Neural Control of Emotional Actions in Response to Affective Vocalizations.

Social-emotional cues, such as affective vocalizations and emotional faces, automatically elicit emotional action tendencies. Adaptive social-emotional behavior depends on the ability to control these automatic action tendencies. It remains unknown whether neural control over automatic action tendencies is supramodal or relies on parallel modality-specific neural circuits. Here, we address this largely unexplored issue in humans. We consider neural circuits supporting emotional action control in response to affective vocalizations, using an approach-avoidance task known to reliably index control over emotional action tendencies elicited by emotional faces. We isolate supramodal neural contributions to emotional action control through a conjunction analysis of control-related neural activity evoked by auditory and visual affective stimuli, the latter from a previously published data set obtained in an independent sample. We show that the anterior pFC (aPFC) supports control of automatic action tendencies in a supramodal manner, that is, triggered by either emotional faces or affective vocalizations. When affective vocalizations are heard and emotional control is required, the aPFC supports control through negative functional connectivity with the posterior insula. When emotional faces are seen and emotional control is required, control relies on the same aPFC territory downregulating the amygdala. The findings provide evidence for a novel mechanism of emotional action control with a hybrid hierarchical architecture, relying on a supramodal node (aPFC) implementing an abstract goal by modulating modality-specific nodes (posterior insula, amygdala) involved in signaling motivational significance of either affective vocalizations or faces.

Discriminating stress from rest based on resting-state connectivity of the human brain: A supervised machine learning study.

Acute stress induces large-scale neural reorganization with relevance to stress-related psychopathology. Here, we applied a novel supervised machine learning method, combining the strengths of a priori theoretical insights with a data-driven approach, to identify which connectivity changes are most prominently associated with a state of acute stress and individual differences therein. Resting-state functional magnetic resonance imaging scans were taken from 334 healthy participants (79 females) before and after a formal stress induction. For each individual scan, mean time-series were extracted from 46 functional parcels of three major brain networks previously shown to be potentially sensitive to stress effects (default mode network (DMN), salience network (SN), and executive control networks). A data-driven approach was then used to obtain discriminative spatial linear filters that classified the pre- and post-stress scans. To assess potential relevance for understanding individual differences, probability of classification using the most discriminative filters was linked to individual cortisol stress responses. Our model correctly classified pre- versus post-stress states with highly significant accuracy (above 75%; leave-one-out validation relative to chance performance). Discrimination between pre- and post-stress states was mainly based on connectivity changes in regions from the SN and DMN, including the dorsal anterior cingulate cortex, amygdala, posterior cingulate cortex, and precuneus. Interestingly, the probability of classification using these connectivity changes were associated with individual cortisol increases. Our results confirm the involvement of DMN and SN using a data-driven approach, and specifically single out key regions that might receive additional attention in future studies for their relevance also for individual differences.

Acute stress alters the 'default' brain processing.

Active adaptation to acute stress is essential for coping with daily life challenges. The stress hormone cortisol, as well as large scale re-allocations of brain resources have been implicated in this adaptation. Stress-induced shifts between large-scale brain networks, including salience (SN), central executive (CEN) and default mode networks (DMN), have however been demonstrated mainly under task-conditions. It remains unclear whether such network shifts also occur in the absence of ongoing task-demands, and most critically, whether these network shifts are predictive of individual variation in the magnitude of cortisol stress-responses. In a sample of 335 healthy participants, we investigated stress-induced functional connectivity changes (delta-FC) of the SN, CEN and DMN, using resting-state fMRI data acquired before and after a socially evaluated cold-pressor test and a mental arithmetic task. To investigate which network changes are associated with acute stress, we evaluated the association between cortisol increase and delta-FC of each network. Stress-induced cortisol increase was associated with increased connectivity within the SN, but with decreased coupling of DMN at both local (within network) and global (synchronization with brain regions also outside the network) levels. These findings indicate that acute stress prompts immediate connectivity changes in large-scale resting-state networks, including the SN and DMN in the absence of explicit ongoing task-demands. Most interestingly, this brain reorganization is coupled with individuals' cortisol stress-responsiveness. These results suggest that the observed stress-induced network reorganization might function as a neural mechanism determining individual stress reactivity and, therefore, it could serve as a promising marker for future studies on stress resilience and vulnerability.

High Endogenous Testosterone Levels Are Associated With Diminished Neural Emotional Control in Aggressive Police Recruits.

Although police officers are carefully selected for their high emotion-regulation abilities, excessive aggression in police officers has been reported, particularly in socially challenging situations known to elicit high state testosterone levels. Adequate regulation of emotional actions depends on the prefrontal cortex's control over the amygdala. We investigated the effects of trait aggression and endogenous testosterone on this emotional-control neurocircuitry in 275 healthy, high-functioning police recruits using a functional MRI social-emotional task eliciting impulsive and controlled approach-and-avoidance actions. Higher levels of aggression were counteracted by increased anterior prefrontal cortex (aPFC) control over the amygdala when control over automatic emotional actions was required. Crucially, testosterone had a detrimental effect on this aggression-dependent aPFC recruitment: Police recruits with relatively high trait aggression and high state testosterone showed reduced aPFC control over the amygdala during emotion regulation. This provides a mechanistic explanation for inadequate behavioral control during socially challenging situations in otherwise well-functioning individuals.

The role of stop-signal probability and expectation in proactive inhibition.

The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop-signal probability and the subjective expectation that a stop-signal will or will not occur. Here we investigated the effects of stop-signal probability and the expectation of a stop-signal on proactive inhibition. Twenty participants performed a modified stop-signal anticipation task while being scanned with functional magnetic resonance imaging. At the beginning of each trial, the stop-signal probability was indicated by a cue (0% or > 0%), and participants had to indicate whether they expected a stop-signal to occur (yes/no/don't know). Participants slowed down responding on trials with a > 0% stop-signal probability, but this proactive response slowing was even greater when they expected a stop-signal to occur. Analyses were performed in brain regions previously associated with proactive inhibition. Activation in the striatum, supplementary motor area and left dorsal premotor cortex during the cue period was increased when participants expected a stop-signal to occur. In contrast, activation in the right inferior frontal gyrus and right inferior parietal cortex activity during the stimulus-response period was related to the processing of contextual cues signalling objective stop-signal probability, regardless of expectation. These data show that proactive inhibition depends on both the processing of objective contextual task information and the subjective expectation of stop-signals.

Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study.

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine's effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19-39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI - a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Acute-stress-induced change in salience network coupling prospectively predicts post-trauma symptom development.

Substantial individual differences exist in how acute stress affects large-scale neurocognitive networks, including salience (SN), default mode (DMN), and central executive networks (CEN). Changes in the connectivity strength of these networks upon acute stress may predict vulnerability to long-term stress effects, which can only be tested in prospective longitudinal studies. Using such longitudinal design, we investigated whether the magnitude of acute-stress-induced functional connectivity changes (delta-FC) predicts the development of post-traumatic stress-disorder (PTSD) symptoms in a relatively resilient group of young police students that are known to be at high risk for trauma exposure. Using resting-state fMRI, we measured acute-stress-induced delta-FC in 190 police recruits before (baseline) and after trauma exposure during repeated emergency-aid services (16-month follow-up). Delta-FC was then linked to the changes in perceived stress levels (PSS) and post-traumatic stress symptoms (PCL and CAPS). Weakened connectivity between the SN and DMN core regions upon acute-stress induction at baseline predicted longitudinal increases in perceived-stress level but not of post-traumatic stress symptoms, whereas increased coupling between the overall SN and anterior cerebellum was observed in participants with higher clinician-rated PTSD symptoms, particularly intrusion levels. All the effects remained significant when controlling for trauma-exposure levels and cortisol-stress reactivity. Neither hormonal nor subjective measures exerted similar predictive or acquired effects. The reconfiguration of large-scale neural networks upon acute-stress induction is relevant for assessing and detecting risk and resilience factors for PTSD. This study highlights the SN connectivity-changes as a potential marker for trauma-related symptom development, which is sensitive even in a relatively resilient sample.

Trauma-induced human glucocorticoid receptor expression increases predict subsequent HPA-axis blunting in a prospective longitudinal design.

One of the hallmarks of post-traumatic stress disorder (PTSD) is abnormalities in the HPA-axis. This includes alterations in its negative feedback regulation. Although altered glucocorticoid receptor (GR) mRNA expression is thought to play a crucial role herein, direct longitudinal evidence in humans is lacking to support this assumption. The current prospective longitudinal study assessed the consequence of repeated trauma exposure on GR mRNA expression from saliva samples in early-career police recruits (n = 112) by assessing them before and after trauma exposure. We did not observe a relationship between change in GR mRNA expression and development of PTSD symptom severity. However, the more traumatic events were experienced during police training the stronger GR mRNA expression was increased. Moreover, increases in GR mRNA expression were associated with blunted HPA-axis stress-reactivity at follow-up compared to baseline. This study provides the first longitudinal evidence of a dose-response relationship between trauma and human GR mRNA expression (extracted from saliva) changes; therefore, replication is warranted. Our finding might contribute a possible explanatory framework for blunted HPA-axis function associated with PTSD.

Anterior prefrontal brain activity during emotion control predicts resilience to post-traumatic stress symptoms.

Regulating social emotional actions is essential for coping with life stressors and is associated with control by the anterior prefrontal cortex (aPFC) over the amygdala. However, it remains unclear to what extent prefrontal emotion regulation capacities contribute to resilience against developing post-traumatic stress disorder (PTSD) symptoms. Here, 185 police recruits who experienced their core trauma in the line of duty participated in a prospective longitudinal study. Pre- and post-trauma, they performed a well-established functional magnetic resonance imaging (fMRI) approach-avoidance task, mapping impulsive and controlled emotional actions. Higher baseline aPFC, dorsal and medial frontal pole activity was related to lower PTSD symptoms after trauma exposure. aPFC activity predicted symptom development over and above self-reported and behavioural measures. Trauma exposure, but not trauma symptoms, predicted amygdala activation at follow-up. These findings suggest that prefrontal emotion regulation activity predicts increased resilience against developing post-traumatic stress symptoms and may provide fruitful starting points for prediction and intervention studies.

Larger dentate gyrus volume as predisposing resilience factor for the development of trauma-related symptoms.

Early interventions to improve resilience require the identification of objective risk biomarkers for PTSD symptom development. Although altered hippocampal and amygdala volumes are consistently observed in PTSD, it remains currently unknown whether they represent a predisposing vulnerability factor for PTSD symptom development or an acquired consequence of trauma exposure and/or the disorder. We conducted a longitudinal, prospective study in 210 police recruits at high risk for trauma exposure (56 females(26.7%); mean[SD] age = 24.02[5.19]). Structural MRI scans and trauma-related symptom severity were assessed at pre-trauma baseline and at 16-month follow-up. Between assessments, police recruits were exposed to various potentially traumatic events during their police training. Police recruits reported a significant increase in police-related trauma exposure and stress-related symptoms between assessments. Smaller hippocampal left dentate gyrus (DG) volumes at baseline predicted increase in self-reported PTSD symptoms (B[SE] = -0.21[0.08], p = 0.011), stress symptoms (B[SE] = -0.16[0.07], p = 0.024) and negative affect (B[SE] = -0.21[0.07], p = 0.005) upon trauma exposure. Amount of police-related trauma exposure between assessments was positively associated with an increase in left basal amygdala nucleus volume (B[SE] = 0.11[0.05], p = 0.026). Taken together, smaller DG-volumes pre-trauma may represent a predisposing neurobiological vulnerability factor for development of trauma-related symptoms. On the other hand, amount of trauma exposure between assessments was positively associated with increased amygdala basal nucleus volume, suggesting acquired neural effects. These findings suggest that preventive interventions for PTSD aimed at improving resilience could be targeted at increasing DG-volume and potentially its functioning.

Individual differences in costly fearful avoidance and the relation to psychophysiology.

Excessive avoidance behaviour is a cardinal symptom of anxiety disorders. Avoidance is not only associated with the benefits of avoiding threats, but also with the costs of missing out on rewards upon exploration. Psychological and psychophysiological mechanisms contributing to these costly avoidance decisions in prospect of mixed outcomes remain unclear. We developed a novel Fearful Avoidance Task (FAT) that resembles characteristics of real-life approach-avoidance conflicts, enabling to disentangle reward and threat effects. Using the FAT, we investigated individual differences in avoidance behaviour and anticipatory psychophysiological states (i.e. startle reflex and skin conductance) in a relatively large sample of 343 (78 females) participants. Avoidance under acute threat of shock depends on a trade-off between perceived reward and threat. Both increased startle and skin conductance in the absence of threat of shock emerged as predictors of increased avoidance (potentially indicative of fear generalization). Increased avoidance was also associated with female sex and trait anxiety, dependent on reward and threat levels. Our findings highlight distinct possible predictors of heightened avoidance and add to mechanistic understanding of how individual propensity for costly avoidance may emerge. Distinct avoidance typologies based on differential reward and threat sensitivities may have different mechanistic origins and thereby could benefit from different treatment strategies.

Human defensive freezing: Associations with hair cortisol and trait anxiety.

The anticipation of threat facilitates innate defensive behaviours including freezing reactions. Freezing in humans is characterised by reductions in body sway and heart rate. Limited evidence suggests that individual differences in freezing reactions are associated with predictors of anxiety-related psychopathology including trait anxiety and hypothalamic-pituitary-adrenal (HPA) axis activity. However, previous human studies focused on acutely circulating cortisol levels, leaving the link between freezing and more stable, individual trait markers of HPA axis activity unclear. We investigated whether individual differences in anticipatory freezing reactions are predicted by accumulated hair cortisol concentrations (HCC) and trait anxiety, in a well-powered mixed sample of police recruits at the start of the police training, and age, sex and education matched controls (total N = 419, mean age = 24, Nwomen = 106, Npolice recruits = 337). Freezing-related reactions were assessed with posturographic and heart rate measurements during an active shooting task under threat of shock. The anticipation of threat of shock elicited the expected reductions in body sway and heart rate, indicative of human freezing. Individual differences in threat-related reductions in body sway, but not heart rate, were related to lower HCC and higher trait anxiety. The observed links between postural freezing and predictors of anxiety-related psychopathology suggest the potential value of defensive freezing as a somatic marker for individual differences in stress-vulnerability and resilience. DATA AVAILABILITY: The datasets analysed during the current study are available from the corresponding authors upon reasonable request.

D-cycloserine as adjunct to brief computerised CBT for spider fear: Effects on fear, behaviour, and cognitive biases.

BACKGROUND AND OBJECTIVES: In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). METHODS: Spider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up. RESULTS: Linear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses. LIMITATIONS: Results might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects. CONCLUSIONS: These findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS.

Good vibrations: An observational study of real-life stress induced by a stage performance.

Stressors induce physiological changes in the brain and periphery that support adaptive defensive responses. The consequences of psychological stress on cognitive functioning are often measured in laboratory settings using experimentally induced stress that leads to mainly negative subjective feelings. There is a need for verification of these studies using real-life stressors that may potentially induce both positive and negative subjective feelings. In an observational study, we investigated real-life stress induced by voluntary stage performance at a large-scale music festival, including 126 participants (60 female, age range = 16-57 years). Our primary measurements involved salivary cortisol, heart rate, blood pressure, and positive and negative affect. In addition, participants completed a 2-back working memory task and a speeded decision-making task. We found that stage performance significantly increased salivary cortisol - with a particularly low number of cortisol non-responders - and heart rate, even when controlling for potential confounding factors, such as sleep, movement, and alcohol use. Interestingly, stage performance significantly decreased negative affect while increasing positive affect. This positively experienced stressor ("eustressor") was related to impaired working memory performance: the stronger the increases in cortisol, the slower participants responded to targets. Decision-making, however, was not affected. In conclusion, we show how stressful experiences in real-life can lead to positive affect, but still have a similar negative impact on cognitive functioning. We suggest that future research should focus more on the consequences of real-life stressors, and the consequences of eustress, in order to extend our understanding of the concept of psychological stress.

A lack of differentiation in amygdala responses to fearful expression intensity in panic disorder patients.

Patients with panic disorder show abnormalities in threat processing and regulation, both on a behavioural and neural level. Better understanding of the underlying mechanisms could help to develop new treatment strategies. In this study, we investigated brain region activation in 18 patients with untreated panic disorder (PD) and 17 healthy controls (HC) during the processing of emotional faces with fearful, happy and neutral expressions, using functional MRI. The intensity of the expressions was either prototypically high, medium or low. PD patients showed significantly increased activity in the dorso-medial prefrontal cortex (dmPFC) in response to faces in general and specifically for happy faces. While HC showed a decreased amygdala response to medium/low fearful versus high fearful faces, this effect was not present in PD: amygdala activation was stable across all fearful faces in this group. Psycho-physiological interaction analyses indicated more negative connectivity between the amygdala and prefrontal areas in the PD group during the task. Amygdala activation in panic patients appears to be less sensitive to decreasing intensities of fearful facial expressions and salience monitoring areas were less active during fearful faces in general in this group. This suggests PD patients might avoid more extensive processing of fearful faces.

Frontal Control Over Automatic Emotional Action Tendencies Predicts Acute Stress Responsivity.

BACKGROUND: The ability to control social-emotional actions is relevant for everyday social interaction and may be indicative of responsiveness to actual social stress situations. This is particularly relevant for predicting stress responsiveness of the hypothalamic-pituitary-adrenal axis, known to be dysregulated in various stress-related affective disorders. Here we tested, in a large sample, whether reduced frontal control over social approach-avoidance actions can indeed signal increased hypothalamic-pituitary-adrenal axis reactivity to subsequent social stress exposure. METHODS: A total of 279 subjects (214 men) participated in a functional magnetic resonance imaging social-emotional approach-avoidance task that involved impulsive and controlled emotional actions. Subsequently, participants underwent a stress induction including a socially evaluated cold pressor task and a mental arithmetic task. Salivary cortisol and α-amylase levels, as well as self-reported negative affect, were measured before and after stress induction. RESULTS: Emotion control was successfully induced by the approach-avoidance task. Namely, instrumental overriding of automatic social approach-avoidance actions was associated with the typical increased bilateral anterior prefrontal cortex activation, longer reaction times, and more errors. Moreover, subsequent stress induction led to significant increases in all stress measures. Critically, bilateral anterior prefrontal cortex activation during emotion control was associated with reduced responses to the subsequent stressor in not only cortisol but also α-amylase and negative affect. CONCLUSIONS: The ability to recruit prefrontal regions during social-emotion regulation predicts cortisol responses to an actual social stress situation. This finding provides the first evidence that instrumental control over social approach avoidance actions can signal stress responsiveness in major stress systems, providing a promising biomarker in stress vulnerability and resilience research relevant for affective disorders.

Neural Dynamics of Shooting Decisions and the Switch from Freeze to Fight.

Real-life shooting decisions typically occur under acute threat and require fast switching between vigilant situational assessment and immediate fight-or-flight actions. Recent studies suggested that freezing facilitates action preparation and decision-making but the neurocognitive mechanisms remain unclear. We applied functional magnetic resonance imaging, posturographic and autonomic measurements while participants performed a shooting task under threat of shock. Two independent studies, in unselected civilians (N = 22) and police recruits (N = 54), revealed that preparation for shooting decisions under threat is associated with postural freezing, bradycardia, midbrain activity (including the periaqueductal gray-PAG) and PAG-amygdala connectivity. Crucially, stronger activity in the midbrain/PAG during this preparatory stage of freezing predicted faster subsequent accurate shooting. Finally, the switch from preparation to active shooting was associated with tachycardia, perigenual anterior cingulate cortex (pgACC) activity and pgACC-amygdala connectivity. These findings suggest that threat-anticipatory midbrain activity centred around the PAG supports decision-making by facilitating action preparation and highlight the role of the pgACC when switching from preparation to action. These results translate animal models of the neural switch from freeze-to-action. In addition, they reveal a core neural circuit for shooting performance under threat and provide empirical evidence for the role of defensive reactions such as freezing in subsequent action decision-making.

On the Control of Social Approach-Avoidance Behavior: Neural and Endocrine Mechanisms.

The ability to control our automatic action tendencies is crucial for adequate social interactions. Emotional events trigger automatic approach and avoidance tendencies. Although these actions may be generally adaptive, the capacity to override these emotional reactions may be key to flexible behavior during social interaction. The present chapter provides a review of the neuroendocrine mechanisms underlying this ability and their relation to social psychopathologies. Aberrant social behavior, such as observed in social anxiety or psychopathy, is marked by abnormalities in approach-avoidance tendencies and the ability to control them. Key neural regions involved in the regulation of approach-avoidance behavior are the amygdala, widely implicated in automatic emotional processing, and the anterior prefrontal cortex, which exerts control over the amygdala. Hormones, especially testosterone and cortisol, have been shown to affect approach-avoidance behavior and the associated neural mechanisms. The present chapter also discusses ways to directly influence social approach and avoidance behavior and will end with a research agenda to further advance this important research field. Control over approach-avoidance tendencies may serve as an exemplar of emotional action regulation and might have a great value in understanding the underlying mechanisms of the development of affective disorders.