Aggression in Borderline Personality Disorder: a Multidimensional Model

Aggression in Borderline Personality Disorder: A Multidimensional Model

Falk Mancke, Sabine C. Herpertz, and Katja Bertsch University of Heidelberg

This article proposes a multidimensional model of aggression in borderline personality disorder (BPD) from the perspective of the biobehavioral dimensions of affective dysregulation, impulsivity, threat hypersensitivity, and empathic functioning. It summarizes data from studies that investigated these biobehavioral dimensions using self-reports, behavioral tasks, neuroimaging, neurochemistry as well as psychophysiology, and identifies the following alterations: (a) affective dysregulation associated with prefrontal-limbic imbalance, enhanced heart rate reactivity, skin conductance, and startle response; (b) impulsivity also associated with prefrontal-limbic imbalance, central serotonergic dysfunction, more electroencephalographic slow wave activity, and reduced P300 amplitude in a 2-tone discrimination task; (c) threat hypersensitivity associated with enhanced perception of anger in ambiguous facial expressions, greater speed and number of reflexive eye movements to angry eyes (shown to be compensated by exogenous oxytocin), enhanced P100 amplitude in response to blends of happy versus angry facial expressions, and prefrontal-limbic imbalance; (d) reduced cognitive empathy associated with reduced activity in the superior temporal sulcus/gyrus and preliminary findings of lower oxytocinergic and higher vasopressinergic activity; and (e) reduced self-other differentiation associated with greater emotional simulation and hyperactivation of the somatosensory cortex. These biobehavioral dimensions can be nicely linked to conceptual terms of the alternative Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) model of BPD, and thus to a multidimensional rather than a traditional categorical approach.

Keywords: alternative DSM-5 model of BPD, borderline personality disorder, neurobiology, personality dimension, reactive aggression

Supplemental materials: http://dx.doi.org/10.1037/per0000098.supp

Aggression can be defined as any behavior directed toward Manual of Mental Disorders, third edition/fourth edition (DSM– another individual that is carried out with the proximate intent to III/IV) diagnosis (e.g., Gardner, Leibenluft, O’Leary, & Cowdry, cause harm (Anderson & Bushman, 2002). The high prevalence of 1991; McCloskey et al., 2009; Soloff, Kelly, Strotmeyer, Malone, aggression in borderline personality disorder (BPD) is demon- & Mann, 2003) or on dimensional severity scores of BPD traits strated by data showing that 73% of individuals diagnosed with (e.g., Hines, 2008; Ostrov & Houston, 2008; Raine, 1993; Whis- BPD have engaged in aggressive behaviors over the course of a man & Schonbrun, 2009). Therefore, aggression has been regarded year (Newhill, Eack, & Mulvey, 2009), 58% have been “occasion- as a core feature of BPD (e.g., Siever et al., 2002; Skodol et al., ally or often” involved in physical fights, and 25% have used a 2002). weapon against others at some point in their lives (Soloff, Meltzer, Aggression is most widely classified into instrumental and re- & Becker, et al., 2003, p. 154). Additionally, individuals with BPD active forms (e.g., Berkowitz, 1993). Instrumental aggression re- constitute a major proportion of aggression-prone populations such fers to planned, goal-directed behavior, whereas reactive aggres- as prison inmates, with prevalence rates of 30% (Black et al., sion is usually triggered by threats, frustration, or provocation and 2007). Studies have found enhanced aggression in BPD compared is strongly associated with negative emotions, particularly anger This document is copyrighted by the American Psychological Association or one of its alliedwith publishers. healthy and clinical controls irrespective of whether the (e.g., Barratt & Felthous, 2003; Poulin & Boivin, 2000). In BPD, This article is intended solely for the personal use ofinclusion the individual user and is not to be disseminated broadly. was based on categorical Diagnostic and Statistical aggression is typically of the reactive type (Blair, 2004; Gardner, Archer, & Jackson, 2012; Herpertz et al., 2001). This has also been confirmed by laboratory tests of aggression, in which BPD patients Falk Mancke, Sabine C. Herpertz, and Katja Bertsch, Department of have been repeatedly found to react more aggressively to provo- General Psychiatry, University of Heidelberg. cations of a (fictitious) opponent compared with healthy individ- This work was supported by two grants of the German Research Foun- uals (Dougherty, Bjork, Huckabee, Moeller, & Swann, 1999; Mc- dation to Sabine C. Herpertz on borderline personality disorder (Clinical Closkey et al., 2009; New et al., 2009). There is broad evidence Research Foundation on Mechanisms of Disturbed Emotion Processing in indicating that aggression in BPD is tightly linked to interpersonal Borderline Personality Disorder, www.kfo256.de; Schmahl et al., 2014: He dysfunction, with negative interpersonal events (Herr, Keenan- 2660/12-1; He 2660/7-2). Correspondence concerning this article should be addressed to Falk Miller, Rosenthal, & Feldblum, 2013) and interpersonal problems Mancke, Department of General Psychiatry, University of Heidelberg, (Stepp, Smith, Morse, Hallquist, & Pilkonis, 2012) predicting Voßstraße 2, 69115 Heidelberg, Germany. E-mail: [email protected] subsequent aggressive behavior in subjects scoring high on BPD heidelberg.de traits. Additionally, BPD-associated aggression has been shown to

278 AGGRESSION IN BPD: A MULTIDIMENSIONAL MODEL 279

primarily emerge in close relationships, with most aggressive acts demonstrated by Trull et al. (2008), who used experience sampling directed against significant others or acquaintances (Newhill et al., methodology (i.e., ambulatory and real-time data collection) to 2009). BPD traits were also linked to intimate partner violence in show that BPD patients more frequently experienced extreme young to late middle-aged individuals (Holtzworth-Munroe, Mee- spikes of hostility than a clinical control group of depressive han, Herron, Rehman, & Stuart, 2000; Ross & Babcock, 2009; patients. The experience of anger may ultimately result in aggres- Weinstein, Gleason, & Oltmanns, 2012). sive behavior, as recently illustrated in a study showing that the DSM-5 offers two concepts of BPD: In Section II (diagnostic expression of anger, for example, arguing with other people, criteria and codes), DSM-5 provides a broad analogy to the cate- predicted subsequent aggressive behaviors in individuals scoring gorical polythetic classification of BPD in DSM–IV (American high on BPD traits (Stepp et al., 2012). The relevance of anger for Psychiatric Association, 2013, p. 663). The alternative model of aggression in BPD was also supported by the identification of a BPD in Section III (emerging measures and models) uses a hybrid subgroup of BPD patients in whom anger proneness and aggres- approach, which still conceptualizes BPD categorically, but in sion were found to co-occur (Hallquist & Pilkonis, 2012). terms of multiple personality dimensions: All BPD individuals are Reactive aggression has also been considered as a consequence located on a spectrum of impairments in personality functioning of impulsivity (Coccaro, Sripada, Yanowitch, & Phan, 2011; (differentiated into self and interpersonal functioning) and patho- Gollan, Lee, & Coccaro, 2005; Goodman & New, 2000). Data logical personality traits on the domains of negative affectivity, from BPD patients showed that impulsivity and aggression were antagonism, and disinhibition (American Psychiatric Association, positively correlated (e.g., Hollander et al., 2005; Soloff, Meltzer, 2013, p. 761; see, e.g., Skodol, 2012, for a review). et al., 2003) and loaded on the same factor in one (Koenigsberg et Our review begins with significant biobehavioral dimensions, al., 2001) but not in all studies (Critchfield, Levy, & Clarkin, meaning fundamental behavioral facets that have been shown to be 2004). Scott et al., (2014) reported that impulsivity did not mediate associated with neurobiological alterations in BPD. The following between BPD traits and aggression. Besides differences in sample dimensions have been discussed to underlie aggression in BPD: characteristics, the latter result might be attributable to the instru- affective dysregulation, impulsivity, threat hypersensitivity, and ment used to assess impulsivity, that is, a composite of different empathic functioning. Our approach is to summarize the data subscales of the NEO Personality Inventory (Costa & McCrae, related to these biobehavioral dimensions comprising self-reports, 1992). As this instrument was designed to assess normative personality behavioral tasks, neuroimaging, neurochemistry, and psychophys- 1 traits, it may have failed to capture the aspects of impulsivity iology. We will then provide a working model of aggression in specifically related to aggression. Given the strong correlation BPD, which illustrates that these biobehavioral dimensions can be between impulsivity and anger (García-Forero, Gallardo-Pujol, nicely linked to conceptual terms of the alternative DSM-5 model Maydeu-Olivares, & Andrés-Pueyo, 2009), one might also specu- of BPD, and thus to a multidimensional rather than a traditional late that the effect of impulsivity on aggression varies as a function categorical approach. The alternative DSM-5 model could there- of anger. That is, poor impulse control might only (or particularly) fore serve as a suitable starting point for future research on result in aggressive behavior under circumstances of momentarily aggression in BPD. experienced anger. Threat hypersensitivity is a central construct in Blair’s model of Self-Reports and Behavioral Tasks reactive aggression (Blair, 2004, 2012). Animal studies indicate that aggressive behavior is displayed when a threat is very close In this section, we will summarize studies that used self-reports and escape is impossible (Blanchard, Blanchard, Takahashi, & and behavioral tasks to investigate the biobehavioral dimensions in Kelley, 1977). In BPD patients, threat hypersensitivity has mainly the context of aggression in BPD. been studied by means of facial recognition tasks. Results indicate Affective dysregulation plays a key role in theories of reactive a biased or enhanced perception of social threat cues in BPD aggression, as they regard reactive aggression to be a result of patients (Domes, Schulze, & Herpertz, 2009): Compared with insufficiently controlled negative affect, predominantly anger (Berkowitz, 2003; Davidson et al., 2000; Siever, 2008). Links healthy controls, they overreported fear when presented with neu- between affective dysregulation and aggression in BPD can be tral faces (Wagner & Linehan, 1999), perceived ambiguous blends seen in studies revealing associations between BPD traits and of facial expression as more angry (Domes et al., 2008), and This document is copyrighted by the American Psychological Association or one of its allied publishers. guilt-, resentment-, and irritation-related self-reported forms of focused more initial attention (von Ceumern-Lindenstjerna et al., This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. aggression that are described as the “more emotional aggressive- 2010a) toward and had difficulties in disengaging from negative ness subdimensions” (Fossati et al., 2004, p. 168). BPD traits also facial expressions (von Ceumern-Lindenstjerna et al., 2010b). In correlated positively with maladaptive forms of emotional coping, addition, in a study using eye tracking, BPD patients were found to such as blaming oneself and venting emotions, which in turn have more and faster initial reflexive eye movements toward the mediated reactive aggression (Gardner, Archer, & Jackson, 2012). eyes of very briefly presented angry faces, thus the most threat- Two prospective studies revealed that affective dysregulation fully ening and arousing region (Bertsch, Gamer, et al., 2013). These mediated the relationship between BPD traits and subsequent findings suggest that BPD patients misattribute facial emotions, aggressive behavior in a mixed clinical and community sample making them susceptible to the experience of threat or provoca- (Scott, Stepp, & Pilkonis, 2014) and in a solely clinical sample of tion, and ultimately to reactive aggression. BPD patients (Newhill, Eack, & Mulvey, 2012). This emphasizes the high relevance of affective dysregulation for aggression in 1 See Table S1 in the supplemental materials for a detailed description of BPD. Affective dysregulation might also predispose the individual the cited studies, including sample characteristics, methodology, and key to increased experiences of anger or hostility. This was empirically findings. 280 MANCKE, HERPERTZ, AND BERTSCH

Threat hypersensitivity may be one of the sources leading to the others, known as emotional contagion (Fonagy & Luyten, 2009; interpersonal hypersensitivity of BPD individuals. According to the Schmahl & Herpertz, 2014). This leaves BPD patients “vulnerable alternative DSM-5 model of BPD, interpersonal hypersensitivity is the to losing a sense of self” (Fonagy & Luyten, 2009, p. 1362) and to “prone[ness] to feel slighted or insulted” (American Psychiatric As- being increasingly overwhelmed by others’ mental states. In the sociation, 2013, p. 766). It has been linked to aggression in BPD by context of dysfunctional intimate relationships, which provoke findings showing that criticism or blame predicted aggressive behav- negative emotions of despair, jealousy (Costa & Babcock, 2008), ior in women scoring high on BPD traits (Herr et al., 2013). Further- fear of abandonment (Gunderson, 1996), mistrust, and/or shame more, fearful forms of attachment that are particularly linked to (Rüsch et al., 2007), this could result in experiences of anger interpersonal hypersensitivity (Gunderson & Lyons-Ruth, 2008) have (Peters, Geiger, Smart, & Baer, 2014), threat, frustration, and been associated with reactive aggression in BPD patients (Critchfield, eventually reactive aggression. Levy, Clarkin, & Kernberg, 2008). Threat hypersensitivity might also Interestingly, the pattern of deficient empathic functioning of interact with fundamental assumptions of BPD patients, such as BPD patients is the opposite of that found in individuals with other seeing the world and others as dangerous and malevolent, which may aggression-prone personality disorders, such as antisocial or psy- lead to feelings of threat and could provoke reactive aggression chopathic individuals. The latter show intact cognitive empathy but (Arntz, Dreessen, Schouten, & Weertman, 2004; Arntz, 1994; Pretzer, impaired affective empathy (Blair, 2013), favoring instrumental 1990). forms of aggression (Blair, Peschardt, Budhani, Mitchell, & Pine, Empathic functioning can be differentiated into cognitive empa- 2006) which have been shown not to be abnormally enhanced in thy, affective empathy, and supplemental regulatory mechanisms. BPD (Herpertz et al., 2001). However, studies directly investigat- Analogously to mentalization or theory of mind, cognitive empathy ing the relationship between empathic functioning and aggression is regarded as the capacity to infer the mental states of others. in BPD are still lacking, and further research is needed to disen- Affective empathy captures the emotional engagement with other tangle the differential contributions of empathic functioning to individuals’ emotional displays. The regulatory mechanisms allow aggression in BPD and related disorders. the distinction between emotional reactions of the self and the In the attempt to capture these findings (hereafter related to other, hereafter called self-other differentiation (see, e.g., Decety, alterations of the biobehavioral dimensions) within the alternative 2011; Jeung & Herpertz, 2014, for reviews). Impaired empathic DSM-5 model of BPD, they can be subsumed under both impair- functioning is fundamental to the evolution of human aggression ments of personality functioning and pathological personality traits (de Waal, 2012; Decety, 2011; Fonagy, 2003). In empirical terms, (American Psychiatric Association, 2013, pp. 766–767), and thus cognitive empathy in particular has been associated with reactive the two descriptive levels provided by this classification. Affective aggression (Fossati et al., 2009; Jolliffe & Farrington, 2004; Re- dysregulation is closely related to emotional lability, a trait facet of nouf et al., 2010; van Langen et al., 2014). In BPD patients, the personality domain negative affectivity. Impulsivity is directly reduced cognitive empathy was found in studies using self-reports addressed as a trait facet of the personality domain disinhibition. (Harari, Shamay-Tsoory, Ravid, & Levkovitz, 2010; New et al., Threat hypersensitivity can be related to both descriptive levels: to 2012) or advanced behavioral tasks that approximate real-life the trait facets of emotional lability and hostility on the one hand, social interactions (Dziobek et al., 2011; Preißler, Dziobek, Ritter, and to impairments in interpersonal functioning on the other. Heekeren, & Roepke, 2010; Ritter et al., 2011). The latter tasks— Within the latter, it can be attributed to the empathic deficit of BPD also referred to as ecologically valid tasks—use, for instance, short patients, namely to interpersonal hypersensitivity and a negatively film clips displaying social interactions, after which participants biased perception of others. The reduced cognitive empathy is have to evaluate the intentions, emotions, and thoughts of the encompassed in the description of the empathic deficit of the interaction partners. Contrary to the finding of reduced cognitive alternative DSM-5 model. However, reduced self-other differenti- empathy, and despite some inconsistencies (Dziobek et al., 2011), ation, regarded as a facet of poor empathy in neuroscientific affective empathy seems to be intact in BPD patients (Harari et al., models (Decety & Jackson, 2004), is not directly addressed as an 2010; Mier et al., 2013; New et al., 2012). empathic deficit in the alternative DSM-5 model. Instead, it is First results indicate that BPD patients try excessively to inter- linked to the “markedly impoverished, poorly developed, or un- pret other people’s mental states and/or overattribute the intentions stable self-image” mentioned as reflecting disturbances of BPD of others, which suggests impairments in self-other differentiation patients’ self-identity. This document is copyrighted by the American Psychological Association or one of its allied publishers. (Sharp et al., 2011). In tasks that can be performed via cognitive or This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. affective empathic involvement, such as the “Reading the Mind in Neuroimaging the Eyes task“ (Baron-Cohen, Jolliffe, Mortimore, & Robertson, 1997), BPD patients outperformed healthy controls (Fertuck et al., Contemporary theories on the neurobiological underpinnings of 2009; Frick et al., 2012), possibly through (compensatory) over- reactive aggression propose a brain circuitry implicating prefron- mobilizing affective empathic strategies, such as emotional simu- tal, limbic, and mesencephalic structures. More specifically, in lation (Gallese & Goldman, 1998). In line with the theory of animals, a pathway has been identified that runs from medial greater emotional simulation in BPD, Matzke et al. (2014) found amygdala areas to the medial hypothalamus via the stria terminalis, that compared with healthy controls, BPD patients exhibited and from there to the dorsal half of the periaqueductal gray. higher electromyographic activity of the frowning muscle while Neurons within the periaqueductal gray matter are activated, caus- viewing negative facial expressions of others such as anger, sad- ing the autonomic and motor aspects of reactive aggression. Areas ness, and disgust. Exaggerated emotional simulation, however, modulating the aggressive response include the hippocampus, the impacts negatively on the capability of self-other differentiation, cingulate and prefrontal cortices (Blair, 2004; Gregg & Siegel, resulting in an affect-dominated and unmediated perception of 2001). In humans, the understanding of the processes leading to AGGRESSION IN BPD: A MULTIDIMENSIONAL MODEL 281

aggression emphasizes the functional relevance of prefrontal and Taken together, structural neuroimaging studies revealed abnor- limbic structures. Prefrontal regions, especially the orbital frontal malities in gray matter volumes of prefrontal and limbic brain and anterior cingulate cortices, fail to control enhanced affective regions in individuals with BPD. These regions are critically reactivity of limbic regions such as the amygdala. We will begin implicated in affect dysregulation (Siever, 2008), impulsivity (Coc- this section by describing structural brain abnormalities in BPD caro et al., 2011), and threat hypersensitivity (Blair, 2012). Hence, patients, and will then summarize results from functional imaging volumetric abnormalities in these regions might be neural corre- studies. lates of aggressive behavior in BPD.

Structural Neuroimaging Functional Neuroimaging Structural neuroimaging studies revealed differences in the Consistent with the assumption of prefrontal-limbic imbalance brain areas mentioned above in BPD patients relative to healthy involved in affective dysregulation, functional neuroimaging stud- controls, with smaller amygdala and hippocampal volumes in BPD ies have revealed increased and prolonged amygdala activity in patients being the most consistent findings across studies (see response to (negative) emotional stimuli in BPD patients compared Nunes et al., 2009, for a meta-analytic review). Less consistent are with healthy controls, as well as reduced activity in prefrontal findings of smaller gray matter volumes in the anterior cingulate regions involved in regulatory processes such as the anterior (Hazlett et al., 2005; Minzenberg, Fan, New, Tang, & Siever, cingulate cortex, the medial frontal cortex, the orbitofrontal cortex, 2008; Tebartz van Elst et al., 2003) and in orbital frontal cortices and the dorsolateral prefrontal cortex (see, e.g., O’Neill & Frodl, (Brunner et al., 2010; Chanen et al., 2008) of BPD patients when 2012, for a review). In addition, compared with healthy controls, compared with healthy controls. Recently, our group reported a individuals with BPD and comorbid intermittent explosive disor- larger gray matter volume in the hypothalamus of female BPD der (BPD-IED) showed impaired functional connectivity between patients compared with healthy women (Kuhlmann, Bertsch, prefrontal and amygdala regions (New et al., 2007). Schmidinger, Thomann, & Herpertz, 2013), a structure which is These brain structures are also implicated in the regulation of critically implicated in the regulation of aggressive behavior impulsivity (Coccaro et al., 2011). In a positron emission tomog- (Haller, 2013). The hypothalamic volume of BPD patients was raphy (PET) study, significant reductions in fluorodeoxyglucose positively correlated with scores on the Childhood Trauma Ques- uptake in the bilateral medial orbitofrontal cortex were found in tionnaire (Bernstein & Fink, 1998), suggesting a role of traumatic BPD subjects compared with healthy controls. Covarying for mea- experiences in volumetric abnormalities of the hypothalamus. In a sures of impulsivity rendered the differences between groups in- related vein, Morandotti et al. (2013) demonstrated that gray significant (Soloff, Meltzer, et al., 2003). Recent studies suggest a matter volume loss in the right ventrolateral prefrontal cortex was more complex role of the orbitofrontal cortex in the regulation of specifically associated with aggression in those BPD patients with impulsivity, with reports of differential abnormalities of its subre- a history of traumatization, indicating a particular impact of trau- gions. The resting state blood flow of BPD patients compared with matization on prefrontal regions and in turn aggression. The rele- healthy subjects was reduced in medial regions but increased in vance of traumatic experiences for aggression is in line with lateral regions, and was positively associated with trait impulsivity findings of higher aggressive behavior in patients with posttrau- in both regions (Wolf et al., 2012). Assessing aggression and the matic stress disorder (Van Voorhees et al., 2014). Future studies brain activity of BPD-IED patients during highly provoking situ- could therefore benefit from the inclusion of patients with post- ations in a PET scanner, one study found that experimentally traumatic stress disorder as a clinical control group, or a subgroup induced provocation led not only to increased aggression in the analysis of BPD patients with and without posttraumatic stress patients, but also to increased glucose uptake in the orbitofrontal disorder to clarify the contribution of traumatic experiences to cortex and the amygdala compared with healthy controls (New et aggression in BPD. Kuhlmann et al. (2013) also reported reduced al., 2009). In addition, compared with healthy controls, BPD-IED gray matter volume in the cerebellar vermis. Cerebellar structures individuals failed to activate anterior, medial, and dorsolateral are connected to the limbic system (Heath & Harper, 1974) and are prefrontal regions during high provocation, suggesting a deficit in involved in the regulation of emotional behavior (Sacchetti, the mobilization of higher “cognitive control” of aggression. Scelfo, & Strata, 2009). Therefore, they might be an additional Whereas the orbitofrontal cortex has often been seen as “put[ting] This document is copyrighted by the American Psychological Association or one of its allied publishers. brain region implicated in affect regulation and aggression. the brakes on” (New et al., 2009, p. 1112) enhanced affective This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. BPD patients’ aggression has also been reported to be nega- reactivity of limbic regions such as the amygdala, these results tively associated with gray matter volume in the hippocampus render the interplay more complex. This is in line with investiga- (Sala et al., 2011; Zetzsche et al., 2007), but not in the amygdala tions in healthy controls which revealed enhanced prefrontal but at (Zetzsche et al., 2006). Comparing male antisocial offenders with the same time reduced orbitofrontal activity during imagined ag- BPD to male antisocial offenders with high psychopathic traits, our gression (Pietrini, Guazzelli, Basso, Jaffe, & Grafman, 2000). group found specific structural abnormalities: Male BPD offenders Thus, activations in the orbital frontal cortex may be associated showed smaller volume in brain regions involved in affect regu- with increased or decreased likelihood of aggressive outbursts lation (orbitofrontal and ventromedial prefrontal cortex), whereas depending on social cues and context (Blair, 2004). A second psychopathic offenders showed less volume in cortical midline analysis of the data used by New et al. (2009) revealed reduced areas (dorsomedial prefrontal cortex and precuneus) that are in- glucose metabolism rates in the striatum of male BPD-IED pa- volved in self-referential emotion processing and self-reflection tients compared with healthy men and might indicate striatal and could thus mirror psychopathic callousness and poor moral deficits in providing an appropriate situational context to prefron- judgment (Bertsch, Grothe, et al., 2013). tal inhibitory areas (Perez-Rodriguez et al., 2012). 282 MANCKE, HERPERTZ, AND BERTSCH

Prefrontal-limbic imbalance may additionally underlie BPD pa- diminished serotonergic synthesis capacity, compared with healthy tients’ threat hypersensitivity, because their exaggerated initial controls (Leyton et al., 2001). Imaging studies located the central fixation changes toward the eyes of angry faces were related to serotonergic deficit of BPD patients mainly in prefrontal brain increased posterior amygdala reactivity to angry facial expressions regions (Leyton et al., 2001; Siever et al., 1999; Soloff, Meltzer, et (Bertsch, Gamer, et al., 2013). al., 2003; Soloff, Meltzer, Becker, Greer, & Constantine, 2005; Functional neuroimaging was also used to investigate neural Soloff et al., 2000). Compared with healthy controls, BPD patients correlates of BPD patients’ deficits in empathic functioning. Dur- were also found to show a reduced serotonin transporter density in ing tasks assessing cognitive empathy, BPD patients showed re- the cingulate cortex (Frankle et al., 2005) as well as decreased duced activations in the superior temporal sulcus and the superior serotonergic functioning in the hypothalamus (Koch et al., 2007) temporal gyrus compared with healthy controls (Dziobek et al., and in hippocampal regions (Soloff et al., 2007). 2011; Frick et al., 2012; Mier et al., 2013), whereas they showed Heritability accounts for about 50% of aggression (Rhee & Wald- enhanced activations in the amygdala (Mier et al., 2013) and insula man, 2002) and serotonergic genes; a polymorphism of the serotonin (Dziobek et al., 2011) during affective empathy. One study also transporter gene (Silva et al., 2007) and a haplotype of the tryptophan revealed a general hypoactivation in the prefrontal cortex and a hydroxylase gene (Perez-Rodriguez et al., 2010) were associated with hyperactivation in the somatosensory cortex of BPD patients com- aggression in BPD patients. However, the identification of a single pared with healthy controls in a paradigm measuring different gene locus with a major effect size on aggression seems unlikely facets of empathy (Mier et al., 2013). This suggests that BPD (Craig & Halton, 2009); rather, gene–environment interactions are patients have an overactive and poorly controlled amygdala, which expected, such as the enhancement of antisocial behavior in might call their unfiltered attention to predominantly negative subjects with a polymorphism of monoamine oxidase A affective social stimuli. Together with emotional simulation pro- (MAOA) when exposed to childhood maltreatment (Byrd & cesses reflected in increased activation of the somatosensory cor- Manuck, 2014; Caspi et al., 2002). BPD gene–environment tex, this may lead to emotional contagion, which—as described studies showed that polymorphisms of the brain-derived growth above—may enhance the likelihood of aggressive reactions. factor (Wagner, Baskaya, Dahmen, Lieb, & Tadic,´ 2010) and the With regard to the alternative DSM-5 model, the neuroimaging catechol-O-methyltransferase (Wagner, Baskaya, Anicker, et al., finding of a prefrontal-limbic imbalance in BPD patients underlies 2010) modulated measures of reactive aggression in BPD patients the trait facets of emotional lability, impulsivity, and hostility. who had experienced severe life events such as physical or sexual Hypoactivity of the superior temporal sulcus/gyrus appears to maltreatment. However, because of methodological challenges in mirror the empathic deficit of BPD patients. Increased activation gene–environment studies (see, e.g., Carpenter, Tomko, Trull, & of the somatosensory cortex can be associated with BPD patients’ Boomsma, 2013), the interpretability of these results is limited. tendency to simulate the feelings of others, which may result in In addition to the serotonin system, several other neurochemicals what the alternative DSM-5 model conceptualizes as identity dis- might play a role in the relationship between BPD and reactive turbance. (American Psychiatric Association, 2013, p. 766). aggression. Oxytocin has been negatively related to reactive aggression by fostering pro-social behavior and secure attachment patterns Neurochemistry (see Meyer-Lindenberg, Domes, Kirsch, & Heinrichs, 2011, for a review). In BPD patients, plasma concentrations of oxytocin were Aggression and related concepts have been linked to a number negatively associated with trait aggressiveness (Bertsch, Schmidinger, of neurochemical substances. This section will begin with a sum- Neumann, & Herpertz, 2013). First findings suggest a beneficial mary of physiological and genetic underpinnings of the serotoner- effect of oxytocin on BPD patients’ threat hypersensitivity,asits gic system, followed by other neurochemical systems and their intranasal administration reduced the speed and number of reflexive association with aggression in BPD. eye movements toward the eyes of angry faces and normalized the Probably the most consistent neurochemical correlate of aggres- hyperactivity of the amygdala for angry compared with happy faces in sion is a reduced prefrontal serotonergic concentration and func- BPD patients (Bertsch, Gamer, et al., 2013). Oxytocin also modulated tion, which has been regarded as a correlate of impulsivity (e.g., neuronal activity in brain areas involved in empathic functioning Coccaro & Kavoussi, 1997; Siever & Trestman, 1993; Oquendo & (Domes, Kumbier, Heinrichs, & Herpertz, 2014)—although this has Mann, 2000). So far, investigations showed reduced concentra- not yet been shown in BPD patients. This document is copyrighted by the American Psychological Association or one of its allied publishers. tions of the serotonin metabolite 5-hydroxyindoleacetic acid in the Studies suggest that vasopressin might have contrary effects to This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. cerebrospinal fluid (CSF) of male BPD patients with comorbid oxytocin in the modulation of social behavior (Meyer-Lindenberg intermittent explosive disorder and/or antisocial personality disor- et al., 2011) and may increase reactive aggression (Haller, 2013). der when compared with clinical controls (Linnoila et al., 1983). In line with this, the concentration of vasopressin in the CSF has 5-Hydroxytryptamine 2a receptor binding abnormalities on plate- been associated with aggression in personality-disordered subjects, lets were positively associated with aggression in a personality- including BPD patients (Coccaro, Kavoussi, Hauger, Cooper, & disordered sample, including BPD patients, but not healthy con- Ferris, 1998). Additionally, an interrelation between polymor- trols (Coccaro, Kavoussi, Sheline, Berman, & Csernansky, 1997). phisms of the vasopressin receptor gene and reactive aggression in Pharmaco-challenge studies that used serotonergic agonists, such BPD patients has been suggested (Vogel et al., 2012). as d-fenfluramine, found a deficit in the central serotonergic func- Abnormalities in the cortisol system have also been reported in tionality in samples solely with BPD patients (Rinne, Westenberg, BPD patients, but the results are lacking a clear direction (Zim- den Boer, & van den Brink, 2000; Soloff, Kelly, et al., 2003)orin merman & Choi-Kain, 2009). Although numerous reports suggest samples with BPD and other personality disorders (Coccaro et al., an association between testosterone and aggressive behavior in the 1989; Herpertz, Sass, & Favazza, 1997). Male BPD patients had general population (Yildirim & Derksen, 2012), findings in BPD AGGRESSION IN BPD: A MULTIDIMENSIONAL MODEL 283

patients are sparse. One study reported that CSF concentrations of Multidimensional Model of Aggression in BPD testosterone did not correlate with previous aggressive behaviors In this concluding section, we will use the reviewed data to propose in a sample of male patients with various personality disorders, a multidimensional model of aggression in BPD. We summarize including BPD (Coccaro, Beresford, Minar, Kaskow, & Geracioti, findings of aggression in BPD from the perspective of the biobehav- 2007). Recently, a probable deficit in the opioid system has been ioral dimensions affective dysregulation, impulsivity, threat hypersen- gaining increased attention in BPD research (Prossin, Love, sitivity, and empathic functioning; and then link these findings to the Koeppe, Zubieta, & Silk, 2010), and dopamine may also be a alternative DSM-5 model of BPD (see also Figure 1). factor in the etiology of reactive aggression (Friedel, 2004; Buck- Based on this approach, affective dysregulation, which has been holtz et al., 2010). However, to date, studies investigating these shown to be associated with prefrontal-limbic imbalance, enhanced substances in aggression of BPD patients are lacking. reactivity of heart rate, skin conductance, and startle response, is close Relating these findings to the alternative DSM-5 model, the to the trait facet of emotional lability in the alternative DSM-5 model. central serotonin deficit of BPD patients appears to underlie the Impulsivity is also associated with prefrontal-limbic imbalance as well trait facet of impulsivity, while there are very preliminary data as central serotonergic dysfunction, more electroencephalographic suggesting that high vasopressinergic and low oxytocinergic ac- slow wave activity and reduced P300 amplitude in a 2-tone discrim- tivity might be related to BPD patients’ empathic deficits. ination task, and is directly addressed as a trait facet in DSM-5. The biobehavioral dimension of threat hypersensitivity reflected in enhanced perception of anger in ambiguous facial expressions, greater Psychophysiology speed and number of reflexive eye movements to angry eyes, The most robust psychophysiological correlates of aggression in prefrontal-limbic imbalance, and enhanced P100 amplitude in re- the general population are as follows: (a) low baseline heart rate, sponse to blends of happy versus angry facial expressions can be which is regarded as an indicator of the underarousal that predisposes linked to the DSM-5 trait facets of emotional lability and hostility. individuals toward compensatory stimulation seeking and thus ag- Additionally, threat hypersensitivity is related to impairments in in- gression. (b) Enhanced reactivity of heart rate and skin conductance terpersonal functioning, more specifically to interpersonal hypersen- have been linked to aggression, most likely reflecting affective dys- sitivity and a negatively biased perception of others, which might be regulation. Regarding further psychophysiological parameters, (c) a modulated by oxytocin. Reduced cognitive empathy was shown to be reduced P300 amplitude in event-related electroencephalographic po- associated with hypoactivity in the superior temporal sulcus/gyrus and DSM-5 tentials, although highly dependent on the experimental context, has is encompassed in the description of the empathic deficit of . Preliminary data suggest an additional role for lower oxytocinergic been associated with impulsivity and aggression, (d) more slow wave and higher vasopressinergic activity in reduced cognitive empathy. activity in resting electroencephalography has also been thought to Finally, reduced self–other differentiation coupled with greater emo- reflect impulsivity, and (e) an augmented potentiation of the startle tional simulation and hyperactivation of the somatosensory cortex eyeblink response to aversive stimuli has been associated with affec- might contribute to BPD patients’ identity disturbance. Notably, these tive dysregulation (Lorber, 2004; Patrick, 2008). various biobehavioral dimensions may contribute to aggression to In line with this, BPD patients, when compared with healthy different extents within the individual BPD patient. controls, showed an enhanced reactivity of heart rate (Ebner- Importantly, we suppose that the biobehavioral dimensions are Priemer et al., 2007) and skin conductance (Barnow et al., 2012), highly interconnected. This is demonstrated by several findings. The more slow wave activity in resting electroencephalography (Sny- serotonergic dysfunction is related not only to impulsivity but also to der & Pitts, 1984), and augmented potentiation of the startle affective dysregulation (Canli & Lesch, 2007; Davidson et al., 2000), response (Ebner-Priemer et al., 2005; Hazlett et al., 2007). Com- and the brain regions implicated in affective dysregulation are also pared with clinical controls, BPD patients demonstrated dimin- linked to impulsivity (Goodman & New, 2000), empathic functioning ished P300 amplitude in a 2-tone discrimination task (Blackwood, (Adolphs, 2009) and threat hypersensitivity (Blair, 2012). Affective St Clair, & Kutcher, 1986). The results of a very recent event- dysregulation mediates the emergence not only of threat hyper- related potential study by our group additionally showed enhanced sensitivity (Gratz, Dixon-Gordon, Breetz, & Tull, 2013) but also early visual potentials (occipital P100) in BPD patients compared of deficits in empathic functioning (Sharp et al., 2011). Finally,

This document is copyrighted by the American Psychological Association or one of its alliedwith publishers. healthy controls in a facial recognition task with blends of within the framework of the alternative DSM-5 model of BPD,

This article is intended solely for the personal use ofhappy the individual user and is not to be disseminated broadly. versus angry expressions (Izurieta, Nagy, Mancke, Her- hostility is a trait facet that has been subsumed under both pertz, & Bertsch, 2014), indicating an involvement of very early pathological personality domains, antagonism and negative af- visual processes in threat hypersensitivity. fectivity (American Psychiatric Association, 2013, p. 780). With regard to the alternative DSM-5 model of BPD, psychophysiological data most notably reflect the trait facets of Limitations emotional lability (enhanced skin conductance, heart rate reac- Interestingly, the biobehavioral dimensions shown to underlie ag- tivity and augmented startle response) and impulsivity (in- gression in BPD can be nicely related to the terminology and defini- creased slow wave activity and reduced P300 amplitude). En- tions of the alternative DSM-5 model of BPD according to Section III. hanced P100 amplitudes probably point to early attentional However, some inconsistencies have to be discussed. In the alterna- hypervigilance to threat-related social cues, favoring hostility. tive DSM-5 model, interpersonal hypersensitivity is related to the These studies, however, have rarely included measures of ag- empathic deficit, whereas reduced self–other differentiation, a facet of gression, making implications for the manifestation of aggres- empathy in concepts of neuroscience (Decety & Jackson, 2004), is sive behaviors in BPD premature. subsumed under the identity disturbance. Although this primarily 284 MANCKE, HERPERTZ, AND BERTSCH

Figure 1. Multidimensional model of reactive aggression in borderline personality disorder (BPD). As depicted in the figure legend (right bottom), the circles represent the alternative DSM-5 model of BPD, the biobehavioral dimensions, as well as the data from behavioral tasks, psychophysiology, neuroimaging, and neurochemistry. Based on this approach reactive aggression in BPD is conceptualized in terms of the biobehavioral dimensions of affective dysregulation, impulsivity, threat hypersensitivity, reduced cognitive empathy, and reduced self-other differentiation, which in turn can be linked to certain aspects of the alternative DSM-5 model of BPD. For This document is copyrighted by the American Psychological Association or one of its allied publishers. instance, affective dysregulation is associated with enhanced reactivity of heart rate, skin conductance, startle This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. response, and prefrontal-limbic imbalance, and can be linked to the trait facet of emotional lability. The biobehavioral dimensions are highly interconnected. For instance, prefrontal-limbic imbalance is associated with affective dysregulation, impulsivity as well as threat hypersensitivty, and emotional lability can be linked to affective dysregulation and threat hypersensitivity. Act. ϭ activity, Ampl. ϭ amplitude, Dis. ϭ discrimination, Diff. ϭ differentiation, EEG ϭ electroencephalographic, Sup. ϭ superior, Temp. ϭ temporal.

seems reasonable to us, interpersonal hypersensitivity also encom- pathological personality traits are not clear-cut and are most likely to passes aspects that are only partially embraced by the concept of be intertwined, as already discussed by Livesley (2012) and, thus, empathy in DSM-5, but also overlaps with descriptions of trait facets, need to be further developed and conceptually sharpened in the future. for example, by partially overlapping with hostility, and closely in- However, the dimensional approach of the alternative DSM-5 teracting with emotional lability and impulsivity in the context of model seems to explain the complex multifaceted behavioral con- escalating transactional processes. Consequently, the conceptual struct of aggression better than a categorical approach to BPD, boundaries between the impaired personality functioning and the which has raised questions such as whether aggression is, in fact, AGGRESSION IN BPD: A MULTIDIMENSIONAL MODEL 285

an inherent characteristic of the disorder, or a subtype of BPD ple, the direction of the neurochemical alterations, their exact (Hallquist & Pilkonis, 2012; Kernberg & Caligor, 2005), or rather localizations within the human brain, and the interplay between a co-occurring phenomenon related to comorbid personality pa- different substances remain unclear. In the future, innovative neu- thology, such as antisocial personality disorder or psychopathy roimaging techniques will elucidate smaller and more definite (Allen & Links, 2012). The latter assumption seemed to be con- anatomical structures, such as orbitofrontal subregions and firmed by the nonsignificant relationship between aggression and amygdala subnuclei, and connectivities within circuits that may BPD after statistical controlling for Axis I or other comorbid help to identify more specific mechanisms underlying trait dimen- Cluster B personality disorders (Berman, Fallon, & Coccaro, 1998; sions and categorical entities. Haller & Miles, 2003; Johnson et al., 2000). However, because Fourth, gender differences in aggression are well known in the almost two thirds (66%) of BPD patients who do not fulfill the general population (Archer, 2004; Campbell, 2006), but still need criteria for antisocial personality disorder still engage in aggres- to be addressed in BPD, as most previous studies concentrated on sion (Newhill et al., 2009), aggression is more likely to be linked female subjects. to BPD psychopathology itself, and further investigations of (neu- Last but not least, therapeutic options for aggression in BPD are ro)biological and psychological correlates of reactive aggression in limited (Látalová & Prasko, 2010). Psychotherapeutic strategies, patients with BPD are highly important. which are said to be the most effective treatment for BPD (Stoffers The specificity of some of the data presented above requires et al., 2012), need to be adapted to the particular needs of patients further exploration. For instance, associations between prefrontal with aggressive behavior. First results in this regard are promising, dysfunction and aggression have been reported in a variety of especially for dialectical behavioral therapy (Evershed et al., 2003; psychiatric conditions (Bassarath, 2001; Brower & Price, 2001) Frazier & Vela, 2014; Nelson-Gray et al., 2006; Shelton, Kesten, and the same holds true for alterations in the serotonin system Zhang, & Trestman, 2011). In terms of biological treatments, the (Bortolato et al., 2013), again questioning a purely categorical search for and investigation of new agents, for instance oxytocin approach. agonists or vasopressin antagonists, could be promising. It should be considered that the range of effect sizes in the In conclusion, the investigation and classification of aggression above-presented data is immense: from as little as 5% shared in BPD requires a multidimensional approach. In our opinion, the variance for BPD traits and reactive aggression (Gardner et al., alternative DSM-5 model can be used as a framework to concep- Ͼ 2012)to 57% mediation of aggression by interpersonal problems tualize BPD-associated aggression and its underlying biobehav- in individuals with BPD traits (Stepp et al., 2012). ioral alterations. Further research pursuing a multimethod ap- Finally, the aim of this article was not to completely reconcep- proach on the behavioral and the pathophysiological level is tualize the relationship between aggression and BPD or to com- needed to explicate the fundamental biobehavioral dimensions in prehensively review all available data. We rather intended to the field of personality disorders. Analogously to research in the provide a specific framework for aggression in BPD that poses major mental disorders (Insel, 2014), these dimensions are signif- unanswered questions and stimulates further discussion and inte- icant for the understanding of etiology and pathophysiology of grative research. BPD, and should facilitate the development of new treatments for those affected. Outlook Pathological forms of aggression are an individual as well as a References societal burden that remain far from being understood (World Health Organization, 2007). With regard to aggression in BPD, a Adolphs, R. (2009). The social brain: Neural basis of social knowledge. number of questions need to be addressed in future research. Annual Review of Psychology, 60, 693–716. http://dx.doi.org/10.1146/ annurev.psych.60.110707.163514 First, the construct validity, that is the accuracy of the existing Allen, A., & Links, P. S. (2012). 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