Adipokines in depressed women with and without adverse childhood experiences.

BACKGROUND: Adverse childhood experiences (ACE) elevate the risk of both major depressive disorder (MDD) and metabolic diseases. The underlying pathophysiology might include alterations of adipokine levels as a consequence of ACE. In this study, we used a full-factorial design to investigate the levels of select adipokines in women with ACE-only (n = 23), MDD-only (n = 27), ACE+MDD (n = 25) and healthy controls (HC, n = 29) to identify metabolic makers associated with vulnerability and resilience of developing MDD after ACE exposure. METHODS: Serum levels of adiponectin, leptin, adiponectin-to-leptin (A/L) ratio, and retinol binding protein 4 (RBP4) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin levels did not differ between groups. Individuals with vs. without MDD showed higher leptin serum concentrations. As predicted, A/L ratio indicated lower values in individuals with vs. without ACE. RBP4 showed a more nuanced pattern with reduced levels in the ACE-only and MDD-only groups compared to HC. Furthermore, the ACE-only group showed lower RBP4 concentrations compared to ACE+MDD. These results were not accounted by BMI or medication status. CONCLUSION: Our results do not support the utility of adiponectin and leptin as predictors of vulnerability or resilience of developing MDD after ACE. In contrast, RBP4 might play a role in resilience towards the development of MDD following ACE. Further research on this more recently discovered adipokine seems warranted.

The Hypothalamus-Pituitary-Adrenal Axis and Social Cognition in Borderline Personality Disorder.

Borderline personality disorder (BPD) is characterized by emotional instability, impulsivity and unstable interpersonal relationships. Patients experience discomforting levels of distress, inducing symptoms like dissociation, aggression or withdrawal. Social situations are particularly challenging, and acute social stress can reduce patients' cognitive and social functioning. In patients with Major Depressive Disorder or Posttraumatic Stress Disorder, which show high comorbidity with BPD, the endocrine stress response is characterized by Hypothalamus-Pituitary-Adrenal (HPA) axis dysfunction, which affects cognitive functioning. Compared to these clinical groups, research on HPA-axis function in BPD is relatively scarce, but evidence points towards a blunted cortisol reactivity to acute stress. Since BPD patients are particularly prone to social stress and experience high subjective difficulties in these situations, it seems plausible that HPA-axis dysregulation might contribute to decreased social cognition in BPD. The present review summarizes findings on the HPA-axis function in BPD and its association with social cognition following acute social stress. For this purpose, we review literature that employed a widely used social stressor (Trier Social Stress Test, TSST) to study the effects of acute social stress on social cognition and the HPA-axis response. We contrast these findings with studies on social cognition that employed Cyberball, another widely used social stressor that lacks HPA-axis involvement. We conclude that research on social cognition in BPD reveals heterogeneous results with no clear relationship between social functioning and HPA-axis response. More research is needed to better understand the psychophysiological underpinnings of impaired social cognition in BPD.

Evidence of deviant parasympathetic response to social exclusion in women with borderline personality disorder.

Stressful social situations like social exclusion are particularly challenging for patients with borderline personality disorder (BPD) and often lead to dysfunctional reactive behaviour of aggression and withdrawal. The autonomous signature of these core symptoms of BPD remains poorly understood. The present study investigated the parasympathetic response to social exclusion in women with BPD (n = 62) and healthy controls (HC; n = 87). In a between-subjects design, participants experienced objective social exclusion or overinclusion in the Cyberball task, a virtual ball-tossing game. Need threat scores served as individual measures of perceived exclusion and the resulting frustration of cognitive-emotional needs. Five-minute measurements of high-frequency heart rate variability (HF-HRV) at three time points (before, during, after Cyberball) indicated parasympathetic tone and regulation. We observed a trend towards lowered baseline HF-HRV in BPD vs. HC in line with previous findings. Interestingly, the parasympathetic response of patients with BPD to objective and perceived social exclusion fundamentally differed from HC: higher exclusion was associated with increased parasympathetic activation in HC, while this autonomic response was reversed and blunted in BPD. Our findings suggest that during social stress, the parasympathetic nervous system fails to display an adaptive regulation in patients with BPD, but not HC. Understanding the autonomous signature of the stress response in BPD allows the formulation of clinically relevant and biologically plausible interventions to counteract parasympathetic dysregulation in this clinical group.

Impact of social exclusion on empathy in women with borderline personality disorder.

Unstable interpersonal relationships and fear of abandonment are core symptoms of borderline personality disorder (BPD) that often intensify during stress. Psychosocial stress, which includes components of social exclusion and increases cortisol secretion, enhances emotional empathy in healthy individuals. Women with BPD, on the contrary, react with reduced emotional empathy. The aim of the present study was to investigate the effects of perceived social exclusion without accompanying cortisol increase on empathy in women with BPD and healthy women. To induce social exclusion, we randomized 98 women with BPD and 98 healthy women to either an exclusion or an overinclusion (control) condition of Cyberball, a virtual ball game. Subsequently, participants underwent the Multifaceted Empathy Test (MET), which assesses cognitive and emotional empathy. There was no increase in cortisol release after Cyberball. Cognitive empathy did not differ between groups or conditions. Women with BPD reported lower emotional empathy for positive emotions (group by valence interaction), but not for negative emotions. Exploratory analyses suggested that this effect might be more pronounced after social exclusion. Our results confirm previous findings that cognitive empathy does not differ between women with BPD and healthy women and extend this evidence to social exclusion. Emotional empathy in women with BPD seems to be more sensitive to the effects of stress or ambiguous social situations. Specifically, emotional empathy seems to be reduced for positive emotions, and might further decline after social exclusion. Empathic reactions to emotional stimuli of different valences and to specific emotions should be further investigated.

Learning from informative losses boosts the sense of agency.

Sense of agency, the feeling of having control over one's actions, is modulated by whether one's choices lead to desired or undesired outcomes. Learning similarly depends on outcome values from previous experience. In the current study, we evaluate a possible link between the sense of agency and learning, by investigating how intentional binding, an implicit measure of agency, changes during a probabilistic learning task. In two experiments, we show increased intentional binding in trials that follow losses, compared with trials that follow wins. Experiment 1 demonstrated that this post-error agency boost (PEAB) effect is rule-specific, as it did not occur if the trial following an error involved different action-outcome contingencies. Furthermore, PEAB was not modulated by the type of outcome presentation (monetary vs. affective). Experiment 2 showed that the PEAB effect can also occur when the current action involves a forced (as opposed to free) choice, but only when the previous, loss-provoking action was chosen freely. Thus, PEAB occurs when current actions are informed by outcomes of one's own previous action choices. Electroencephalography (EEG) data linked these effects to two event-related potential components, namely, the Feedback Related Negativity and the P300. Taken together, these results support the notion that PEAB reflects an adaptive property of human sense of agency, facilitating effective learning about the action-outcome structure of a specific task, to optimise future performance. By clarifying the conditions for enhancing the sense of agency through learning, this work adds to our understanding of human learning and agency.

Dissociable effects of prediction and integration during language comprehension: evidence from a large-scale study using brain potentials.

Composing sentence meaning is easier for predictable words than for unpredictable words. Are predictable words genuinely predicted, or simply more plausible and therefore easier to integrate with sentence context? We addressed this persistent and fundamental question using data from a recent, large-scale (n = 334) replication study, by investigating the effects of word predictability and sentence plausibility on the N400, the brain's electrophysiological index of semantic processing. A spatio-temporally fine-grained mixed-effect multiple regression analysis revealed overlapping effects of predictability and plausibility on the N400, albeit with distinct spatio-temporal profiles. Our results challenge the view that the predictability-dependent N400 reflects the effects of either prediction or integration, and suggest that semantic facilitation of predictable words arises from a cascade of processes that activate and integrate word meaning with context into a sentence-level meaning. This article is part of the theme issue 'Towards mechanistic models of meaning composition'.

Large-scale replication study reveals a limit on probabilistic prediction in language comprehension.

Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment ('cloze'). In our direct replication study spanning 9 laboratories (N=334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words.

I could have done otherwise: Availability of counterfactual comparisons informs the sense of agency.

Personal control and agency are closely associated with the counterfactual notion that a person could have done otherwise (CDO). In both philosophy and law, this counterfactual evaluation determines responsibility and punishment, yet little is known about its influence on agents' experience during action. We used a risky decision-making task to study how counterfactual evaluations influenced participants' sense of agency. Two factors were manipulated independently: the presence/absence of counterfactual comparisons between actions and the presence/absence of counterfactual comparisons between outcomes of these actions. Perceived agency was highest when both counterfactual comparisons were available. Interestingly, this pattern persisted even when counterfactual information was only revealed after action, suggesting a purely reconstructive evaluation effect. These findings allow a more precise phrasing of the CDO element of personal agency: a person feels most control when she could have performed another action, thereby obtaining another outcome.

Understanding Counterfactuality: A Review of Experimental Evidence for the Dual Meaning of Counterfactuals.

Cognitive and linguistic theories of counterfactual language comprehension assume that counterfactuals convey a dual meaning. Subjunctive-counterfactual conditionals (e.g., 'If Tom had studied hard, he would have passed the test') express a supposition while implying the factual state of affairs (Tom has not studied hard and failed). The question of how counterfactual dual meaning plays out during language processing is currently gaining interest in psycholinguistics. Whereas numerous studies using offline measures of language processing consistently support counterfactual dual meaning, evidence coming from online studies is less conclusive. Here, we review the available studies that examine online counterfactual language comprehension through behavioural measurement (self-paced reading times, eye-tracking) and neuroimaging (electroencephalography, functional magnetic resonance imaging). While we argue that these studies do not offer direct evidence for the online computation of counterfactual dual meaning, they provide valuable information about the way counterfactual meaning unfolds in time and influences successive information processing. Further advances in research on counterfactual comprehension require more specific predictions about how counterfactual dual meaning impacts incremental sentence processing.

Pragmatic skills predict online counterfactual comprehension: Evidence from the N400.

Counterfactual thought allows people to consider alternative worlds they know to be false. Communicating these thoughts through language poses a social-communicative challenge because listeners typically expect a speaker to produce true utterances, but counterfactuals per definition convey information that is false. Listeners must therefore incorporate overt linguistic cues (subjunctive mood, such as in If I loved you then) in a rapid way to infer the intended counterfactual meaning. The present EEG study focused on the comprehension of such counterfactual antecedents and investigated if pragmatic ability-the ability to apply knowledge of the social-communicative use of language in daily life-predicts the online generation of counterfactual worlds. This yielded two novel findings: (1) Words that are consistent with factual knowledge incur a semantic processing cost, as reflected in larger N400 amplitude, in counterfactual antecedents compared to hypothetical antecedents (If sweets were/are made of sugar). We take this to suggest that counterfactuality is quickly incorporated during language comprehension and reduces online expectations based on factual knowledge. (2) Individual scores on the Autism Quotient Communication subscale modulated this effect, suggesting that individuals who are better at understanding the communicative intentions of other people are more likely to reduce knowledge-based expectations in counterfactuals. These results are the first demonstration of the real-time pragmatic processes involved in creating possible worlds.

Marking the counterfactual: ERP evidence for pragmatic processing of German subjunctives.

Counterfactual conditionals are frequently used in language to express potentially valid reasoning from factually false suppositions. Counterfactuals provide two pieces of information: their literal meaning expresses a suppositional dependency between an antecedent (If the dice had been rigged…) and a consequent (… then the game would have been unfair). Their second, backgrounded meaning refers to the opposite state of affairs and suggests that, in fact, the dice were not rigged and the game was fair. Counterfactual antecedents are particularly intriguing because they set up a counterfactual world which is known to be false, but which is nevertheless kept to when evaluating the conditional's consequent. In the last years several event-related potential (ERP) studies have targeted the processing of counterfactual consequents, yet counterfactual antecedents have remained unstudied. We present an EEG/ERP investigation which employed German conditionals to compare subjunctive mood (which marks counterfactuality) with indicative mood at the critical point of mood disambiguation via auxiliary introduction in the conditional's antecedent. Conditional sentences were presented visually one word at a time. Participants completed an acceptability judgment and probe detection task which was not related to the critical manipulation of linguistic mood. ERPs at the point of mood disambiguation in the antecedent were compared between indicative and subjunctive. Our main finding is a transient negative deflection in frontal regions for subjunctive compared to indicative mood in a time-window of 450-600 ms. We discuss this novel finding in respect to working memory requirements for rule application and increased referential processing demands for the representation of counterfactuals' dual meaning. Our result suggests that the counterfactually implied dual meaning is processed without any delay at the earliest point where counterfactuality is marked by subjunctive mood.

Processing counterfactual and hypothetical conditionals: an fMRI investigation.

Counterfactual thinking is ubiquitous in everyday life and an important aspect of cognition and emotion. Although counterfactual thought has been argued to differ from processing factual or hypothetical information, imaging data which elucidate these differences on a neural level are still scarce. We investigated the neural correlates of processing counterfactual sentences under visual and aural presentation. We compared conditionals in subjunctive mood which explicitly contradicted previously presented facts (i.e. counterfactuals) to conditionals framed in indicative mood which did not contradict factual world knowledge and thus conveyed a hypothetical supposition. Our results show activation in right occipital cortex (cuneus) and right basal ganglia (caudate nucleus) during counterfactual sentence processing. Importantly the occipital activation is not only present under visual presentation but also with purely auditory stimulus presentation, precluding a visual processing artifact. Thus our results can be interpreted as reflecting the fact that counterfactual conditionals pragmatically imply the relevance of keeping in mind both factual and supposed information whereas the hypothetical conditionals imply that real world information is irrelevant for processing the conditional and can be omitted. The need to sustain representations of factual and suppositional events during counterfactual sentence processing requires increased mental imagery and integration efforts. Our findings are compatible with predictions based on mental model theory.