Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
Siever and Davis’ (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT.
Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale.
fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale).
These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity—part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation.
Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI
Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional MRI to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the IAPS set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared to rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD’s in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared to rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions than HC’s, when processing negative social emotional pictures compared to rest. They activate neural networks in emotion processing that are phylogenetically older and more reflexive than healthy controls.
Affective Instability; Emotion; fMRI; Social-Emotional Cues; Borderline Personality Disorder
Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-α, phosphorylated-PKC-α (p-PKCα), PKC-β II, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-α levels were lower in patients than controls. p-PKC-α and PKC-βII were lower at trend levels. In the entire sample, platelet p-PKC α and PKC-α activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide.
PKC; BDNF; Neurotrophic Factors; Second Messengers; Personality Disorders; Borderline Personality Disorder
Borderline personality disorder (BPD) often presents during adolescence. Early detection and intervention decreases its subsequent severity. However, little is known about early predictors and biological underpinnings of BPD. The observed abnormal functional connectivity among brain regions in BPD led to studies of white matter, as the neural substrate of connectivity. However, diffusion tensor imaging (DTI) studies in adult BPD have been inconclusive, and, as yet, there are no published DTI studies in borderline adolescents.
We conducted DTI tractography in 38 BPD patients (14-adolescents,24-adults) and 32 healthy controls (13-adolescents,19-adults).
We found bilateral tract-specific decreased fractional anisotropy (FA) in inferior longitudinal fasciculus (ILF) in BPD adolescents compared to adolescent controls. ILF FA was significantly higher in adolescent controls compared to BPD adolescents, BPD adults and adult controls (WilksF(3,57)=3.55, p<0.02). Follow-up voxelwise TBSS analysis demonstrated lower FA in BPD adolescents compared to adolescent controls also in uncinate and occipitofrontal fasciculi.
FA generally develops along an inverted U-shape curve, increasing through adolescence, and slowly decreasing in adulthood. Our findings suggest that, in adolescent BPD, this normal developmental “peak” in FA, which is seen in healthy controls, is not achieved. This suggests a possible neural substrate for the previously reported OFC-amygdala disconnect in adults with BPD. It raises the possibility that a white matter tract abnormality in BPD present in adolescence may not be appreciable in adulthood, but a functional abnormality in the coordination among brain regions persists. Our finding represents a possible biological marker to identify those at risk for developing BPD.
The National Institute of Mental Health convened an international group of experts to examine the conduct of treatment trials for persons with borderline personality disorder (BPD). The rapid growth of treatment research had led to the recognition that investigators face unique methodological issues with these challenging patients.
Conference members reviewed critical aspects of psychotherapy and pharmacotherapy trial design for patients with BPD.
This article summarizes discussions held on March 17-18, 2005.
This paper addresses the most pressing issues in sample selection and trial design pertaining to BPD; issues that have bedeviled both investigators submitting applications and reviewers trying to assess the merit of these grants. By disseminating this work, conference members hope to make this process more consistent and productive for all concerned.
Borderline personality disorder; treatment; guidelines
Borderline personality disorder (BPD) is characterized by an inability to regulate emotional responses. The amygdala is important in learning about the valence (goodness and badness) of stimuli and has been reported to function abnormally in BPD.
Event-related functional MRI (fMRI) was employed in three groups: unmedicated BPD (n=33) and schizotypal personality disorder (SPD;n=28) participants and healthy controls (n=32) during a task involving an intermixed series of unpleasant, neutral, and pleasant pictures each presented twice within their respective trial block/run. The amygdala was hand-traced on each participant’s structural-MRI scan which was co-registered to their BOLD-scan. Amygdala responses were examined with a mixed-model MANOVA with repeated measures.
Compared with both control groups, BPD patients showed greater amygdala activation, particularly to the repeated emotional but not neutral pictures and a prolonged return to baseline for the overall BOLD response averaged across all pictures. Despite amygdala overactivation, BPD patients showed a blunted response on the self-report ratings of emotional but not neutral pictures. Fewer dissociative symptoms in both patient groups were associated with greater amygdala activation to repeated unpleasant pictures.
The increased amygdala response to the repeated emotional pictures observed in BPD was not observed in SPD patients suggesting diagnostic specificity. This BPD-related abnormality is consistent with the well-documented clinical feature of high sensitivity to emotional stimuli with unusually strong and long-lasting reactions. The finding of a mismatch between physiological and self-report measures of emotion reactivity in BPD patients suggests they may benefit from treatments which help them recognize emotions.
borderline personality disorder; schizotypal personality disorder; amygdala; emotion; fMRI; arousal; valence
Over the past two decades, neurobiological studies in adult onset borderline personality disorder have made important strides, but inquiry into adolescent-onset BPD is still in its infancy and our understanding of the neurobiology of adolescent BPD remains highly tentative.
This paper highlights recent findings in genetics, neuroendocrinology and neuroimaging for adult and adolescent-onset BPD.
Neurobiological studies of adolescent-onset BPD to date have focused mainly on volumetric studies of various brain regions and measurements of HPA axis components, with comparatively few publications on brain functioning.
Such information is essential to developing more effective screening, treatment and preventive strategies.
Borderline Personality Disorder; adolescent; neurobiology; neuroimaging; trouble de la personnalité limite; adolescent; neurobiologie; neuroimagerie
Borderline Personality Disorder (BPD) is associated with behavioral and emotional dysregulation, particularly in social contexts; however, the underlying pathophysiology at the level of brain function is not well understood. Previous studies found abnormalities in frontal cortical and limbic areas suggestive of poor frontal regulation of downstream brain regions. However, the striatum, which is closely connected with the medial frontal cortices and plays an important role in motivated behaviors and processing of rewarding stimuli, has been understudied in BPD. Here we hypothesized that, in addition to frontal dysfunction, BPD patients may show abnormal striatal function. In this study, 38 BPD patients with intermittent explosive disorder (BPD-IED) and 36 healthy controls (HC) participated in the Point Subtraction Aggression Paradigm (PSAP), a computer game played with a fictitious other player. 18Fluoro-deoxyglucose positron emission tomography (FDG-PET) measured relative glucose metabolism (rGMR) within caudate and putamen in response to aggression-provoking and non-provoking versions of the PSAP. Male BPD-IED patients had significantly lower striatal rGMR than all other groups during both conditions, although male and female BPD-IED patients did not differ in clinical or behavioral measures. These sex differences suggest differential involvement of frontal-striatal circuits in BPD-IED, and are discussed in relation to striatal involvement in affective learning and social decision-making.
Borderline personality disorder; intermittent explosive disorder; striatum; aggression; positron emission tomography
It has been reported that borderline personality related characteristics can be observed in children, and that these characteristics are associated with increased risk for the development of borderline personality disorder. It is not clear whether borderline personality related characteristics in children share etiological features with adult borderline personality disorder. We investigated the etiology of borderline personality related characteristics in a longitudinal cohort study of 1,116 pairs of same-sex twins followed from birth through age 12 years. Borderline personality related characteristics measured at age 12 years were highly heritable, were more common in children who had exhibited poor cognitive function, impulsivity, and more behavioral and emotional problems at age 5 years, and co-occurred with symptoms of conduct disorder, depression, anxiety, and psychosis. Exposure to harsh treatment in the family environment through age 10 years predicted borderline personality related characteristics at age 12 years. This association showed evidence of environmental mediation and was stronger among children with a family history of psychiatric illness, consistent with diathesis–stress models of borderline etiology. Results indicate that borderline personality related characteristics in children share etiological features with borderline personality disorder in adults and suggest that inherited and environmental risk factors make independent and interactive contributions to borderline etiology.
There is decreased serotonergic function in impulsive aggression and borderline personality disorder (BPD), and genetic association studies suggest a role of serotonergic genes in impulsive aggression and BPD. Only one study has analyzed the association between the tryptophan-hydroxylase 2 (TPH2) gene and BPD. A TPH2 “risk” haplotype has been described that is associated with anxiety, depression and suicidal behavior.
We assessed the relationship between the previously identified “risk” haplotype at the TPH2 locus and BPD diagnosis, impulsive aggression, affective lability, and suicidal/parasuicidal behaviors, in a well-characterized clinical sample of 103 healthy controls (HCs) and 251 patients with personality disorders (109 with BPD). A logistic regression including measures of depression, affective lability and aggression scores in predicting “risk” haplotype was conducted.
The prevalence of the “risk” haplotype was significantly higher in patients with BPD compared to HCs. Those with the “risk” haplotype have higher aggression and affect lability scores and more suicidal/parasuicidal behaviors than those without it. In the logistic regression model, affect lability was the only significant predictor and it correctly classified 83.1% of the subjects as “risk” or “non-risk” haplotype carriers.
We found an association between the previously described TPH2 “risk” haplotype and BPD diagnosis, affective lability, suicidal/parasuicidal behavior, and aggression scores.
Borderline personality disorder; TPH2; suicidal behavior; affective instability; impulsive aggression
Impulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the 5-HT2A receptor (5-HT2AR). We sought to examine the role of the 5-HT2AR in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT2AR function in the OFC is a state phenomenon which promotes impulsive aggression.
5-HT2AR availability was measured with positron emission tomography and the selective 5-HT2AR antagonist radioligand [11C]MDL100907 in two groups of impulsively aggressive personality disordered patients --14 with current physical aggression, and 15 without current physical aggression --and 25 healthy controls. Clinical ratings of various symptom dimensions were also obtained.
Orbitofrontal 5-HT2AR availability was greater in patients with current physical aggression compared to patients without current physical aggression and healthy controls; no differences in OFC 5-HT2AR availability were observed between patients without current physical aggression and healthy controls. No significant differences in 5-HT2AR availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT2AR availability was correlated, specifically, with a state measure of impulsive aggression.
These findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT2AR function in the OFC.
Aggression; Personality Disorder; Intermittent Explosive Disorder; Serotonin; Positron Emission Tomography; Orbitofrontal Cortex
Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one’s self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D1 and D2 receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
schizotypal personality; schizotypy; schizophrenia spectrum; cognition; pergolide; dopamine; Schizophrenia/Antipsychotics; Dopamine; Cognition; Clinical Pharmacology/Trials; schizotypal personality; pergolide
Borderline personality disorder (BPD) is often associated with symptoms of impulsive aggression, which pose a threat to patients themselves and to others. Preclinical studies show that orbital frontal cortex (OFC) plays a role in regulating impulsive aggression. Prior work has found OFC dysfunction in BPD.
We employed a task to provoke aggressive behavior, the Point Subtraction Aggression Paradigm (PSAP), which has never previously been used during functional brain imaging. Thirty-eight BPD patients with impulsive aggression (BPD-IED) and 36 age-matched healthy controls (HC) received 18FDG-PET on two occasions with a provocation and non-provocation version of the PSAP. For each participant, we measured mean relative glucose metabolism in cortical Brodmann areas (BAs) in each hemisphere; difference scores (Provoked–Non-provoked) were calculated. A whole brain exploratory analysis for the double difference of BPD-IED–HC for Provoked–Non-provoked was also conducted.
BPD-IED patients were significantly more aggressive than HC on the PSAP. BPD-IED patients also increased relative glucose metabolic rate (rGMR) in OFC and amygdala when provoked, while HC decreased rGMR in these areas. However, HC increased rGMR in anterior, medial, and dorsolateral prefrontal regions during provocation more than BPD-IED patients.
Patients responded aggressively and showed heightened rGMR in emotional brain areas, including amygdala and OFC in response to provocation, but not in more dorsal brain regions associated with cognitive control of aggression. In contrast, HC increased rGMR in dorsal regions of PFC during aggression provocation, brain regions involved in top-down cognitive control of aggression and, more broadly, of emotion.
brain imaging; Point Subtraction Aggression Paradigm; PSAP; emotion
Emotional instability is a defining feature of borderline personality disorder (BPD), yet little is understood about its underlying neural correlates. One possible contributing factor to emotional instability is a failure to adequately employ adaptive cognitive regulatory strategies such as psychological distancing.
To determine whether there are differences in neural dynamics underlying this control strategy, between BPD patients and healthy volunteers (HC’s), BOLD fMRI signals were acquired as 18 BPD and 16 HC subjects distanced from or simply looked at negative and neutral pictures depicting social interactions. Contrasts in signal between distance and look condition were compared between groups to identify commonalities and differences in regional activation.
BPD patients show a different pattern of activation compared to HC subjects when looking at negative vs. neutral pictures. When distancing vs. looking at negative pictures, both groups showed decreased negative affect in rating and increased activation of the dorsolateral prefrontal cortex, areas near/along the intraparietal sulcus (IPS), ventrolateral prefrontal cortex and posterior cingulate/precuneus regions. However, the BPD group showed less BOLD signal change in dorsal anterior cingulate cortex and IPS, less deactivation in the amygdala and greater activation in the superior temporal sulcus and superior frontal gyrus.
BPD and HC subjects display different neural dynamics while passively viewing social emotional stimuli. In addition, BPD patients do not engage the cognitive control regions to the extent that HC’s do when employing a distancing strategy to regulate emotional reactions, which may be a factor contributing to the affective instability of BPD.
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Psychological Distancing; Emotion Regulation; fMRI
Borderline personality disorder (BPD) is marked by aggression and impulsive, often self-destructive behavior. Despite the severe risks associated with BPD, relatively little is known about the disorder’s etiology. Identification of genetic correlates (endophenotypes) of BPD would improve the prospects of targeted interventions for more homogeneous subsets of borderline patients characterized by specific genetic vulnerabilities. The current study evaluated behavioral measures of aggression and impulsivity as potential endophenotypes for BPD. Subjects with BPD (N = 127), a non cluster B personality disorder (OPD N = 122), or healthy volunteers (HV N = 112) completed self report and behavioral measures of aggression, motor impulsivity and cognitive impulsivity. Results showed that BPD subjects demonstrated more aggression and motor impulsivity than HV (but not OPD) subjects on behavioral tasks. In contrast, BPD subjects self-reported more impulsivity and aggression than either comparison group. Subsequent analyses showed that among BPD subjects behavioral aggression was associated with self-reported aggression, while behavioral and self-report impulsivity measures were more modestly associated. Overall, the results provide partial support for the use of behavioral measures of aggression and motor impulsivity as endophenotypes for BPD, with stronger support for behavioral aggression measures as an endophenotype for aggression within BPD samples.
Borderline personality disorder; Endophenotype; Aggression; Impulsivity