Journal of Neural Transmission (2022) 129:409–419

https://doi.org/10.1007/s00702-022-02482-9

PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE

Reduced vagal activity in borderline personality disorder is unaffected

by intranasal oxytocin administration, but predicted by the interaction
between childhood trauma and attachment insecurity
Sarah N. Back1 · Marius Schmitz1,2 · Julian Koenig3 · Max Zettl4 · Nikolaus Kleindienst5 · Sabine C. Herpertz2 ·
Katja Bertsch1,2

Received: 7 September 2021 / Accepted: 22 February 2022 / Published online: 11 March 2022
© The Author(s) 2022

Abstract
Individuals with borderline personality disorder (BPD) show self-regulatory deficits, associated with reduced heart-rate
variability (HRV). However, results on reduced HRV in BPD remain heterogeneous, thus encouraging the search for devel-
opmental constructs explaining this heterogeneity. The present study first examined predictors of reduced resting-state
HRV in BPD, namely the interaction between self-reported adult attachment insecurity and childhood trauma. Second, we
investigated if alterations in resting-state HRV are modified by intranasal oxytocin administration, as oxytocin may enhance
HRV and is implicated in the interaction between childhood trauma and disturbed attachment for the pathogenesis of BPD.
In a randomized, placebo-controlled trial, 53 unmedicated women with BPD and 60 healthy controls (HC) self-administered
either 24 I.U. of oxytocin or placebo and underwent a 4-min electrocardiogram. Our results replicate significantly reduced
HRV in women with BPD, explained up to 16% by variations in childhood trauma and attachment insecurity. At high levels
of acute attachment insecurity, higher levels of childhood trauma significantly predicted reduced HRV in BPD. However,
our results do not support a significant effect of oxytocin on mean HRV, and no interaction effect emerged including child-
hood trauma and attachment insecurity. Our findings highlight a complex interaction between reduced vagal activity and
developmental factors in BPD.

Keywords Heart-rate variability · Vagal activity · Borderline personality disorder · Attachment · Oxytocin · Early life
adversity · Childhood trauma

Introduction

Borderline personality disorder (BPD) is a severe mental

* Sarah N. Back
disorder, which affects around 15–28% patients in clinical
[email protected]
populations (APA 2001). Core symptoms of BPD are emo-
1
Department of Psychology, Ludwig-Maximilians-University tional dysregulation, impulsivity, and interpersonal hyper-
Munich, Leopoldstraße 13, 80802 Munich, Germany sensitivity, all of which have been shown to be associated
2
Department of General Psychiatry, Center for Psychosocial with alterations in heart-rate-variability (HRV; Lane et al.
Medicine, University of Heidelberg, Heidelberg, Germany 2009; Thayer and Brosschot 2005; Ottaviani et al. 2018;
3
Department of Child and Adolescent Psychiatry, Weise et al. 2020a).
Psychosomatics and Psychotherapy, Faculty of Medicine HRV is defined as the beat-to-beat variability of heart rate
and University Hospital Cologne, University of Cologne, (Berntson et al. 1997) indicating different autonomic states
Cologne, Germany
4
(i.e. higher variability indicating majorly vagal and lower
Institute of Psychosocial Prevention, Center for Psychosocial variability reflecting majorly sympathetic predominance of
Medicine, University of Heidelberg, Heidelberg, Germany
5
the autonomic nervous system; ANS). While the sympathetic
Medical Faculty Mannheim, Institute of Psychiatric system is associated with energy mobilization during stress,
and Psychosomatic Psychotherapy, Central Institute
of Mental Health, Heidelberg University, Mannheim, the parasympathetic system reflects vegetative and restora-
Germany tive functions (Thayer and Brosschot 2005). According to

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Vol.:(0123456789)
410 S. N. Back et al.

the model of neurovisceral integration, these two states are self-regulatory capacities and, therefore, contribute to the
in dynamic balance and interplay with different environmen- pathogenesis of dysregulated autonomic- and endocrine-
tal demands (Thayer and Brosschot 2005). Chronic auto- functions in critical developmental periods, epigenetically
nomic imbalance, in which the sympathetic stress system is priming physiological functioning towards heightened
hyperactive and the parasympathetic system is hypoactive stress sensitivity (McLaughlin et al. 2015; Oosterman et al.
(e.g., lower HRV at rest), in turn, is theorized to be associ- 2010; Ferrer et al. 2021). Meyer et al. (2016) supported this
ated with various pathological conditions (Thayer and Bro- strain of research concerning HRV as marker of ANS func-
sschot 2005), including BPD (for meta-analysis, see Koenig tioning, by showing that levels of childhood trauma were
et al. 2016). Indeed, unaltered HRV has been proposed as a negatively associated with resting-state HRV in a sample
biomarker of self-regulation and mental health (Beauchaine including women with BPD. Childhood trauma might, there-
and Thayer 2015). With regard to the aetiology of BPD, vari- fore, generally prime the ANS towards higher sympathetic
ous results on reduced HRV point to a chronic reduction of dominance, with different levels of early traumatization
the vagal ANS component, potentially reflecting a lack for contributing to different HRV resting-states within BPD
efficient self-regulation (Thayer et al. 2009; Koenig et al. women (Meyer et al. 2016). Although childhood trauma can
2017; Weise et al. 2020a, b). Longitudinal studies suggest be considered a robust risk factor for BPD, early research
that changes in adolescent resting-state HRV are associated already showed that some affected individuals nonetheless
with changes in BPD symptomatology (Koenig et al. 2018; display a history of little or no traumatic experiences (Her-
Sigrist et al. 2021), and even predicted clinical symptom man et al. 1989; Zanarini and Frankenburg 1997), thus child-
reduction in adolescent BPD patients receiving dialectical hood trauma does not necessarily and robustly precede BPD
behavioural therapy (Weise et al. 2020b). development (Gunderson et al. 2018). This suggests that
However, findings on resting-state HRV in BPD remain additional mechanisms than only childhood trauma might
heterogeneous: Several studies failed to find a significant be implicated in BPD pathogenesis.
reduction of resting HRV in women with BPD as compared A growing number of studies emphasizes that inter-
to healthy controls (Austin et al. 2007; Gratz et al. 2013; individual differences in attachment insecurity impor-
Meyer et al. 2016; Krause-Utz et al. 2019). Mixed findings tantly contextualize the impact of childhood trauma on
can be attributed to the high heterogeneity of resting-state BPD symptoms (Crow and Levy 2019; Baryshnikov et al.
HRV among individuals with BPD (Koenig et al. 2020), as 2017; Peng et al. 2021), such as on personality function-
compared to healthy (Koenig et al. 2016) and other clinical ing (Gander et al. 2020) as well as on pathophysiological
conditions, such as post-traumatic stress disorder (Meyer mechanisms of BPD related to sympathetic hyperactiv-
et al. 2016). High heterogeneity in physiological baseline ity/stress sensitivity (Ehrenthal et al. 2018; Simeon et al.
activity within groups of BPD and across studies seems to 2011). Children living in conditions with severe disrup-
be a common phenomenon, equally observed when inspect- tions in the parent–child relationship (e.g., relational child-
ing other biobehavioral indices linked to stress physiology hood trauma) are at greater risk to develop and maintain
(Scott et al. 2013; Wingenfeld et al. 2010; Ehrenthal et al. unresolved internal working models of social interac-
2018). In a recent review, Koenig et al. (2020) concluded tions, contributing to attachment insecurity and personal-
that these alterations in ANS function within individuals ity pathology until adulthood (Bowlby 1982; Liotti 2004;
with BPD might be linked to severe experiences of early Cyr et al. 2010). Internal working models are conceptual-
maltreatment and trauma. ized as cognitive self-regulatory mechanisms (Mikulincer
et al. 2009). Therefore, individuals with very low levels of
Heart‑rate variability, childhood trauma integration and coherence of internal working models (i.e.
and the moderating role of attachment insecurity higher attachment insecurity) may have also developed
an altered biological predisposition to stress regulation
A history of childhood traumatic experiences and attach- (Ehrenthal et al. 2018). Empirically, subgroups of severely
ment insecurity are the most studied developmental risk fac- insecure attached individuals with BPD show heightened
tors of BPD (Gunderson et al. 2018; Ehrenthal et al. 2018), cortisol activity related to heightened sympathetic activity
both being linked to disturbed vagal activity (Oosterman in an interpersonal context (Ehrenthal et al. 2018). Con-
et al. 2010; Sigrist et al. 2020). cerning ANS functioning, insecurely attached individu-
Childhood trauma is associated with a higher risk to als show reduced HRV when confronted with traumatic
develop BPD (see Gunderson et al. 2018 for review), with experiences, indicative for heightened sympathetic activity
affected individuals being more than four times more (Farina et al. 2015; Decarli et al. 2020). Although former
likely to report childhood adversity as compared to non- psychophysiological studies support the moderating role
clinical individuals (Porter et al. 2020; Kleindienst et al. of attachment insecurity when inspecting cortisol activity
2020). Childhood trauma has been shown to exhaust early in women with BPD (Ehrenthal et al. 2018; Simeon et al.

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Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin… 411

2011), no study tested the moderating role of attachment The current study
security on the association between childhood trauma and
resting-state HRV in individuals with BPD yet. Within the central project of the Clinical Research Unit 256
(Schmahl et al. 2014), the current study presents a secondary
analysis of the subproject “Social Perception II”, encom-
Heart‑rate variability, childhood trauma, passing a randomized-controlled trial studying the effects
attachment insecurity and oxytocin of oxytocin on social perception in BPD (Trial Registration
Number: DRKS00009815). The aim of the present second-
A potential pharmacological intervention for reduced ary investigation was to (1) replicate reduced baseline vagal
vagal activity as a physiological target mechanism underly- activity in unmedicated BPD women as indexed by reduced
ing inefficient self-regulation in BPD might be intranasal time-domain measures of HRV (i.e. the root-mean-square
administration of oxytocin (IN-OT; Herpertz and Bertsch of successive R–R-interval differences, RMSSD). RMSSD
2015; Norman et al. 2011; Kemp et al. 2012). Oxytocin may has been shown to be one of the most robust and reliable
especially impact the relationship between HRV, childhood indicators of vagally mediated HRV and to be mostly unaf-
trauma and attachment insecurity, as being conceptually and fected by breathing artefacts (Penttilä et al. 2001). To further
empirically linked to (1) the interaction between early-life resolve the high level of heterogeneity in resting-state HRV
stress and disturbed attachment in the pathogenesis of BPD activity within BPD women and across studies, we examined
(Herpertz and Bertsch 2015) and (2) IN-OT in dampening (2) the moderating role of adult attachment insecurity in the
sympathetic activity at rest to facilitate capacity for adaptive association between childhood trauma and RMSSD. How-
self-regulatory behaviour (Norman et al. 2011; Kemp et al. ever, we expect a smaller or no moderation effect within the
2012; Porges 2007). sample of healthy women, in line with recent meta-analytic
Oxytocin is an important regulator of social cognition results showing a lack of relationship between CT and HRV
and behaviour (Kemp et al. 2012), implicated in successfully in the absence of a concomitant psychopathological status
establishing early attachment relationship between child and (Sigrist et al. 2021). Lastly, we investigated (3) potential
caregivers following pregnancy (Rilling and Young 2014). modulatory effects of oxytocin on RMSSD in women with
According to a pathophysiological model of BPD (Herpertz BPD and healthy controls (HC) and (4) explored interactive
and Bertsch 2015), BPD could both result from and result effects of childhood trauma, attachment and clinical group
in low parental oxytocin levels, activating a neuroendocrine with oxytocin on RMSSD.
cascade associated with elevated risk for childhood stress,
poor parental attachment, promoting attachment insecurity,
hypersensitivity to stress, and impeding regulation capacities Materials
until adulthood. Indeed, reduced baseline oxytocin levels
have been found in serum of women with BPD compared Participants
with HC (Bertsch et al. 2013a) and in cerebrospinal fluid of
women with childhood trauma compared to women without A total of 53 medication-free adult female women with a
childhood trauma (Heim et al. 2009). current DSM-IV diagnosis of BPD (Mage = 30.02, SD = 7.42,
IN-OT has been shown to reduce threat hypersensitivity range = 30) and 60 healthy female controls (Mage = 27.82,
and approach (Bertsch et al. 2013b; Schneider et al. 2019), SD = 7.1, range = 34) participated in the study. Recruitment
such as amygdala and insular reactivity to stimuli of negative and diagnostic assessment were performed by the central
valence in women with BPD (Lischke et al. 2012). Oxytocin project of the Clinical Research Unit 256 (Schmahl et al.
receptors are especially dense in specific limbic regions and 2014). The study was approved by the Ethics Committee
their connections to the prefrontal cortex (Bartels and Zeki of the Medical Faculty of the University of Heidelberg. All
2004), which may also modulate ANS activity (Fatisson participants provided their written informed consent prior to
et al. 2016). Peripherally, oxytocin receptors are located in study participation and were paid for their participation. All
the heart and surrounding vagal pathways. Thereby, oxytocin projects from this research group include participants from
may upregulate parasympathetic and downregulate sympa- a joint database. Therefore, the BPD and HC sample was
thetic responses, with IN-OT showing an enhancing effect included in a publication of Schmitz et al. (2020) and Sch-
on HRV at rest in healthy male individuals (Norman et al. neider et al. (2020) which, however, did not include investi-
2011; Kemp et al. 2012). Although former studies support gation of HRV of patients with BPD compared to HC, which
a beneficial effect of IN-OT on interpersonal pathology in is the focus of the current study.
BPD, no study investigated effects of IN-OT on intraper- BPD women and healthy controls were matched for age
sonal mechanisms reflecting self-regulatory capacities, i.e. (t(111) = 1.61, p = 0.109), and body mass index (BMI; cal-
resting-state HRV in females with BPD, yet. culated as body weight (kg)/body height (m)2) (t(111) = 1.5,

13
412 S. N. Back et al.

p = 0.137) and did not differ in heart rate (mean = 69.4 bpm; overall level of attachment insecurity, with a Cronbach’s α
t(111) = 1.8, p = 0.075). Both groups neither encountered of 0.97 in the present sample.
any neurological disease, severe physical or psychiatric A standardised questionnaire was used to measure demo-
condition (including cardiac condition, pregnancy, current graphic information, age, weight, height and BMI (see
alcohol and/or drug abuse, drug and/or alcohol dependency Table 1).
2 months prior testing, lifetime diagnosis of schizophrenia,
schizoaffective or bipolar disorder), nor took any acute med- Procedure
ication (except contraceptives and need-based medication,
maximum 1 day prior to laboratory testing). Additionally, After an extensive telephone screening, participants under-
healthy controls did neither receive any lifetime psychiatric went a face-to-face clinical diagnostic interview. On the
diagnosis, nor underwent any psychotherapeutic/psychiatric day of the experiment, participants were instructed not to
treatment. smoke, take caffeine or analgesics and to relinquish eating
2 h prior to the experimental session. Testing took place in
Materials a sound-attenuated, dimly-lit room, followed by the collec-
tion of biological samples (not reported here). In a double-
Qualified and trained diagnosticians assessed BPD and other blind design, participants were randomly assigned via block
psychiatric diagnoses with semi-structured interviews, i.e. randomisation (computerized algorithm, performed by an
the Structured Clinical Interview for DSM IV for Axis I independent person not involved in the study), either to a
disorders (SCID-VI-I; First et al. 1995) and the International single intranasal dose of 24 I.U. of oxytocin (six puffs of 2
Personality Disorder Examination for Axis II disorders I.U. to each nostril) or a placebo condition (spray with the
(IPDE; Loranger et al. 1997). same inactive ingredients but without oxytocin). The oxy-
Childhood traumatic experiences were assessed using tocin and placebo nasal sprays were prepacked in identical
the Childhood Trauma Questionnaire (CTQ; Bernstein et al. bottles and consecutively numbered with each number being
2003). Participants rated the frequency of traumatic expe- subdivided in “A” and “B” according to the randomisation
riences on a five-point Likert scale (ranging from “never schedule. The allocation sequence was concealed from both
true” to “very often true”), for five scales (“physical abuse”, participant and the researcher conducting the study. Sealed
sexual abuse”, “emotional abuse”, “physical neglect” and and stapled envelopes, containing information about the
“emotional neglect”). The total sum score was calculated, allocation between number and content of the nasal spray,
ranging from 25 to 125, with a Cronbach’s α of 0.87 in the were locked and only opened after the last participant had
present sample. completed the study. Electrodes were applied and partici-
Adult romantic attachment style was operationalised pants performed several experimental tasks (see Schneider
by the Experiences in Close Relationships Scale (ECR-R; et al. 2020; Schmitz et al. 2020 for a detailed description).
Ehrenthal et al. 2009), with the two subscales of anxiety 85 min after spray administration, 4 min of ECG measure-
and avoidance of attachment. A total mean score of the two ment were taken in a comfortable upright position, and par-
scales was calculated, ranging from 1 to 7, indicative for the ticipants were instructed to sit still and stay awake.

Table 1  Demographic, psychometric and self-reported data of women with borderline personality disorder (BPD) and healthy controls (HC) in
the oxytocin (oBPD, N = 26; oHC, N = 30) and placebo condition (pBPD = 27; pHC, N = 30)
oBPD (n = 26) pBPD (N = 27) oHC (N = 30) pHC (N = 30) BPD vs HC oBPD vs. oHC vs. pHC
pBPD
M + SD M + SD M + SD M + SD t p t p t p

Age (years) 29.0 + 7.9 31.0 + 6.9 27.6 + 7.8 28.0 + 6.4 1.62 0.109 − 1.02 0.313 − 0.20 0.842
Body mass index (BMI) 24.0 + 5.0 25.4 + 6.0 22.5 + 2.6 24.1 + 5.3 1.49 0.139 − 0.93 0.358 − 1.5 0.140
Heart rate (bpm) 69.0 + 8.4 73.0 + 9.6 65.2 + 9.2 70.3 + 10.5 1.80 0.075 − 1.58 0.121 − 2.03 0.048
BPD Dimensional Score (IPDE) 14.7 + 1.8 14.6 + 1.6 0.0 + 0.0 0.0 + 0.0 62.1 0.000 0.92 0.532 – –
Early traumatization (CTQ) 58.9 + 22.2 63.0 + 18.1 31.2 + 6.3 31.4 + 9.3 9.96 0.000 − 0.73 0.467 − 0.10 0.921
Adult attachment style (ECR-R) 4.5 + 0.6 4.2 + 1.4 1.8 + 0.2 1.8 + 0.3 16.2 0.000 1.17 0.250 − 0.42 0.673

Explanatory note: Heart rates were calculated via ARTIIFACT (Kaufmann et al. 2011)
BMI body mass index, BPD women with borderline personality disorder, CTQ Childhood Trauma Questionnaire, ECR-R Experiences in Close
Relationships Scale, HC healthy controls, IPDE International Personality Disorder Examination

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Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin… 413

Physiological data acquisition and processing of attachment insecurity score on the association between
the childhood trauma score and mean RMSSD score in
ECG was measured using 2 Ag/AgCl electrodes with the BPD group, and in the HC group (all predictors were
micropore tape and solid gel (3 M Health Care) according mean centred; hypothesis 2). Moreover, we exploratory
to Eindhoven II configuration and stored at a sampling rate tested for potential interactions of childhood trauma, attach-
of 1000 Hz (72-chanel QuickAmp amplifier; Brain Products ment insecurity, substance and clinical status on RMSSD
GmbH). Heart rate (HR) and R-peaks were detected offline (exploratory question 4) by running an ANCOVA with
with EDF-Browser Software (Version 1.71; van Beelen, the between-subjects factor group (BPD, HC), substance
2019) employing combined adaptive thresholding (Chris- (oxytocin, placebo) as well as childhood trauma (continu-
tov 2004). Raw ECG was visually inspected for artefacts ously) and attachment (continuously) as covariates, check-
and correct R-trigger location. Three participants (BPD = 1, ing for every specific interaction with substance (child-
HC = 2) had to be excluded from further HRV-Analysis due hood trauma*substance, attachment*substance, childhood
to poor raw ECG signal quality and concomitant fail of auto- trauma*attachment*substance, childhood trauma*attachm
matic R-Trigger detection. Inter-beat-intervals (IBI) were ent*group*substance). Partial eta-squared (η2) are reported
transferred to ASCII format, cleaned and processed using as effect size (0.01, 0.06, 0.14 are considered small, medium
the RHRV package, an automatic tool for HRV analysis in and large effects, respectively (Cohen 1988)).
R (Martínez et al. 2017). Cleaned and processed IBIs were
additionally visually reviewed for potential artefacts. In a
final step, RMSSD indices were derived automatically and Results
transferred to SPSS (IBM SPSS 26). Zhang and colleagues
suggested that RHRV-extracted indices for HRV display As expected (hypothesis 1), women with BPD had signifi-
high reliability and validity (r > 0.8) compared to respective cantly lower mean RMSSD values than HC (F(1,107) = 4.6;
indices retrieved from the gold-standard software Kubios p = 0.034, η2 = 0.04, see Fig. 1). Concerning hypothesis
(Zhang et al. 2020). 2, neither the main effect of substance (F(1,107) = 2.4,
p = 0.121, η2 = 0.02) nor the group by substance interaction
Statistical analysis (F(1,107) = 0.5; p = 0.475, η2 = 0.01) reached statistical
significance. Thus, contrary to hypothesis 3, there was no
Group differences in RMSSD (hypothesis 1) as well as evidence that IN-OT modulated HRV activity in the current
effects of oxytocin administration on RMSSD (hypoth- study, neither in women with BPD, nor HC.
esis 3) were analysed using a 2 × 2 analysis of variance Concerning hypothesis 2, moderated regression analysis
(ANOVA; SPSS 26), with the between-subject factors for the BPD group revealed that the R2 for the overall model
group (BPD, HC) and substance (oxytocin, placebo). A within the BPD group was R2 = 0.16 (adjusted R2 = 0.11),
moderated linear regression analysis using the PROCESS indicative for a medium goodness-of-fit (R 2 = 0.16,
plug-in for SPSS was performed (model number 1, version F(3,48) = 3.15, p = 0.033) according to Cohen (1988). Hence,
3.4.1; Hayes 2017) to test for a potential moderating effect the model including the three variables “childhood trauma”,

Fig. 1  Box-plot diagram of the

RMSSD of women with current
borderline personality disorder
(BPD; N = 52), and healthy con-
trols (HC; N = 58). *p > 0.05

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414 S. N. Back et al.

Fig. 2  Johnson–Neyman plot of the conditional effect of X (= Child- between Childhood Trauma and RMSSD transitions from statistically
hood Trauma, CTQ) on Y (= HRV, RMSSD) of moderator (= Attach- non-significant (red) to significant (blue) according to Johnson–Ney-
ment Insecurity, ECR). The dashed blue vertical line (mean attach- man analysis. Note: The range of observed values of attachment inse-
ment score = 4.69) represents the point where the relationship curity (ECR) is [1.73; 6.36]

“attachment” and “childhood trauma*attachment” explained The respective moderated regression model for the
16% of the total variance in RMSSD in BPD women. At the HC group did not reach statistical significance (R2 = 0.09,
individual level of the predictors, “attachment” (R2 = 0.16, F(1,55) = 7.2, p = 0.540). As expected, (see hypothesis 2),
F(3,48) = 3.15, p = 0.033, b = 0.18, t(48) = 2.08, p = 0.042) the predictive model between CT, attachment insecurity and
and the interaction “childhood trauma*attachment” HRV does not seem to apply for healthy women, due to a
(R2 = 0.16, F(3,48) = 3.15, p = 0.03, b = − 0.01, t(48) = 2.03, lack of variance within the predictors.
p = 0.048) significantly predicted RMSSD in the BPD group. With regard to exploratory hypothesis 4, we found no
Concerning the predictor “attachment”, the regression interaction including the factor substance: neither the inter-
indicated that higher levels of attachment insecurity were action substance by childhood trauma (F(2,108) = 1.019;
linearly associated with lower basal HRV levels in women p = 0.365), substance by attachment (F(2,108) = 0.121;
with BPD. The interaction term between childhood trauma p = 0.886), substance by childhood trauma by attach-
and attachment accounted significantly for 7% of the total ment (F(2,108) = 0.538; p = 0.585), or substance by child-
variance in RMSSD (ΔR2 = 0.07, ΔF(3,48) = 3.15, p = 0.03, hood trauma by attachment by group (F(2,108) = 0.345;
b = − 0.01, t(48) = 2.03, p = 0.048). Johnson–Neyman tech- p = 0.709). Thus, there was no evidence that IN-OT modu-
nique revealed a significant interaction between childhood lated HRV depending on different levels of attachment inse-
trauma and RMSSD only when attachment values exceeded curity, childhood trauma, or having a diagnosis of BPD or
a total mean score of 4.69 (p = 0.05; 40.38% of BPD sam- not.
ple, see Fig. 2). When the mean attachment score is below
the respective interval [4.69; 6.36], the slope of childhood
trauma on RMSSD was non-significant (p = 0.110–0.900).
Therefore, the moderation analysis revealed that the associa- Discussion
tion between childhood trauma and HRV levels was signifi-
cant in those women with BPD demonstrating high levels of The aim of the current study was to (1) replicate findings
attachment insecurity. Thus, in accordance with hypothesis on reduced HRV at rest in women with BPD compared to
2, attachment insecurity moderated the relationship between HC, and to test if the (2) interaction between childhood
childhood trauma and HRV in women with BPD. trauma and attachment insecurity predicted reduced HRV
in women with BPD and HC. Moreover, we investigated (3)

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Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin… 415

modulations of oxytocin administration on HRV at rest and childhood trauma and adult attachment insecurity on BPD
(4) explored interactions with childhood trauma, attachment symptoms (Carlson et al. 2009; Baryshnikov et al. 2017;
insecurity and clinical status. Godbout et al. 2019), as well as the psychophysiological
Most importantly, a significantly diminished HRV at results pointing to the specific role of unresolved attach-
rest in women with BPD compared to healthy women was ment on heightened stress sensitivity in BPD (Simeon et al.
predicted by interactions between high attachment insecu- 2011). The lack of significant regressions within the HC
rity and increased childhood trauma in the current sample. group provides further evidence for the above-mentioned
Only individuals with BPD and high attachment insecurity moderation to interact with psychopathological status. This
showed a significantly negative association between child- is in line with the results of a current meta-analysis (Sigrist
hood trauma and HRV at rest. We found no evidence for et al. 2020) which outlined the evidence of the negative rela-
linear relationships between CT and attachment insecurity tionship between childhood trauma and HRV only in the
predicting HRV, neither when accounting for a potential presence of psychopathology. Due to the almost absence
modulation between those predictors, in healthy women. of traumatic childhood experiences and attachment insecu-
Moreover, (3) IN-OT had no effect on HRV at rest, neither rity in the healthy control group (see Table 1), the variance
in the BPD, nor in the HC group and this lack of effect in those predictors might have most likely been too low to
remained stable after (4) exploring interactions with child- explain sufficient variance within HRV for the regression
hood trauma and attachment insecurity. model to become significant.
In line with hypothesis 1, women with BPD showed sig- In conclusion, our results provide further support for the
nificantly reduced vagally mediated HRV as indexed by a relevance of developmental constructs in contextualizing
commonly reported time domain measures RMSSD, com- biobehavioural mechanisms and interindividual variations
pared to HC. Our result of reduced resting HRV in BPD in BPD (Ehrenthal et al. 2018). Following the interpretations
women is in line with the results of Koenig et al. (2016), of Sigrist et al. (2020), we suppose that CT might poten-
but the effects of the current study were smaller than the tially contribute to alterations within ANS development
medium-sized effects as proposed by meta-analysis (Koenig in childhood, as indexed by low vagal activity (low HRV),
et al. 2016). Reduced baseline autonomic functioning in eventually perpetuating into adulthood as a function of acute
BPD could display a chronic state of physiological imbal- insecurity in current relationships, and increasing the risk for
ance towards less vagal activity, reflecting reduced biologi- psychopathology related to self- and interpersonal dysfunc-
cal capacity for efficient self-regulatory mechanisms (Thayer tioning (e.g., BPD).
and Brosschot 2005; Austin et al. 2007). Whereas we found Contrary to hypothesis 3, resting-state HRV was not
a small but significant difference in HRV, many other stud- modulated by oxytocin administration, as there was neither
ies reported no significant differences in HRV between BPD a significant main effect of substance, nor an interaction
and HC (Meyer et al. 2016; Austin et al. 2007; Gratz et al. effect with clinical status. In contrast to our results, intra-
2013). The differences in results and effect sizes might be nasal administration of oxytocin has been found to enhance
explained by the inconsistency in study design, assessed baseline HRV in male HC (Norman et al. 2011; Kemp et al.
confounding factors (e.g., physical activity), BPD sample 2012) as well as in a male clinical sample (Martins et al.
characteristics (e.g., medication) and size, as well as indices 2020). As recent studies point to a pattern of interactive
of HRV throughout the studies, calling for more replicability effects with childhood trauma and attachment insecurity
in HRV and BPD research designs. (Schoormans et al. 2020; Riem et al. 2021), we conducted
The current results provide evidence for childhood trauma exploratory analysis (hypothesis 4) but found no significant
and attachment insecurity as relevant predictors explaining interaction of neither childhood trauma, attachment inse-
16% of HRV variance in women with BPD. In line with curity nor clinical group with oxytocin on RMSSD at rest.
hypothesis 2, we found that higher reports of childhood In contrast, it has been suggested that oxytocin is involved
trauma predicted lower basal HRV in BPD, but only in those in attachment security and that methylation of the oxytocin
individuals with high levels of acute attachment insecurity, receptor may be involved in the epigenetic modulation of
and no linear relationship between those constructs within childhood trauma (see Brüne 2016 for a review).
the HC sample. The lack of IN-OT effect is generally obedient with
In the light of the neurovisceral integration model (Thayer the social salience hypothesis, which states that oxytocin
and Brosschot 2005), a chronic state of sympathetic stress solely impacts neurophysiological activity under circum-
mobilization may represent a maladaptive physiological stances of salient social cues (Wigton et al. 2015). Our
threat adaptation resulting from a combination of very early findings match those reported by Schmitz et al. (2020),
traumatic experiences and the presence of insecurity in cur- who did not find alterations in heartbeat evoked brain
rent relationships. These interpretations are in line with potentials at rest following oxytocin administration in
previous research suggesting an interactive influence of BPD women within the same sample. Moreover, our

13
416 S. N. Back et al.

results match the interpretations by Riem et al. (2021), be a suitable intervention in enhancing autonomic function-
attributing altered HRV after oxytocin administration to ing at rest in women with BPD. Further research on female
an increased attentional salience as induced by the social individuals with BPD, controlling for menstrual cycle and
presence during the experiment. Concerning the interac- employing interpersonal contexts are needed to draw clear
tive effects with early trauma, in accordance to our results, conclusions on oxytocin’s pharmacological potential.
childhood trauma did not modulate IN-OT on salivary
oxytocin in male adolescents (Fragkaki et al. 2020) and Acknowledgements We kindly thank Dr. Jan Dörendahl for his
expertise in statistical analysis. We also thank the team of the Clinical
HRV was unaffected by IN-OT in individuals with adverse Research Group on Mechanisms of Disturbed Emotion Processing in
childhood experiences (Schoormans et al. 2020). Matching Borderline Personality Disorder (KFO 256) for participant recruitment
the conclusions as initially drawn by Herpertz and Bertsch and organization.
(2015), IN-OT might, therefore, be more suited in improv-
ing BPD associated symptoms/mechanisms (including dis- Author contributions Conceptualization: KB, SCH; funding acquisi-
tion: KB, SCH; resources: KB, SCH; project administration: KB, SCH;
turbed vagal activity) in the context of social interactions data curation: MS; investigation: MS; methodology: SNB, KB; soft-
with and attachment to familiar people (e.g., before seeing ware: SNB, MZ, JK; formal analysis: SNB; validation: MZ, MS, JK,
a psychotherapist). Study designs following this hypoth- NK, SCH; writing—original draft: SNB; writing—review and editing:
esis would be of interest. SNB, MS, JK, MZ, SCH, NK, KB; supervision: KB.
Several limitations should be considered. First, we did not
Funding Open Access funding enabled and organized by Projekt
control for physical activity, smoking and menstrual cycle, DEAL. The study was supported by financial grants from the Ger-
as well as age and BMI, despite official recommendations man Research Foundation (DFG) awarded to K. Bertsch and S.C. Her-
for their inclusion into HRV research (Quintana et al. 2016). pertz within the Clinical Research Unit 256 (KFO-256, BE5292/2-1,
Therefore, we cannot exclude the possibility that differences HE2660/14-1 and HE2660/16-2).
in HRV between groups and their interaction with oxytocin
Availability of data and material The datasets generated during and/or
and developmental constructs might be influenced by the analysed during the current study are available from the corresponding
above-mentioned intervening variables. Nevertheless, the author on reasonable request.
groups were matched according to age, gender, and did
not differ in terms of heart rate or BMI. Moreover, we only Code availability Not applicable.
investigated RMSSD as indicator of HRV activity, although
frequency domain indicators (such as high-frequency HRV) Declarations
are also adequate, especially in capturing vagal activity
(Task Force of the European Society of Cardiology 1996). Conflict of interest The authors have no conflict of interest to declare
that are relevant to the content of this article.
As we only measured ECG for 4 min, and did not control for
breathing artifacts, we decided to rely on a relatively robust, Ethics approval All procedures performed in studies involving human
single indicator of HRV (e.g., RMSSD, Penttilä et al. 2001; participants were in accordance with the ethical standards of the insti-
Quintana et al. 2016). The interpretations concerning the tutional and/or national research committee and with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards.
lacked oxytocin effect should be treated with caution: Most The study was approved by the Ethics Committee of the Medical Fac-
studies which found an effect of IN-OT on resting HRV ulty of the University of Heidelberg.
relied on male individuals (Norman et al. 2011; Kemp et al.
2012), and those studies on females controlled for menstrual Consent to participate All participants provided their written informed
consent prior to study participation.
cycle (Schoormans et al. 2020), which we did not. There-
fore, possible effects of oxytocin on HRV in females with Consent for publication Not applicable.
BPD might eventually be present, as a function of menstrual
cycle. Last, we employed a cross-sectional design, includ- Open Access This article is licensed under a Creative Commons Attri-
ing the well documented limitations for reporting past trau- bution 4.0 International License, which permits use, sharing, adapta-
matization (Maughan and Rutter 1997), hindering causal tion, distribution and reproduction in any medium or format, as long
inference. as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
We conclude that reduced vagal activity (e.g., reduced were made. The images or other third party material in this article are
HRV) in BPD might be a promising target of intervention, included in the article's Creative Commons licence, unless indicated
as being associated with severity of early traumatic expe- otherwise in a credit line to the material. If material is not included in
riences in insecurely attached females with BPD. Future the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
studies should aim to replicate our findings controlling need to obtain permission directly from the copyright holder. To view a
for important covariates influencing HRV (e.g., physical copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
activity, smoking, breath) employing longitudinal research
designs. Moreover, our results suggest that IN-OT may not

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Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin… 417

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