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1.  Trait anxiety modulates fronto-limbic processing of emotional interference in borderline personality disorder 
Previous studies of cognitive alterations in borderline personality disorder (BPD) have yielded conflicting results. Given that a core feature of BPD is affective instability, which is characterized by emotional hyperreactivity and deficits in emotion regulation, it seems conceivable that short-lasting emotional distress might exert temporary detrimental effects on cognitive performance. Here we used functional magnetic resonance imaging (fMRI) to investigate how task-irrelevant emotional stimuli (fearful faces) affect performance and fronto-limbic neural activity patterns during attention-demanding cognitive processing in 16 female, unmedicated BPD patients relative to 24 age-matched healthy controls. In a modified flanker task, emotionally negative, socially salient pictures (fearful vs. neutral faces) were presented as distracters in the background. Patients, but not controls, showed an atypical response pattern of the right amygdala with increased activation during emotional interference in the (difficult) incongruent flanker condition, but emotion-related amygdala deactivation in the congruent condition. A direct comparison of the emotional conditions between the two groups revealed that the strongest diagnosis-related differences could be observed in the dorsal and, to a lesser extent, also in the rostral anterior cingulate cortex (dACC, rACC) where patients exhibited an increased neural response to emotional relative to neutral distracters. Moreover, in the incongruent condition, both the dACC and rACC fMRI responses during emotional interference were negatively correlated with trait anxiety in the patients, but not in the healthy controls. As higher trait anxiety was also associated with longer reaction times (RTs) in the BPD patients, we suggest that in BPD patients the ACC might mediate compensatory cognitive processes during emotional interference and that such neurocognitive compensation that can be adversely affected by high levels of anxiety.
doi:10.3389/fnhum.2013.00054
PMCID: PMC3585713  PMID: 23459637
borderline personality disorder; cognition-emotion interaction; anxiety; fMRI; amygdala; anterior cingulate cortex
2.  Frontolimbic dysfunction in response to facial emotion in borderline personality disorder: an event-related fMRI study 
Psychiatry research  2007;155(3):231-243.
Clinical hallmarks of borderline personality disorder (BPD) include social and emotional dysregulation. We tested a model of frontolimbic dysfunction in facial emotion processing in BPD. Groups of 12 unmedicated adults with BPD by DSM-IV and 12 demographically-matched healthy controls (HC) viewed facial expressions (Conditions) of neutral emotion, fear and anger, and made gender discriminations during rapid event-related functional magnetic resonance imaging (fMRI). Analysis of variance of Region of Interest signal change revealed a statistically significant effect of the Group-by-Region-by-Condition interaction. This was due to the BPD group exhibiting a significantly larger magnitude of deactivation (relative to HC) in the bilateral rostral/subgenual anterior cingulate cortex (ACC) to fear and in the left ACC to fear minus neutral; and significantly greater activation in the right amygdala to fear minus neutral. There were no significant between-group differences in ROI signal change in response to anger. In voxel-wise analyses constrained within these ROIs, the BPD group exhibited significant changes in the fear minus neutral contrast, with relatively less activation in the bilateral rostral/subgenual ACC, and greater activation in the right amygdala. In the anger minus neutral contrast this pattern was reversed, with the BPD group showing greater activation in the bilateral rostral/subgenual ACC and less activation in the bilateral amygdala. We conclude that adults with BPD exhibit changes in fronto-limbic activity in the processing of fear stimuli, with exaggerated amygdala response and impaired emotion-modulation of ACC activity. The neural substrates underlying processing of anger may also be altered. These changes may represent an expression of the volumetric and serotonergic deficits observed in these brain areas in BPD.
doi:10.1016/j.pscychresns.2007.03.006
PMCID: PMC2084368  PMID: 17601709
anterior cingulate cortex; amygdala; fear; anger; functional magnetic resonance imaging
3.  Functional Connectivity of Pain-Mediated Affect Regulation in Borderline Personality Disorder 
PLoS ONE  2012;7(3):e33293.
Affective instability and self-injurious behavior are important features of Borderline Personality Disorder. Whereas affective instability may be caused by a pattern of limbic hyperreactivity paired with dysfunctional prefrontal regulation mechanisms, painful stimulation was found to reduce affective arousal at the neural level, possibly underlying the soothing effect of pain in BPD.
We used psychophysiological interactions to analyze functional connectivity of (para-) limbic brain structures (i.e. amygdala, insula, anterior cingulate cortex) in Borderline Personality Disorder in response to painful stimulation. Therefore, we re-analyzed a dataset from 20 patients with Borderline Personality Disorder and 23 healthy controls who took part in an fMRI-task inducing negative (versus neutral) affect and subsequently applying heat pain (versus warmth perception).
Results suggest an enhanced negative coupling between limbic as well as paralimbic regions and prefrontal regions, specifically with the medial and dorsolateral prefrontal cortex, when patients experienced pain in addition to emotional arousing pictures. When neutral pictures were combined with painful heat sensation, we found positive connectivity in Borderline Personality Disorder between (para-)limbic brain areas and parts of the basal ganglia (lentiform nucleus, putamen), as well areas involved in self-referential processing (precuneus and posterior cingulate).
We found further evidence for alterations in the emotion regulation process in Borderline Personality Disorder, in the way that pain improves the inhibition of limbic activity by prefrontal areas. This study provides new insights in pain processing in BPD, including enhanced coupling of limbic structures and basal ganglia.
doi:10.1371/journal.pone.0033293
PMCID: PMC3299768  PMID: 22428013
4.  Emotional modulation of motor response inhibition in women with borderline personality disorder: an fMRI study 
Background
Both emotion regulation and impulsivity are core aspects of borderline personality disorder (BPD) pathology. Although both problems may be combined specifically in BPD, few studies to date have investigated the emotional modulation of impulsivity in BPD.
Methods
Women with BPD and matched healthy controls performed go/no-go tasks after induction of anger, joy or a neutral mood by vocally presented short stories. Dependent variables were the behavioural results and functional magnetic resonance imaging data.
Results
We included 17 women with BPD and 18 controls in our study. No behavioural group differences were found. However, patients with BPD showed stronger activation of the left amygdala and weaker activation of the subgenual anterior cingulate during anger induction than controls. Inhibition in the go/no-go task after anger induction increased activity in the left inferior frontal cortex in controls, but not in women with BPD, who, in turn, showed increased activation in the subthalamic nucleus.
Limitations
Findings cannot be generalized to men, and 4 patients were taking antidepressant medication (selective serotonin reuptake inhibitors). In addition, no patient control group was investigated, thus we do not know whether findings are specific to BPD compared with other disorders.
Conclusion
Our findings are consistent with the view that a disturbed amygdala–prefrontal network in patients with BPD is compensated by a subcortical loop involving the subthalamic nucleus, leading to normal behavioural inhibition in these patients.
doi:10.1503/jpn.120029
PMCID: PMC3633709  PMID: 23046830
5.  Pain sensitivity and neural processing during dissociative states in patients with borderline personality disorder with and without comorbid posttraumatic stress disorder: a pilot study 
Background
Stress-induced dissociative states involving analgesia are a common feature of borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD). Our aim was to investigate the psychologic, somatosensory (pain sensitivity) and neural correlates of dissociative states in patients with these disorders.
Methods
We included 15 women with BPD who were not taking medication; 10 of these women had comorbid PTSD. While undergoing functional magnetic resonance imaging at 1.5 Tesla, participants were exposed to a script describing a personalized dissociation-inducing situation and a personalized script describing a neutral situation. We assessed dissociative psychopathology and pain sensitivity.
Results
Dissociative psychopathology scores were significantly higher and pain sensitivity was lower after the dissociation-inducing script was read compared with the neutral script. The blood oxygen level–dependent (BOLD) signal was significantly increased in the left inferior frontal gyrus (Brodmann area [BA] 9) during the presentation of the dissociation-inducing script. Regression analyses revealed positive correlations between BOLD signal and dissociative psychopathology in the left superior frontal gyrus (BA 6) and negative correlations in the right middle (BA 21) and inferior temporal gyrus (BA 20). In the subgroup of participants with comorbid PTSD, we also found increased activity in the left cingulate gyrus (BA 32) during script-driven imagery-induced dissociation, a positive correlation between dissociation scores and activity in the right and left insula (BA 13) and a negative correlation in the right parahippocampal gyrus (BA 35).
Limitations
The main limitation of this pilot study is the absence of a control group. Therefore, the results may also reflect the neural correlates of non–BPD/PTSD specific dissociative states or the neural correlates of emotionally stressful or “loaded” memories. Another limitation is the uncorrected statistical level of the functional magnetic resonance imaging results.
Conclusion
Our results showed that the script-driven imagery method is capable of inducing dissociative states in participants with BPD with and without comorbid PTSD. These states were characterized by reduced pain sensitivity and a frontolimbic activation pattern, which resembles the findings in participants with PTSD while in dissociative states.
doi:10.1503/jpn.090022
PMCID: PMC2861134  PMID: 20420768
6.  Functional Imaging of Emotion Reactivity in Opiate-Dependent Borderline Personality Disorder 
Personality disorders  2011;2(3):230-241.
Opiate dependence (OD) and Borderline Personality Disorder (BPD), separately and together, are significant public health problems with poor treatment outcomes. BPD is associated with difficulties in emotion regulation, and brain imaging studies in BPD individuals indicate differential activation in prefrontal-cingulate cortices and their interactions with limbic regions. Likewise, a similar network is implicated in drug cue responsivity in substance abusers. The present, preliminary study uses functional magnetic resonance imaging (fMRI) to examine activation of this network in comorbid OD/BPD participants when engaged in an “oddball” task that requires attention to a target in the context of emotionally negative distractors. Twelve male OD/BPD participants and 12 male healthy controls participated. All OD/BPD participants were taking the opiate replacement medication Suboxone, and a subset of participants were positive for substances of abuse on scan day. Relative to controls, OD/BPD participants demonstrated reduced activation to negative stimuli in the amygdala and anterior cingulate. Unlike previous studies that demonstrated hyperresponsivity in neural regions associated with affective processing in individuals with BPD versus healthy controls, comorbid OD/BPD participants were hyporesponsive to emotional cues. Future studies that also include BPD-only and OD-only groups are necessary to help clarify the individual and potentially synergistic effects of these two conditions.
doi:10.1037/a0022228
PMCID: PMC3555434  PMID: 22448769
Borderline Personality Disorder; Opiate Dependence; fMRI; Amygdala; Emotion
7.  Structural brain abnormalities in borderline personality disorder: A voxel-based morphometry study 
Psychiatry Research  2008;164(3):223-236.
Imaging studies using ROI morphometry and PET have contributed to our understanding of structural and functional abnormalities in BPD; however, both methods have practical limitations to their usefulness for exploratory studies of brain-behavior relationships. We used voxel based morphometry (VBM) in 34 subjects with BPD and 30 healthy controls (HC) to study effects of diagnosis, gender, childhood sexual abuse, depressed mood, impulsivity and aggression on group differences. VBM is a computer-based method for whole brain analysis that combines the advantages of a functional study with a structural method. The BPD subjects, diagnosed with the Diagnostic Interview for Borderline Patients and the International Personality Disorders Examination, were compared with 30 HC, with age and gender covaried. Analyses were repeated separately by gender and, in women, by histories of childhood sexual abuse. Depressed mood, impulsivity, and aggression were covaried in separate analyses. Compared with HC, BPD subjects had significant bilateral reductions in gray matter concentrations in ventral cingulate gyrus and several regions of the medial temporal lobe, including the hippocampus, amygdala, parahippocampal gyrus, and uncus. BPD women (and abused BPD women), but not BPD men, had significant reductions in medial temporal lobe, including the amygdala. BPD men, but not BPD women, showed diminished gray matter concentrations in the anterior cingulate gyrus compared with findings HC. Covarying for depressed mood rendered group differences non-significant in the ventral cingulate but had little effect on differences in medial temporal cortex. Covarying for aggression (LHA) had relatively little effect on group differences, while covarying for impulsivity (BIS) rendered all previously noted voxel-level group differences non-significant. Diminished gray matter in the prefrontal cortex and the medial temporal cortex may mediate the dysregulation of impulse and affect in BPD. Group differences varied greatly by gender, levels of depression, and impulsivity. VBM is an efficient method for exploratory study of brain-behavior relationships.
doi:10.1016/j.pscychresns.2008.02.003
PMCID: PMC3286221  PMID: 19019636
Magnetic resonance imaging; Personality Disorders; Suicide; Aggression
8.  Amygdala Functional Connectivity in Young Women with Borderline Personality Disorder 
Brain Connectivity  2011;1(1):61-71.
Abstract
Borderline personality disorder (BPD) is a complex psychiatric disorder that involves the core feature of affect dysregulation. Prior neuroimaging studies have indicated that BPD patients have (1) excessive amygdala activation to negative emotion and (2) diminished frontal regulation. This study examined amygdala functional connectivity in 12 women with BPD and 12 matched healthy comparison volunteers. We explored how connectivity patterns would change in the context of processing neutral, overt fear, or masked fear face expressions. Each participant underwent three 5-min fMRI scans in which they primarily viewed: (1) neutral, (2) overt fear, and (3) masked fear faces. In comparison to their healthy counterparts, young women with BPD showed (1) lower connectivity between bilateral amygdala and mid-cingulate cortex during the neutral scan; (2) higher connectivity between bilateral amygdala and rostral anterior cingulate cortex during the overt fear scan; and (3) higher right amygdala connectivity with bilateral thalamus and right caudate during the masked fear scan. Exploratory analyses revealed interesting correlations between amygdala connectivity in these conditions with multiple clinical measures. Results from the neutral scan add to the few prior connectivity studies in BPD that have been suggestive of lower fronto-limbic connectivity in BPD. However, the connectivity findings during fear processing are novel, and map onto basic research models for amygdala connectivity, that is, connections to frontal areas for overt fear processing versus connections to thalamus for automatic fear processing. Further, results suggest that BPD subjects tap into both pathways more strongly than healthy comparisons.
doi:10.1089/brain.2010.0001
PMCID: PMC3621316  PMID: 22432955
amygdala; borderline personality disorder; functional connectivity; functional neuroimaging; masked fear; overt fear
9.  Potentiated amygdala response to repeated emotional pictures in borderline personality disorder 
Biological psychiatry  2012;72(6):448-456.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2012.03.027
PMCID: PMC3415575  PMID: 22560044
borderline personality disorder; schizotypal personality disorder; amygdala; emotion; fMRI; arousal; valence
10.  Dysfunctional affect regulation in borderline personality disorder and in somatoform disorder 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.19566.
Background
Although affect dysregulation is considered a core component of borderline personality disorder (BPD) and somatoform disorders (SoD), remarkably little research has focused on the prevalence and nature of affect dysregulation in these disorders. Also, despite apparent similarities, little is known about how dysfunctional under- and overregulation of affect and positive and negative somatoform and psychoform dissociative experiences inter-relate. Prior studies suggest a clear relationship between early childhood psychological trauma and affect dysregulation, especially when the caretaker is emotionally, sexually, or physically abusing the child, but how these relate to under- and overregulation while differentiating for developmental epochs is not clear. Although an elevated risk of childhood trauma exposure or complex posttraumatic stress disorder (CPTSD) symptoms has been reported in BPD and SoD, trauma histories, dysfunctional affect regulation, dissociation, PTSD, and CPTSD were never assessed in unison in BPD and/or SoD.
Method
BPD and/or SoD diagnoses were confirmed or ruled out in 472 psychiatric inpatients using clinical interviews. Dysfunctional under- and overregulation of affect and somatoform and psychoform dissociation, childhood trauma-by-primary-caretaker (TPC), PTSD, and CPTSD were all measured using self reports.
Results
No disorder-specific form of dysfunctional affect regulation was found. Although both BPD and SoD can involve affect dysregulation and dissociation, there is a wide range of intensity of dysfunctional regulation phenomena in patients with these diagnoses. Evidence was found for the existence of three qualitatively different forms of experiencing states: inhibitory experiencing states (overregulation of affect and negative psychoform dissociation) most commonly found in SoD, excitatory experiencing states (underregulation of affect and positive psychoform dissociation) most commonly found in BPD, and combination of inhibitory and excitatory experiencing states commonly occurring in comorbid BPD+SoD. Almost two-thirds of participants reported having experienced childhood TPC. Underregulation of affect was associated with emotional TPC and TPC occurring in developmental epoch, 0–6 years of age. Overregulation of affect was associated with physical TPC. Almost a quarter of all participants met the criteria for CPTSD. BPD+SoD patients had the most extensive childhood trauma histories and were most likely to meet CPTSD criteria, followed by BPD, psychiatric comparison (PC), and SoD. The BPD+SoD and BPD reported significantly higher levels of CPTSD than the SoD or PC groups but did not differ from each other except for greater severity of CPTSD somatic symptoms by the BPD+SoD group.
Conclusion
Three qualitatively different forms of dysfunctional regulation were identified: inhibitory, excitatory, and combined inhibitory and excitatory states. Distinguishing inhibitory versus excitatory states of experiencing may help to clarify differences in dissociation and affect dysregulation between and within BPD and SoD patients. Specific interventions addressing overregulation in BPD, or underregulation in SoD, should be added to disorder-specific evidence-based treatments. CPT is particularly prevalent in BPD and BPD+SoD and is differentially associated with under- and overregulation of affect depending on the type of traumatic exposure. CPTSD warrants further investigation as a potential independent syndrome or as a marker identifying a sub-group of affectively, or both affectively and somatically, dysregulated patients diagnosed with BPD who have childhood trauma histories.
doi:10.3402/ejpt.v3i0.19566
PMCID: PMC3443400  PMID: 22984638
traumatic event; childhood; BPD; somatoform disorders; complex PTSD; affect regulation; dissociation
11.  Neuronal correlates of social cognition in borderline personality disorder 
Patients with borderline personality disorder (BPD) have severe problems in social interactions that might be caused by deficits in social cognition. Since the findings about social-cognitive abilities in BPD are inhomogeneous, ranging from deficits to superior abilities, we aimed to investigate the neuronal basis of social cognition in BPD. We applied a paradigm with three social cognition tasks, differing in their complexity: basal processing of faces with a neutral expression, recognition of emotions, and attribution of emotional intentions (affective ToM). A total of 13 patients with BPD and 13 healthy matched controls (HCs) were included in a functional magnet resonance imaging study. BPD patients showed no deficits in social cognition on the behavioral level. However, while HCs showed increasing activation in areas of the mirror neuron system with increasing complexity in the social-cognitive task, BPD patients had hypoactivation in these areas and hyperactivation in the amygdala which were not modulated by task complexity. This activation pattern seems to reflect an enhanced emotional approach in the processing of social stimuli in BPD that allows good performance in standardized social-cognitive tasks, but might be the basis of social-cognitive deficits in real-life social interactions.
doi:10.1093/scan/nss028
PMCID: PMC3682436  PMID: 22362841
borderline personality disorder; social cognition; functional magnetic resonance imaging; mirror neuron system; amygdala
12.  Voxel-Based Morphometry in Women with Borderline Personality Disorder with and without Comorbid Posttraumatic Stress Disorder 
PLoS ONE  2013;8(6):e65824.
Patients with Borderline Personality Disorder (BPD) showed reduced volume of amygdala and hippocampus, but similar findings are evident in Posttraumatic Stress Disorder (PTSD). Applying voxel-based morphometry (VBM) in a larger cohort of patients with BPD, we sought to extend earlier findings of volume abnormalities in limbic regions and to evaluate the influence of co-occurring PTSD in BPD patients. We used voxel-based morphometry to study gray matter volume (GMV) in 60 healthy controls (HC) and 60 patients with BPD. Subgroup analyses on 53 patients concerning the role of co-occurring PTSD were conducted. Additionally, regression analyses were calculated to assess the relation between borderline symptom severity as well as dissociative experiences and GMV. Differences in local GMV between patients with BPD and HC were observed in the amygdale and hippocampus as well as in the fusiform and cingulate gyrus. Co-occurring PTSD was accompanied by increased GMV in the superior temporal gyrus and dorsolateral prefrontal cortex. Independent of co-occurring PTSD, severity of BPD symptoms predicted smaller GMV in the amygdala and dorsal ACC. Dissociation was positively related to GMV in the middle temporal gyrus. We could replicate earlier findings of diminished limbic GMV in patients with BPD and additionally show that patients with co-morbid PTSD feature increased GMV in prefrontal regions associated with cognitive control.
doi:10.1371/journal.pone.0065824
PMCID: PMC3680473  PMID: 23776553
13.  Frontolimbic structural changes in borderline personality disorder 
Journal of psychiatric research  2007;42(9):727-733.
Objective
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation.
Methods
12 unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC.
Results
The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC.
Conclusions
This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).
doi:10.1016/j.jpsychires.2007.07.015
PMCID: PMC2708084  PMID: 17825840
borderline personality disorder; frontolimbic; amygdala; anterior cingulate cortex; gray matter; voxel-based morphometry
14.  Structural Brain Abnormalities and Suicidal Behavior in Borderline Personality Disorder 
Journal of Psychiatric Research  2012;46(4):516-525.
Background
Structural brain abnormalities have been demonstrated in subjects with BPD in prefrontal and fronto-limbic regions involved in the regulation of emotion and impulsive behavior, executive cognitive function and episodic memory. Impairment in these cognitive functions is associated with increased vulnerability to suicidal behavior. We compared BPD suicide attempters and non-attempters, high and low lethality attempters to healthy controls to identify neural circuits associated with suicidal behavior in BPD.
Methods
Structural MRI scans were obtained on 68 BPD subjects (16 male, 52 female), defined by IPDE and DIB/R criteria, and 52 healthy controls (HC: 28 male, 24 female). Groups were compared by diagnosis, attempt status, and attempt lethality. ROIs were defined for areas reported to have structural or metabolic abnormalities in BPD, and included: mid-inf. orbitofrontal cortex, mid-sup temporal cortex, anterior cingulate, insula, hippocampus, amygdala, fusiform, lingual and parahippocampal gyri. Data were analyzed using optimized voxel-based morphometry implemented with DARTEL in SPM5, co-varied for age and gender, corrected for cluster extent (p<.001).
Results
Compared to HC, BPD attempters had significantly diminished gray matter concentrations in 8 of 9 ROIs, non-attempters in 5 of 9 ROIs. Within the BPD sample, attempters had diminished gray matter in Lt. insula compared to non-attempters. High lethality attempters had significant decreases in Rt. mid-sup. temporal gyrus, Rt. mid-inf. orbitofrontal gyrus, Rt. insular cortex, Lt. fusiform gyrus, Lt. lingual gyrus and Rt. parahippocampal gyrus compared to low lethality attempters.
Conclusions
Specific structural abnormalities discriminate BPD attempters from non-attempters and high from low lethality attempters.
doi:10.1016/j.jpsychires.2012.01.003
PMCID: PMC3307855  PMID: 22336640
15.  Laboratory Induced Aggression: A PET Study of Aggressive Individuals with Borderline Personality Disorder 
Biological psychiatry  2009;66(12):1107-1114.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2009.07.015
PMCID: PMC2788117  PMID: 19748078
brain imaging; Point Subtraction Aggression Paradigm; PSAP; emotion
16.  Biobehavioral Reactivity to Social Evaluative Stress in Women With Borderline Personality Disorder 
Personality disorders  2012;4(2):91-100.
Several clinical theories propose that borderline personality disorder (BPD) is characterized by a biologically based affective vulnerability to intense affective experiences and impaired modulation of affective states, which might manifest in high emotional intensity, hyperreactivity, and impaired recovery to baseline. However, few studies have tested these theories based on emotional and biological responses of BPD participants in response to psychosocial stressors. This study examined cortisol, alpha-amylase, and subjective emotional reactivity to social evaluative stress among women with BPD compared with two healthy female control groups: a trait-matched (TM) group scoring similarly to the BPD group on trait measures of negative affect and impulsivity, and a non-trait-matched (NTM) group. Results generally suggested high emotional intensity and high baseline psychobiological arousal among individuals with BPD, but not emotional hyperreactivity or impaired recovery specific to the stressor. Relative to both control groups, BPD participants had higher baseline and overall subjective negative affect, higher baseline cortisol levels, and attenuated stress-related cortisol reactivity. In addition, both the BPD and TM groups had attenuated alpha-amylase reactivity in comparison to the NTM group. The differences between BPD and TM groups on most of the dependent measures suggest that emotional dysregulation in BPD is not merely an extreme variant of normative personality traits. These results suggest that women with BPD demonstrate intense and chronic negative affectivity along with high resting psychobiological arousal and attenuated psychobiological reactivity specific to laboratory stressors.
doi:10.1037/a0030117
PMCID: PMC3635672  PMID: 23244772
borderline personality disorder; emotional dysregulation; psychobiological; hypothalamicpituitary-adrenal axis; autonomic nervous system
17.  Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders 
Translational Psychiatry  2014;4(5):e389-.
Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB−TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB−TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB−TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses.
doi:10.1038/tp.2014.26
PMCID: PMC4035720  PMID: 24802307
18.  Neural Correlates of Using Distancing to Regulate Emotional Responses to Social Situations 
Neuropsychologia  2010;48(6):1813-1822.
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.
doi:10.1016/j.neuropsychologia.2010.03.002
PMCID: PMC2905649  PMID: 20226799
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
19.  Hypersensitivity in Borderline Personality Disorder during Mindreading 
PLoS ONE  2012;7(8):e41650.
Background
One of the core symptoms of borderline personality disorder (BPD) is the instability in interpersonal relationships. This might be related to existent differences in mindreading between BPD patients and healthy individuals.
Methods
We examined the behavioural and neurophysiological (fMRI) responses of BPD patients and healthy controls (HC) during performance of the ‘Reading the Mind in the Eyes’ test (RMET).
Results
Mental state discrimination was significantly better and faster for affective eye gazes in BPD patients than in HC. At the neurophysiological level, this was manifested in a stronger activation of the amygdala and greater activity of the medial frontal gyrus, the left temporal pole and the middle temporal gyrus during affective eye gazes. In contrast, HC subjects showed a greater activation in the insula and the superior temporal gyri.
Conclusion
These findings indicate that BPD patients are highly vigilant to social stimuli, maybe because they resonate intuitively with mental states of others.
doi:10.1371/journal.pone.0041650
PMCID: PMC3411703  PMID: 22870240
20.  Enhanced ‘Reading the Mind in the Eyes’ in borderline personality disorder compared to healthy controls 
Psychological medicine  2009;39(12):1979-1988.
Background
Borderline personality disorder (BPD) is partly characterized by chronic instability in interpersonal relationships, which exacerbates other symptom dimensions of the disorder and can interfere with treatment engagement. Facial emotion recognition paradigms have been used to investigate the bases of interpersonal impairments in BPD, yielding mixed results. We sought to clarify and extend past findings by using the Reading the Mind in the Eyes Test (RMET), a measure of the capacity to discriminate the mental state of others from expressions in the eye region of the face.
Method
Thirty individuals diagnosed with BPD were compared to 25 healthy controls (HCs) on RMET performance. Participants were also assessed for depression severity, emotional state at the time of assessment, history of childhood abuse, and other Axis I and personality disorders (PDs).
Results
The BPD group performed significantly better than the HC group on the RMET, particularly for the Total Score and Neutral emotional valences. Effect sizes were in the large range for the Total Score and for Neutral RMET performance. The results could not be accounted for by demographics, co-occurring Axis I or II conditions, medication status, abuse history, or emotional state. However, depression severity partially mediated the relationship between RMET and BPD status.
Conclusions
Mental state discrimination based on the eye region of the face is enhanced in BPD. An enhanced sensitivity to the mental states of others may be a basis for the social impairments in BPD.
doi:10.1017/S003329170900600X
PMCID: PMC3427787  PMID: 19460187
Borderline personality disorder; depression; facial emotion recognition; mentalization; social cognition; theory of mind
21.  Striatal Activity in Borderline Personality Disorder with Comorbid Intermittent Explosive Disorder: Sex Differences 
Journal of psychiatric research  2012;46(6):797-804.
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.
doi:10.1016/j.jpsychires.2012.02.014
PMCID: PMC3645307  PMID: 22464337
Borderline personality disorder; intermittent explosive disorder; striatum; aggression; positron emission tomography
22.  GENETIC COVARIANCE STRUCTURE OF THE FOUR MAIN FEATURES OF BORDERLINE PERSONALITY DISORDER 
Journal of personality disorders  2010;24(4):427-444.
The patient population of borderline personality disorder (BPD) is heterogeneous; many different combinations of BPD symptoms can lead to a BPD diagnosis. We investigated to what extent the covariance among four main components of BPD is explained by shared genetic and environmental factors. Using an extended twin design, multivariate genetic models were applied to the scales of the PAI-BOR, a self-report questionnaire tapping four main features of BPD (affective instability, identity problems, negative relationships, and self-harm). Data on the four BPD scales were available for 5,533 twins and 1,202 siblings from the Netherlands, Belgium, and Australia. The correlations among the scales ranged from 0.23 to 0.50 and were best explained by a genetic common pathway model. This model specifies that genes and environment influence the covariance between four main features of BPD in qualitatively similar ways, through a single latent factor representing the BPD construct. The heritability of the latent BPD factor was 51% and the remainder of its variance was explained by unique environmental influences. For each BPD scale, except self-harm, around 50% of its variance was explained by the latent BPD factor. The remaining variance for each of the four scales was explained by genetic (4% for affective instability to 20% for self-harm) and environmental (38% for negative relationships to 67% for self-harm) factors that were specific to each scale.
doi:10.1521/pedi.2010.24.4.427
PMCID: PMC3705216  PMID: 20695804
23.  “Missing links” in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control 
Objective
Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD.
Methods
Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0–150 ms post stimulus) and late (250–500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance.
Results
Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity.
Conclusions
These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.
PMCID: PMC1449878  PMID: 16699604
brain; borderline personality disorder; cognition; electroencephalography; gamma synchrony
24.  Neural Activation During Facial Emotion Processing in Unmedicated Bipolar Depression, Euthymia, and Mania 
Biological psychiatry  2011;71(7):603-610.
Background
Studies incorporating direct comparisons across all phases of bipolar (BP) disorder are needed to elucidate the pathophysiology of bipolar disorder. However, functional neuroimaging studies that differentiate bipolar mood states from each other and from healthy subjects are few and have yielded inconsistent findings.
Methods
One hundred five unmedicated adults were recruited: 30 with current bipolar depression (BPD), 30 with current bipolar hypomania or mania (BPM), 15 bipolar euthymic (BPE), and 30 healthy control subjects (HC). All subjects were diagnosed with DSM-IV BP (type I or II) using a structured clinical interview. Groups were age- and gender-ratio matched. In 3T functional magnetic resonance imaging experiments, subjects completed a negative facial emotion matching task.
Results
Bipolar euthymic and BPD groups exhibited increased amygdala activation compared with HCs in response to the negative faces; however, in the BPM group, this increase was not seen. Conversely, both BPE and BPM groups had increased activation in the insula relative to HCs, but in the BPD group, this effect was not seen. All three BP groups exhibited increased activation of the putamen compared with HCs. In the cortical areas, the BPM group exhibited decreased left lateral orbitofrontal cortex activation compared with both BPEs and HCs, increased dorsal anterior cingulate cortex activation compared with the BPD group, and increased dorsolateral prefrontal cortical activation compared with all other groups.
Conclusions
Both state- and trait-related abnormalities in corticolimbic activation were seen in response to the negative facial emotion processing in a large sample of unmedicated adults across BP mood states.
doi:10.1016/j.biopsych.2011.10.038
PMCID: PMC3703667  PMID: 22206876
Bipolar disorder; depression; emotion processing; euthymia; fMRI; mania; MRI; neuroimaging
25.  Anger, preoccupied attachment, and domain disorganization in borderline personality disorder 
Emotional dysregulation and attachment insecurity have been reported in borderline personality disorder (BPD). Domain disorganization, evidenced in poor regulation of emotions and behaviors in relation to the demands of different social domains, may be a distinguishing feature of BPD. Understanding the interplay between these factors may be critical for identifying interacting processes in BPD and potential subtypes of BPD. Therefore, we examined the joint and interactive effects of anger, preoccupied attachment, and domain disorganization on BPD traits in clinical sample of 128 psychiatric patients. The results suggest that these factors contribute to BPD both independently and in interaction, even when controlling for other personality disorder traits and Axis I symptoms. In regression analyses, the interaction between anger and domain disorganization predicted BPD traits. In recursive partitioning analyses, two possible paths to BPD were identified: high anger combined with high domain disorganization and low anger combined with preoccupied attachment. These results may suggest possible subtypes of BPD or possible mechanisms by which BPD traits are established and maintained.
doi:10.1521/pedi.2009.23.3.240
PMCID: PMC2821703  PMID: 19538080

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