Hyper-modulation of brain networks by the amygdala among women with Borderline Personality Disorder: Network signatures of affective interference during cognitive processing

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Highlights

  • Emotion dysregulation in BPD may result from an imbalance in fronto-limbic network function.

  • PPI analysis demonstrated network dysfunction in BPD during an affective Go No-Go task.

  • In the negative condition, amygdala exerted greater modulation of its targets in BPD compared to HC subjects.

  • Amygdala modulation was greatest in regions relevant for processing response inhibition.

  • BPD vulnerability to affective interference with cognition is related to underlying dysfunctional brain networks.

Abstract

Emotion dysregulation is a core characteristic of patients with Borderline Personality Disorder (BPD), and is often attributed to an imbalance in fronto-limbic network function. Hyperarousal of amygdala, especially in response to negative affective stimuli, results in affective interference with cognitive processing of executive functions. Clinical consequences include the impulsive-aggression, suicidal and self-injurious behaviors which characterize BPD. Dysfunctional interactions between amygdala and its network targets have not been well characterized during cognitive task performance. Using psychophysiological interaction analysis (PPI), we mapped network profiles of amygdala interaction with key regulatory regions during a Go No-Go task, modified to use negative, positive and neutral Ekman faces as targets. Fifty-six female subjects, 31 BPD and 25 healthy controls (HC), completed the affectively valenced Go No-Go task during fMRI scanning. In the negative affective condition, the amygdala exerted greater modulation of its targets in BPD compared to HC subjects in Rt. OFC, Rt. dACC, Rt. Parietal cortex, Rt. Basal Ganglia, and Rt. dlPFC. Across the spectrum of affective contrasts, hypermodulation in BPD subjects observed the following ordering: Negative > Neutral > Positive contrast. The amygdala seed exerted modulatory effects on specific target regions important in processing response inhibition and motor impulsiveness. The vulnerability of BPD subjects to affective interference with impulse control may be due to specific network dysfunction related to amygdala hyper-arousal and its effects on prefrontal regulatory regions such as the OFC and dACC.

Introduction

Emotion dysregulation is a core diagnostic characteristic of Borderline Personality Disorder (BPD), and is considered by some to be the primary source of behavioral pathology in this illness (Linehan, 1993). In laboratory studies, patients with BPD respond more intensely and for longer durations to negative emotional stimuli, and are slower to return to baseline than healthy controls (Jacob et al., 2008, Levine et al., 1997). In studies using electronic monitoring in the natural environment, BPD subjects demonstrate more affective instability, hypersensitivity, extreme changes of mood, negative and conflicting emotions compared to controls (Ebner-Priemer et al., 2007a, Ebner-Priemer et al., 2007b, Ebner-Priemer et al., 2008, Reisch et al., 2008, Trull et al., 2008). Current theories of emotion regulation postulate a balance between “top down” cortical modulation and “bottom up” limbic arousal. i.e. Dysregulation of emotion may result from either hyper-arousal of the limbic system, especially in response to aversive stimuli, or, conversely, diminished efficacy of tonic cortical inhibition (Ochsner and Gross, 2006, Gross and Thompson, 2006, Phillips et al., 2008, Davidson et al., 2000). The affective instability of the borderline patient is attributed to an imbalance in fronto-limbic network function involving the amygdala and associated regions of the limbic system, and regulatory regions in prefrontal cortex (PFC), including the orbital frontal cortex (OFC), anterior cingulate cortex (ACC), dorso-lateral PFC (dlPFC) and associated areas (Schulze et al., 2016). fMRI studies have repeatedly demonstrated increased arousal of the amygdala in BPD compared to control subjects in response to provocations using emotional stimuli such as the affectively valenced Ekman faces (Donegan et al., 2003, Minzenberg et al., 2007), aversive IAPS scenes (Herpertz et al., 2001, Schulze et al., 2011, Hazlett et al., 2012), unresolved life events (Beblo et al., 2006), emotional scripts (Schmahl et al., 2003, Schmahl and Bremner, 2006), and negative social pictures (Koenigsberg et al., 2014). BPD subjects show prolonged BOLD responses in amygdala to emotional stimuli, indicating longer time to return to baseline, and a failure to down-regulate (habituate) amygdala responses with repeated presentations of emotional pictures, suggesting a deficit in regulating emotional arousal (Hazlett et al., 2012). Hyper-arousal of the amygdala is clinically important, given its role in appraising the affective salience of stimuli, especially facial expressions (Calder and Young, 2005), and in the appraisal of perceived threat and mediation of fear responses (LeDoux, 1993). In this investigation we extend previous work in BPD by assessing dysfunctional network profiles of the amygdala in the context of an affective impulsivity paradigm (Soloff et al., 2015).

Anatomical network connectivity, and functional interactions of the amygdala have been systematically studied using both animal and human models (Diwadkar et al., 2012, Phelps and LeDoux, 2005); however, dysfunctional interactions between the amygdala and its network targets have not been well-characterized in BPD. Thus, while hyper-activation of the amygdala is a characteristic of impaired functional brain responses in BPD, the directional network effects exerted by the amygdala in BPD are relatively under-studied using network analyses of fMRI signals. Understanding these network profiles will contribute greatly toward assessing the contribution of “bottom-up” signals in driving some of the core characteristics of emotional dysregulation and how they might affect cognitive processing in BPD.

While it is clear that the brain's cognitive systems are not insulated from affective interference, the network profiles of the amygdala during cognitive processing have not been well characterized (Phelps, 2006). The OFC, ACC, dlPFC, and associated areas, are involved in executive cognitive functions such as focused attention, response inhibition, conflict resolution, encoding and recall of memory. Through extensive feedback loops to limbic structures, these prefrontal regions exercise a measure of “top-down” tonic control to maintain emotional homeostasis (Davidson and Irwin, 1999). In patients with BPD, affective interference, especially by negative stimuli, impairs functioning of brain networks that sub-serve cognitive processing of executive functions required for adaptive responding (Sebastian et al., 2013, Soloff et al., 2015, Winter et al., 2014).

We have been studying the effects of affect on brain responses during cognitive processing in BPD using paradigms specifically modified to utilize and permute affective context. In relying on affective appraisal to gate cognitive processing, we seek to force integration of affective and cognitive domains (Blair et al., 2007), and to assess if this integration differentially affects brain responses in BPD.

A particular focus of our work is the borderline patient's trait impulsivity, a diagnostic characteristic of the disorder which is clinically associated with affective instability, aggression, suicidal and self-destructive behaviors (Brodsky et al., 2006). Impulsive-aggressive behavior in BPD is associated with structural, metabolic, and functional abnormalities in fronto-limbic networks (Berlin et al., 2005, Sebastian et al., 2013, Siever, 2008). Impulsive, aggressive, and self-destructive behaviors in BPD occur most often in the context of negative affectivity, especially perceived rejection (Yen et al., 2004). fMRI studies of impulse control which incorporate negative emotional stimuli, demonstrate fronto-limbic dysfunction in BPD compared to control subjects (Jacob et al., 2008, Sebastian et al., 2014). Given the clinical relevance of impulsivity in BPD, we have focused attention on the role of emotional interference with this executive function using an affectively-modified Go-No-Go paradigm.

The classic version of this paradigm requires participants to gate their responses to rapidly presented stimuli based on perceptual identity. In our affective Go No-Go paradigm, positive, negative and neutral Ekman faces are used to mediate impulse control (i.e. response inhibition), depending on the affective (rather than perceptual) gating of the response (Soloff et al., 2015). As a result, it is possible to isolate the selective effects of the affective context of the response on fMRI responses, and particularly, on brain network interactions. Using the affective Go No-Go paradigm under negative affective conditions in subjects with BPD, we previously reported increased activation in amygdala, and increased and decreased activation in different regions of the middle-inferior OFC. Robust increases were also noted in areas reflecting task-relevant processing: the superior parietal/precuneus (for visuo-spatial processing and episodic visual memory), and the basal ganglia (for reward-based decision-making) (Soloff et al., 2015). The current extension of our work is specifically focused on the network profiles of the amygdala, relying on modeling psycho-physiological interactions (PPI) in the fMRI data (Friston et al., 1997, Horwitz et al., 2005, O'Reilly et al., 2012).

The use of PPI was motivated by its analytic value, positioned as it is between techniques of functional and maximal effective connectivity analyses (Stephan et al., 2016, Silverstein et al., 2016), providing a robust model for investigation of seed-based network interactions (Friston, 2011, Friston et al., 1997, Kim and Horwitz, 2008, Woodcock et al., 2016). PPI estimates directional modulation by an a priori defined seed region (e.g., amygdala) on target regions (e.g.,OFC) in the context of a psychological contrast of interest (e.g., negative > positive affective context) (Friston et al., 1997). The framework for network explorations using fMRI data is vast, with the availability of a rich set of well defined quantitative models. We chose PPI to explore differential interactions between the amygdala and its targets, in BPD relative to controls. PPIs afford rapid and efficient exploration of pairwise directional network effects between seed regions and targets (Silverstein et al., 2016) and are particularly useful when the choice of seed is well motivated (in our case, the amygdala). This model is more simplistic than more complex dynamic causal models of network interactions (or “effective connectivity” analyses) yet is a useful “first step” in divining dysfunctional network profiles in disorders ranging from schizophrenia (Wadehra et al., 2013) to obsessive compulsive disorder (Diwadkar, 2015, Friedman et al., 2017). In this analysis, we use PPI in elucidating “bottom-up” profiles of the amygdala during response inhibition in BPD, as well as mechanisms of affective interference at the level of brain network interactions.

Section snippets

Method

The study was approved by the University of Pittsburgh Institutional Review Board. Fifty-six (56) female subjects, 31 cases and 25 controls, 18–45 years of age, were recruited from the PI's ongoing longitudinal studies of BPD, from psychiatric outpatient clinics, and by advertisement from the surrounding community. The study was restricted to females as they comprise 75% of BPD patients in clinical settings, avoiding any confounds due to gender. All subjects gave written informed consent. To be

Subject characteristics

The mean (s.d.) age of the BPD sample was 30 (8.2) years, compared to 24.5 (5.5) years for healthy controls, (t 3.00, df 52.4, p = 0.004). At the time of the scan, current co-morbid Axis I diagnoses were noted in 27 BPD subjects (87.1%), the most frequent being MDD (in 19 subjects (61.3%)) and Generalized Anxiety Disorder (in 11 subjects (35.5%), with some overlap. A current Substance Use Disorder was noted in only 2 subjects (6.5%). Additional Axis II co-morbidity was diagnosed in 18 BPD

Discussion

Using an affectively valenced Go No-Go task, we evaluated network profiles of the amygdala that might underpin affective interference in BPD compared to control subjects. Consistent with a model of “bottom up” arousal to emotional stimuli, the amygdala exerted hyper-modulatory effects on specific target regions that are relevant in processing response inhibition and motor impulsiveness. The resulting pattern of network dysfunction suggests that BPD subjects may be more vulnerable to affective

Role of funding source

This work was supported by the National Institute of Mental Health (grant number MH 048063 to Dr. Soloff). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.

Contributors

Paul Soloff was involved in the study design, analysis, interpretation and manuscript writing. Kristy Abraham, Karthik Ramaseshan, and Ashley Burgess were involved in data analysis. Vaibhav A. Diwadkar was involved in the study design, analysis, interpretation, and manuscript writing.

Conflicts of interest

There are no conflicts of interest with any of the authors.

Acknowledgement

This work was funded by the National Institute of Mental Health, grant # MH 048463 to Dr. Soloff.

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