Higher trait neuroticism is associated with greater fatty acid amide hydrolase binding in borderline and antisocial personality disorders.

Borderline personality disorder (BPD) and antisocial personality disorder (ASPD) are the two most frequently diagnosed and researched DSM-5 personality disorders, and both are characterized by high levels of trait neuroticism. Fatty acid amide hydrolase (FAAH), an enzyme of the endocannabinoid system (ECS), has been linked to regulation of mood through modulation of anandamide, an endocannabinoid. We hypothesized that prefrontal cortex (PFC) FAAH binding would relate to trait neuroticism in personality disorders. Thirty-one individuals with personality disorders (20 with BPD and 11 with ASPD) completed the investigation. All participants completed the revised NEO Personality Inventory, which yields standardized scores (e.g., T scores) for the traits of neuroticism, openness, conscientiousness, agreeableness, and extraversion. All participants were medication free and were not utilizing illicit substances as determined by drug urinalysis. Additionally, none of the participants had a comorbid major depressive episode, bipolar disorder, psychotic disorder, or substance use disorder. Each participant underwent one [11C]CURB PET scan. Consistent with our hypothesis, neuroticism was positively correlated with PFC FAAH binding (r = 0.42, p = 0.021), controlling for genotype. Neuroticism was also positively correlated with dorsal putamen FAAH binding (r = 0.53, p = 0.0024), controlling for genotype. Elevated brain FAAH is an endophenotype for high neuroticism in BPD and ASPD. Novel pharmacological therapeutics that inhibit FAAH could emerge as potential new treatments for BPD and ASPD with high neuroticism.

Association between childhood maltreatment, psychopathology and DNA methylation of genes involved in stress regulation: Evidence from a study in Borderline Personality Disorder.

Previous research suggests that childhood maltreatment is associated with epigenetic modification of genes involved in hypothalamic-pituitary-adrenal (HPA) functioning, which could cause dysregulation of the stress response system. If pervasive, this may be associated with the development of stress-related disorder in adults, including affective disorders, anxiety disorders, post-traumatic stress disorder (PTSD) or borderline-personality disorder (BPD). The majority of studies have focused on DNA methylation of the glucocorticoid receptor gene (NR3C1) and the FKBP5 encoding gene, which regulates the sensitivity of the glucocorticoid receptor (GR). How methylation of NR3C1 and FKBP5 interferes with childhood adversity and psychopathology as well as empathy is an under-researched issue. Here, we sought to investigate the association of childhood maltreatment in a sample of 89 individuals (44 healthy participants and 45 patients diagnosed with BPD) with the methylation of the 1F promoter region of NR3C1 and the intron 7 of FKBP5 as well as with different measures of psychopathology and empathy. Methylation of FKBP5 (bin 2) correlated with anxiety (SCL-90-R) and the global psychopathological symptom load index (GSI), as well as with lower empathic perspective-taking abilities. Psychopathology and empathy impairments correlated with the level of childhood maltreatment. No difference in FKBP5 methylation was observed between the clinical and the non-clinical group. Methylation of NR3C1 was lower in BPD patients compared to controls, yet with small differences. The results are discussed regarding their biological relevance, including possible evolutionary explanations. In short, the regulation of the GR sensitivity by methylation of FKBP5 correlated with psychopathology and empathy scores, while no correlation emerged with the severity of childhood adversity.

Stress Response in Suicide Attempters with Borderline Personality Disorder: The Role of Behavioral Problems in Childhood.

Objective: Suicidal individuals are a heterogeneous population and may differ in systematic ways in their responsiveness to stress. The primary aim of the present study was to identify whether a different pattern of physiological stress response exists among adult suicide attempters with a history of behavioral problems during childhood and adolescence, which earlier studies have related to both decreased activity of the HPA axis and to suicidal behaviors. Method: Seventy-eight participants with Borderline Personality Disorder were assessed using the SCID-II, and completed self-report measures assessing their history of suicide attempts, history of aggressive behaviors, depressive symptoms, history of lifetime abuse and demographics. Participants' cortisol reactivity was assessed using the Trier Social Stress Test. Results: Analyses indicated that suicide attempters with a history of behavioral problems in youth (n = 30) had a significantly lower response to stress than both suicide attempters without such a history (n = 26) and non-attempters (n = 22), when controlling for lifetime history of abuse. The groups did not differ in basal cortisol. Conclusions: These findings suggest a unique subtype of suicide attempter among those with Borderline Personality Disorder, characterized by a blunted physiological stress response.

Childhood stress impairs social function through AVP-dependent mechanisms.

Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during childhood increase risk for mental illness, however it is currently unclear whether stress early in life plays a direct role in the development of social difficulties. Using a rat model of pre-pubertal stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP) in the periphery (plasma) and centrally in the paraventricular and supraoptic hypothalamic nuclei. We also explored social performance and AVP expression (plasma) in participants with borderline personality disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural deficits in animals were rescued through administration of the AVPR1a antagonist Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated in BPD participants only. In conclusion, early life stress plays a role in the precipitation of social dysfunction, and AVP mediates at least part of this effect.

Ovarian Hormones as a Source of Fluctuating Biological Vulnerability in Borderline Personality Disorder.

PURPOSE OF REVIEW: To examine the potential role of ovarian hormones in biological vulnerability to borderline personality disorder (BPD). The review focuses primarily on research examining the menstrual cycle as a source of short-term lability of BPD symptom expression, while discussing the currently understudied possibility of ovarian hormone influence in the developmental course of BPD. FINDINGS: Several patterns of menstrual cycle effects on BPD symptoms and relevant features in non-clinical samples have been observed in empirical studies. Most symptoms demonstrated patterns consistent with perimenstrual exacerbation; however, timing varied between high and low arousal symptoms, potentially reflecting differing mechanisms. Symptoms are typically lowest around ovulation, with an exception for proactive aggression and some forms of impulsive behaviors. Preliminary evidence suggests ovarian hormones may exert strong effects on BPD symptom expression, and further research is warranted examining mechanisms and developing interventions. Recommendations for researchers and clinicians working with BPD are provided.

Differential COMT DNA methylation in patients with Borderline Personality Disorder: Genotype matters.

Differential DNA methylation in peripheral tissues has been associated with Borderline Personality Disorder (BPD). Alterations have been found in several genes, among them the Catechol-O-methyltransferase (COMT) gene. COMT is a known neuropsychiatric candidate gene, which contains a genotype variant (Val108/158Met) that affects protein function and has been found associated with several psychiatric disorders. In addition, this variant also affects COMT DNA methylation. However, in previous epigenetic studies, the DNA methylation results have not always been controlled for genotype, even though overrepresentation of the Met allele has been frequently reported in cohorts of BPD patients. Therefore, in the present study, we investigated whether alteration of COMT DNA methylation in BPD patients is indeed associated with mental health status or merely influenced by a differential distribution of the COMT genotype between BPD patients and healthy control individuals. We found significant group differences, as well as a strong effect of genotype on COMT DNA methylation. While the direction of effect was different compared to a previous study, our study supports the finding of altered COMT DNA methylation in patients with BPD and reinforces the need to include genotype information in future DNA methylation studies of COMT.

The glutamate to γ-aminobutyric acid ratio in the posterior insula is associated with pain perception in healthy women but not in women with borderline personality disorder.

This study aimed to investigate whether the differences in pain perception between patients with borderline personality disorder (BPD) and healthy subjects (HCs) can be explained by differences in the glutamate/GABA ratio in the posterior insula. In total, 29 BPD patients and 31 HCs were included in the statistical analysis. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli between 32 and 512 mN on a numeric rating scale. The metabolites were measured in the right posterior insula using the MEshcher-GArwood Point-RESolved Spectroscopy sequence for single-voxel magnetic resonance spectroscopy (1H-MRS). The 256- and the 512-mN pinprick stimuli were perceived as significantly less painful by the BPD patient group compared with HCs. No differences were found between groups for the glutamate/GABA ratios. A positive correlation between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks could be found in the combined and in the HC group. In the BPD patient group, the correlations between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks did not reach significance. In conclusion, the study showed that individual differences in pain perception may in part be explained by the individual glutamate/GABA ratio in the posterior insula. However, this possible mechanism does not explain the differences in pain perception between BPD patients and HCs.

Toward an animal model of borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation, impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1-3% of the US population as reported by Torgersen et al. (Arch Gen Psychiatry 58:590-596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry 62:553-564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734-750, Tomko et al. 2014). One major obstacle to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of the disorder to a system that is amenable to study. OBJECTIVE: To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building an animal model of BPD by choosing key components of the disorder that can be implemented in rodents. RESULTS: We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and impaired extinction, habituation, and social interactions. CONCLUSION: Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD. These model, when compared with available human data, will inform research and treatment in humans for better understanding of systems from the micro-molecular level to more global physiology underlying BPD.

Mineralocorticoid receptor function and cognition in health and disease.

The steroid hormone cortisol is released in response to stress and exerts its effects in the brain via two different receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This review - dedicated to Dirk Hellhammer - focusses on the role of MR on cognitive and emotional function in healthy individuals and in stress-associated disorders such as major depressive disorder (MDD) or borderline personality disorder (BPD). Animal data and studies from healthy individuals converge such that MR play an important role in the appraisal of new situations and the following response selection. Decision-making and empathy are important determinants of this response selection and both are affected by MR function. Furthermore, MR are crucially involved in visuospatial navigation and memory in young and elderly healthy individuals whereas the exact physiological role of MR in verbal learning and verbal memory needs to be further characterized. In contrast to studies in healthy participants, age played a moderating role on the effects of MR stimulation on cognition in depressed patients. In young depressed patients, MR stimulation exerted beneficial effects on verbal memory and executive function, whereas in elderly depressed patients MR stimulation led to impaired verbal learning and visuospatial memory. Similar to healthy controls, BPD patients showed enhanced emotional empathy but not cognitive empathy after MR stimulation. Accordingly, this make MR an interesting target for potential pharmacological augmentation of psychotherapy in BPD. Given the important role MR play in cognitive and emotional function in health and disease, further studies should examine whether MR modulation can alleviate cognitive and emotional problems in patients with stress-associated disorders.

Patterns of altered regional brain glucose metabolism in borderline personality disorder and bipolar II disorder.

OBJECTIVE: The relationship between borderline personality disorder (BPD) and bipolar II disorder (BIP-II) is disputed but understudied. Here, we investigated brain glucose metabolism in these patient groups and healthy control subjects (HCs). METHODS: Sixty-five subjects, 22 BPD (19 females), 22 BIP-II (17 females), and 21 HC (14 females), were examined using 2-deoxy-2[18F]-fluoro-d-glucose positron-emission tomography (PET) scanning. Only patients without reciprocal comorbidity were recruited; BPD participants without bipolar spectrum pathology; BIP-II participants without cluster A/B personality pathology. Groups were compared pairwise. Associations with mood state and childhood trauma were analyzed. RESULTS: Both patient groups exhibited hypometabolism compared with HCs in insula, brainstem, and frontal white matter. Additionally, BPD patients showed hypometabolism in hypothalamus, midbrain, and striatum; BIP-II patients in cerebellum. Uncorrected analyses showed cortical areas of higher metabolism in BIP-II than BPD, and associations with clinical variables differed between the groups. CONCLUSION: Reduced metabolism in the insula regions was shown in both disorders, suggesting shared pathophysiological mechanisms. The observed patterns of altered metabolism specific to each patient group, as well as the uncorrected results, may also suggest differential pathophysiology. However, these latter findings must be interpreted cautiously given the non-significant corrected results in the direct comparison between the disorders.

Systematic review and meta-analysis of basal cortisol levels in Borderline Personality Disorder compared to non-psychiatric controls.

OBJECTIVE: Borderline personality disorder (BPD) is a prevalent, complex, and serious mental disorder involving multiple symptoms and maladaptive behaviour. The underlying psychobiological mechanisms involved are not yet fully understood, but increasing evidence indicates that changes in hypothalamic-pituitary-adrenal stress axis (HPA) activity may contribute to BPD. Whilst various studies have demonstrated elevated levels of cortisol (the end-product of the HPA axis) in BPD sufferers, others have presented opposite findings. Inconsistent findings may be attributable to comorbidities, collection and measurement methods, gender, and sample size. Considering these discrepancies, the aim of this systematic review and meta-analysis was to assess available studies in the scientific literature examining basal/ baseline cortisol levels in patients diagnosed with borderline personality disorder compared to non-psychiatric controls. METHODS: A systematic literature review was conducted with descriptions of primary studies in addition to a meta-analysis of studies with a control group. Meta-analysis was performed using Comprehensive Meta-analysis software (CMA version 2). The effect size (Hedges' g) was calculated with random-effect model. RESULTS: A systematic literature search identified 16 studies that met the eligibility criteria from a total of 1076 unique records initially examined. Twelve studies (N = 546; 278 borderline personality disorder and 268 non-psychiatric controls) fulfilled the inclusion criteria for meta-analysis. The standardised mean difference (Hedges' g) of basal cortisol level between BPD and control groups was -0.32 (pooled data from 12 studies; 95% confidence interval -0.56 to -0.06, p = 0.01), indicating significantly lower mean cortisol level for the BPD group. CONCLUSION: Cortisol as a biomarker of the HPA axis is an important and helpful measure in the study of stress disorders such as BPD. However, considerations of potential confounding factors must be considered.

Biomarker correlates of psychotherapy outcomes in borderline personality disorder: A systematic review.

Studies of neurobiological mechanisms in borderline personality disorder (BPD) have increased our understanding of the pathophysiology of its development and course. Less is known about how psychotherapy may influence these neurobiological factors, and also whether biomarkers may predict psychotherapy outcomes. We conducted a systematic review using PRISMA guidelines. Fourteen studies providing data from 467 participants diagnosed with BPD met inclusion criteria to: (a) investigate biomarkers predicting response to psychotherapy for BPD; or (b) examine neurobiological factors altered by psychotherapy. Neuroimaging studies (n = 11) used mostly functional magnetic resonance imaging methods to scope brain regions related to emotion regulation and cognitive control. Three studies examined genetic or neuroendocrine markers. The evidence suggests that psychotherapy alters neural activation and connectivity of regions subserving executive control and emotion regulation. Additionally, hypoactivation in prefrontal and cingulate regions predicted treatment response. Further work in this area may inform personalised treatment approaches in clinical practice for BPD through elucidating neural mechanisms of evidence-based psychotherapy.

Perimenstrual exacerbation of symptoms in borderline personality disorder: evidence from multilevel models and the Carolina Premenstrual Assessment Scoring System.

BACKGROUND: Individuals with a borderline personality disorder (BPD) suffer from a constellation of rapidly shifting emotional, interpersonal, and behavioral symptoms. The menstrual cycle may contribute to symptom instability among females with this disorder. METHODS: Fifteen healthy, unmedicated females with BPD and without dysmenorrhea reported daily symptoms across 35 days. Urine luteinizing hormone and salivary progesterone (P4) were used to confirm ovulation and cycle phase. Cyclical worsening of symptoms was evaluated using (1) phase contrasts in multilevel models and (2) the Carolina Premenstrual Assessment Scoring System (C-PASS), a protocol for evaluating clinically significant cycle effects on symptoms. RESULTS: Most symptoms demonstrated midluteal worsening, a perimenstrual peak, and resolution of symptoms in the follicular or ovulatory phase. Post-hoc correlations with person-centered progesterone revealed negative correlations with most symptoms. Depressive symptoms showed an unexpected delayed pattern in which baseline levels of symptoms were observed in the ovulatory and midluteal phases, and exacerbations were observed during both the perimenstrual and follicular phases. The majority of participants met C-PASS criteria for clinically significant (⩾30%) symptom exacerbation. All participants met the emotional instability criterion of BPD, and no participant met DSM-5 criteria for premenstrual dysphoric disorder (PMDD). CONCLUSIONS: Females with BPD may be at elevated risk for perimenstrual worsening of emotional symptoms. Longitudinal studies with fine-grained hormonal measurement as well as hormonal experiments are needed to determine the pathophysiology of perimenstrual exacerbation in BPD.

Reduced levels of the endocannabinoid arachidonylethanolamide (AEA) in hair in patients with borderline personality disorder - a pilot study.

Endocannabinoids are involved in depressive and anxious symptoms and might play a role in stress-associated psychiatric disorders. While alterations in the endogenous cannabinoid system have been repeatedly found in patients with posttraumatic stress disorder (PTSD), this system has been mostly neglected in borderline personality disorder (BPD). However, there is first evidence for elevated serum levels of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonyl-sn-glycerol (2-AG) in BPD patients compared to healthy controls and PTSD patients. In this study, hair endocannabinoids were analyzed, reflecting long-term endocannabinoid concentrations. We assessed AEA concentrations as well as 2-AG and the 2-AG main isomer 1-AG (1-AG/2-AG) in hair in women with BPD (n = 15) and age- and education-matched healthy women (n = 16). We found significantly reduced log AEA in BPD patients compared to healthy women (p = .03) but no differences in log 1-AG/2-AG concentrations. In addition, there was no association between 1-AG/2-AG and hair cortisol, but we found a non-significant correlation between hair concentrations of AEA and cortisol (p = .06). Our data indicate altered long-term release of endogenous cannabinoids in women with BPD depending on type of endocannabinoid. AEA has been suggested to modulate the basal activity of the endocannabinoid system and seems to attenuate depressive and anxious symptoms. Thus, chronically reduced AEA might contribute to psychiatric symptoms in BPD.

Attachment-Related Regulatory Processes Moderate the Impact of Adverse Childhood Experiences on Stress Reaction in Borderline Personality Disorder.

In this study, the authors explored whether attachment insecurity moderates the effects of adverse childhood experiences on stress reactivity in the context of borderline personality disorder (BPD). Participants were 113 women (39 with BPD, 15 with some BPD criteria present, 59 without any BPD symptoms) who participated in the Trier Social Stress Test. Saliva samples were collected before and after the stressor and assayed for salivary alpha-amylase (sAA) and cortisol. Adverse childhood experiences were measured using the Childhood Trauma Questionnaire, and attachment by the Experiences in Close Relationships-Revised questionnaire. Results revealed that attachment avoidance and a combination of more adverse childhood experiences and attachment insecurity resulted in higher sAA levels and differences in reactivity to the stressor. Interactions between attachment anxiety and adverse childhood experiences were related to blunted cortisol reactivity. The results suggest that the influence of adverse childhood experiences on stress regulation in BPD may be moderated by attachment-related regulatory processes.

Endogenous oxytocin is associated with the experience of compassion and recalled upbringing in Borderline Personality Disorder.

BACKGROUND/OBJECTIVE: The role of the neuropeptide oxytocin (OT) in Borderline Personality Disorder (BPD) is poorly understood. It is particularly unknown how early experiences with caregivers moderate the action of OT in BPD. Here, we examined the association of plasma OT levels in BPD patients with the experience of compassion and recalled parental behavior during childhood. METHODS: Fifty-seven BPD patients and 43 healthy controls participated in the study. OT plasma levels were analyzed by radioimmunoassay. Subjects additionally completed questionnaires focusing on fears of compassion (FOC) and recalled upbringing ("Questionnaire of Recalled Parental Rearing Behavior/Fragebogen zum erinnerten elterlichen Erziehungsverhalten," FEE). RESULTS: BPD patients had significantly lower OT plasma levels than healthy controls and differed significantly on all FOC and FEE scales; BPD patients had higher FOC scores (indicating more aversion of being compassionate to themselves and others and receiving compassion from others). They also differed in recalled parenting. In the BPD group, scores of the FOC scale "fear of compassion from others" were significantly negatively correlated with OT levels. Moreover, recalled "emotional warmth" of their parents during childhood was positively correlated with OT plasma levels of BPD subjects. No such correlations were found in the control group. CONCLUSION: Our results corroborate findings from previous studies reporting lower OT levels in patients with BPD. Moreover, peripheral OT seems to be linked with the tolerance of compassionate feelings and early experiences with caregivers. This is consistent with other findings that OT is an important mediator of the experience of emotional warmth from others.

DNA methylation of APBA3 and MCF2 in borderline personality disorder: Potential biomarkers for response to psychotherapy.

Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information.

Brain activity to transitional objects in patients with borderline personality disorder.

Adult patients with borderline personality disorders (BPD) frequently have attachments to inanimate transitional objects (TOs) such as stuffed animals. Using event-related potential (ERP) recordings, we determined in patients with BPD the neural correlates of the processing of these attachment-relevant objects and their functional significance. Sixteen female patients with BPD viewed pictures of their TOs, other familiar stuffed toys (familiar objects, FOs), and unfamiliar objects (UOs). ERPs in the patients were compared to those in 16 matched healthy controls who possessed a stuffed animal of comparably high familiarity. Here, we found a specific increase of frontal P3/LPP amplitude in patients with BPD, which was related to attachment anxiety and depression scores. Attachment-related TO stimuli in patients with BPD specifically modulated stages of emotional stimulus evaluation reflecting processing of self-relevance. The relation of the frontal ERP effect to patients' attachment anxiety and depression highlights the function of TOs for coping with anxiety about being abandoned by significant others and for dealing with depressive symptoms.

The Interaction of Childhood Maltreatment, Sex, and Borderline Personality Features in the Prediction of the Cortisol Awakening Response in Adolescents.

AIMS: The study aimed to investigate childhood maltreatment, sex, and borderline personality disorder (BPD) symptoms as prospective predictors of adolescent hypothalamic-pituitary-adrenal (HPA) axis reactivity. METHOD: A sample of 69 adolescents (30 female and 39 male) were selected from a larger longitudinal study of adolescent development and assessed at 3 time points. BPD symptoms were assessed at T1 (approx. 12.5 years), childhood maltreatment was assessed at T2 (approx. 14.9 years), and multiple assessments of salivary cortisol (cortisol awakening response; CAR) were undertaken at T3 (approx. 15.5 years). RESULTS: Multivariate linear regression analysis revealed a significant main effect for childhood maltreatment but not for early BPD symptoms as a predictor of lower CAR in adolescence (p = 0.047). The association between childhood maltreatment and attenuated CAR was moderated by both early BPD symptoms (p = 0.024; no childhood maltreatment-dependent attenuation of CAR in the presence of BPD symptoms) and sex (p = 0.012; childhood maltreatment-dependent attenuation of CAR in females only). Furthermore, a 3-way BPD × childhood maltreatment × sex interaction (p = 0.041) indicated that the moderating effect of BPD symptoms was present in females only. CONCLUSION: These findings indicate that attenuation of the HPA axis occurs as a response to early maltreatment rather than being related to the early occurrence of BPD pathology. Traumatized female individuals with BPD symptoms might bypass adaptive HPA axis attenuation.

ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder.

Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by γ-Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto-striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task-dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within-group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC-caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto-striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC-caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task-dependent BOLD activation and functional connectivity in the fronto-striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC-caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto-striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD.