Jaime Wilsnack, MA

A. Hyperactivity of the amygdala and prefontal cortex is characteristic of patients with BPD.

B. Increased acetylcholine activity in the hippocampus and neocortex accounts for impulsive aggression in patients with BPD.

C. Treatment of BPD with oxytocin increases hypermentalization by decreasing activity in the prefrontal cortex. 

D. Use of emotion regulation strategies taught in DBT correlates with decreased activity in the amygdala.

E. fMRI studies show that affective, cognitive, behavioral, and interpersonal difficulties are inherited rather than BPD itself.

 Use of emotion regulation strategies taught in 

 (DBT) correlates with decreased activity in the amygdala.

 of functional MRI (fMRI) findings in persons with borderline personality disorder (BPD) revealed heightened activation during processing of negative emotional stimuli in the left amygdala, left hippocampus, and posterior cingulate cortex as well as diminished activation in prefrontal regions (including the dorsal lateral prefrontal cortex).

 in the insula and less activation in the subgenual anterior cingulate cortex in persons with BPD but did not find amygdala hyperactivity.

Conflicting amygdala results are believed to result from the medication status of research participants because psychoactive drugs attenuate limbic activity. Pharmacologic probes have also shown 

 in the anterior cingulate cortex and orbital frontal cortex in response to serotonergic challenge in impulsive-aggressive and affectively unstable BPD populations, and decreased coupling of resting metabolism between the orbital frontal cortex and the ventral anterior cingulate cortex has been reported.

amygdala hyperactivity at baseline, which correlated with changes in a measure of emotion regulation and increased use of emotion regulation strategies.

 Taken together, these findings highlight that dysfunctional circuits involving hyperactive limbic regions and hypoactive prefrontal modulation-most pronounced in the dorsal lateral prefrontal cortex-represent the anatomical corollaries to BPD.

The Neurobiology of Borderline Personality Disorder

Neural correlates of disturbed emotion processing in borderline personality disorder: a multimodal meta-analysis

2. Ruocco AC, Amirthavasagam S, Choi-Kain LW, McMain SF. 

Neural correlates of negative emotionality in borderline personality disorder: an activation-likelihood-estimation meta-analysis

3. New AS, Hazlett EAB, Buchsbaum AS, et al. 

Amygdala-prefrontal disconnection in borderline personality disorder

4. Goodman M, Carpenter D, Tang CY, et al. 

Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder

This quiz was originally published on February 13, 2017, and has since been updated. -Ed

Poll

What do functional magnetic resonance neuroimaging findings reveal about the neurobiology of borderline personality disorder? Take the quiz and learn more.

Mini Quiz: Neurobiology of Borderline Personality Disorder

Clarification of the molecular and biological underpinnings of borderline personality disorder (BPD) is imperative for a more thorough understanding of the disorder, one that anchors our quest for effective treatment. This article provides a brief overview of the neurobiology of BPD. Anatomical structures are reviewed as well as genetic and epigenetic factors that contribute to the pathophysiology and, potentially, to the treatment of this disorder.

Over the past decade, much of the literature concerning the biological basis of BPD has shifted to direct visualization of brain structure and function using neuroimaging. Most of the findings pertain to brain regions involved in emotional processing, such as the amygdala, insula, posterior cingulate cortex, hippocampus, anterior cingulate cortex, and prefrontal regulatory regions (

). These include the orbital frontal cortex, dorsal lateral prefrontal cortex, and ventral lateral prefrontal cortex.

. A meta-analysis of brain volume-which comprised 281 persons with BPD and 293 healthy controls-and 19 imaging studies noted left amygdala and right hippocampus gray volume decreases in persons with BPD.

 Volume studies in adolescent-onset BPD populations also exist but are limited by small sample size, discrepant imaging techniques, and highly comorbid presentations. They do not reproduce the volume differences reported in studies of adult BPD.

. A meta-analysis of functional MRI (fMRI) findings in persons with BPD revealed heightened activation during processing of negative emotional stimuli in the left amygdala, left hippocampus, and posterior cingulate cortex as well as diminished activation in prefrontal regions (including the dorsal lateral prefrontal cortex).

 Another meta-analysis showed heightened activity in the insula and less activation in the subgenual anterior cingulate cortex in persons with BPD but did not find amygdala hyperactivity.

Conflicting amygdala results are believed to result from the medication status of research participants because psychoactive drugs attenuate limbic activity. Pharmacologic probes have also shown decreased metabolic activity in the anterior cingulate cortex and orbital frontal cortex in response to serotonergic challenge in impulsive-aggressive and affectively unstable BPD populations, and decreased coupling of resting metabolism between the orbital frontal cortex and the ventral anterior cingulate cortex has been reported.

 (DBT) was found to attenuate amygdala hyperactivity at baseline, which correlated with changes in a measure of emotion regulation and increased use of emotion regulation strategies.

. Connectivity studies developed over the past 2 years introduced novel research strategies that heavily rely on fMRI. Connectivity can be described in terms of anatomical and functional connectivity. Diffusion tensor variables of mean diffusivity and fractional anisotropy are measures of white matter integrity and anatomical connections. While such work in BPD is in its infancy, initial data suggest that deficits in frontolimbic connections relate to the severity of symptoms such as affective instability, avoidance of abandonment, and anger.

Functional connectivity analyses provide information about which brain regions are co-activated and can be studied using seed-based correlations (most often with the amygdala and dorsal anterior cingulate cortex) and independent component analysis. The 3 networks most salient in BPD are:

• The default mode: a network activated when the brain is at rest in the absence of goal-directed activity; it is influenced by the medial prefrontal cortex and posterior cingulate cortex and is responsible for self-referential thinking

• The salience network, including the orbital frontal insula and the dorsal anterior cingulate cortex

• The medial temporal lobe network, which is responsible for processing negative emotions

In BPD, there are alterations in the connections between these 3 networks with particularly problematic connectivity between salience detection and self-referential encoding. This results in misidentification with neutral stimuli as well as a failure to integrate salience information with internal representations.

These networks can be mapped on fMRI, which shows dampening of the negative correlations between the dorsal anterior cingulate cortex and the posterior cingulate cortex as well as increased connectivity of the amygdala and rostral anterior cingulate cortex. Connectivity is also heightened between the amygdala and parahippocampus as well as the ventral anterior cingulate cortex and insula. In a study that examined neural correlates of emotional distraction, persons with BPD showed positive connectivity between the amygdala and prefrontal regions (right default mode prefrontal cortex and left dorsolateral prefrontal cortex).

Symptoms of BPD are typically categorized into 4 phenotypes-the “borderline sectors”-that coexist in varying degrees within individuals with BPD and, often, in their family members.

 The affective sector includes emotions that are characteristically challenging for patients with BPD. These include loneliness, emptiness, inappropriate and intense anger, and quick fluctuations in mood.

The interpersonal sector of BPD refers to these patients’ penchant for intense and volatile relationships and their tendency to be at once manipulative, entitled, and devaluing as well as dependent, idealizing, and fearful of abandonment.

 The cognitive sector encompasses distressing perceptual disturbances, including dissociation and paranoia during times of stress.

The behavioral sector of BPD describes risky, impulsive behaviors as well as self-injury and threats of self-harm common in this population.

It is thought that the phenotypic expression of each of these sectors represents a confluence of genetic and environmental influences.

 conducted a family study to investigate the degree to which BPD clustered within families as well as how much of this clustering was attributable to genetic predispositions for borderline sectors as opposed to the disorder itself. In their study, the prevalence of BPD among relatives of probands with BPD was 14.1% compared with 4.9% in the family members of controls. The relative risk that if one family member had BPD, so too would another was 3.9 (95% confidence interval, 1.7 - 9.0) when compared with controls. Aggregation of BPD in families occurred in this study more than aggregation of any of the sectors, which supports a common pathway model of inheritance. In this model, borderline traits concentrate in families because of a genetic predisposition for the disorder rather than for the sectors themselves.

While family studies provide convincing evidence that BPD is inherited, twin studies have been invaluable to the study of heritability, the phenotypic variance attributable to genetic rather than environmental influences. A 2011 web-based study looked at the heritability of the disorder using responses to well-validated personality questionnaires.

 Study participants included 542 same-sex twin pairs, 441 of whom were monozygotic. The 4 dimensions of BPD loaded as one factor and provided further support for the common pathway model used by Gunderson and colleagues.

 Findings from the study indicate a heritability of 60%. This is similar to other twin and extended twin studies that estimate heritability to fall somewhere between 40% and 70%.

Molecular genetic studies have focused on the rate-limiting enzyme in serotonin (5-hydroxytryptamine [5-HT]) synthesis, as well as 5-HT receptor and transporter genes. 5-HT derives from tryptophan through a process mediated by tryptophan hydroxylase. Tryptophan hydroxylase 2 (TPH2) is a neuron-specific enzyme responsible for producing 5-HT in the CNS. Single nucleotide polymorphism and haplotype analyses have revealed that a gene encoding a specific TPH2 isoform is associated with higher rates of anxiety, depression, and suicidal behavior.

 genotyped patients with BPD and compared them with patients who had other personality disorders and healthy controls. They found that the previously identified TPH2 risk haplotype was more prevalent in patients with BPD (P < .05) than in controls. Subjects with the TPH2 risk haplotype exhibited higher aggression and emotional lability scores and increased suicidal behavior.

Of the serotonin receptor genes, polymorphisms in 

 have been most closely correlated with BPD. Variants of the 5HT2A receptor are known to correlate with suicide, affective lability, and impulse control. 5HTR2A polymorphisms correlate with borderline traits.

 analyzed polymorphisms in serotonin receptor genes in patients with BPD and matched controls. Their results showed an association between BPD and the 

 gene. Moreover, subjects who were homozygous for the 

 genotype had a higher frequency of the TPH2 “risk” haplotype. Taken together, the data suggest that a TPH2 “risk” haplotype may change serotonin in a way that predisposes to BPD. Patients may be more susceptible to a specific variant of 5HTR2C, which may further contribute to the pathogenesis of BPD.

Genetic and epigenetic changes to the oxytocin system, especially the oxytocin receptor (

) gene on chromosome 3p25.3, are associated with the pathophysiology of BPD (

). Polymorphisms, genotypes, and haplotypes within this gene are variably linked with both aggressive and prosocial behaviors.

 allele are more likely to perceive others negatively, experience loneliness, and endorse subjective symptoms of psychological stress with correspondingly high cortisol and other stress-related biomarkers. Prosocial behaviors, such as empathy, confidence, and positivity, decrease.

Just as genetics may predispose an individual to the development of BPD, epigenetic changes are also likely to play a role. Epigenetic modifications influence gene expression without altering DNA sequences and are dynamically shaped through environmental factors (eg, trauma). Epigenetic modifications often occur via methylation of 5´-cytosine-phosphate-guanine-3´ (CpG) dinucleotide pairs. CpG methylation within the first 3 exons of the 

 gene reduces transcription of the OXTR protein, thereby diminishing the effects of oxytocin.

 The unavailability of OXT receptors may account for the unexpectedly low treatment response to oxytocin administration in patients with BPD.

Oxytocin is believed to regulate social cognition through the frontolimbic system, in which structural and functional differences have been identified in persons with BPD.

 In facial recognition studies, individuals with BPD are more likely to perceive negative and untrustworthy emotions, which suggests that oxytocin’s role in the salience network influences interpersonal hypersensitivity in BPD.

 Oxytocin is also involved in regulating the hypothalamic-pituitary-adrenal axis, helping to habituate the fear circuitry and extinguish the startle response in the face of previously emotionally charged stimuli. Lastly, oxytocin’s modulation of attachment and affiliative systems may influence the anger, impulsivity, and emotional lability exhibited by persons with BPD in response to perceived insult.

Three studies support the use of oxytocin in the treatment of BPD. Simeon and colleagues

 concluded that oxytocin moderately decreased stress reactivity, measured from subjective reports of dysphoria and objective measurements of plasma cortisol, in response to the Trier Social Stress Test. Bertsch and associates

 demonstrated that oxytocin decreased threat hypersensitivity, measured via eye fixation and amygdala activity, in response to angry faces. BrÃ¼ne and colleagues

 also found reduced attention and avoidant reactions to angry faces in subjects with BPD after oxytocin administration. Their data suggest that oxytocin administration may interfere with trust in patients with BPD, especially in those who have been exposed to trauma.

In addition to supplementary trials that directly examine the effects of oxytocin administration in patients with BPD and the influence of epigenetics on the oxytocin system, future research is warranted regarding oxytocin’s role as adjunctive treatment to current modalities. For example, oxytocin might be used to augment individual and group DBT by increasing social cognition while decreasing hypermentalization and interpersonal hypersensitivity.

Another potential area for research is oxytocin’s role in the prevention of BPD. It is possible that oxytocin can increase attachment and enhance psychosocial interventions among struggling parents, thereby mitigating maladaptive responses to childhood trauma.

During most of the 20th century, BPD was conceptualized in psychodynamic terms: a pattern of primitive defenses adaptive in aversive childhood experiences but increasingly maladaptive in adulthood. Despite the tremendous toll BPD takes on patients and society, its existence is frequently questioned and patients are stigmatized. Research clearly demonstrates that BPD evolves from a complex interaction between environmental, anatomical, functional, genetic, and epigenetic factors. There are many risk factors, and each one serves to strengthen the others.

To treat BPD more effectively, it helps to conceptualize the major symptoms as neuropsychiatric. fMRI findings have revealed tracking changes in connectivity between complex brain networks, and epigenetic research has shown that environment influences gene expression, perpetuating maladaptive cognitions and behaviors at the neurobiological level. While functional imaging and genetic studies are beginning to gain momentum, these preliminary findings await replication with larger sample sizes, longitudinal capacities, and more refined methodologies.

Drs Pier, Marin, and Goodman are psychiatrists at Icahn School of Medicine at Mount Sinai in New York. Dr Pier is a third-year resident, Dr Marin is a second-year resident, and Dr Goodman is Clinical Professor. Dr Goodman is also the Director of Dialectical Behavioral Therapy & Suicide Prevention Studies Clinical and Research Program at the James J. Peters Veterans Affairs Medical Center, and Mental Illness Research Education and Clinical Center (MIRECC), in Veterans Integrated Service Network (VISN) 3. Ms Wilsnack is a Research Coordinator for the VISN 3 MIRECC. The authors report no conflicts of interest concerning the subject matter of this article.

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There is more to BPD than meets the eye. A complex interaction exists between environmental, anatomical, functional, genetic, and epigenetic factors. 

Author | Jaime Wilsnack, MA

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