رفتاردرمانی دیالکتیکی، تنظیم احساسات و فعالیت آمیگدال در بیماران مبتلا به اختلال شخصیت مرزی را تغییر می دهد

Objective Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. Methods Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale.

Borderline Personality Disorder (BPD) affects 2% of the population and is characterized by impulsivity and poor affect regulation (Links et al., 1998), and severe morbidity and mortality, including reported suicide rates 50 times the general population (Skodol et al., 2002). BPD patients experience more frequent psychiatric hospitalizations, greater use of outpatient psychotherapy and emergency room use than individuals with any other psychiatric disorder (Bender et al., 2001 and Lieb et al., 2004b). Affective Instability (AI) is responsible for the considerable morbidity across psychiatric disorders including aggression, suicidality, and disrupted relationships. AI is defined as “rapid and reactive oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioral consequences” (Marwaha et al., 2013). It is further characterized by heightened intensity of affect, usually in negative valence, rapid affective shifts lasting minutes to hours, hypersensitivity to environmental triggers, usually interpersonal in nature and, dysregulated affect modulation (Koenigsberg, 2010, Renaud and Zacchia, 2012, Carpenter and Trull, 2013 and Links et al., 2008). AI contrasts with the affective/mood dysregulation seen in major depression and bipolar disorder where the mood disorder is sustained for days to weeks and relatively autonomous of environmental triggers. While AI is expressed in other disorders, AI is at the core of BPD and subsumes many of the diagnostic criteria including affective lability, intense anger, chronic emptiness and behaviors like suicide and self-mutilation that may reflect misguided efforts to modulate strong and aversive emotional states (Linehan, 1993). Siever and Davis' (1991) psychobiological approach to the understanding of personality disorders highlights the dimension of AI in BPD. Linehan's Biosocial Theory (1993) conceptualization of emotional dysregulation in BPD, overlaps with the construct of AI and delineates two components: a) heightened emotional responsivity characterized by high sensitivity to emotional stimuli and heightened emotional intensity, and b) difficulties in effortful modulation of negative affect. The emotional hyper-responsivity is postulated to be biologically mediated, arising from genetic vulnerabilities, intrauterine and/or early childhood events that interact with an “invalidating” environment (Linehan, 1993), as is supported by multiple studies indicating high rates of childhood trauma and neglect in this population (Fossati et al., 1999 and Goodman et al., 2004). Empirical research on emotional hyper-responsivity in BPD includes subjective reports of heightened affective experiences to various emotional stimuli such as films, audiotapes, and pictures from the International Affective Picture System (IAPS) (Arntz et al., 2000, Herpertz et al., 1999 and Yen et al., 2002). More recently, the use of objective psychophysiological parameters including affective startle modulation, skin conductance, and heart rate measures of emotional arousal have been employed, also revealing heightened responsivity in BPD, e.g., (Hazlett et al., 2007 and Herpertz and Koetting, 2005). The second part of Linehan's Biosocial Theory focusing on difficulties in effortful modulation of negative affect is supported by neuroimaging data demonstrating inefficient regulatory control of the amygdala by prefrontal cortex (PFC) regions (Lis et al., 2007, Minzenberg et al., 2007, Wingenfeld et al., 2009 and Silbersweig et al., 2007) and dysfunctional coupling of fronto-limbic structures (New et al., 2007). Building on the substantial literature in both animals and humans that implicates amygdala in emotional processes, including the perception and production of emotion (Davidson et al., 1999), there is growing evidence supporting the role of amygdala in the emotion processing disturbances observed in BPD. Functional magnetic resonance imaging (fMRI) studies in BPD show increased amygdala activity to specific types of stimuli, e.g.,“unresolved” life events (Schmahl et al., 2006), emotional faces (Donegan et al., 2003), positive and negative emotional pictures (Herpertz et al., 2001) and emotionally-triggering scripts (Beblo et al., 2006). More recently, our group has demonstrated exaggerated amygdala response to repeated emotional pictures in two separate BPD studies. The first, in the largest sample size of unmedicated BPD patients (n = 33) studied with fMRI to date ( Hazlett et al., 2012) were compared with healthy controls (HC) and schizotypal personality disorder (SPD) patients while viewing socially-relevant IAPS pictures. The main finding was that compared with the other two groups, BPD patients failed to show amygdala habituation to repeated emotional (unpleasant and pleasant) but not neutral pictures. The second study, ( Koenigsberg et al., 2014), using a similar IAPS habituation paradigm but an avoidant personality disorder psychiatric-control group, examined functional connectivity differences between groups. The BPD group showed greater amygdala activity to unpleasant pictures collapsed across novel and repeated conditions compared with both the HC and avoidant groups and less functional connectivity between the midposterior insula and the left and right amygdala relative to the HC group ( Koenigsberg et al., 2014). Taken together, these findings suggest that affective instability in BPD may be mediated by an overactive amygdala that manifests as increased emotionality, sensitivity and slow return to baseline. In addition to functional differences in amygdala activity, some (Driessen et al., 2000 and Tebartz van Elst et al., 2003) but not all (Goldstein et al., 2009 and Rusch et al., 2003) structural MRI studies report significantly smaller amygdala volumes in BPD patients compared with HCs, with discrepant findings possibly due to posttraumatic stress disorder (PTSD) comorbidity (de-Almeida et al., 2012). Dialectical Behavior Therapy (DBT) emphasizes the role of emotion regulation (Bohus et al., 2004 and Linehan et al., 1991) and targets the acquisition of skills and techniques to encourage cognitive control over maladaptive behavioral patterns (Neacsiu et al., 2010). It has achieved widespread proliferation due to its robust empirical basis and exportability and is included as a component of the APA Practice Guideline for the treatment of BPD. With over 17 randomized clinical trials, DBT is the psychotherapy approach for BPD with the largest empirical base, however, minimal data exists regarding neurobiological mechanisms of change with DBT, or the existence of specific predictors for positive treatment response (Kleindienst et al., 2011) that might guide clinician treatment decisions. While neuroimaging and psychophysiological studies of a psychotherapeutic treatment have been conducted in major depressive disorder (MDD) (Brody et al., 2001, Goldapple et al., 2004 and Mayberg, 2003), few such studies exist in BPD. A small neuroimaging pilot on DBT (Schnell and Herpertz, 2007) highlights the role of amygdala normalization. This study scanned six BPD and six HC participants at five time points over a 12-week inpatient DBT program, with an IAPS paradigm. DBT treatment response was not operationalized but rather was defined as whether two of three treatment goals were met. DBT treatment decreased activity in anterior cingulate cortex (ACC), posterior cingulate, and insula to unpleasant stimuli. DBT responders (four of six) also demonstrated diminished activation in left amygdala and bilateral hippocampus (Schnell and Herpertz, 2007). The present study examines DBT treatment effect on emotion regulation in unmedicated outpatients with BPD as measured by changes in the Difficulties in Emotion Regulation Scale (DERS) (Gratz and Roemer, 2004) and uses an emotional processing task to investigate amygdala changes after a standard 12-month course of DBT. A yoked HC group was included as a benchmark for normal amygdala activity and change over 12 months. Given our prior finding of exaggerated amygdala response and impaired habituation to unpleasant pictures in BPD, this investigation focused on the effects of DBT on the amygdala—our a priori region of interest. Individual differences in treatment response were also examined with correlations between the change in emotion regulation as measured by the DERS and amygdala activity from pre- to post-DBT treatment. Lastly, we examined change in emotion regulation with the DERS, independent of the amygdala as well, comparing baseline, 6, and 12 months. We hypothesized that the BPD patients would show a decrease in amygdala reactivity following treatment, and that the magnitude of this change would be associated with improved emotion regulation as measured by the DERS. In contrast, we hypothesized that the HC group would show consistent amygdala activation over time and their emotion regulation scores on the DERS would also remain stable over time (i.e. baseline, 6 months, 12 months).

3. Results We report on 11 BPD subjects who completed 12 months of DBT treatment and pre/post fMRI. While 16 subjects finished the 12 month DBT trial, 5 participants were unable to complete the imaging paradigms for various reasons including claustrophobia (n = 2), acquisition of metal braces for teeth (n = 1), diagnosis of metastatic cancer (n = 1), refusal of scan (n = 1). 3.1. Self-report of difficulties in emotion regulation (DERS) We examined the DERS total scores for the HC and BPD groups at baseline (0), 6 months, and 12 months. The DERS scores were stable over time for the HC group and in contrast, showed a decline with DBT treatment in the BPD group, Group × Time interaction, F[2,36] = 3.71, p < 0.04, H–F, epsilon = 1.00, ƞ2 = 0.21 ( Fig. 2). The main effect of Group was also significant reflecting higher overall total DERS scores in the BPD group compared with the HCs, F[1,18] = 32.39, p < 0.0001. The main effect of Time was also significant, primarily reflecting the overall decline across time in DERS scores for patients, F[2,36] = 7.09, p < 0.003. Full-size image (26 K) Fig. 2. DERS total scores for the HC and BPD groups at baseline (0), 6 months, and 12 months. DERS scores showed a decline with DBT treatment in the BPD group, but were stable over time for the HC group, Group × Time interaction, F[2,36] = 3.71, p < 0.04, H–F, epsilon = 1.00. Figure options 3.2. fMRI The HC group showed overall amygdala activation (averaged across picture type, hemisphere, and novel/repeated pictures) that was similar at baseline and 12 months, whereas the BPD group exhibited an overall decrease in amygdala activation post-treatment, Group × Time interaction, F[1,20] = 4.89, p < 0.04; ƞ2 = 0.24, HC > BPD post-hoc, p < 0.08, trend level, Fig. 3). In order to confirm that BPD patients showed a change (i.e. decrease) in amygdala activity with DBT while the HC group showed no change over 12 months, we followed-up this significant interaction effect with post-hoc t-tests examining the amygdala change scores (0–12 months) for each group (compared to 0) and between-group differences. The resulted indicated that the HC group did not show a significant change in amygdala activity over time, whereas the BPD group did (0–12 month difference scores: HC: 1.99 ± 16.67 (vs. 0, p = 0.70) vs. BPD:-11.54 ± 11.73 (vs. 0, t(10) = 3.26, p < 0.01); (Cohen's d = 0.95), and this between-group difference was significant, t(20) = 2.20, p < 0.04. Full-size image (28 K) Fig. 3. Compared with the healthy control (HC) group (which was yoked and did not receive treatment), the BPD group showed a pattern of higher amygdala activity at baseline (pre-treatment) that decreased following a standard 12-month DBT intervention. The HC group was scanned to provide a benchmark for normal amygdala activity at baseline and a 12-month interval. *p = 0.08, Fisher's LSD post-hoc, trend-level. Figure options There was also a significant for Group × Time × Picture type × Picture repetition × Hemisphere interaction, F[2,19] = 3.71 p < 0.05, ƞ2 = 0.16, Fig. 4. Compared with healthy controls, individuals with BPD showed a pattern of greater decrease from pre- to post-treatment in amygdala activity for all three pictures types, but particularly in the left hemisphere and during the repeated emotional picture conditions (unpleasant and pleasant). None of the other interactions with Group reached statistical significance. Full-size image (150 K) Fig. 4. Compared with healthy controls, the individuals with BPD showed a pattern of greater decrease from pre- to post-treatment in amygdala activity for all three pictures types, but particularly in the left hemisphere and during the repeated emotional (unpleasant, pleasant) picture conditions (see red boxes in figure), Group × Time × Picture type × Picture repetition × Hemisphere interaction, F[2,19] = 3.71 p < 0.05. None of the post-hoc tests were significant. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Figure options 3.3. Self-report ratings of picture valence Neither the Group × Time × Picture Type interaction, nor any interaction with Diagnostic group was significant for the SAM self-report ratings of picture valence. Both groups showed the standard, linear, stepwise self-report rating pattern of pleasant pictures being the most unpleasant, pleasant being the least unpleasant, and neutral being intermediate. The valence ratings for the HC group did not change over time (i.e. 0-vs.-12 months). However, it is noteworthy that compared with the HC group, the BPD group showed a trend for rating the unpleasant pictures as less unpleasant following DBT (p < 0.06). We followed this finding up with a paired t-test for the BPD group comparing ratings for unpleasant pictures pre- and post-DBT which indicated that the patients rated the unpleasant pictures as less unpleasant post-DBT (pre-DBT: 7.99 ± 0.52 post-DBT: 7.42 ± 0.62, t(9) = 2.90, p < 0.02). Compared with HCs, there was a trend for the BPD group to rate the pleasant pictures as less pleasant at both the baseline and post-DBT time points (HC-vs.-BPD, p < 0.07). 3.4. Amygdala and clinical change with DBT Among the BPD patients, reduction in amygdala activity to repeated unpleasant pictures following DBT was associated with improved emotion regulation as measured by the change in total DERS score and the DERS Strategy subscale score (r = 0.70, p < 0.02, r = 0.69, p < 0.02, respectively; Fig. 5). Full-size image (51 K) Fig. 5. Scatterplots and Pearson correlation coefficients for the BPD group show the relationship between change (pre-treatment minus post-treatment, i.e. 0–12 months) in amygdala activation to repeated unpleasant pictures and emotional regulation (measured by change in the DERS total score (Top) and the DERS strategy subscale (Bottom). Among the patient group, greater reduction in amygdala activity to repeated-unpleasant pictures (i.e. better habituation) following DBT was associated with greater clinical improvement in emotional regulation and use of emotion regulation strategies.