The Neurobiology of Empathy in Borderline Personality Disorder

Curr Psychiatry Rep (2013) 15:344 DOI 10.1007/s11920-012-0344-1 PERSONALITY DISORDERS (C SCHMAHL, SECTION EDITOR) The Neurobiology of Empathy in Borderline Personality Disorder Luis H. Ripoll & Rebekah Snyder & Howard Steele & Larry J. Siever Published online: 7 February 2013 # Springer Science+Business Media New York 2013 Abstract We present a neurobiological model of empathic dysfunction in borderline personality disorder (BPD) to guide future empirical research. Empathy is a necessary component of interpersonal functioning, involving two distinct, parallel neural networks. One form of empathic processing relies on shared representations (SR) of others’ mental states, while the other is associated with explicit mental state attribution (MSA). SR processing is visceral and automatic, contributing to attunement, but also emotional contagion. MSA processing contributes to deliberate, perspectival forms of empathic understanding. Empathic dysfunction in BPD may involve hyper-reactivity of SR networks and impairment of MSA networks. Nevertheless, this empathic dysfunction is subtle, but contributes to interpersonal difficulties. Interaction between genetic factors and traumatic attachment stressors may contribute to development of BPD, with painful attachment insecurity and This article is part of the Topical Collection on Personality Disorders L. H. Ripoll (*) : L. J. Siever Department of Psychiatry One Gustave L. Levy Place, Mount Sinai School of Medicine, Box 1230, New York, NY 10029, USA e-mail: Luis.ripoll@mssm.edu L. H. Ripoll New York Psychoanalytic Institute, New York, NY, USA R. Snyder Department of Psychology, Barnard College, Columbia University, New York, NY, USA H. Steele Department of Psychology, New School for Social Research, New York, NY, USA L. J. Siever James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), Bronx, NY, USA disorganization affecting SR and MSA network functioning. Future avenues for BPD research will include developmental assessment of attachment and neurobiological functioning under varying conditions. Keywords Borderline personality disorder . BPD . Personality; Empathy . Attachment theory . Social cognition . Aggression . Social affectivity . Neuropeptides . Neurobiology . Psychiatry Introduction Empathy is the ability to understand others’ mental states, with reference to guiding future interpersonal behavior [1, 2•]. In early childhood, empathy involves visceral recognition of mental states without fully understanding implications or regulating affective consequences [3, 4•, 5], relying on neuronal representation of others’ feelings as they are experienced in the self. The result is similarity in neural activation while both experiencing and observing others experiencing mental states. This processing involves shared representations (SR) of mental states. Owing to similarity in neuronal representations of self and other, such automatic mirroring risks distress in response to others’ distress. SR processing persists, although further neural development supplements it. Thus, deliberate empathic processing, characterized by explicit mental state attribution (MSA), progresses beyond reflexive SR processing to incorporate perspective and context in reflective interpersonal narratives. Empathic processing entails parallel, dissociable networks with variable relative activity. Refractory symptoms of borderline personality disorder (BPD) include affective instability and interpersonal dysfunction [6]. BPD symptoms may result from neurobiological predisposition to persistent, excessive SR-based attunement and impairment in MSA-based, empathic 344, Page 2 of 11 deliberation. Patients suffer from interpersonal hypersensitivity [7], contributing to affectivity, impulsivity , social dysfunction , aggression, and suicidality [8–11]. Projections between SR networks and limbic or reward processing regions may influence evaluations of social threat. During interpersonal stress, dysfunctional empathic processing may contribute to symptoms and fluctuation between idealization and distrust. Across theoretical orientations, BPD is defined by severe disturbances in mentalizing about self and other [12, 13]. Severe BPD symptoms occur in the context of social threat [7, 10, 11, 13, 14], contributing to transient episodes of paranoia, erotomania, or dissociation; relationships marked by projective identification and conflicted dependency; emptiness and identity diffusion; and impulsive suicidality or aggression [8, 12, 13]. Increasing research documents interactions between genetic and developmental risk factors for interpersonal dysfunction and BPD [7, 15•], but specific neurobiological effects remain unclear. In particular, the present model may assist in devising neurobiological assessments, predicting individuals at risk for BPD and response of refractory symptoms to therapeutic intervention. Corroborative research shows SR processing during laboratory tasks focused on patients’ automatic recognition of others’ pain, disgust, or basic sensorimotoric intentions. Tasks associated with MSA research have focused primarily on deliberate evaluation of more complex emotions and intentions. BPD patients likely engage in SR processing to greater extent and MSA processing to lesser extent than individuals without personality disorders (see Tables 1 and 2) [16•, 17•, 18–22]. Improving empathic deliberation has become a focus of evidencebased psychotherapy for BPD [23, 24]. A neurobiological model of empathic processing may assist in understanding mechanisms of action of treatments. Despite extensive theoretical literature, relevant empirical research on empathy in BPD remains limited. The present neurobiological model offers potential to bridge future empirical research with past theory. Affective symptoms concerning intolerance of aloneness and conflicted dependency are aspects of BPD that are least likely to remit [6], likely perpetuated by empathic dysfunction. By improving adaptive regulation of empathic processing, particularly during social threat, treatments may better target refractory symptoms. Tracking effects of interventions upon neurobiological functioning could elucidate specific mechanisms to improve interpersonal resilience. Genetic, neurocognitive, and developmental risk factors are associated with the etiology of BPD [7, 15•, 25]. Multiple genetic factors interact with attachment stressors over the course of development, resulting in attachment insecurity and disorganization [15•]. It remains unclear whether similar gene-by-environment interactions specifically cause Curr Psychiatry Rep (2013) 15:344 maladaptive regulation of empathic networks. Naturalistic functional neuroimaging paradigms [2•, 16•, 18, 22, 26] are needed to capture real-life interpersonal functioning, to understand the effects of genes and development on empathic processing. In the context of genetic polymorphisms associated with altered neuropeptide signaling, early experiences of attachment insecurity may disrupt functional connectivity of empathic networks. In securely-attached individuals, a gradual shift from SR- to MSA-based empathic processing occurs over the lifespan. By contrast, the inability to produce organized, hopeful evaluations of relationships defines attachment insecurity associated with BPD [13, 27, 28]. With genetic predisposition, attachment stressors may contribute to SR hyper-reactivity and MSA impairment, neuropeptide dysregulation, painful attachment insecurity, and refractory symptoms (see Fig. 1). Empathy Successful interpersonal functioning requires social cue recognition, understanding context, and affect regulation [1, 29]. Empathy is defined as perceivers’ ability to understand mental states in targets to thus guide interpersonal behavior. Empathic accuracy leads to prosocial behavior and genuine empathic concern [2•], but may decrease owing to psychopathology. We distinguish two neural processes underlying empathy. SR processing relies on visceral identification of mental states via commonality in neural activation in both social targets and perceivers. Thus, perceivers observing social targets experiencing pain or disgust, performing simple, goal-directed actions, producing emotional facial expressions, and experiencing non-painful touch engage similar limbic, paralimbic, or sensorimotor neural systems activated when perceivers themselves experience these phenomena [2•, 30]. ‘Mirror neuron’ research describes SR processing as embodied simulation, with neural representations of others’ mental states as experienced viscerally in the self (see Table 1). MSA research focuses on perceivers’ explicit judgments of social targets’ intentions, thoughts, or feelings. Temporal and parietal regions mediate shifts in perspective, and medial prefrontal regions integrate semantic, contextual, and sensory data [2•, 30–32]. In comparison to SR processing, MSA networks are slower, explicit, and capable of inferential abstraction [2•, 30, 32, 33]. MSA processing is responsible for serial adjustment of visceral, SR-based attunement [34], predicting others’ behavior, and preventing shortsighted decisions [35]. MSA processing is also required for deliberate, self-relevant evaluation [31, 32], depending on the extent of inference and abstraction needed (see Table 2) [36–38]. Curr Psychiatry Rep (2013) 15:344 Page 3 of 11, 344 Table 1 Borderline personality disorder (BPD) and the shared representation (SR) network-visceral, automatic attunement Brain region Nonclinical findings BPD findings Amygdala Results: perceivers observe targets posing facial affect, resulting in similar activation in targets experiencing and perceivers observing emotional facial expressions [2•, 30] Hyper-reactivity in BPD in perception of affective arousal for positive and negative valence [17•, 21], aggression provocation [22], during attempts at psychological distancing [19]; lack of habituation associated with limitations in subjective perception of social support (Ripoll and New, unpublished data) Some question role of amygdala hyper-reactivity in BPD, particularly when pooling studies of negative valence stimuli [57] Deficiency associated with impaired regulation of affect in BPD [21] Function in detection of affective salience, basic affective processing, and facial affect recognition Anterior dingulate Anterior insula Inferior parietal lobe Inferior frontal gyrus Results: perceivers observe others experiencing pain, resulting in similar activation in targets experiencing and perceivers observing pain, covarying with severity of pain in others [2•, 30] Functions in regulation of pain and possibly other affective extremes, and regulating the affect of others’ pain on self Results: perceivers observe targets’ faces or behavior while experiencing pain or disgust, resulting in similar activation in targets experiencing and perceivers observing these states [2•, 30] Functions in monitoring visceral experiences of pain and disgust in self and others, though distinct subregions of anterior and posterior insula may subserve different functions Results: perceivers observe others experiencing non-painful touch, resulting in similar activation during perceivers’ observation and targets’ experience of touch [2•, 30] Results: perceivers observe others performing simple motor tasks, gestures, or facial expressions, resulting in similar activation during perceivers’ observation and targets’ experience of action and facial expression intentionality [2•, 30] Greater automaticity or deliberation in empathy is associated with varying implementation of SR and MSA networks, respectively [33]. Functional connectivity of MSA networks predicts adaptive empathic concern for others’ pain, indicative of a protective role in regulating whether others’ distress heightens personal distress [39]. Extreme, SR-based emotional contagion involves maladaptive attunement to others’ distressing affect, leading to personal distress and autonomic arousal [1]. By contrast, perspectivetaking distinguishes between mental states in self and other, requiring functional MSA circuitry and inhibition of SR reactivity. Intimacy and social threat may bias empathic processing, influencing perspective-taking or emotional contagion. BPD patients’ interpersonal hypersensitivity [7] may fundamentally affect perceptions of social threat, resulting in attunement and contagion without perspective. When confronted with either nonverbal or abstract contextual cues whose content conflicts with other social Despite SR hyper-reactivity in other regions, deficient activation in BPD may indicate a more specific role primarily in affect-regulation rather than empathic understanding Hyper-reactive in BPD during affective empathy task [16•], indicative of heightened visceral empathic processing of salient social stimuli Dysfunction associated with inability of BPD patients to coax cooperation [18], although unclear whether consisted in insula hyper-reactivity during fair offers (especially given BPD patients insula hyper-reactivity during general negative affective processing [57]) or hypoactivation to unfair offers based on paradigm Limited findings in BPD may indicate involvement only in basic empathic processing of sensorimotor intention Limited findings in BPD may indicate involvement only in basic empathic processing of sensorimotor intention information, healthy subjects demonstrate biased recruitment of SR or MSA circuits, respectively [40]. This demonstrates normative capacity for differential modulation of empathic networks in order to understand aspects of the interpersonal environment. Greater SR processing yields heightened attention to nonverbal empathic cues, but reliance on MSA processing yields contextualized empathic judgments. Owing to empathic network dysregulation, BPD patients may automatically attend to nonverbal cues of questionable significance, remaining unable to engage in contextualized empathic deliberation. BPD Psychopathology BPD patients engage in concrete mentalizing, impulsive judgments , dissociative lapses [23], and have difficulty integrating multimodal, socially-relevant information [41]. 344, Page 4 of 11 Curr Psychiatry Rep (2013) 15:344 Table 2 Borderline personality disorder (BPD) and the mental state attribution (MSA) network-deliberate empathic inference Brain region Nonclinical findings BPD findings Posterior cingulate/precuneus Results: activated when perceivers are asked to explicitly evaluate targets in vignettes or their associated visual or verbal social cues, when comparing first- to third-person perspectives, and when projecting the self into the future or other circumstances [2•, 30, 31] Activation associated with explicit mentalizing, perspective-taking, processing self-relevance, and mental prospection or navigation Results: activated when perceivers are asked to explicitly infer targets’ mental states from complex cues, evaluate those considered self-similar [37] or about versions of the self closer in time [36], or when projecting the self into other situations [31, 35] Activation associated with accuracy of explicit empathic inferences, processing self-relevance. One of two regions most commonly involved in perspectival inhibition of mirroring [2•, 13, 30, 91] During psychological distancing from affective stimuli, BPD subjects demonstrate higher activation [19], though relative lack of results specific to BPD may indicate role in basic processing of spatial perspective Medial prefrontal cortex Temporo-parietal junction Superior temporal sulcus Results: activated when perceivers are asked to infer whether targets have false or true beliefs, evaluate targets’ familiarity to the perceiver, explicitly infer mental states from cues, or projecting the self into the future or other situations [13, 31, 91] Activation associated with accuracy of explicit empathic inferences, processing self-relevance. One of two regions most commonly involved in perspectival inhibition of mirroring [13, 91] Results: activated when perceivers are asked to evaluate complex, socially meaningful actions by targets, perform explicit attributions of targets’ mental states [2•, 30] Activation associated with accuracy of explicit empathic inferences, processing self-relevance Identity disturbance, impulsive aggression, affective instability, and transient paranoia [8, 12] are often exacerbated by interpersonal stressors, and empathic dysfunction may perpetuate this pattern. A neurobiological model of empathic dysfunction is crucial to future research on BPD psychopathology. In non-clinical subjects, social exclusion and induced loneliness motivate perceptions of purposelessness [42], decrease general cognitive abilities [43], activate ventral striatal appetitive regions, and inhibit MSA networks during empathic processing [44]. BPD may involve similar, more intense or persistent experiences of perceived exclusion, differentially affecting social reward, cognition, and empathic processing. A persistent experience of interpersonal hypersensitivity [7] and intrapsychic pain [45, 46], associated with attachment insecurity [8, 12–14, 47], contributes to severe interpersonal dysfunction in BPD. Decreased in BPD during regulation of provoked aggression [22], possibly indicating role in selfrelevant reflection or efforts to infer other’s intentions, as means to regulate aggressive impulses When paradigms do not allow opportunity for behavioral response, rejection may provoke mPFC hyperactivation [26], emphasizing need to distinguish empathic understanding from pure affect regulation. Lack of findings in BPD may indicate a basic role in distinguishing self and other, establishing perspective Decreased activity in BPD during deliberate empathic processing [16•, 20] During efforts at psychological distancing from affective stimuli, BPD subjects demonstrate higher activation [19], emphasizing need to distinguish empathic understanding from affect regulation Known to relate to affect regulation [28], neurobiological effects of attachment insecurity in BPD remain unclear. Preliminary evidence suggests an association between attachment insecurity, rejection sensitivity, or fearfulness of abandonment on the one hand, and dysregulation of empathic circuitry on the other [26, 48–50]. Painful attachment insecurity may alter empathic processing through aberrant perceptions of social threat. During interpersonal contexts posing this risk, empathic network dysregulation may contribute to a vicious cycle perpetuating BPD symptoms via heightened SR-based attunement and less MSA-based deliberation. BPD patients demonstrate heightened affective empathy and impaired cognitive empathy [51], likely corollaries of SR hyper-reactivity and MSA impairment. They show subtle impairment in recognizing others’ intentions in everyday social interactions, correlated with intrusiveness of traumatic symptoms [52]. Enduring aspects of attachment insecurity Curr Psychiatry Rep (2013) 15:344 Fig. 1 A neurobiological model of empathic dysfunction in borderline personality disorder (BPD). Genetic risk factors (i.e., monoamine and neuropeptide genetic polymorphisms) interact with developmental risk factors (i.e., maladaptive caregiving, abuse, neglect, attachment trauma), leading to attachment insecurity and intrapsychic pain. The epigenetic mechanism of interaction deserves further research. Intrapsychic pain and attachment insecurity may be associated with dysregulation of endogenous opioids and oxytocin, contributing to dysregulation of empathic networks during ambiguous or stressful interpersonal contexts, such as rejection or perceived abandonment. Resultant empathic dysfunction contributes to impulsive, aggressive, affective, and interpersonal BPD symptoms, conferring greater risk for interpersonal stressors and ultimately resulting in a chaotic, vicious cycle perpetuating refractory affective and interpersonal symptoms painfully intrude upon empathic processing. BPD patients show greater SR activation and lesser MSA recruitment in response to increasing task complexity [20]. In comparing tasks designed to elicit automatic affective judgments with those prompting empathic deliberation, BPD subjects show SR hyper-reactivity and psychophysiologic arousal compared to controls on the former, but recruit MSA regions less on the latter, again correlated with intrusive severity of BPD [16•]. In laboratory empathy paradigms, BPD patients show subtle dysfunction primarily under conditions of heightened social threat, ambiguity, or stimulus complexity. BPD subjects demonstrate difficulty integrating stimuli of multiple sensory modalities, associated with suspiciousness [41]. Impairment in facial affect recognition is evident primarily for neutral faces, with impairment also associated with anger or disgust [53•]. Thus, meta-analytic scrutiny highlights empathic dysfunction associated with conditions of ambiguity or social threat. Otherwise, BPD patients perform as well as or better than controls in the static Reading the Mind in the Eyes Test [54] and another affect recognition task involving Morphed Faces [55]. In more syntactically complex theory of mind tasks, they show little impairment in affective theory of mind and inconsistent evidence for impairment in cognitive theory of mind [51, 56]. Unlike autistic or schizophrenia spectrum patients, BPD patients’ empathic Page 5 of 11, 344 dysfunction may only manifest during specific circumstances of ambiguity, complexity, or social threat [13, 53•]. The result is impairment in deliberate, cognitive empathy and reliance on automatic, affective empathy. Individual variability within BPD may depend on varying task conditions. Not all BPD patients engage in the same type of empathic processing at all times. Mentalizationbased therapy identifies ‘psychic equivalence modes’ plagued by concrete errors in mentalizing, as well as ‘pretend modes’ involving hyperactive mentalizing and maladaptive abstraction [23], each implemented to a varying degree depending on context. Thus, although some neuroimaging paradigms identify hypoactivation of medial prefrontal (MSA) regions, others show hyperactivation in response to rejection, at least prior to judgment or interpersonal response [26]. Despite aforementioned evidence of SR hyper-reactivity, BPD patients’ neural responses to negative valence stimuli of various types include amygdala [57] or anterior cingulate hypoactivation [21]. Nevertheless, when evaluating positive or negative, interpersonal stimuli, BPD patients show amygdala hyper-reactivity and lack of habituation [17•]. Amygdala hyper-reactivity is also evident during aggression provocation [22] and efforts at psychological distancing [22]. Greater research attention is needed to parse how differing levels of social salience and arousal differentially affect empathic processing, and potential differences in processing depending on the extent to which tasks implicate affect-regulation versus empathic understanding. Aggression Greater rejection sensitivity motivates increasing needs for control or belonging and aggressive responses to rejection [58]. BPD severity correlates with rejection sensitivity, but capacity for effortful behavioral control is protective [59]. Provoked aggression necessarily involves implicit or explicit empathic processing to recognize provocation as such. Rejection-sensitive BPD patients may show SR hyperreactivity or impairment in regions associated with deliberation or control, resulting in malevolent bias and aggressive responses. In BPD, impulsive aggression likely results from aberrant mentalizing and rejection sensitivity. Rejection sensitivity is associated with vulnerability to attentional disruption by social threat [60]. Individuals with higher social belonging needs demonstrate greater attention to nonverbal affective cues, but lower empathic accuracy after rejection [61]. This combination of heightened attunement to nonverbal cues and impaired accuracy may reflect SR hyper-reactivity. SR processing may be implicitly employed to protect BPD patients from potential exclusion via attunement to nonverbal cues suggesting social threat. Nevertheless, reliance on 344, Page 6 of 11 SR processing also contributes to decreased accuracy and impulsive aggression. Similarly, preoccupied attachment classification (associated with BPD) heightens propensity towards violence towards intimate partners specifically during instances of partner withdrawal [62]. BPD patients produce more hostile evaluations of naturalistic interpersonal interactions [63–65] and more readily recognize anger in ambiguous facial stimuli [66]. This malevolent bias suggests attunement to cues of otherwise questionable significance driven by SR hyper-reactivity. This may be employed as protective vigilance, but also contributes to paranoia or aggression. Thus, SR hyper-reactivity and MSA hypoactivity correlate with BPD patients’ inability to control impulsive aggression in response to experimental provocation [22]. BPD patients either repeatedly imagine hostility that is not actually present or perceive hostile cues that others ignore. Generally, either interpretation may be a consequence of SR hyper-reactivity, and whether empathic dysfunction results in malevolent bias versus heightened attunement could always be explained by an opposite ‘bias’ in healthy individuals’ neglecting social threat. Future research will focus on differential effects of social threat on attentional disruption or paradigms designed with subtly controlled variations in degree of threat content. Social Affectivity Adolescent BPD patients show nonspecific difficulty in disengaging visual attention from negative facial expressions [67]. Overall, facial affect recognition research shows that BPD subjects perform worst in identifying neutral affect, attributing neutral faces with emotions not actually present, but also demonstrate difficulty with angry and disgusted faces [53•]. Anger and disgust constitute potential social threat, and may specifically recruit SR networks designed to detect basic, salient stimuli. Although controlled SR processing results in vigilant attunement, SR hyper-reactivity in BPD may ultimately diminish empathic accuracy for ambiguous or arousing stimuli conveying social threat. BPD subjects implicitly react to social exclusion with greater, other-focused negative affect and less frequent, positive affect than healthy individuals [68], perhaps explained by effects of intrapsychic pain on mentalizing [45]. This is prominent in patients with histories of abuse or neglect [69], contributing to implicit shame [14, 70], aversive tension, and dissociation [71]. Intrapsychic pain may result from interactions between genetic risk factors and attachment stressors, contributing to attachment insecurity and dysregulation of empathic networks. Empathic network dysfunction during social exclusion may thereby contribute to negative affectivity. Curr Psychiatry Rep (2013) 15:344 Owing to painful attachment insecurity, BPD patients are highly alexithymic, unable to describe their own affect in social situations [72]. BPD patients demonstrate exaggerated psychophysiological indicators of arousal and amygdala hyper-reactivity in response to social stimuli (of positive or negative valence) on the one hand, and blunted subjective appraisal of these stimuli on the other [17•, 19, 21]. They also show lack of psychophysiological and amygdala habituation in response to repeated social affective stimuli, which correlates with deficient ratings of tangibility of social support (Ripoll and New, unpublished data). Thus, BPD patients’ SR hyper-reactivity in response to social affect likely affects their subjective appraisal of tangible support. Empathic network dysregulation also affects trust and cooperation. BPD patients demonstrate differential neural activity in SR regions during iterative economic exchange games requiring cooperation [18], remaining unable to detect adverse monetary offers and subsequently coax cooperation. In this paradigm, BPD subjects do not show insula (SR) hyper-reactivity, but lack the normative decrease in insula activity associated with higher offers. Lacking variation in insula activity during the appraisal of offers’ potential for cooperative reward discourages subsequent cooperation and indicates pervasive distrust. In BPD, insula hyper-reactivity is also associated with processing negative valence stimuli [57]. Without facial affective cues from putative partners during cooperation games, BPD patients rate their own behavior as unfair, whenever partners provide adverse offers [73]. Similarly, BPD patients experience selfreproach and rupture of cooperation when confronted with ambiguity in relationships. Both phenomena indicate impairment in empathic deliberation and appraisal of social reward. Theoretical descriptions of BPD patients’ reliance on projective identification are consistent with developmental failure to recruit MSA circuitry to perspectivally distinguish self and other, and an ongoing reliance on SR-based attunement. MSA impairment and SR hyper-reactivity may also be associated indirectly with identity diffusion, dissociation, and chaotic idealization and devaluation. The present model suggests that dysregulated empathic networks may contribute to tumultuous appraisal of self and other in ambiguous, threatening, or intimate contexts. Neuropeptides BPD patients demonstrate subtly dysfunctional empathic processing, otherwise remaining exquisitely attuned to others’ mental states. A threshold for dysregulation may be associated with abiding intrapsychic pain and attachment insecurity, set by complex interactions between genetics and early attachment experiences [7, 15•]. In BPD, this Curr Psychiatry Rep (2013) 15:344 may result in dysregulation of empathic networks, leading to protective vigilance for potential social threat, but overall empathic dysfunction. We hypothesize that dynamic dysregulation of these networks, experienced as ongoing intrapsychic pain, may be mediated by aberrant neuropeptide signaling. Reflection on romantic or maternal significant others activates appetitive reward brain regions, rich in opioid and oxytocin receptors, and concomitantly deactivates circuitry that overlaps heavily with MSA networks [5, 74]. With greater intimacy, SR processing heightens at the expense of MSA processing, while imagining others experiencing pain [75]. Intimacy and social reward affect empathic processing, perhaps owing to heightened potential for social threat. This may adversely affect empathic processing via oxytocin- and opioid-responsive neuromodulation reaching a pathological extreme in BPD, with persistent SR hyperreactivity and MSA impairment. Relationships may thereby be evaluated as closely attuned but brittle, or intrusively malevolent. Neuropeptides may regulate MSA and SR activity according to specific contexts and levels of potential intimacy or social reward [15•, 45, 76]. Developmental experience promoting attachment insecurity may interfere with empathic network regulation by influencing endogenous opioid or oxytocin neurotransmission. As a result of neuropeptide dysregulation, BPD patients reflexively implement SR networks and remain unable to engage in MSA-based deliberation. Endogenous opioid signaling is associated with consummatory reward, affiliative behavior, and regulation of physical pain [77]. At baseline, BPD patients evidence decreased physical pain sensitivity, contrasting with heightened intrapsychic pain [45]. Moreover, opioid dysregulation, particularly in SR and reward processing regions, is associated specifically with affective instability in BPD [46]. Moreover, BPD subjects demonstrate diminished opioid tone at baseline and dysregulation with sadness induction. Opioid dysregulation may account for links between interpersonal dysfunction and impulsive self-injury in BPD [45]. In BPD subjects, experimental application of pain results in downregulation of SR regions otherwise hyper-reactive to affective stimuli [78]. In parallel and consistent with many possible psychological functions subserved by self-injury [79], neurobiologically, self-injury may thus dampen intrapsychic pain and SR hyper-reactivity. Oxytocin coordinates affiliative behavior, mediates trust, and regulates stress [80]. Exogenous administration increases biases in moral decision-making, benefiting those considered similar to oneself and derogating those considered dissimilar [81, 82] and motivating prosocial behavior towards the former [83]. Oxytocin improves empathic accuracy in individuals with autistic symptoms [84] and heightens Page 7 of 11, 344 positive recollections of maternal attachment figures in individuals reporting less attachment anxiety, while those reporting high attachment anxiety remember their mothers as less caring when given oxytocin [85]. Effects of oxytocin on parental aggression or altruism are similarly moderated by parents’ own history of supportive caregiving [86, 87]. Oxytocin administration attenuates social stress-induced dysphoria in BPD patients reporting childhood trauma, lower selfesteem, and attachment insecurity [88]. Nevertheless, BPD patients administered oxytocin cooperate less during an economic exchange game, an effect driven by attachment anxiety [89]. Oxytocin may increase intimacy and diminish arousal, but also decrease empathic deliberation, diminishing negative affectivity while paradoxically exacerbating interpersonal dysfunction. Limited, conflicting, evidence exists for oxytocin or opioid medications as treatment of BPD. Differences in attachment history and other personality and situational differences moderate effects of oxytocin [76]. Patients’ clinical response to opioid administration may also differ depending on genetic, developmental, or situational factors, as well as past exposure to opioids. Clinical use of neuropeptides is further complicated by the complexity and potential trade-off of concomitantly altering social reward processing and empathic accuracy. Future neuropeptide research must combine several methodologies to further characterize empathy and interpersonal functioning in BPD: assessment of attachment and genetic factors, experimental administration of neuropeptides or manipulation of social threat, and imaging of neuropeptide signaling. Developmental Neurobiology BPD is a result of interactions between genetics and environment [7, 15•]. Functional impairment in synthetic neurobiological systems may serve as predisposition, interacting with adverse early experiences to yield attachment insecurity and metacognitive impairment [25]. Behavioral [3] and neurobiological evidence [90] indicates an early role for SR processing in infant empathic processing. Reciprocal coregulation of arousal by parent and infant ideally build upon SR-based mirroring with increasingly symbolic reflection [3, 5]. The ability to inhibit imitative behavior is associated with effective empathic deliberation [91], and inhibition of SR networks may be necessary for MSA recruitment. Perspectival decoupling of neural representations of self and others, and homeostatic affect regulation are necessary in order to progress beyond reflexive attunement [92, 93] to develop coherent empathic concern [94]. SR activity decreases from childhood to middle age in response to observations of others’ experiences of pain, with changes in insula activation 344, Page 8 of 11 further indicating shifts from visceral to abstract empathic processing [4•]. Age-related increases in activation of prefrontal MSA regions [4•, 95] are associated with increasing social abstraction. As a likely result of interactions between genetic and neurocognitive factors with early caregiving experiences [7, 15•, 25], attachment insecurity prospectively influences the capacity for empathic understanding [96]. Without basic security in early attachment relationships, empathy may be limited to SR hyper-reactivity, implemented as attunement for potential social threat. BPD may involve developmental failure of progression to MSA processing. Preoccupied and disorganized attachment classifications are prevalent in BPD [47], along with lower reflective functioning [27], the focus of both mentalization-based [23] and transference-focused psychotherapies [24]. Insecure attachment may reflect dysfunctional neuropeptide signaling and empathic network dysregulation. Adverse influences of development upon empathic processing also indicate potential for therapeutic neuroplasticity in empathic networks. Healthy individuals who develop expertise in alleviating pain eventually increase MSA and inhibit SR processing while viewing painful stimuli [97]. Training in emotional reappraisal similarly decreases SR and increases MSA activity, tempering affective responses [98]. BPD subjects continue to demonstrate SR hyper-reactivity and MSA impairment despite such training [19]. Given the success of psychotherapy in treating BPD [99, 100], fostering mentalization or skills-based learning through psychotherapy and the psychotherapeutic relationship may improve interpersonal functioning by improving adaptive regulation of empathic networks. The most empirically effective psychotherapeutic interventions in this process remain unclear for BPD. Curr Psychiatry Rep (2013) 15:344 The value of this model lies in its potential ability to explain clinical phenomena associated with BPD, bridging gaps between theory and empirical research. It may inspire testable hypotheses for a more comprehensive understanding of BPD. Future neurobiological research will assess the impact of attachment classification, developmental history, and genetics on the functional neurobiology of empathic networks. Ideally, prospective research will distinguish the respective roles of genetics, trauma, and neurocognitive dysfunction in contributing to empathic dysfunction. Careful study of empathic network connectivity across the lifespan could assist in predicting BPD or defining prognostic factors. Neuroimaging research should include naturalistic paradigms similar to real-life interpersonal experience, as a complement to basic, laboratory tasks isolating components of social cognition [2•, 30]. Empathic dysfunction may only manifest itself during naturalistic contexts involving salient social threat. By testing for correlation between epigenetics, attachment classification, empathic performance, and neural activity we can understand effects of genes and development on everyday empathy. An experimental approach, in which task conditions vary in terms of ambiguity, complexity, or social threat provocation may be necessary to trigger aberrant empathic processing. Attachment insecurity, intrapsychic pain, and empathic dysfunction in BPD cause significant distress and disability, despite advances in evidence-based psychotherapy and psychopharmacology. Integrative, neurodevelopmental research may improve the ability to intervene earlier and more effectively in the course of BPD. Neurobiological research on dysregulation of empathic networks shall bring a more precise understanding of the mechanism via which BPD psychopathology wreaks havoc in patients’ lives, assist in earlier identification, and lead to more effective treatments. Conclusions Despite severe interpersonal symptoms, empathic dysfunction is subtle in BPD. Interactions between genetic, neurocognitive, and developmental risk factors may entrain hyper-reactive SR and impaired MSA networks via abnormal neuropeptide signaling and painful attachment insecurity [45]. Empathic dysfunction may exacerbate BPD symptoms, especially during perceived social threat. A focus on attachment and neurobiological functioning is needed for comprehensive understanding of the heterogenous etiology and psychopathology of BPD. This could provide earlier clinical identification of BPD and more effective treatments targeting refractory symptoms [6]. The present model should be tested with naturalistic neuroimaging paradigms over the course of BPD and imaging results of experimental interventions. Disclosure No potential conflicts of interest relevant to this article were reported. References Papers of particular interest, published recently, have been highlighted as: • Of importance 1. Leiberg S, Anders S. The multiple facets of empathy: A survey of theory and evidence. Prog Brain Res. 2006;156:419–40. 2. • Zaki J, Ochsner K. The neuroscience of empathy: progress, pitfalls and promise. Nat Neurosci. 2012;15(5):675–80. 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