Georgia Koppe

Cerebral processing of social rejection in patients with borderline personality disorder

An intense fear of abandonment or rejection is a central feature of social relationships for individuals with borderline personality disorder (BPD). A total of 20 unmedicated BPD patients and 20 healthy participants (HC, matched for age and education) played a virtual ball-tossing game including the three conditions: exclusion, inclusion and a control condition with predefined game rules, whereas cerebral activity was assessed using functional magnetic resonance imaging. Subjective experiences of exclusion were assessed after each blocked condition. Both groups felt similarly excluded during the exclusion condition; however, BPD subjects felt more excluded than HC during the inclusion and control conditions. In all three conditions, BPD patients showed a stronger engagement of the dorsal anterior cingulate and medial prefrontal cortex. For HC, activation in several cerebral regions such as the insula and the precuneus differed depending on the interaction situation, whereas for BPD subjects activation in these regions was not modulated by experimental conditions. Subjects with BPD differed from HC in both their subjective reactions to and their neural processing of social interaction situations. Our data suggest that individuals with BPD have difficulty in discriminating between social situations, and tend to hypermentalize during social encounters that are not determined by the intentions of others.

Executive functions in borderline personality disorder

Different domains of executive function such as working memory and response inhibition were investigated together with elementary cognitive processes in borderline personality disorder (BPD). Patients with BPD (N=28) were compared to nonpatient controls (NP, N=28) on eight tasks (e.g. n-back, Go/NoGo, CPT-AX). In order to separate impairments in different cognitive domains and to assess the influence of more elementary cognitive processes on executive functioning, tasks were embedded in a reaction-time-decomposition approach. BPD patients solved tasks with accuracies comparable to those of nonpatients. The only exception was the n-back task, for which working memory is required: here, error rates were higher and increased more prominently in BPD patients depending on working memory load. In most tasks, movement times were shorter for BPD patients than for nonpatients, while the quality of task-solving was comparable. The faster processing in the BPD group was observable starting with the simplest task, i.e. a simple reaction-time task. These findings suggest that domains of executive functioning are differentially affected in BPD. In contrast to load-dependent deficits in working memory, response inhibition processes were unimpaired. Faster action-related processes could be observed in BPD patients in a variety of tasks; however, these did not influence executive functioning.

Pain Processing after Social Exclusion and Its Relation to Rejection Sensitivity in Borderline Personality Disorder.

Objective There is a general agreement that physical pain serves as an alarm signal for the prevention of and reaction to physical harm. It has recently been hypothesized that “social pain,” as induced by social rejection or abandonment, may rely on comparable, phylogenetically old brain structures. As plausible as this theory may sound, scientific evidence for this idea is sparse. This study therefore attempts to link both types of pain directly. We studied patients with borderline personality disorder (BPD) because BPD is characterized by opposing alterations in physical and social pain; hyposensitivity to physical pain is associated with hypersensitivity to social pain, as indicated by an enhanced rejection sensitivity. Method Twenty unmedicated female BPD patients and 20 healthy participants (HC, matched for age and education) played a virtual ball-tossing game (cyberball), with the conditions for exclusion, inclusion, and a control condition with predefined game rules. Each cyberball block was followed by a temperature stimulus (with a subjective pain intensity of 60% in half the cases). The cerebral responses were measured by functional magnetic resonance imaging. The Adult Rejection Sensitivity Questionnaire was used to assess rejection sensitivity. Results Higher temperature heat stimuli had to be applied to BPD patients relative to HCs to reach a comparable subjective experience of painfulness in both groups, which suggested a general hyposensitivity to pain in BPD patients. Social exclusion led to a subjectively reported hypersensitivity to physical pain in both groups that was accompanied by an enhanced activation in the anterior insula and the thalamus. In BPD, physical pain processing after exclusion was additionally linked to enhanced posterior insula activation. After inclusion, BPD patients showed reduced amygdala activation during pain in comparison with HC. In BPD patients, higher rejection sensitivity was associated with lower activation differences during pain processing following social exclusion and inclusion in the insula and in the amygdala. Discussion Despite the similar behavioral effects in both groups, BPD patients differed from HC in their neural processing of physical pain depending on the preceding social situation. Rejection sensitivity further modulated the impact of social exclusion on neural pain processing in BPD, but not in healthy controls.

Temporal unpredictability of a stimulus sequence affects brain activation differently depending on cognitive task demands

Within cognitive neuroscience, in nearly every experimental setting, subjects are presented with stimuli that appear at either constant or variable points in time, referred to as interstimulus intervals (ISIs). These temporal patterns differ in the degree to which an exact stimulus onset may be predicted. We investigated whether this experimental feature affects brain and behavior, and whether the impact is modulated by the cognitive demands of a task. Subjects (N=26) were assessed via fMRI while solving three different tasks under either temporally predictable (constant ISI) or unpredictable (variable ISI) conditions. The tasks differed with regard to demands on working memory and response uncertainty. Compared to constant ISIs, variable (i.e., less predictable) ISIs led to a general increase in reaction time and in right amygdala activation. Depending on the cognitive demands required by the specific task, the left amygdala, the parietal cortex, the supplementary motor area, and the dorsolateral prefrontal cortex were engaged as well. The results indicate that the temporal structure in a stimulus sequence affects both overt and covert behaviors. Implicit temporal uncertainty increases activation in several brain regions depending on cognitive demands. Thus, an often-overlooked basic design feature, the application of constant or variable ISIs, may contribute to heterogeneity in cognitive neuroscience findings.

Social Interaction Behavior in ADHD in Adults in a Virtual Trust Game

Objective: Social cognitive functions in adults with ADHD were investigated in a virtual social exchange game. Method: The sample consisted of 40 participants (20 adult ADHD participants, 20 healthy controls). Participants played a multiround trust game with virtual trustees who differed in regard to fairness and presence of emotional facial cues. Results: Investments were higher in ADHD participants than in healthy participants except for partners who played fair with constant neutral expressions. ADHD patients did not adapt their behavior to the fairness of the trustee. In the presence of emotional facial cues, ADHD and healthy participants transferred more monetary units to happy rather than angry-looking trustees. Differences in investment behavior were not linked to deficits in emotion-recognition abilities or cognitive dysfunctions. Conclusion: Alterations in interaction behavior and in the formation of a general attitude toward social partners could be shown in adults with ADHD.

Computational models as statistical tools

Traditionally, models in statistics are relatively simple ‘general purpose’ quantitative inference tools, while models in computational neuroscience aim more at mechanistically explaining specific observations. Research on methods for inferring behavioral and neural models from data, however, has shown that a lot could be gained by merging these approaches, augmenting computational models with distributional assumptions. This enables estimation of parameters of such models in a principled way, comes with confidence regions that quantify uncertainty in estimates, and allows for quantitative assessment of prediction quality of computational models and tests of specific hypotheses about underlying mechanisms. Thus, unlike in conventional statistics, inferences about the latent dynamical mechanisms that generated the observed data can be drawn. Future directions and challenges of this approach are discussed.

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation

Background Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response. Methods We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response. Results Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus. Conclusions Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This implies that more research is required before therapeutic interventions may benefit from a combination with reconsolidation processes.

CACNA1C gene regulates behavioral strategies in operant rule learning

Behavioral experiments are usually designed to tap into a specific cognitive function, but animals may solve a given task through a variety of different and individual behavioral strategies, some of them not foreseen by the experimenter. Animal learning may therefore be seen more as the process of selecting among, and adapting, potential behavioral policies, rather than mere strengthening of associative links. Calcium influx through high-voltage-gated Ca2+ channels is central to synaptic plasticity, and altered expression of Cav1.2 channels and the CACNA1C gene have been associated with severe learning deficits and psychiatric disorders. Given this, we were interested in how specifically a selective functional ablation of the Cacna1c gene would modulate the learning process. Using a detailed, individual-level analysis of learning on an operant cue discrimination task in terms of behavioral strategies, combined with Bayesian selection among computational models estimated from the empirical data, we show that a Cacna1c knockout does not impair learning in general but has a much more specific effect: the majority of Cacna1c knockout mice still managed to increase reward feedback across trials but did so by adapting an outcome-based strategy, while the majority of matched controls adopted the experimentally intended cue-association rule. Our results thus point to a quite specific role of a single gene in learning and highlight that much more mechanistic insight could be gained by examining response patterns in terms of a larger repertoire of potential behavioral strategies. The results may also have clinical implications for treating psychiatric disorders.

Temporal unpredictability of a stimulus sequence and the processing of neutral and emotional stimuli

Most experimental settings in cognitive neuroscience present a temporally structured stimulus sequence, i.e., stimuli may occur at either constant and predictable or variable and less predictable inter-stimulus intervals (ISIs). This experimental feature has been shown to affect behavior and activation of various cerebral structures such as the parietal cortex and the amygdala. Studies employing explicit or implicit cues to manipulate predictability of events have shown that unpredictability particularly accentuates the response to events of negative valence. The present study investigates whether the effects of unpredictability are similarly affected by the emotional content of stimuli when unpredictability is induced simply by the temporal structure of a stimulus sequence, i.e., by variable as compared to constant ISIs. In an fMRI study, we applied three choice-reaction-time tasks with stimuli of different social-emotional content. Subjects (N=30) were asked to identify the gender in angry and happy faces, or the shape of geometric figures. Tasks were performed with variable and constant ISIs. During the identification of shapes, variable ISIs increased activation in widespread areas comprising the amygdala and fronto-parietal regions. Conversely, variable ISIs during gender identification resulted in a decrease of activation in a small region near the intraparietal sulcus. Our findings reveal that variability in the temporal stimulus structure of an experimental setting affects cerebral activation depending on task demands. They suggest that the processing of emotional stimuli of different valence is not much affected by the decision of employing a constant or a variable temporal stimulus structure, at least in the context of implicit emotion processing tasks. In contrast, temporal structure diversely affects the processing of neutral non-social compared to emotional stimuli, emphasizing the relevance of considering this experimental feature in studies which aim at differentiating social-emotional from cognitive processing in general, and more particularly, aim at identifying circumscribed alterations of social cognition in mental disorders.

Difficulties with being socially accepted: An experimental study in borderline personality disorder.

Anxious preoccupation with real or imagined abandonment is a key feature of borderline personality disorder (BPD). Recent experimental research suggests that patients with BPD do not simply show emotional overreactivity to rejection. Instead, they experience reduced connectedness with others in situations of social inclusion. Resulting consequences of these features on social behavior are not investigated yet. The aim of the present study was to investigate the differential impact of social acceptance and rejection on social expectations and subsequent social behavior in BPD. To this end, we developed the Mannheim Virtual Group Interaction Paradigm in which participants interacted with a group of computer-controlled avatars. They were led to believe that these represented real human coplayers. During these interactions, participants introduced themselves, evaluated their coplayers, assessed their social expectations and received feedback signaling either acceptance or rejection by the alleged other participants. Subsequently, participants played a modified trust game, which measured cooperative and aggressive behavior. Fifty-six nonmedicated BPD patients and 56 healthy control participants were randomly and double-blindly assigned to either the group-acceptance or group-rejection condition. BPD patients showed lower initial expectations of being socially accepted than healthy controls. After repeated presentation of social feedback, they adjusted their expectations in response to negative, but not to positive feedback. After the experience of social acceptance, BPD patients behaved less cooperatively. These experimental findings point to a clinically relevant issue in BPD: Altered cognitive and behavioral responses to social acceptance may hamper the forming of stable cooperative relationships and negatively affect future interpersonal relationships.