McGowan and collaborators [82] found that in humans
the cytosine methylation levels of the NR3C1 promoter
were significantly increased in the postmortem hippocampus obtained from suicide victims with a history of
childhood abuse as compared with those from suicide
victims with no childhood abuse or with control samples. Decreased levels of NR3C1 mRNA were also identified, suggesting an effect of childhood abuse on NR3C1
methylation status and gene expression, independently
from suicide.
Several epigenetic studies have been also conducted in
control subjects characterized for a history of childhood
trauma compared to those with no childhood trauma. In
this context, Suderman and colleagues [85] have demonstrated, by using a genome-wide promoter DNA methylation approach, an abuse-associated hypermethylation
in 31 miRNAs in a sample of control adult males
exposed to childhood abuse. The hypermethylated state
for 6 of these miRNAs was consistent with an hypomethylation status of their target genes.
Reduced methylation levels of FKBP5 gene within
regions containing functional glucocorticoid responsive
elements (GRE) were also found in the blood of control
individuals exposed to childhood abuse when compared
to subjects without a history of trauma [86]. This demethylation was linked to increased stress-dependent
gene transcription followed by a long-term dysregulation
of the stress hormone system and a global effect on the
function of immune cells and brain areas associated with
stress regulation. Thus, according to the authors, the
changes in FKBP5 methylation levels might increase the
differential responsiveness of FKBP5 to GR activation
that can remain stable over time. Moreover, Labontè and
colleagues [87] have conducted a genome-wide study of
promoter methylation in the hippocampus of individuals
with a history of severe childhood abuse and control
subjects. Methylation profiles were then compared with
corresponding genome-wide gene expression profiles.
Among all the differentially methylated promoters, 248
showed hypermethylation whereas 114 demonstrated hypomethylation and genes involved in cellular/neuronal
plasticity were among the most significantly differentially
methylated.
Despite the contribution of DNA methylation has been
extensively investigated in association with childhood
trauma in the context of pathologies related to stress,
studies on the possible involvement of epigenetic
Page 9 of 14
mechanisms in BPD vulnerability are only at their birth.
Indeed, only few studies are available. In particular,
Martin-Blanco and colleagues, investigated the association between NR3C1 methylation status, history of
childhood trauma and clinical severity in blood samples
of BPD subjects, showing an association between
NR3C1 methylation and childhood trauma, in the form
of physical abuse, and a trend towards significance for
emotional neglect [88]. Regarding NR3C1 methylation
and clinical severity, the authors also found a significant
association with self injurious behavior and previous
hospitalizations. All these findings support the hypothesis that alterations in NR3C1 methylation can occur
early in life as consequence of stress exposure and can
persist up to adulthood where subjects with higher
NR3C1 methylation levels are also those with enhanced
vulnerability to develop BPD.
Above to DNA methylation changes within NR3C1,
hypo- or hyper-methylation within other genes have
been found to play a key role in mediating the impact of
early life stress on the development of stress-related disorders, including BPD [89–92]. For example, in a study
conducted by Dammann and colleagues [89] DNA
methylation pattern of 14 genes, selected because previously associated with BPD and other psychiatric disorders, (COMT, Dopamine Transporter 1 (DAT1),
Gamma-Aminobutyric Acid Type A Receptor Alpha1
Subunit (GABRA1), G Protein Subunit Beta 3 (GNB3),
Glutamate Ionotropic Receptor NMDA Type Subunit 2B
(GRIN2B), 5-Hydroxytryptamine Receptor 1B (HTR1B),
5-Hydroxytryptamine Receptor 2A (HTR2A), Serotonin
Transporter 1 (5-HTT), Monoamine Oxidase A
(MAOA), Monoamine Oxidase B (MAOB), Nitric Oxide
Synthase 1 (NOS1), NR3C1, Tryptophan Hydroxylase 1
(TPH1) and Tyrosine Hydroxylase (TH)), was analyzed
in the whole blood of BPD patients and controls. An increase in the methylation levels of HTR2A, NR3C1,
MAOA, MAOB and COMT was observed in BPD
patients as compared to controls, suggesting that an increased methylation of CpG sites within these genes
may contribute to BPD aetiopathogenesis. Recently,
Perroud and colleagues [91] investigated the role of
childhood trauma on the methylation status of the
Serotonin 3A Receptor (5-HT3AR), including several
CpGs located within or upstream this gene. They analyzed its association with clinical severity outcomes, also
in relation with a functional genetic SNP (rs1062613)
within 5-HT3AR in adult patients with Bipolar Disorder,
BPD, and Attention Deficit Hyperactivity Disorder
(ADHD). The results showed that differential 5-HT3AR
methylation status was dependent on the history of
childhood maltreatment and the clinical severity of the
psychiatric disorder; this association was not specifically
restricted to one specific psychiatric disorders
Cattane et al. BMC Psychiatry (2017) 17:221
investigated by the authors, but was found in patients
who reported the higher severity indexes of childhood
maltreatment, mainly represented by BPD patients. In
particular, childhood physical abuse was associated with
higher 5-HT3AR methylation levels, whereas childhood
emotional neglect was inversely correlated with CpG1 I
methylation levels. As suggested by the authors, these
results highlight the need to search for history of childhood maltreatment in patients suffering from psychiatric
disorders as these events could be associated with the
worse negative outcomes. Moreover, the authors found a
modulation of the 5HT3AR methylation status by
rs1062613 at CpG2 III, where patients carrying the risk
CC genotype showed the highest levels of methylation at
CpG2 III. Since C allele has been also associated with a
lower expression levels of 5HT3AR, the authors suggested that increased methylation, due to exposure to
childhood maltreatment, could lead to a further decrease
in the expression of 5HT3AR mRNA.
Aiming to identify novel genes that may exhibit aberrant DNA methylation frequencies in BPD patients,
Teschler and collaborators [93] performed a genomewide methylation analysis in the blood of BPD female
patients and female controls. The authors reported increased methylation levels of several genes, including
neuronal adaptor proteins (Amyloid Beta Precursor
Protein Binding Family A Member 2 (APBA2) and
Amyloid Beta Precursor Protein Binding Family A Member 3 (APBA3)), zinc-finger transcription factors (GATA
Binding Protein 4 (GATA4)), voltage-gated potassium
channel gene (Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1)), guanine nucleotide exchange factors (Proto-Oncogene MCF-2 (MCF2)),
adhesion molecules (Ninjurin 2 (NINJ2)) and G proteincoupled receptors (Trace Amine Associated Receptor 5
(TAAR5)) in BPD samples compared to controls. Similarly, using a whole-genome methylation approach, Prados and colleagues [94] analyzed the global DNA
methylation status in the peripheral blood leukocytes of
BPD patients with a history of childhood adversity and
also in patients with MDD characterized by a low rate of
childhood maltreatment. Contrary to Teschler [93], who
used control subjects as reference group, in this study
the authors used MDD subjects, most of them suicide
attempters, thus controlling not only for MDD but also
for a history of suicide. The authors also assessed possible correlations between methylation signatures and
the severity of childhood maltreatment. Data showed
that several CpGs within or near genes involved in inflammatory processes (Interleukin 17 Receptor A
(IL17RA)), regulation of gene expression (miR124–3)
and neuronal excitability and development/maintenance
of the nervous system (Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2)) were differentially
Page 10 of 14
methylated, either in BPD compared with MDD or in relation to the severity of childhood maltreatment.
In a more recent study, Teschler and collaborators
[95] have analyzed also DNA methylation patterns of the
ribosomal RNA gene (rDNA promoter region and 5′-external transcribed spacer/5′ETS) and the promoter of
the proline rich membrane anchor 1 gene (PRIMA1) in
peripheral blood samples of female BPD patients and
controls. The authors have identified a significant aberrant methylation of rDNA and PRIMA1 in the group of
BPD patients. Specifically, the average methylation of 6
CpG sites in the promoter of PRIMA1 was 1.6-fold
higher in BPD patients compared to controls. In contrast, the methylation levels of the rDNA promoter region and the 5′ETS were significantly lower (0.9-fold) in
patients with BPD compared to controls. Furthermore,
decreased methylation levels were found for nine CpGs
located in the rDNA promoter region and for 4 CpGs at
the 5′ETS in peripheral blood of patients compared to
controls. These results suggest that aberrant methylation
of rDNA and PRIMA1 could be associated with the
pathogenesis of BPD.
Taken together, all these studies reveal a complex
interplay between BPD, early-life stressful adversities and
epigenetic signatures.
BPD and neuroplasticity (the role of BDNF)
Neuroplasticity refers to brain-related mechanisms
associated with the ability of the brain to perceive, adapt
and respond to a variety of internal and external stimuli
[96, 97], including stress.
The exposure to acute stressful challenges can induce
several beneficial and protective effects for the body,
which responds to almost any sudden, unexpected events
by releasing chemical mediators – i.e. catecholamines that
increase heart rate and blood pressure – and help the individual to cope with the situation [20, 98–101]. However,
a chronic exposure to stress and thus a chronic exposure
to glucocorticoids can have negative and persistent effects
on the body, including altered metabolism, altered immunity, enhanced inflammation, cognitive deficits, and
also an enhanced vulnerability for psychiatric disorders
and for medical conditions such as cardiovascular disease,
metabolic disorders and cancer [102, 103].
Neurotrophic factors, and in particular the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), have
been identified as key mediators of stress on neuronal
connectivity, dendritic arborization, synaptic plasticity
and neurogenesis [104–107]. Since its crucial role in
brain development and brain plasticity, BDNF has been
widely investigated also in several psychiatric diseases,
including BPD [108].
For example, Koenigsberg and colleagues [109] found
a decrease of Protein Kinase C (PKC) isoenzyme, which
Cattane et al. BMC Psychiatry (2017) 17:221
is a molecule downstream the activation of BDNF, and
BDNF protein levels in the blood of BPD patients, suggesting an alteration of BDNF signaling and consequently of neuroplasticity-related mechanisms in BPD.
In another study, Tadic and collaborators [49] investigated the association between BPD and genetic variants
within HTR1B and BDNF genes. Although data showed
no significant differences in genotype or haplotype distribution for both HTR1B and BDNF variants between
BPD patients and controls, logistic regression analyses
revealed an association between the HTR1B A-161 variant and the functional BDNF 196A allele in BPD.
Importantly, several findings have also documented epigenetic modifications on BDNF gene in patients with
BPD, suggesting that childhood maltreatment in BPD patients can cause long term epigenetic alterations of genes
crucially involved in brain functions and neurodevelopment, including BDNF, and that these alterations may
contribute to enhanced vulnerability to develop BPD pathology. In this regard, Perroud and collaborators [90] measured the percentage of methylation at BDNF CpG exons
I and IV and also plasma BDNF protein levels in subjects
with BPD and controls. The authors reported significantly
higher methylation status in both CpG regions in patients
than in controls, with the number of childhood trauma
exposures associated with the high levels of BDNF methylation. Moreover, BPD patients had significantly higher
BDNF plasma protein levels than controls, but this increase was not associated with changes in BDNF methylation status. More recently, Thaler and collaborators [92]
analyzed DNA methylation patterns in the promoter region of BDNF gene in women with bulimia nervosa and
with history of BPD and/or trauma events. They reported
that bulimia nervosa was associated per se with an hypermethylation within BDNF promoter region sites. This was
particularly evident when co-occurring with childhood
abuse or BPD.
Overall, these studies support the hypothesis that childhood trauma could be associated with changes in BDNF
epigenetic signature, that in turn could contribute to alter
cognitive functions in BPD patients. Indeed, higher levels
of gene methylation are commonly accompanied by a reduced gene expression. Thus higher BDNF methylation
levels should determine reduced expression of BDNF gene
and reduced BDNF mRNA levels are widely observed in
patients with psychiatric diseases [110–112].
Conclusions
Up to now, neither a specific gene variant or biological
mechanism has been exclusively associated with BPD,
but the onset of this disorder has been suggested to
depend on the combination of a vulnerable genetic background with adverse environmental factors during
childhood.
Page 11 of 14
Among the biological systems found involved in BPD
pathogenesis and particularly affected by childhood
trauma events, there are: the HPA axis, the neurotransmission mechanisms, the endogenous opioid system and
the neuroplasticity. In line with the involvement of these
processes, neuroimaging studies in BPD patients have
shown volume reductions in the hippocampus and amygdala, both brain regions mainly involved in stress
responses, cognition, memory and emotion regulation and
an increase in the μ-opioid receptors in the same areas.
Among the environmental factors, early life stressful
events, in particular childhood trauma, have been proposed to negatively impact brain development through
epigenetic mechanisms. Although a complex interplay
between BPD, early-life stressful adversities and epigenetic signatures has been suggested, further investigations
are needed in order to better understand the role of genetic background and traumatic events during childhood
in the onset of BPD. A better comprehension of these
interactions could allow to identify at risk subjects, who
could be treated with preventive therapies, such as psychotherapy, and to prevent or minimize the development of the disease later in life.
Abbreviations
5-HT3AR: Serotonin 3A Receptor; 5-HTT: Serotonin Transporter 1; 5-HTTLPR: Serotonin
transporter gene; ACTH: Adrenocorticotropic Hormone; ADHD: Attention Deficit
Hyperactivity Disorder; ADRB2: Adrenoceptor Beta 2; APBA2: Amyloid Beta Precursor
Protein Binding Family A Member 2; APBA3: Amyloid Beta Precursor Protein Binding
Family A Member 3; AVP: Arginine Vasopressin; BDHI: Buss-Durkee-Hostility Inventory;
BDNF: Brain-Derived Neurotrophic Factor; BIS: Barratt Impulsiveness Scale;
BPD: Borderline Personality Disorder; CA: Cornu Ammonis; CNS: Central Nervous
System; COMT: Catechol-O-methyltransferase; CpG: CG dinucleotides;
cPTSD: complex Post-Traumatic Stress Disorder; CRF: Corticotropin-Releasing Factor;
CRHR: Corticotropin Releasing Hormone Receptor; DAT1: Dopamine Transporter 1;
DBH: Dopamine Beta-Hydroxylase; DESNOS: Disorders of Extreme Stress Not
Otherwise Specified; DEX: Dexamethasone; DG: Dentate Gyrus; FKBP5: FK506 Binding
Protein 5; GABRA1: Gamma-Aminobutyric Acid Type A Receptor Alpha1 Subunit;
GATA4: GATA Binding Protein 4; GNB3: G Protein Subunit Beta 3; GR: Glucocorticoid
Receptor; GRE: Glucocorticoid Responsive Elements; GRIN2B: Glutamate Ionotropic
Receptor NMDA Type Subunit 2B; HPA axis: Hypothalamic-Pituitary-Adrenal axis;
HTR1B: 5-Hydroxytryptamine Receptor 1B; HTR2A: 5-Hydroxytryptamine Receptor 2A;
IL17RA: Interleukin 17 Receptor A; KCNQ1: Potassium Voltage-Gated Channel Subfamily Q Member 1; KCNQ2: Potassium Voltage-Gated Channel Subfamily Q Member
2; MAOA: Monoamine Oxidase A; MAOB: Monoamine Oxidase B; MCF2: ProtoOncogene MCF-2; MDD: Major Depressive Disorder; miRNAs: microRNAs;
MR: Mineralcorticoid Receptor; NINJ2: Ninjurin 2; NMDA: N-methyl-D-aspartate;
NOS1: Nitric Oxide Synthase 1; NR3C1: Glucocorticoid receptor gene; PET: Positron
Emission Tomography; PKC: Protein Kinase C; PRIMA1: Prolin Rich Membrane Anchor
1; PTSD: Post-Traumatic Stress Disorder; PVN: Paraventricular Nucleus; SLC6A2: Solute
Carrier Family 6 Member 2; SNP: Single nucleotide polymorphism; TAAR5: Trace
Amine Associated Receptor 5; TH: Tyrosine Hydroxylase; TPH1: Tryptophan
Hydroxylase 1
Acknowledgements
Not applicable.
Funding
This work was supported by an Eranet-Neuron Grant to A.C. (Inflame-D
project) and by funding from the Italian Ministry of Health (MoH) to A.C.
Availability of data and materials
The data supporting the conclusions of this article are included within the
article.
Cattane et al. BMC Psychiatry (2017) 17:221
Authors’ contributions
N.C. managed the literature searches and wrote the first draft of the manuscript.
R.R. and M.L. managed the literature searches and completed the manuscript.
A.C. revised and approved the final version of the manuscript. All authors gave
their scientific contribution and have approved the final manuscript.
Page 12 of 14
13.
Competing interests
All the authors declare that they have no conflicts of interest.
All the authors certify that the submission is an original work and it is not
under review at any other journal.
14.
Consent for publication
Not applicable- as the submitted manuscript is a review.
16.
Ethics approval and consent to participate
Not applicable- as the submitted manuscript is a review.
17.
Author details
1
Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, via Pilastroni 4, Brescia, Italy. 2Psychiatry Unit, IRCCS Istituto
Centro San Giovanni di Dio - Fatebenefratelli, via Pilastroni 4, Brescia, Italy.
3
Stress, Psychiatry and Immunology Laboratory, Department of Psychological
Medicine, Institute of Psychiatry, King’s College London, 125 Coldharbour
Lane, London SE5 9NU, UK. 4Department of Psychological Medicine, Institute
of Psychiatry, Psychology and Neuroscience, King’s College London, 125
Coldharbour Lane, London SE5 9NU, UK.
15.
18.
19.
20.
Received: 7 February 2017 Accepted: 6 June 2017
21.
References
1. Regier DA, Kuhl EA, Kupfer DJ. The DSM-5: classification and criteria
changes. World psychiatry : official journal of the World Psychiatric
Association. 2013;12(2):92–8. doi:10.1002/wps.20050.
2. Leichsenring F, Leibing E, Kruse J, New AS, Leweke F. Borderline personality
disorder. Lancet. 2011;377(9759):74–84. doi:10.1016/S0140-6736(10)61422-5.
3. Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M. Borderline personality
disorder. Lancet. 2004;364(9432):453–61. doi:10.1016/S0140-6736(04)16770-6.
4. Linehan MM. Dialectical behavior therapy for treatment of borderline
personality disorder: implications for the treatment of substance abuse.
NIDA Res Monogr. 1993;137:201–16.
5. Hughes AE, Crowell SE, Uyeji L, Coan JA. A developmental neuroscience of
borderline pathology: emotion dysregulation and social baseline theory. J
Abnorm Child Psychol. 2012;40(1):21–33. doi:10.1007/s10802-011-9555-x.
6. van Dijke A, Ford JD, van der Hart O, van Son M, van der Heijden P, Buhring
M. Affect dysregulation in borderline personality disorder and somatoform
disorder: differentiating under- and over-regulation. J Personal Disord. 2010;
24(3):296–311. doi:10.1521/pedi.2010.24.3.296.
7. Battle CL, Shea MT, Johnson DM, Yen S, Zlotnick C, Zanarini MC, et al.
Childhood maltreatment associated with adult personality disorders:
findings from the collaborative longitudinal personality disorders study. J
Personal Disord. 2004;18(2):193–211.
8. Yen S, Shea MT, Battle CL, Johnson DM, Zlotnick C, Dolan-Sewell R, et al.
Traumatic exposure and posttraumatic stress disorder in borderline,
schizotypal, avoidant, and obsessive-compulsive personality disorders:
findings from the collaborative longitudinal personality disorders study. J
Nerv Ment Dis. 2002;190(8):510–8. doi:10.1097/01.NMD.0000026620.66764.78.
9. Zanarini MC, Frankenburg FR, Hennen J, Reich DB, Silk KR. Prediction of the
10-year course of borderline personality disorder. Am J Psychiatry. 2006;
163(5):827–32. doi:10.1176/ajp.2006.163.5.827.
10. Martin-Blanco A, Soler J, Villalta L, Feliu-Soler A, Elices M, Perez V, et al.
Exploring the interaction between childhood maltreatment and
temperamental traits on the severity of borderline personality disorder.
Compr Psychiatry. 2014;55(2):311–8. doi:10.1016/j.comppsych.2013.08.026.
11. Gunderson JG, Weinberg I, Daversa MT, Kueppenbender KD, Zanarini MC,
Shea MT, et al. Descriptive and longitudinal observations on the relationship
of borderline personality disorder and bipolar disorder. Am J Psychiatry.
2006;163(7):1173–8. doi:10.1176/appi.ajp.163.7.1173.
12. Widom CS, Czaja SJ, Paris J. A prospective investigation of borderline
personality disorder in abused and neglected children followed up into
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
adulthood. J Personal Disord. 2009;23(5):433–46. doi:10.1521/pedi.2009.23.5.
433.
Pagura J, Stein MB, Bolton JM, Cox BJ, Grant B, Sareen J. Comorbidity of
borderline personality disorder and posttraumatic stress disorder in the U.S.
population. J Psychiatr Res. 2010;44(16):1190–8. doi:10.1016/j.jpsychires.2010.
04.016.
Herman JL. Complex PTSD: A syndrome in survivors of prolonged and
repeated trauma. J Trauma Stress 1992;5(3):377–391. doi:10.1002/jts.
2490050305.
Luxenberg T, Spinazzola, J., Hidalgo, J., Hunt, C., Van Der Kolk, B.A. Complex
trauma and disorders of extreme stress (DESNOS) diagnosis, Part One:
Assessment Directions in Psychiatry 2001;21:373–393.
D'Andrea W, Ford J, Stolbach B, Spinazzola J, van der Kolk BA.
Understanding interpersonal trauma in children: why we need a
developmentally appropriate trauma diagnosis. The American journal of
orthopsychiatry. 2012;82(2):187–200. doi:10.1111/j.1939-0025.2012.01154.x.
Cloitre M, Garvert DW, Weiss B, Carlson EB, Bryant RA. Distinguishing PTSD,
Complex PTSD, and borderline personality disorder: a latent class analysis.
Eur J Psychotraumatol 2014;5. doi:10.3402/ejpt.v5.25097.
MacIntosh HG, N.; Dubash, N.;. Borderline personality disorder: disorder of
trauma or personality, a review of the empirical literature. Can Psychol
2015;56:227–241.
Pompili M, Serafini G, Innamorati M, Moller-Leimkuhler AM, Giupponi G,
Girardi P, et al. The hypothalamic-pituitary-adrenal axis and serotonin
abnormalities: a selective overview for the implications of suicide
prevention. Eur Arch Psychiatry Clin Neurosci. 2010;260(8):583–600. doi:10.
1007/s00406-010-0108-z.
Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE. The effects of stress and
stress hormones on human cognition: implications for the field of brain and
cognition. Brain Cogn. 2007;65(3):209–37. doi:10.1016/j.bandc.2007.02.007.
Harris BN, Carr JA. The role of the hypothalamus-pituitary-adrenal/interrenal
axis in mediating predator-avoidance trade-offs. General and comparative
endocrinology. 2016;230–231:110–42. doi:10.1016/j.ygcen.2016.04.006.
De Kloet ER. Why dexamethasone poorly penetrates in brain. Stress.
1997;2(1):13–20.
Carpenter LL, Carvalho JP, Tyrka AR, Wier LM, Mello AF, Mello MF, et al.
Decreased adrenocorticotropic hormone and cortisol responses to stress in
healthy adults reporting significant childhood maltreatment. Biol Psychiatry.
2007;62(10):1080–7. doi:10.1016/j.biopsych.2007.05.002.
Maniam J, Antoniadis C, Morris MJ. Early-life stress, HPA Axis adaptation, and
mechanisms contributing to later health outcomes. Front Endocrinol.
2014;5:73. doi:10.3389/fendo.2014.00073.
Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction
in chronic fatigue syndrome. Nat Rev Endocrinol. 2012;8(1):22–32. doi:10.
1038/nrendo.2011.153.
Southwick SM, Axelrod SR, Wang S, Yehuda R, Morgan CA 3rd, Charney D,
et al. Twenty-four-hour urine cortisol in combat veterans with PTSD and
comorbid borderline personality disorder. J Nerv Ment Dis. 2003;191(4):261–
2. doi:10.1097/01.NMD.0000061140.93952.28.
Wingenfeld K, Driessen M, Adam B, Hill A. Overnight urinary cortisol release
in women with borderline personality disorder depends on comorbid PTSD
and depressive psychopathology. European psychiatry : the journal of the
Association of European Psychiatrists. 2007;22(5):309–12. doi:10.1016/j.
eurpsy.2006.09.002.
Rinne T, de Kloet ER, Wouters L, Goekoop JG, DeRijk RH, van den Brink W.
Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined
dexamethasone/corticotropin-releasing hormone challenge in female
borderline personality disorder subjects with a history of sustained
childhood abuse. Biol Psychiatry. 2002;52(11):1102–12.
Carvalho Fernando S, Beblo T, Schlosser N, Terfehr K, Wolf OT, Otte C, et al.
Acute glucocorticoid effects on response inhibition in borderline personality
disorder. Psychoneuroendocrinology. 2013;38(11):2780–8. doi:10.1016/j.
psyneuen.2013.07.008.
Martin-Blanco A, Ferrer M, Soler J, Arranz MJ, Vega D, Calvo N, et al. The role
of hypothalamus-pituitary-adrenal genes and childhood trauma in
borderline personality disorder. Eur Arch Psychiatry Clin Neurosci.
2016;266(4):307–16. doi:10.1007/s00406-015-0612-2.
Friedel RO. Dopamine dysfunction in borderline personality disorder: a
hypothesis. Neuropsychopharmacology : official publication of the American
College of Neuropsychopharmacology. 2004;29(6):1029–39. doi:10.1038/sj.
npp.1300424.
Cattane et al. BMC Psychiatry (2017) 17:221
32. Figueroa E, Silk KR. Biological implications of childhood sexual abuse in
borderline personality disorder. J Personal Disord. 1997;11(1):71–92.
33. Snyder MA, Gao WJ. NMDA hypofunction as a convergence point for
progression and symptoms of schizophrenia. Front Cell Neurosci. 2013;7:31.
doi:10.3389/fncel.2013.00031.
34. Kahn RS, Sommer IE. The neurobiology and treatment of first-episode
schizophrenia. Mol Psychiatry. 2015;20(1):84–97. doi:10.1038/mp.2014.66.
35. Grosjean B, Tsai GE. NMDA neurotransmission as a critical mediator of
borderline personality disorder. Journal of psychiatry & neuroscience : JPN.
2007;32(2):103–15.
36. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, et al. Magnetic
resonance imaging volumes of the hippocampus and the amygdala in
women with borderline personality disorder and early traumatization. Arch
Gen Psychiatry. 2000;57(12):1115–22.
37. Ruocco AC, Amirthavasagam S, Zakzanis KK. Amygdala and hippocampal
volume reductions as candidate endophenotypes for borderline personality
disorder: a meta-analysis of magnetic resonance imaging studies. Psychiatry
Res. 2012;201(3):245–52. doi:10.1016/j.pscychresns.2012.02.012.
38. Schmahl C, Berne K, Krause A, Kleindienst N, Valerius G, Vermetten E, et al.
Hippocampus and amygdala volumes in patients with borderline
personality disorder with or without posttraumatic stress disorder. Journal
of psychiatry & neuroscience : JPN. 2009;34(4):289–95.
39. Ni X, Sicard T, Bulgin N, Bismil R, Chan K, McMain S, et al. Monoamine
oxidase a gene is associated with borderline personality disorder. Psychiatr
Genet. 2007;17(3):153–7. doi:10.1097/YPG.0b013e328016831c.
40. Pascual JC, Soler J, Barrachina J, Campins MJ, Alvarez E, Perez V, et al. Failure
to detect an association between the serotonin transporter gene and
borderline personality disorder. J Psychiatr Res. 2008;42(1):87–8. doi:10.1016/
j.jpsychires.2006.10.005.
41. Tadic A, Baskaya O, Victor A, Lieb K, Hoppner W, Dahmen N. Association
analysis of SCN9A gene variants with borderline personality disorder. J
Psychiatr Res. 2008;43(2):155–63. doi:10.1016/j.jpsychires.2008.03.006.
42. Wagner S, Baskaya O, Lieb K, Dahmen N, Tadic A. The 5-HTTLPR
polymorphism modulates the association of serious life events (SLE) and
impulsivity in patients with borderline personality disorder. J Psychiatr Res.
2009;43(13):1067–72. doi:10.1016/j.jpsychires.2009.03.004.
43. Harkness KL, Bagby RM, Stewart JG, Larocque CL, Mazurka R, Strauss JS, et al.
Childhood emotional and sexual maltreatment moderate the relation of the
serotonin transporter gene to stress generation. J Abnorm Psychol. 2015;
124(2):275–87. doi:10.1037/abn0000034.
44. Benedetti F, Riccaboni R, Poletti S, Radaelli D, Locatelli C, Lorenzi C, et al.
The serotonin transporter genotype modulates the relationship between
early stress and adult suicidality in bipolar disorder. Bipolar Disord. 2014;
16(8):857–66. doi:10.1111/bdi.12250.
45. Duman EA, Canli T. Influence of life stress, 5-HTTLPR genotype, and SLC6A4
methylation on gene expression and stress response in healthy Caucasian males.
Biology of mood & anxiety disorders. 2015;5:2. doi:10.1186/s13587-015-0017-x.
46. Paaver M, Nordquist N, Parik J, Harro M, Oreland L, Harro J. Platelet MAO
activity and the 5-HTT gene promoter polymorphism are associated with
impulsivity and cognitive style in visual information processing.
Psychopharmacology. 2007;194(4):545–54. doi:10.1007/s00213-007-0867-z.
47. Wagner S, Baskaya O, Anicker NJ, Dahmen N, Lieb K, Tadic A. The catechol
o-methyltransferase (COMT) val(158)met polymorphism modulates the
association of serious life events (SLE) and impulsive aggression in female
patients with borderline personality disorder (BPD). Acta Psychiatr Scand.
2010;122(2):110–7. doi:10.1111/j.1600-0447.2009.01501.x.
48. Wagner S, Baskaya O, Lieb K, Dahmen N, Tadic A. Lack of modulating effects
of the COMT Val(158)met polymorphism on the association of serious life
events (SLE) and impulsivity in patients with borderline personality disorder.
J Psychiatr Res. 2010;44(2):121–2. doi:10.1016/j.jpsychires.2009.06.008.
49. Tadic A, Elsasser A, Victor A, von Cube R, Baskaya O, Wagner S, et al.
Association analysis of serotonin receptor 1B (HTR1B) and brain-derived
neurotrophic factor gene polymorphisms in borderline personality disorder.
J Neural Transm. 2009;116(9):1185–8. doi:10.1007/s00702-009-0264-3.
50. Martin-Blanco A, Ferrer M, Soler J, Arranz MJ, Vega D, Bauza J, et al. An
exploratory association study of the influence of noradrenergic genes and
childhood trauma in borderline personality disorder. Psychiatry Res. 2015;
229(1–2):589–92. doi:10.1016/j.psychres.2015.07.046.
51. Bandelow B, Schmahl C, Falkai P, Wedekind D. Borderline personality
disorder: a dysregulation of the endogenous opioid system? Psychol Rev.
2010;117(2):623–36. doi:10.1037/a0018095.
Page 13 of 14
52. Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid
receptor function. Curr Drug Targets. 2012;13(2):230–46.
53. Dikshtein Y, Barnea R, Kronfeld N, Lax E, Roth-Deri I, Friedman A, et al. Betaendorphin via the delta opioid receptor is a major factor in the incubation
of cocaine craving. Neuropsychopharmacology : official publication of the
American College of Neuropsychopharmacology. 2013;38(12):2508–14. doi:
10.1038/npp.2013.155.
54. Roth-Deri I, Green-Sadan T, Yadid G. Beta-endorphin and drug-induced
reward and reinforcement. Prog Neurobiol. 2008;86(1):1–21. doi:10.1016/j.
pneurobio.2008.06.003.
55. Esch T, Stefano GB. The neurobiology of Love. Neuro endocrinology letters.
2005;26(3):175–92.
56. Stanley B, Siever LJ. The interpersonal dimension of borderline personality
disorder: toward a neuropeptide model. Am J Psychiatry. 2010;167(1):24–39.
doi:10.1176/appi.ajp.2009.09050744.
57. Kalin NH, Shelton SE, Barksdale CM. Opiate modulation of separationinduced distress in non-human primates. Brain Res. 1988;440(2):285–92.
58. Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA, et al.
Regulation of human affective responses by anterior cingulate and limbic
mu-opioid neurotransmission. Arch Gen Psychiatry. 2003;60(11):1145–53.
doi:10.1001/archpsyc.60.11.1145.
59. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al.
Regional mu opioid receptor regulation of sensory and affective dimensions
of pain. Science. 2001;293(5528):311–5. doi:10.1126/science.1060952.
60. Love TM, Stohler CS, Zubieta JK. Positron emission tomography measures of
endogenous opioid neurotransmission and impulsiveness traits in humans. Arch
Gen Psychiatry. 2009;66(10):1124–34. doi:10.1001/archgenpsychiatry.2009.134.
61. Prossin AR, Love TM, Koeppe RA, Zubieta JK, Silk KR. Dysregulation of
regional endogenous opioid function in borderline personality disorder. Am
J Psychiatry. 2010;167(8):925–33. doi:10.1176/appi.ajp.2010.09091348.
62. Nunes PM, Wenzel A, Borges KT, Porto CR, Caminha RM, de Oliveira IR.
Volumes of the hippocampus and amygdala in patients with borderline
personality disorder: a meta-analysis. J Personal Disord. 2009;23(4):333–45.
doi:10.1521/pedi.2009.23.4.333.
63. Rodrigues E, Wenzel A, Ribeiro MP, Quarantini LC, Miranda-Scippa A, de
Sena EP, et al. Hippocampal volume in borderline personality disorder with
and without comorbid posttraumatic stress disorder: a meta-analysis.
European psychiatry : the journal of the Association of European
Psychiatrists. 2011;26(7):452–6. doi:10.1016/j.eurpsy.2010.07.005.
64. Irle E, Lange C, Sachsse U. Reduced size and abnormal asymmetry of
parietal cortex in women with borderline personality disorder. Biol
Psychiatry. 2005;57(2):173–82. doi:10.1016/j.biopsych.2004.10.004.
65. Brambilla P, Soloff PH, Sala M, Nicoletti MA, Keshavan MS, Soares JC.
Anatomical MRI study of borderline personality disorder patients. Psychiatry
Res. 2004;131(2):125–33. doi:10.1016/j.pscychresns.2004.04.003.
66. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K, Lemieux L,
et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54(2):163–71.
67. Rossi R, Lanfredi M, Pievani M, Boccardi M, Beneduce R, Rillosi L, et al.
Volumetric and topographic differences in hippocampal subdivisions in
borderline personality and bipolar disorders. Psychiatry Res. 2012;203(2–3):
132–8. doi:10.1016/j.pscychresns.2011.12.004.
68. Rossi R, Pievani M, Lorenzi M, Boccardi M, Beneduce R, Bignotti S, et al.
Structural brain features of borderline personality and bipolar disorders.
Psychiatry Res. 2013;213(2):83–91. doi:10.1016/j.pscychresns.2012.07.002.
69. O'Neill A, D'Souza A, Carballedo A, Joseph S, Kerskens C, Frodl T. Magnetic
resonance imaging in patients with borderline personality disorder: a study
of volumetric abnormalities. Psychiatry Res. 2013;213(1):1–10. doi:10.1016/j.
pscychresns.2013.02.006.
70. Kreisel SH, Labudda K, Kurlandchikov O, Beblo T, Mertens M, Thomas C, et al.
Volume of hippocampal substructures in borderline personality disorder.
Psychiatry Res. 2015;231(3):218–26. doi:10.1016/j.pscychresns.2014.11.010.
71. Boen E, Westlye LT, Elvsashagen T, Hummelen B, Hol PK, Boye B, et al.
Smaller stress-sensitive hippocampal subfields in women with borderline
personality disorder without posttraumatic stress disorder. Journal of
psychiatry & neuroscience : JPN. 2014;39(2):127–34.
72. Teicher MH, Anderson CM, Polcari A. Childhood maltreatment is associated
with reduced volume in the hippocampal subfields CA3, dentate gyrus, and
subiculum. Proc Natl Acad Sci U S A. 2012;109(9):E563–72. doi:10.1073/pnas.
1115396109.
Cattane et al. BMC Psychiatry (2017) 17:221
73. Kuhlmann A, Bertsch K, Schmidinger I, Thomann PA, Herpertz SC.
Morphometric differences in central stress-regulating structures between
women with and without borderline personality disorder. Journal of
psychiatry & neuroscience : JPN. 2013;38(2):129–37. doi:10.1503/jpn.120039.
74. Klengel T, Binder EB. Epigenetics of stress-related psychiatric disorders and
Gene x environment interactions. Neuron. 2015;86(6):1343–57. doi:10.1016/j.
neuron.2015.05.036.
75. Slatkin M. Epigenetic inheritance and the missing heritability problem.
Genetics. 2009;182(3):845–50. doi:10.1534/genetics.109.102798.
76. Levine A, Worrell TR, Zimnisky R, Schmauss C. Early life stress triggers
sustained changes in histone deacetylase expression and histone H4
modifications that alter responsiveness to adolescent antidepressant
treatment. Neurobiol Dis. 2012;45(1):488–98. doi:10.1016/j.nbd.2011.09.005.
77. Issler O, Chen A. Determining the role of microRNAs in psychiatric disorders.
Nat Rev Neurosci. 2015;16(4):201–12. doi:10.1038/nrn3879.
78. Kaffman A, Meaney MJ. Neurodevelopmental sequelae of postnatal
maternal care in rodents: clinical and research implications of molecular
insights. Journal of child psychology and psychiatry, and allied disciplines.
2007;48(3–4):224–44. doi:10.1111/j.1469-7610.2007.01730.x.
79. McGowan PO, Suderman M, Sasaki A, Huang TC, Hallett M, Meaney MJ,
et al. Broad epigenetic signature of maternal care in the brain of adult rats.
PLoS One. 2011;6(2):e14739. doi:10.1371/journal.pone.0014739.
80. Kammerer M, Marks MN, Pinard C, Taylor A, von Castelberg B, Kunzli H, et al.
Symptoms associated with the DSM IV diagnosis of depression in
pregnancy and post partum. Archives of women's mental health. 2009;12(3):
135–41. doi:10.1007/s00737-009-0062-9.
81. Plant DT, Pariante CM, Sharp D, Pawlby S. Maternal depression during
pregnancy and offspring depression in adulthood: role of child
maltreatment. The British journal of psychiatry : the journal of mental
science. 2015;207(3):213–20. doi:10.1192/bjp.bp.114.156620.
82. McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M, et al.
Epigenetic regulation of the glucocorticoid receptor in human brain
associates with childhood abuse. Nat Neurosci. 2009;12(3):342–8. doi:10.
1038/nn.2270.
83. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM.
Prenatal exposure to maternal depression, neonatal methylation of human
glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.
Epigenetics. 2008;3(2):97–106.
84. Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R,
et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in
adults with a history of childhood maltreatment: a link with the severity and
type of trauma. Transl Psychiatry. 2011;1:e59. doi:10.1038/tp.2011.60.
85. Suderman M, Borghol N, Pappas JJ, Pinto Pereira SM, Pembrey M, Hertzman
C, et al. Childhood abuse is associated with methylation of multiple loci in
adult DNA. BMC Med Genet. 2014;7:13. doi:10.1186/1755-8794-7-13.
86. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM,
et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood
trauma interactions. Nat Neurosci. 2013;16(1):33–41. doi:10.1038/nn.3275.
87. Labonte B, Suderman M, Maussion G, Navaro L, Yerko V, Mahar I, et al.
Genome-wide epigenetic regulation by early-life trauma. Arch Gen
Psychiatry. 2012;69(7):722–31. doi:10.1001/archgenpsychiatry.2011.2287.
88. Martin-Blanco A, Ferrer M, Soler J, Salazar J, Vega D, Andion O, et al.
Association between methylation of the glucocorticoid receptor gene,
childhood maltreatment, and clinical severity in borderline personality
disorder. J Psychiatr Res. 2014;57:34–40. doi:10.1016/j.jpsychires.2014.06.011.
89. Dammann G, Teschler S, Haag T, Altmuller F, Tuczek F, Dammann RH.
Increased DNA methylation of neuropsychiatric genes occurs in borderline
personality disorder. Epigenetics. 2011;6(12):1454–62. doi:10.4161/epi.6.12.
18363.
90. Perroud N, Salzmann A, Prada P, Nicastro R, Hoeppli ME, Furrer S, et al.
Response to psychotherapy in borderline personality disorder and
methylation status of the BDNF gene. Transl Psychiatry. 2013;3:e207. doi:10.
1038/tp.2012.140.
91. Perroud N, Zewdie S, Stenz L, Adouan W, Bavamian S, Prada P, et al.
Methylation of serotonin receptor 3a in Adhd, borderline personality, and
bipolar disorders: link with severity of the disorders and childhood
maltreatment. Depression and anxiety. 2016;33(1):45–55. doi:10.1002/da.
22406.
92. Thaler L, Gauvin L, Joober R, Groleau P, de Guzman R, Ambalavanan A, et al.
Methylation of BDNF in women with bulimic eating syndromes:
associations with childhood abuse and borderline personality disorder. Prog
Page 14 of 14
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
Neuro-Psychopharmacol Biol Psychiatry. 2014;54:43–9. doi:10.1016/j.pnpbp.
2014.04.010.
Teschler S, Bartkuhn M, Kunzel N, Schmidt C, Kiehl S, Dammann G, et al. Aberrant
methylation of gene associated CpG sites occurs in borderline personality
disorder. PLoS One. 2013;8(12):e84180. doi:10.1371/journal.pone.0084180.
Prados J, Stenz L, Courtet P, Prada P, Nicastro R, Adouan W, et al. Borderline
personality disorder and childhood maltreatment: a genome-wide methylation
analysis. Genes Brain Behav. 2015;14(2):177–88. doi:10.1111/gbb.12197.
Teschler S, Gotthardt J, Dammann G, Dammann RH. Aberrant DNA Methylation
of rDNA and PRIMA1 in Borderline Personality Disorder. International journal of
molecular sciences. 2016;17(1). doi:10.3390/ijms17010067.
Cattaneo A, Macchi F, Plazzotta G, Veronica B, Bocchio-Chiavetto L, Riva MA,
et al. Inflammation and neuronal plasticity: a link between childhood
trauma and depression pathogenesis. Front Cell Neurosci. 2015;9:40. doi:10.
3389/fncel.2015.00040.
Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G. Mechanisms of long
non-coding RNAs in mammalian nervous system development, plasticity,
disease, and evolution. Neuron. 2015;88(5):861–77. doi:10.1016/j.neuron.
2015.09.045.
McIntyre CK, McGaugh JL, Williams CL. Interacting brain systems modulate
memory consolidation. Neurosci Biobehav Rev. 2012;36(7):1750–62. doi:10.
1016/j.neubiorev.2011.11.001.
Dhabhar FS. Enhancing versus suppressive effects of stress on immune
function: implications for immunoprotection and immunopathology.
Neuroimmunomodulation. 2009;16(5):300–17. doi:10.1159/000216188.
McEwen BS. Physiology and neurobiology of stress and adaptation: central role
of the brain. Physiol Rev. 2007;87(3):873–904. doi:10.1152/physrev.00041.2006.
McEwen BS. Understanding the potency of stressful early life experiences
on brain and body function. Metab Clin Exp. 2008;57(Suppl 2):S11–5. doi:10.
1016/j.metabol.2008.07.006.
McEwen BS. Protection and damage from acute and chronic stress: allostasis
and allostatic overload and relevance to the pathophysiology of psychiatric
disorders. Ann N Y Acad Sci. 2004;1032:1–7. doi:10.1196/annals.1314.001.
Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER, Lightman
SL, et al. Do corticosteroids damage the brain? J Neuroendocrinol. 2006;
18(6):393–411. doi:10.1111/j.1365-2826.2006.01429.x.
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood
disorders. Biol Psychiatry. 2006;59(12):1116–27. doi:10.1016/j.biopsych.2006.02.013.
Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant'Anna M, Cunha AB, Post
RM. Increased oxidative stress as a mechanism for decreased BDNF levels in
acute manic episodes. Rev Bras Psiquiatr. 2008;30(3):243–5.
Waterhouse EG, Xu B. New insights into the role of brain-derived
neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 2009;42(2):81–9.
doi:10.1016/j.mcn.2009.06.009.
Calabrese F, Molteni R, Gabriel C, Mocaer E, Racagni G, Riva MA. Modulation
of neuroplastic molecules in selected brain regions after chronic
administration of the novel antidepressant agomelatine.
Psychopharmacology. 2011;215(2):267–75. doi:10.1007/s00213-010-2129-8.
Ansorge MS, Hen R, Gingrich JA. Neurodevelopmental origins of depressive
disorders. Curr Opin Pharmacol. 2007;7(1):8–17. doi:10.1016/j.coph.2006.11.
006.
Koenigsberg HW, Yuan P, Diaz GA, Guerreri S, Dorantes C, Mayson S, et al.
Platelet protein kinase C and brain-derived neurotrophic factor levels in
borderline personality disorder patients. Psychiatry Res. 2012;199(2):92–7.
doi:10.1016/j.psychres.2012.04.026.
Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter
ML. BDNF as a biomarker for successful treatment of mood disorders: a
systematic & quantitative meta-analysis. J Affect Disord. 2015;174:432–40.
doi:10.1016/j.jad.2014.11.044.
Cattaneo A, Bocchio-Chiavetto L, Zanardini R, Milanesi E, Placentino A,
Gennarelli M. Reduced peripheral brain-derived neurotrophic factor mRNA
levels are normalized by antidepressant treatment. The international journal
of neuropsychopharmacology / official scientific journal of the Collegium
Internationale Neuropsychopharmacologicum. 2010;13(1):103–8. doi:10.
1017/S1461145709990812.
Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, et al.
Candidate genes expression profile associated with antidepressants
response in the GENDEP study: differentiating between baseline 'predictors'
and longitudinal 'targets'. Neuropsychopharmacology : official publication of
the American College of Neuropsychopharmacology. 2013;38(3):377–85. doi:
10.1038/npp.2012.191.
Linda Baird
CHILDHOOD TRAUMA IN THE
ETIOLOGY OF BORDERLINE
PERSONALITY DISORDER:
THEORETICAL CONSIDERATIONS AND
THERAPEUTIC INTERVENTIONS
Linda Baird, M.A., LPC, CHT
Editor’s Note: It is a pleasure to have Linda Baird’s helpful perspective on working with those who display the signs and
symptoms of Borderline Personality Disorder in this edition of the Hakomi Forum. Normal Hakomi Therapy trainings
concentrate on teaching the principles, methods, and techniques of the work with only passing reference to various clinical
conditions. As the editorial policy of the Forum indicates, those who have had experience applying Hakomi Therapy to various
client groups and disorders are encouraged to share their work in these pages.
Linda Baird, MA, LPC, CHT is in private practice in Denver and Boulder, CO. Linda received a B.S. in Business
Administration, with additional education toward a B.A. in Biochemistry from the University of Colorado. She worked as a
research scientist for 16 years, with particular interest in neuroscience, prior to beginning her path as a Hakomi therapist in 1995.
Linda received her M.A. from Regis University in Denver. This paper is taken, in part, from her primary research paper, which
included an in-depth case study at Regis, and her presentation at the 2005 Hakomi conference, as well as from her work with
clients over the last ten years. Contact information: firewoman619@msn.com; 303 507-6310. Website:
www.bodymindintegrativetherapy.com..
ABSTRACT: Borderline Personality Disorder (BPD) has notoriously been one of the most challenging conditions to treat in
therapy. This paper addresses the etiology of BPD in childhood trauma, specifically in the lack of secure attachment. The effects of
trauma on the development of limbic structures involved in attachment and affect regulation is discussed, as well as how traumatic
events are encoded in implicit memory. The dysregulated affect states of BPD, which present as the diagnostic criteria, are
considered in terms of state-dependent memory that is triggered by present day relational events. Shame is discussed as a
foundation of attachment failures and BPD. Key elements of individual therapy with borderline clients are discussed, including
mindfulness, development of resources, establishment of a safe container within the therapeutic relationship, addressing shame
dynamics, and the resolution of past trauma. Therapeutic interventions are presented, both in theory and practice.
Introduction
When I was introduced to the concept of “trauma” during
my first psychotherapy training in 1996, while living in
Boston, I had little interest. I thought it did not apply to me.
I was more interested in character theory and childhood
development. Then I attended my first workshop with Pat
Ogden, founder of Hakomi Bodywork, with later became
Hakomi Somatics Institute and recently, Sensorimotor
Psychotherapy Institute. The workshop, called “Trauma and
the Body”, was a week-long experiential workshop at the
Omega Institute outside of New York City. As I learned
about how the nervous system is affected by perceived lifethreatening events, and as I was guided through
experiencing this in my own body, my interest and passion
for working with trauma was awakened.
This paper is an excerpt from a primary research paper
written for the completion of my Master’s degree. It
combines my passion for neuroscience with the study of
personality development, addressing the etiology of
Borderline Personality Disorder in early childhood trauma.
In particular, repeated misattunement in childhood, when
the neural circuitry is developing, can result in personality
traits, or, in more extreme situations personality disorders
such as BPD and Antisocial Personality Disorder.
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Linda Baird
Role of Childhood Trauma
According to van der Kolk (1988), there seems to exist a
spectrum of trauma-related disorders, such as BPD and
multiple personality disorder, precipitated by early traumatic
events that become integrated into the totality of a person’s
personality organization. There is a high correlation
between the degree of BPD psychopathology and the
severity of childhood trauma (Famularo, 1991; van der
Kolk, 1996; Schore 1994). Clinical descriptions of
borderline personality disorder and post-traumatic stress
disorder are very similar, especially when there is a history
of repeated trauma over time. Overlaps include
disturbances in affect regulation including heightened
aggression, hypervigilance and increased startle response,
depression and dysphoric mood, poor impulse control
including risk-taking behavior, self-mutilation and
substance abuse, dissociative episodes and paranoid
ideation, and intrusive memories.
Van der Kolk (1987) states “the most significant descriptive
discrepancy between BPD and chronic PTSD is the absence
in the criteria for BPD of a recognizable stressor in the
patient’s history” (p. 115). Van der Kolk (1987) and
Famularo et al. (1991) indicated that until recently, the links
between childhood traumatic events and the development of
BPD in adulthood have not been consistently recognized
among professionals trained to work with BPD. The
connection between early childhood trauma and adult
relational difficulties has been completely out of awareness
for many people diagnosed with BPD, as well (Perry et al.,
1990). The tendency to re-enact abusive childhood
scenarios of physical, sexual, and psychological/emotional
abuse will continue until the “sense of injustice and fear of
retribution is clarified and validated” (Perry et al., 1990, p.
40).
Herman et al. (1988, as cited in Goodwin, 1990) found that
in a sample of clients carefully diagnosed with BPD, 81%
gave a history of major childhood trauma including
significant physical abuse (71%), sexual abuse (68%), and
witnessing serious domestic violence (62%). There was
also a significant link between childhood sexual abuse and
development of BPD that cannot be overlooked. Although
borderline clients in this study did not meet criteria for
PTSD as measured on the Impact of Experience Scale, the
authors postulate that BPD might be conceptualized as a
complicated posttraumatic syndrome and that validation and
integration of the childhood trauma might be a precondition
for successful treatment. An earlier study by the same
authors (Herman et al., 1987, as cited in van der Kolk,
1996), concluded “Our explanation is that BPD is a function
of having been chronically terrified during one’s early
development . . . the superimposition of childhood terror
upon adult situations is most likely to be the key [in the
development of BPD]”.
Adolf Stern (1938, as cited in Perry, et al., 1990) wrote the
first paper differentiating borderline from neurotic disorders.
The first feature he described was a sort of narcissism,
meaning an early developmental disturbance of selfpreserving functions, leading to psychotic-like
transferences. Features included lack of maternal affection,
parental quarrels, including outbursts directed at the child,
early divorce, separation or desertion, cruelty, brutality, and
neglect by the parents over many years duration.
For many borderline clients, the connection between early
trauma and current problems in close relationships often
remains out of awareness. These clients may repetitively reenact scenarios in which they feel threatened, attacked, or
abused, and then become enraged. The characteristic selfdestructive and stormy interpersonal behaviors that follow
are an attempt to cope with unbearable feelings of rage,
shame, guilt, and terror associated with the symbolic reexperiencing of the trauma.
Lack of secure attachment plays, for a number of reasons
including neglect and abuse, a central role in the object
relations of those who develop borderline pathology. An
essential feature in BPD is the lack of development of object
constancy that is generally accomplished during the second
and third years of life in the separation and individuation
stages (Herman et al., 1987, as cited in van der Kolk, 1996).
Alder (as cited in Perry, 1990) described borderline
pathology as a “developmental failure in the formation of
self-soothing capacities based on evocative memory. These
capacities derive from the child’s ability to recall
comforting memories of significant caregivers, even when
they are not present” (p. 42). Because of this inability to
internalize nurturing caregivers and in turn develop the
ability to self-sooth, borderline clients are prone to intense
feelings of loneliness and panic. The ability to self-sooth
may begin to develop in some abused children; it may be
destroyed, however, when the child has no choice but to
turn to the abuser for comfort (Perry, 1990).
Again, Herman (1997) describes the adult relationships of
those who have survived severe childhood abuse in terms
that exemplify borderline diagnostic criteria. These
relationships are characterized by intense periods of
searching for intimacy combined with idealization of the
other person, which often put them at risk for re-enactment
of childhood abuse, alternating with periods of angry
withdrawal and denigration. This “splitting” behavior is
classic characteristic of BPD:
The survivor’s intimate relationships are driven by the
hunger for protection and care and are haunted by the
fear of abandonment or exploitation. . . . In quest for a
rescue, she may seek out powerful authority figures
who seem to offer the promise of a special care taking
relationship. By idealizing the person to whom she
become attached, she attempts to keep at bay the
constant fear of being either dominated or betrayed. . .
. Inevitably, however, the chosen person fails to live up
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Linda Baird
to her fantastic expectations. When disappointed, she
may furiously denigrate the same person whom she so
recently adored. Ordinary interpersonal conflicts may
provoke intense anxiety, depression, or rage. In the
mind of the survivor, even minor slights evoke past
experiences of callous neglect, and minor hurts evoke
past experiences of deliberate cruelty. These
distortions are not easily corrected by experience, since
the survivor tends to lack the verbal and social skills
for resolving conflict. Thus the survivor develops a
pattern of intense, unstable relationships, repeatedly
enacting dramas of rescue, injustice, and betrayal (p.
111).
Adults traumatized as children often retreated into isolation
after years of frantically searching for rescuers (Herman et
al., 1987, as cited in van der Kolk, 1996). Symptoms of
abuse manifest in power differentials in relationships based
on dominance and submission. There is a tendency to either
be in the position of power, where they “inspire fear and
loathing” (p. 197), or to be in the subordinate position where
they feel helpless and behave submissively. In the latter
case, the classic borderline tendency toward “splitting” may
appear as idealization alternating with devaluation of the
abusive partner. In either case, what is lost is the ability to
experience competence in a mutually respectful relationship.
Attachment
Numerous studies have concluded that sudden and
uncontrollable loss of attachment bonds is an essential
element in the development of PTSD, and could be a key to
understanding why some people develop PTSD and some
do not when exposed to similar traumatic events (van der
Kolk, 1988). Borderline Personality Disorder is now being
diagnosed in childhood, with an emphasis on mismatched
parenting, leading to neurobiological impairment (Schore,
1994). Research by Bowlby (1969), in particular, has
demonstrated the profound psychobiological effects of
disruptions in the mother-infant attachment bond and the
subsequent behavioral effects that often become the
personality traits of BPD (as cited in Masterson, 1988). The
roots of traumatic re-enactment have also been shown to be
related to disruption in attachment bonds with primary care
givers (Scaer, 2001). The protest and despair responses
displayed in response to parental separation, as observed by
Bowlby, parallel the hyperarousal and numbing states found
in PTSD (van der Kolk, 1988).
The attachment system in an infant is an in-born system that
promotes the chances of survival (Siegel, 1999). Recent
research has shown that the mother or primary caregiver is
the regulator of the infant’s neural development and affect
states (Schore, 2000). Because the brain of the infant is
undifferentiated aside from the brainstem and the amygdala,
the psychological and emotional health of the mother, as
well as her ability to be present with her child, are
fundamental to attachment bonding (Schore, 1994, 2000).
Infants tend to seek increased attachment in the face of
danger, even when the attachment object no longer provides
nourishment and safety (van der Kolk, 1988).
Briefly, Ainsworth, and later Main and Solomon, developed
a measure of distinct attachment patterns called the Strange
Situation. There are four classifications of attachment,
determined at one year of age, that have been correlated
with specific behavior patterns at one year of age and also
with adult behavior. The four attachment categories are:
secure, avoidant, resistant or ambivalent, and
di...
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