Neurobiological Mechanisms of Borderline Personality Disorder
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Borderline personality disorder is a severe mental disordercharacterized by variable combinations of complex symptoms such as affective instability, deficit in impulse control, lack of stable self-identity, and interpersonal dysfunction.[1] BPD is the most prevalent personality disorder affecting 0.7%-2.7% of the general adult population.[1] As a result of high rates of suicide attempts and self-mutilating acts, those with BPD make up 40% of all psychiatric inpatients.[1] Due to the spectrum of complex symptoms which characterize this disorder, it is difficult to identify a single organic marker that gives rise to BPD. Therefore diagnosis of BDP based on symptomology alone is unreliable as symptoms change over time and vary over individuals.[2] Understanding the neurobiological mechanisms and morphological changes in the brain that contribute to the borderline symptomology is pivotal for diagnosis and treatment options.

Neuroimaging studies have revealed structural changes in prefrontal regions, amygdala, and the hippocampus important for affective control. Dysfunctional serotonergic neurotransmission within these regions has been associated with impulsive aggression and instability in affect and behaviour. Regulatory responses of the hypothalamic-pituitary-adrenal systemare also shown to be altered.[2] Genetic studies have revealed that the interplay between specific genetic polymorphisms and the environment is important in the development of BPD.[3]


Brain_art_3.jpg 1.1 Symptomology and behavioral deviations from norm


Although the diagnosis of borderline personality disorder is complicated and multifactorial, it can be concisely summarized by one word: instability.[4] Individuals with BPD experience instability in identity, behaviour, mood, and relationships.[4] According to DSM-IV-TR diagnosis criteria, patients with BPD demonstrate an “instability of interpersonal relationships, self-image, and affects, and marked impulsivity beginning by early adulthood and present in a variety of contexts"[5] , and must also exhibit six out of the nine symptoms of: fear of abandonment, unstable interpersonal relationships, unstable self-image, self-damaging impulsivity, recurring suicidal or self-mutilating behaviours, affective instability, chronic feelings of worthlessness, erratic aggression, and transient dissociative symptoms.
[5] Because BPD is a heterogeneous construct and multiple combinations of hereditary and environmental factors can act together leading to its development, using the DSM-IV-TR diagnosis criteria is controversial. As a result it is critical to identify biological markers that give rise to the symptoms of BPD for improved diagnosis.

BPD is significantly more prevalent in women than men, and manifests in mid-to-late adolescence.[6] Identity disturbances in these individuals is a result of unclear focus for life goals, merging of own identity with someone’s else identity leading to dependency, and identifying self as “all good” or “all bad”.[6] As a result, their views of themselves can oscillate between extreme narcissism or severe self-criticism.[4] Abandonment fears may manifest due to early experiences of sexual abuse or parental negligence. There is also significant clinical comorbidity between BPD and other psychiatric disorders such as depression, schizotypal personality disorder, and post-traumatic stress disorder.[6]



[7]















Brain_art_2.jpg1.2 Abnormalities of and structural changes in brain structures and transmission systems


Neuroimaging studies have found a correlation between dysfunction of frontolimbic circuits and the disturbances of impulse control, affect and interpersonal relationships that characterize BDP. It has also been found that there is a relationship between the altered circuitry and altered structure of these implicated regions as variety of rodent models have suggested a morphological basis for the functional alterations found in BPD.[8] BPD symptomology has been postulated to be caused by prefrontal abnormalities and hyperactivity of the limbic system.[8]
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1.2a Abnormalities in the prefrontal cortex

external image si2047.jpgThe prefrontal cortex is the site of executive functions and top-down processing guided by internal states or intentions. Deficits in this region are often implicated with failed emotional regulation, interpersonal dysfunction, impulsive aggression, and disordered behaviour.[9] Affective dysregulation is a core symptom of BPD and has been associated with dysfunctions of the dorsomedial and ventrolateral prefrontal cortex, areas associated with voluntary control of emotions and reward processing.[9] When subjects in one study were asked to suppress their emotional response to sad images presented as stimuli, subjects with BPD exhibited lower levels of oxygenated hemoglobin in the dorsolateral prefrontal cortex relative to healthy subjects.[9] This raises the possibility that decreased activity in the dorsolateral prefrontal cortex is a biological substrate for the symptom of emotional vulnerability displayed in individuals with BPD, which results in a combination of sensitivity to emotional stimuli and unusually strong reactions they have difficulty suppressing.[9]


BPD_1.jpgAbnormalities in the medial prefrontal cortex may be associated with another hallmark symptom of BPD: interpersonal dysfunction.[10] The mPFC is critical for a variety of social-cognitivefunctions such as managing social and interpersonal interactions. One neuroimaging study has found that under situations of social exclusion, subjects with BPD exhibited an increased mPFC relative to the healthy control subjects.[10] In another study, induced oxygenation of this region resulted in feelings of rejections and abandonment fears.[10] This suggests that alterations in the activity of the mPFC may be associated with the symptom of interpersonal dysfunction and fears of abandonment found in BPD.[10]


Impulsive aggression in BPD patients has been implicated with hypometabolism in the medial orbital frontal cortex leading to reduced serotonergic activity.[11] Within the PFC, the medial orbital frontal cortex receives input from limbic structuressuch as the amygdala and the hippocampus.[11] This region regulates many social behaviours such as recognizing social cues, identifying emotional expression of others (especially aggression), violations of social behaviour, and decision making.[11] Animal models show that lesions to this area or dysfunction of its serotonergic function results in disinhibition of socially inappropriate behaviours.[12] As a result, characteristics such as impulsivity and impulsive aggression may be modulated by altered metabolic processes in the medial orbital frontal cortex.[12] Neuroimaging of BPD subjects reveal a decreased rate of metabolism in the orbitofrontal cortex, which indicates a possible inverse correlation with the symptom of impulsive aggression.[11]


1.2b Abnormalities in the hippocampus and amygdala

BPD_3.jpgThe amygdala is important for mediating a range of social and emotional processes such as the fear processing, evaluation of potentially threatening situations, and the generation of negative emotional states.[13] Neuroimaging studies in BPD subjects have shown an increased amygdala activation, which may help to explain the greater emotional reactivity of BPD individuals.[14] The hippocampus, which plays an important role in learning and memory consolidation, is also implicated with BPD. Volumetric brain studies reveal decreased amygdala and hippocampus volumes than average in BPD patients with early history of traumatic experiences occurring between the ages of two and eleven.[15] Increased levels of cortisol under highly stressful conditions, such as early childhood sexual or physical abuse, may contribute to the emergence of this abnormality.[16] Hyper-glucocorticoid levels induced by stress in an animal study had shown to have neurodegenerative effects on the hippocampus causing neuronal death in the CA1 region and apical dendritic atrophy in the CA3 region.[17] Hence, it is postulated that decreased volumes of the amygdala and hippocampus in BPD subjects impair retrieval and processing of childhood traumatic experiences facilitating a self-protective response.[16]


1.2c Abnormalities in the anterior cingulate cortex

Structural abnormalities in the anterior cingulate cortex may contribute to the psychopathology of borderline personality disorder (BPD). The anterior cingulate cortex is essential for processing emotional information and the regulation of affective responses.[18] Lesion studies have shown that individuals with lesions to the ACC show abnormal autonomic responses to emotional stimuli and show an inability to experience emotions in a normally emotion-inducing setting. Because BPD individuals show comparable symptoms, volumetric studies have found that there is an association between ACC volume and BPD symptomology, such that patients with smaller gray and white matter volume of the ACC exhibited greater BPD symptomology.[17] Positron emission tomography(PET) imaging revealed that healthy subjects had greater glucose metabolism in the ACC relative to subjects with BPD.[18] A likely explanation for these results may be that ACC structural abnormalities and dysfunction is related to emotional dysregulation and reduced cognitive control observed in BPD subjects.[1]


Brain_art_3.jpg 1.3 Neuroendocrine abnormalities of the hypothalamic-pituitary-adrenocortical axis


The hypothalamic-pituitary-adrenal axis is a major coordinator of both the behavioural and physiological responses to stress. Under stress-inducing situations, corticotropin-releasing factor (CRF) is released from the hypothalamus and is transported to the anterior pituitary where it stimulates the release of adrenocorticotropin hormone (ACTH), which in turn stimulates the synthesis and secretion of glucocorticoids from the adrenal cortex.[19] A negative-feedback response by circulating glucocorticoids targets the pituitary, hypothalamus, and hippocampus to turn the axis off to regulate the HPA axis and the stress response.[19]

[19]
BPD_2.jpgHormones from the hypothalamic-pituitary-adrenal axis play an important role in the regulation of brain areas associated with emotional regulation, response inhibition, and decision making, especially prefrontal cortex, the hippocampus, the amygdala, and the anterior cingulate cortex.[20] Some studies suggest BPD is characterized by an enhanced cortisol release and a reduced feedback sensitivity under basal conditions resulting in a hyperactive HPA axis; however evidence for this is variable and inconsistent.[20] It is also suggested BPD is a heterogeneous disorder with at least two subgroups of BPD patients with different endocrine patterns: one group is predominately characterized by trauma-associated symptoms and another subgroup with symptoms associated with mood disturbances.[20] It was found that patients who had suffered an early traumatic event such as childhood abuse exhibited post-traumatic stress disorder-related symptoms and showed decreased levels of glucocorticoid receptor mRNA, which indicates an association of reduced negative feedback with affective dysregulation. [19]
These patients also exhibited hippocampal atrophy as a result of the greater levels of glucocorticoids released by the unregulated hyperactive HPA axis.[19] Patients with mood disturbances as core symptoms revealed HPA axis dysfunction in the form of enhanced cortisol release and reduced feedback sensitivity. In both cases, dysregulated cortisol levels causes damaging effects on the brain.[19]

Brain_art_3.jpg1.4 Heredity and specific gene polymorphisms


A high occurrence of borderline personality disorder in identical (∼35%) than in fraternal (∼7%) twins, and a higher frequency in biological than in adoptive relatives suggest the possibility of hereditary transmission of this disorder. However, the evidence for hereditary transmission is still unclear. To better understand the development of and genetic influences on BPD, it is critical to study the specific symptoms within the disorder, and the associations between these symptoms and genetic variants influencing the chemistry of the brain.

1.4a Polymorphisms of the DRD2 and DRD4 dopamine receptor genes

Dopamine dysfunction has been associated with BPD symptoms. Genetics studies have shown a correlation between certain polymorphisms of the dopamine receptor, particularly variants in the DRD4 and DRD2 genes, and BPD trait of impulsive self-mutilating behaviour in a sample of young BPD patients.[21] Dopamine transporter gene, DAT1, on chromosome 5 regulates dopaminergic neurotransmission and functions to rapidly reuptake dopamine neurotransmitters present in the synaptic cleft.[22] A particular 9-repeat polymorphism of this gene has been identified as a risk factor for BPD.[22]

1.4b Polymorphisms of 5-HTT serotonin transporter gene

Variants of the 5-HTT serotonin transporter gene have been implicated with emotional and social behaviour.[23] Particularly serotonin transporter gene polymorphism 5-HTTLPR of the 5-HTT gene has been associated as a risk factor for the development of affective disorders.[23] The presence of one or two short copies of 5-HTTLPR is correlated with reduced expression and function of the serotonin transporter protein, and increased behaviour related to fear and anxiety.[23] When two short copies of this gene polymorphism is present, an increased vulnerability to depressive symptoms under stress is exhibited along with increased cortisol production.[23] It is possible that this variant of the 5-HTT serotonin transporter gene may be a risk factor for the development of BPD as individuals with BPD exhibits symptoms that are characteristic for serotonin dysfunction.[23] In one study, BPD patients were genotyped in the 5-HTTLPR polymorphism and were asked to report on their borderline-specific symptoms.[23] The results show: “carriers of two short alleles of the 5-HTTLPR reported more symptoms of borderline, depression, anxiety and obsessive-compulsivebehaviours compared to carriers of a long allele”.[23] This indicates that the presence of two short 5-HTTLPR copies may be correlated with serotonin functions that impact borderline-specific traits such as affective dysregulation and anxiety.

Brain_art_3.jpg1.5 Environmental risk factors


Brain_Art_5.jpgMost research support the hypothesis that the etiology of BPD is multifactorial and various environmental factors contribute to the development of this disorder.[1] Studies have found a correlation between BPD diagnosis and a history of childhood sexual abuse, physical abuse, parental alcoholism, and emotional and physical neglect.[24] In comparison to other psychiatric disorders, diagnosis for BPD is the highest among patients with a history of childhood abuse.[24] The high incidence of sexual abuse reported in BPD patients raise the issue of whether BPD represents a form of post-traumatic stress disorder.

A significant number of BPD patients report being raised in deranged family environments such as foster homes, adoption, domestic violence in family, lack of emotional support, and parental negligence.[24] Susceptibility to BPD may be caused by fetal, perinatal or postnatal brain damage, as some studies report complications during pregnancy, premature birth, major childhood illness, or organic brain lesions.[24] According to most studies, trauma between the ages of 0-5 is most important contributing factor than events occurring later in life. Having a first degree relative with BPD, such as mother or father is also identified as an important risk factor of BPD.[24]
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