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Review                                                                                                                                        Open Access

## Neurobiological Findings in Youth with Borderline Personality Disorder

Romuald Brunner 1* , Romy Henze 1,2 , Julia Richter 1,2 , Michael Kaess 1

1 Section for Disorders of Personality Development, Clinic for Child and Adolescent Psychiatry, University of Heidelberg, Heidelberg, Germany 2 Department of Radiology, German Cancer Research Center, Heidelberg, Germany

*Corresponding author: romuald.brunner@med.uni-heidelberg.de

## Abstract

This  review  summarizes  recent  neurobiological  research  into  youth  with  borderline  personality  disorder  (BPD)  to  better delineate  the  biological  factors  involved  in  the  development  of  this  disorder.  Psychobiological  studies  when  BPD  first becomes  manifest  are  of  particular  interest,  because  there  are  fewer  confounding  factors  (e.g.,  duration  of  illness,  drug abuse,  medication,  other  therapeutic  interventions)  at  this  time.  This  article  focuses  on  recent  findings  in  the  field  of neuroimaging, neuropsychology, neuroendocrinology, genetics, and pain perception, and it aims to integrate these findings in a developmental psychopathology model of BPD. In studies of clinical samples of adults with BPD, structural imaging studies revealed abnormalities predominantly in the frontolimbic areas. Disturbances in emotional information processingparticularly involving negative stimuli-may mediate affective dysregulation as a core feature of BPD. Genetic studies could reveal  that  the  stability  of  BPD  traits  in  youth  is  largely  influenced  by  a  combination  of  genetic  and  non-shared environmental factors. Hyporesponsiveness to a laboratory stressor indicates an enduring alteration of the hypothalamicpituitary-adrenal axis. Findings of a higher pain threshold indicate that pain processing is already disturbed during the early stages  of  BPD,  which  could  contribute  to  the  initiation  or  maintenance  of  self-injurious  behavior.  All  biological  factors, together with environmental risk factors, may contribute to the core symptoms of BPD: severe emotional and behavioral dysregulation.  Further  research  should  investigate  the  development  of  BPD  in  youth  by  using  longitudinal  designs  to determine whether the neurobiological factors are a cause, an effect, or an epiphenomenon of BPD.

Keywords: borderline  personality  disorder;  adolescents,  developmental  pathways;  neurobiology;  neuroimaging;  genetics; pain perception; neuroendocrinology; neuropsychology

## Introduction

Although neurobiological aspects of borderline personality disorder (BPD) in adulthood have been the  subject  of  scientific  interest  during  the  last  15 years,  few  studies  of  BPD  in  youth  using  a  basic neuroscience approach have been conducted so far. The  delay  of  research  activities  involving  BPD  in this age group may be the result of a longstanding controversy surrounding the diagnosis of personality  disorders  in  adolescents  (1).  However, recent  evidence  has  clearly  demonstrated  that  the diagnosis  of  BPD  is  as  reliable  and  valid  during adolescence  as  it  is  during  adulthood  (1,2).  Thus, the  proposed International Classification of Diseases, 11th Revision, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, have recently confirmed the legitimacy of the diagnosis of BPD in adolescents (3,4).

Neurobiological studies of BPD in clinical samples of adolescents and young  adults have focused  mainly  on  structural  morphological  brain alterations and changes in the neuroendocrine system (5). Such psychobiological studies conducted when BPD first becomes manifest are of particular interest.  At  this  stage  of  the  process  of  BPD development,  there  are  fewer  confounding  factors (e.g.,  duration  of  illness,  drug  abuse,  medication, other therapeutic interventions) that can cause morphological  changes  or  alterations  in  the  stress response system, and this is particularly relevant for identifying biological vulnerabilities (6,7). This review summarizes findings from studies that have included young people between 14 and 24 years of age.

## Genetics

Only  moderate  influence  has  been  attributed  to genetics  in  the  etiology  of  BPD  (8).  It  has  been suggested that genetic vulnerability is more likely to be linked to certain factors of temperament, such as negative  emotionality,  impulsivity,  and  introversion (8). In accordance with the psychobiological model of temperament and character developed by Cloninger (9), a temperamental constellation of high novelty seeking and high harm avoidance has been considered to be prototypical  for  BPD  during adulthood  (9). It has been  suggested  that this specific temperamental profile reflects an 'approach-avoidance'  conflict  that  may  affect  the affective  instability  feature of  BPD  (9).  This BPDspecific temperamental pattern that comprises these opposing  temperamental  traits  was  recently  found in a clinical sample of adolescents  with  BPD compared  with  clinical  and  healthy  controls  (10). This finding was in accordance with those obtained from samples of adults with BPD (11).

In particular, serotonergic and dopaminergic genes  have  been  found  to  be  associated  with  the temperamental  dimensions  of  novelty  seeking  and harm avoidance (12). Genetic polymorphisms have also  been  found  to  be  closely  linked  to  different temperamental traits. Therefore, altered synthesis of the biogenic amines may contribute to the configuration  of  temperamental  factors,  which  in turn  could  form  the  basis  for  specific  reactions  to stress and for the development of a psychopathological condition. The clinically apparent  coincidence  of  externalizing  symptoms and internalizing symptoms  is characteristic of adolescents with BPD,  and  it may  reflect the underlying  temperamental  factors  of  BPD  (10). Recently, a neuroimaging study found a relationship between rightward  hippocampal  asymmetry  and temperamental  factors  in  adolescents  with  BPD traits, which emphasizes the importance of considering interactions between biological and temperamental factors (13).

A  genetic  study  in  adults  with  BPD  provided evidence  that  both  gene-environment  interaction and gene-environment correlation contribute to the development  of  BPD  (14).  Another  study  found that the  stability  of  borderline  personality  traits appears to be significantly influenced by a combination  of  genetic  and  environmental  (nonshared)  factors  from  mid  to  late  adolescence  (15). However, at a later age (24 years), the influences of shared  environmental  factors  (e.g.,  socioeconomic status, parent-child relationships, peer-group relationships) were not significant. Thus, the stability  of  borderline  symptoms  over  the  study period  appeared  to  be  primarily  influenced  by  a combination  of  genetic  and  non-shared  environmental  factors.  This  finding  suggests  that  older adolescents play a more active role in selecting the environments  and  determining  the  social  relationships that influence their behavior.

Studies of candidate genes in the serotonergic and dopaminergic systems have not yielded any convincing  empirical  or  sufficiently  reliable  results (16). A single study of adolescents postulated that a specific gene polymorphism (i.e., the short allele of the  serotonin  transporter  gene,  5-HTTLPR)  was  a risk  factor  for  the  development  of  BPD  (17).  In  a nationally representative birth cohort of 1116 pairs of  same-sex  twins,  a  highly  significant  interaction was  found  between  harsh  treatment  in  the  family environment and BPD-related characteristics measured at the age of 12 years (18). This association  demonstrated  environmental  mediation and  was  stronger  among  children  with  a  family history of psychiatric illness, thereby indicating that inherited and environmental risk factors make independent  and  interactive  contributions  to  the etiology  of  BPD  (18).  This  means  that  individuals with a 'sensitive' genotype may be at greater risk of developing BPD in the presence of a predisposing environment. In addition, genes that influence BPD characteristics  also  increase  the  likelihood  of  being exposed to certain adverse life events (19).

Although a recent meta-analysis revealed an estimated heritability of approximately 40% on the basis of familial and twin studies, association studies demonstrated  no  significant  relationship  for  the serotonin transporter gene, the tryptophan hydrolase 1 gene, or the serotonin 1 B receptor gene (20).  Against  the  background  of  this  discrepancy, the authors suggested that both positive and negative  life  events  may  interact  with  'plasticity' genes  rather  than  the  'vulnerability'  genes  that contribute to the pathogenesis of BPD (20).

## Neuroimaging

Functional imaging studies have replicated the evidence of altered  neural mechanisms of emotion processing,  and  morphological  changes  in  adult patients with BPD have been found as well (21). In addition to the often replicated finding of hyperactivity  of  the  limbic  system,  imaging  studies showed simultaneous deactivation of prefrontal structures  that  are  associated  with  the  ability  to control  emotions,  thus  supporting  the  model  of frontolimbic dysfunction in patients  with  BPD (22,23). This model suggests that a reduced cognitive  ability  to  control  (top-down  regulation  is reduced)  in  combination  with  pronounced  limbic activation  (bottom-up  reactivity  is  increased)  may lead to an impaired ability to regulate emotions. It is assumed  that  this  dysfunction  is  the  basis  for  the imbalance between behavioral and affective regulation. Experimental  studies with functional imaging methods in youth have not been published so far. However,  only  a few studies of brain morphology among youth with BPD exist.

## Structural brain imaging

In adults with BPD, alterations in the frontal lobe, the anterior cingulate cortex, the amygdala, and the hippocampus  have  been  repeatedly  identified  (21). A recently published meta-analysis provided information  about  the  role  of  the  insula  in  adults with BPD  (24). The authors described a link between hyperarousal and negatively valenced emotional  stimuli, which  may  be  the  result of heightened activity in the insular cortex. Alterations of the insula have not been identified in adolescents with BPD. Neuroanatomical changes in adult subjects with BPD are probably caused not only by neuroanatomical correlates of the disorder itself but also by confounding factors (e.g., long-term medication  use,  the  chronicity  of  the  disorder). However, the findings of a recent study suggest that modest  volume  reductions  of  the  amygdala  and hippocampus bilaterally among individuals BPD are not influenced by illness state or comorbid psychopathology  (25).  These  changes  have  been repeatedly found in adults with BPD, but they have rarely been identified in adolescents with the disorder.

Nevertheless,  examining  adolescents  with  BPD provides  a  unique  opportunity  to  identify  cerebral alterations that represent neuroanatomical correlates of  the  disorder,  because  confounding  factors  are minimized during the early stages of BPD.

## Volumetric and morphometric studies

Several  volumetric  and  morphometric studies  have examined  adolescents  with  BPD  to  identify  brain alterations that occur during the early stages of the disorder. As compared with healthy controls, decreases  in  the  gray  matter  volume  of  the  right orbitofrontal cortex (7) and the left anterior cingulate  cortex  (26)  as  well  as  a  shorter  adhesio interthalamica  have  been  found  among  individuals with  BPD  (27).  Another  study  found  a  smaller volume of the left caudal superior temporal gyrus in individuals  with  BPD  who had violent  episodes  as compared with those without violent episodes (28). Goodman  and  colleagues  (29)  detected  a  reduced gray matter volume in the anterior cingulate cortex of  adolescents  with  BPD  and  comorbid  major depressive disorder as compared with healthy adolescents.  Brunner  and  colleagues  (6)  examined adolescents with BPD and compared them to both healthy controls and adolescents with other psychiatric diagnoses. Among individuals with BPD as  compared with healthy controls, the researchers found decreased gray matter density in the dorsolateral  prefrontal  cortex  bilaterally  and  in  the left  orbitofrontal  cortex.  In  adolescents  with  other psychiatric disorders as compared  with healthy control  individuals,  the  researchers  identified  gray matter decreases in the right dorsolateral prefrontal cortex,  which  demonstrated  that  frontal  alterations are not specific to BPD.

In  contrast  with  the  well-replicated  finding  of volumetric alterations in the amygdala  and  the hippocampus among adults with BPD (21), volume differences  in  adolescent  patients  with  BPD  were thought  to  be  restricted  to  the  aforementioned neuroanatomical structures (6,7,26,29). Only recently were differences in the hippocampus bilaterally and the right amygdala found in adolescents  with  BPD  as  compared  with  a  clinical group  and  a  healthy  control  group  using  a  very sensitive  method  to  assess  subcortical  structures (30).  However,  these  differences  were  not  specific for  BPD.  Investigating  whether  adolescents  with BPD  had  alterations  in  cortical  thickness-which together  with  the  cortical  surface  area  determines the  volume  of  gray  matter  (31,32)-did  not  reveal any differences in the BPD group as compared with a clinical group and a healthy control group (30).

Structural brain differences have also been found to be associated with childhood maltreatment (33). Because  a  history  of  a  broad  range  of  adverse childhood  experiences  have  been  found  in  both adults (34) and youth with BPD (16), this raises the question of whether these early adverse life experiences may also be linked to the neuroanatomical changes seen in patients with BPD.  So  far,  no  imaging  studies  involving  young patients  with  BPD  have  investigated  the  effect  of prior exposure to early life stressors on  brain anatomy.

Although the findings among children who have experienced childhood maltreatment were inconsistent  with  respect  to  differences  in  their prefrontal cortices, reduced corpus callosum volume  was  found  in  several  studies  (35).  Adults who experienced childhood maltreatment had reduced gray matter volume in the prefrontal cortex, the anterior cingulate cortex, the hippocampus, and the cerebellum (36-38). These findings may correspond with similar neuroanatomical findings in adult  patients  with  BPD.  The  discrepancies  in  the imaging findings between adults and younger people may be caused by variations in developmental timing, the age at the time of measurement, or the plasticity of the brain (39-41). A  recent  study  of  young  adults  with  a  history  of maltreatment revealed the potential for the decreased centrality of the brain regions involved in emotional regulation and internal emotional perception;  this  may  contribute  to  the  risk  for  the development of borderline pathology (42).

## Diffusion tensor imaging studies

Two  diffusion  tensor  imaging  studies  examined adolescents with BPD. Both research groups used a combination of tractography and tract-based spatial statistics. New and colleagues (43) found decreased fractional  anisotropy  in  the  inferior  longitudinal fasciculus  bilaterally,  in  the  uncinate,  and  in  the occipitofrontal  fasciculus  in  patients  with  BPD  as compared  with  healthy  controls.  Maier-Hein  and colleagues (44) identified decreased fractional anisotropy in the fornices of patients with BPD as compared  with  clinical  controls;  they  also  found significant  BPD-specific  white-matter  alterations  in the  long  association  bundles  interconnecting  the heteromodal association cortex and in the connections between the thalamus and hippocampus.  Because  parts  of  the  heteromodal association cortex are also related to emotion recognition,  it  was  concluded  that  deficits  in  both emotion regulation and recognition may simultaneously contribute to the disorder (44). These findings suggest that a large-scale network of emotion processing is disrupted, which goes beyond an isolated frontolimbic disconnectivity hypothesis.

## Other radiological and nuclear medicine techniques

To  the knowledge of the authors, no studies involving  the  use  of  computed  tomography  (CT), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or single-photon emission computed tomography (SPECT) have examined adolescents with BPD.

## Neuropsychology

A recent review of neurocognitive profiles in adults with  BPD  reported  inconsistent  findings.  There  is an ongoing debate as to whether a general impairment or a selective deficit  of  neurocognitive function  is  related  to  BPD  (45).  Higher  executive functions have been considered to be crucial determinants of self-regulation (46), and deficits in these areas have been linked to the phenomenology of increased impulsivity and to both self-destructive and aggressive behaviors, which are characteristic of patients with BPD. It has been argued that patients with  BPD  may  particularly  display  deficits  when performing tasks that require controlled information processing (cognitive flexibility); an impairment in 'controlled cognitive processes' may underlie  the  impulsive  and  uncontrolled  behavior associated  with  this  disorder  (47).  Some  studies  of adult samples with BPD have replicated alterations in higher executive functions, which include cognitive  flexibility  and  non-verbal  functions  such as  visual  memory  performance  and  visuospatial abilities (48-53). The  only  meta-analysis in this research area suggested the possibility of widespread neuropsychological  deficits  in  adult  patients  with BPD, particularly with regard to global dimensions of  planning  and  visuospatial  abilities  (54).  So  far, there has only been one study of young school-aged children with borderline pathology that has suggested impaired cognitive flexibility early during the course of BPD (55).

With regard to alterations in emotional information processing, a meta-analysis (56) of studies of facial emotion processing found disturbances in emotion recognition and discrimination, which may contribute to interpersonal difficulties among patients with BPD (57). A further selective  meta-analysis  (58)  determined  that  these individuals had difficulty recognizing specific negative emotions on faces; this corresponded partly with experimental studies in youth with BPD by  focusing  on  possible  alterations  in  emotional information  processing  (59-61).  A  prior  study  of adolescent patients with BPD  demonstrated a stronger orientation toward negative emotional stimuli  (i.e.,  the  dot-probe  paradigm)  as  compared with  healthy  control  subjects  (61).  This  finding could  not  be  replicated  in  another  study  using  the face  morph task  (59)  in  a  sample  of  young  people (15 to 24 years old) with BPD features in whom no evidence  of  a  heightened  sensitivity  to  emotional facial  expressions  was  found.  In  another  study, Jovev and colleagues (62) found an attentional bias toward  fearful  faces  that  reflected  difficulty  with disengaging attention from threatening information during preconscious stages of attention  among youth  with  features  of  BPD.  In  the  study  by  von Ceumern  and  colleagues  (60),  it  was  of  particular interest that adolescent patients with BPD were not able to disengage their attention from negative facial expressions during attentional maintenance when in a negative mood. The increase in narrowing attention  to  negative  emotional  stimuli  while  in  a negative mood may indicate that functional strategies to  regulate  emotions are absent  (60). On the basis of this finding, the development of therapeutic strategies aimed at changing the focus of attention  when  in  a  negative  mood  may  help  to disrupt the vicious cycle of escalating negative emotions (60).

Further neuropsychological studies of BPD during adolescence found evidence of disturbances with  regard  to  taking  a  social  perspective  (63-65).

Jennings  and  colleagues  (63)  found  an  impaired capacity to differentiate and integrate the perspective  of  self  with  the  perspectives  of  others (i.e., the social perspective  coordination  model) among youth with BPD as compared with a group of  patients  with  major  depressive  disorder.  With respect to the theory of mind concept (i.e., 'mentalizing'),  Sharp  and  colleagues  (64)  found that  adolescents  with  BPD  features  demonstrated an  overinterpretive  mental  state  reasoning  rather than impairment in the theory of mind capacity per se. In line with this finding, a psychometric study of a population-based sample of adolescents demonstrated  a  prospective  relationship  between the avoidance of internal states and BPD features in a short-term follow-up investigation. A recent study of decision making and reward behavior revealed a preference for immediate gratification and a tendency  to  discount  longer-term  rewards  among youth with BPD (66); this finding was not independent of the extent of the impulsivity trait. A study  of  social  cognition  involving  the  Cyberball paradigm revealed no differences between a group of youth with BPD and healthy controls with regard to emotional response and regulation, although the respondents  reported  a  higher  extent  of  negative emotions  when  they  were  confronted  with  this interpersonal rejection experiment (67).

## Endocrinology

Clinically,  adolescents  with  BPD  seem  to  suffer from  increased stress reactivity,  which  may  be closely  related  to  aggressive  and  auto-aggressive behavior  (16).  The  idea  of  stress  vulnerability  in BPD led to the investigation of both the autonomic nervous system (ANS) and the hypothalamicpituitary-adrenal axis.

Experimental studies involving the use of a laboratory  stress  paradigm  (i.e.,  the  Trier  Social Stress  Test)  demonstrated  an  attenuated  cortisol response to an acute psychosocial stressor in both adult  patients  (68)  and  in  a  group  of  adolescent patients engaged in repetitive self-injurious behavior; this group included a significant percentage of patients (43%)  who  fulfilled the diagnostic  criteria  for  BPD  (69).  In  addition,  an imaging study found increased pituitary gland volumes  in  a  group  of  adolescent  patients  and young  adult  patients  with  BPD  who  frequently engaged in self-injurious behaviors (70), which may indicate increased basal activity of the hypothalamic-pituitary-adrenal axis. Because the experience of early chronic stress has been linked to a pattern of hypothalamic-pituitary-adrenal  axis hyperresponsiveness  during  early  life,  a  switch  to hyporesponsiveness of central cortisol release, peripheral  cortisol  release,  or  both  may  take  place later in life (71).

Studies  of  ANS  reactivity  among  young  people with  BPD  are  not  yet  available.  Studies  of  adults investigated ANS indicators such as skin conductance, heart rate, and the startle reflex; however, they revealed contradictory findings. Although the study by Herpertz and colleagues (22) involved no evidence of autonomic hyperarousal or enhanced  startle reaction, the  study  by  EbnerPriemer and colleagues (72) discovered a significantly reduced startle response in a subgroup of patients with  BPD  and a high degree of dissociative  symptoms.  This  finding  supports  the corticolimbic  disconnection  model  of  dissociation, which  suggest  that  dissociation  is  related  to  the inhibited  processing  of  stress  in  the  limbic  system and  the  concomitant  dampened  reactivity  of  the ANS (73).

## Pain perception

Because  frequent  self-injurious  behavior  is  highly associated with BPD,  the  question of whether altered pain perception contributes to the initiation or maintenance of these symptoms in patients with BPD was investigated (74). Significantly higher pain thresholds have been reported for both adult patients (75) and adolescent patients (76) with BPD. No  differences  from  healthy  subjects  were  found with regard to thermal detection thresholds or indices for alterations of somatosensory functioning. The extent of general psychopathology or dissociative symptoms did not correlate with pain sensitivity in the sample of adolescent patients with BPD  (76).  This  finding  supports  the  assumption that disturbed pain processing is not a consequence of  a  chronic  course  of  illness  but  rather  that  it  is already present when BPD  becomes manifest. However, a strong tendency for pain thresholds to normalize  was  found  in  adult  patients  with  BPD who  had  stopped  their  self-injurious  behavior  as compared  with  patients  who  still  engaged  in  selfinjurious behavior (77). These findings would argue against an enduring and hereditary alteration of pain perception. Reduced pain sensitivity may also be a consequence  of  chronic  stress  experience  rather than  an  adaptive  effect related to self-injurious behavior (76).

A functional imaging study of adult patients with BPD demonstrated evidence of the dysfunction of the affective-motivational component of pain perception,  with  intact  sensory  discrimination  (78). No  group  differences  were  found  with  regard  to intensity  and  quality;  however,  the  deactivation  of the anterior cingulate cortex and the amygdala was associated with simultaneous activation of the dorsolateral prefrontal cortex (78).  The  authors Primary Etiologic Factors Sequela III

Environment unable to adequately cope with

"emotionality" (e.g. inflexible caregiver, early trauma)

Biological predisposition to "emotionality"

(genes and neurophysiology)

concluded that reduced activity in these brain areas may reflect the neglect of painful stimuli in patients with BPD (78).

It  has  also  been  discussed  that  reduced  pain sensitivity may  be a side effect of an altered endogenous  opioid  system,  because  stress-induced analgesia  (79)  and  changes  in  beta-endorphin  and metekephalin levels in the cerebrospinal fluid could be  found  in  adult  patients  with  BPD  (79).  No studies of the endogenous opioid systems of youth with BPD have been conducted so far.

Disruption of

hippocampal

function Difficulty ignoring task-irrelevant affective stimuli

## Conclusion

As  a  result  of  the  lack  of  longitudinal  studies,  it remains unclear whether the reported neurobiological  findings  are  a  cause,  an  effect,  or  an epiphenomenon  of  BPD  (16).  Despite  the  lack  of longitudinal studies, recent advances  have  been made  in  neurobiological  research  into  youth  with BPD, as outlined in the present article.

emotional

Limited access

to effective

social support

FIGURE 1. A develonmental osvchonathology model of borderline personality disorder. From Putnam KM. Silk KR: Emotion

FIGURE 1. A developmental psychopathology model of borderline personality disorder. From Putnam KM, Silk KR: Emotion dysregulation and the development of borderline personality disorder. Dev Psychopathol 17:899-925, 2005

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Note. OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex

Nonetheless, empirical research addressing the development  of  BPD  is  still  limited,  and  it  seems rather  early  to  create  a  comprehensive  developmental model for the genesis of BPD in youth. The proposed  biosocial  model  of  the  development  of BPD,  as  outlined  by  Linehan  and  coworkers  (80), has the potential to expand our current understanding of the etiology of the disorder, and it may stimulate future research and contribute to the deduction  of  treatment  concepts.  In  this  model, early  vulnerability-including specific temperamental patterns-forms the basis of heightened impulsivity  and  emotional  sensitivity,  which  will further  lead  to  the  core  symptoms  of  extreme emotional,  behavioral,  and  cognitive  dysregulation when  interacting  with  environmental  risk  factors such as abuse, neglect, or severe invalidation.

The findings  of  the  current  review  are  in  partial accordance with the proposed model. The structural brain differences that especially involve the orbitofrontal  and  dorsolateral  areas  in  adolescents and  young  adults  with  BPD  may  be  related  to heightened impulsivity as well as impaired cognitive control over the emotions. Studies of brain connectivity  among  adolescents  with  BPD  have demonstrated alterations in brain networks that are important for both emotional regulation and emotional perception (44). Alterations in emotional information processing, especially when in a negative mood, may  further contribute to the

(e.g. substance use,

self-harm)

characteristic interpersonal difficulties. Psychophysiological studies have reported the hyporeactivity  of  a  specific  biological  stress  response system (i.e., cortisol reactivity) that has been found to be related to increased adverse stress reactions in human experiments (81). However, studies of ANS reactivity have been inconclusive, and further studies  are  needed  to  delineate  possible  psychophysiological indices.

To summarize, BPD  is a severe and often debilitating  psychiatric  disorder  that  can  become manifest during adolescence. To enhance our understanding of this condition's development, increased research efforts in the field of neuroscience are urgently required. A better understanding  of  the  developmental  pathways  of BPD may consequently provide essential suggestions for improving early detection and intervention for youth with BPD. Future biological studies should focus on the core features of BPD: affective  dysregulation,  dysfunctional  self-concepts, and  difficulties  with  social  interaction  domains.  A combination  of  methods  that  includes  new  basic science approaches and the assessment of environmental interactions appears to be necessary to clarify the etiology of BPD. The field may benefit from  recent  studies  of  the  impact  of  childhood adversity  on  the  developing  brain,  especially  by investigating the associated possible disturbances of the brain network architecture (42) and the biological stress response systems (19,82). The etiopathogenic model of BPD  as outlined by Putnam  and  Silk  (83)  (Figure  1) illustrates the potential interactions among  biological,  psychological, and social factors in the genesis of BPD and identifies  various  areas  and  indicators  for  further investigation.  To  enhance  our  understanding  of these areas and their interactions, an interdisciplinary approach that includes a wide range of clinical research as well as basic neuroscience research is mandatory.

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