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.

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.

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.

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.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

The role of automatic defensive responses in the development of posttraumatic stress symptoms in police recruits: protocol of a prospective study.

Background: Control over automatic tendencies is often compromised in challenging situations when people fall back on automatic defensive reactions, such as freeze-fight-flight responses. Stress-induced lack of control over automatic defensive responses constitutes a problem endemic to high-risk professions, such as the police. Difficulties controlling automatic defensive responses may not only impair split-second decisions under threat, but also increase the risk for and persistence of posttraumatic stress disorder (PTSD) symptoms. However, the significance of these automatic defensive responses in the development and maintenance of trauma-related symptoms remains unclear due to a shortage of large-scale prospective studies. Objective: The 'Police-in-Action' study is conducted to investigate the role of automatic defensive responses in the development and maintenance of PTSD symptomatology after trauma exposure. Methods: In this prospective study, 340 police recruits from the Dutch Police Academy are tested before (wave 1; pre-exposure) and after (wave 2; post-exposure) their first emergency aid experiences as police officers. The two waves of data assessment are separated by approximately 15 months. To control for unspecific time effects, a well-matched control group of civilians (n = 85) is also tested twice, approximately 15 months apart, but without being frequently exposed to potentially traumatic events. Main outcomes are associations between (changes in) behavioural, psychophysiological, endocrine and neural markers of automatic defensive responses and development of trauma-related symptoms after trauma exposure in police recruits. Discussion: This prospective study in a large group of primary responders enables us to distinguish predisposing from acquired neurobiological abnormalities in automatic defensive responses, associated with the development of trauma-related symptoms. Identifying neurobiological correlates of (vulnerability for) trauma-related psychopathology may greatly improve screening for individuals at risk for developing PTSD symptomatology and offer valuable targets for (early preventive) interventions for PTSD.

Planteamiento: El control de las tendencias automáticas a menudo se ve comprometido en situaciones complicadas cuando las personas recurren a las reacciones defensivas automáticas, como las respuestas de 'congelación-lucha-huida'. La falta de control sobre las respuestas defensivas automáticas inducida por el estrés constituye un problema endémico de las profesiones de alto riesgo, como la policía. Las dificultades para controlar las respuestas defensivas automáticas pueden no solo perjudicar las decisiones inmediatas frente a una amenaza, sino también aumentar el riesgo y la persistencia de los síntomas del trastorno por estrés postraumático (TEPT). Sin embargo, aún no está clara la importancia de estas respuestas defensivas automáticas en el desarrollo y el mantenimiento de los síntomas relacionados con el trauma debido a la escasez de estudios prospectivos a gran escala.Objetivo: El estudio 'Policía en acción' se lleva a cabo para investigar el papel de las respuestas defensivas automáticas en el desarrollo y mantenimiento de la sintomatología del TEPT después de haber sido expuestos a un trauma.Métodos: en este estudio prospectivo, se pasó un test a 340 reclutas de la policía de la Academia de Policía holandesa antes (onda 1, pre-exposición) y después (onda 2, post-exposición) de sus primeras experiencias de ayuda de emergencia como agentes de policía. Las dos ondas de evaluación de datos están separadas por unos 15 meses. Para controlar los efectos no específicos del tiempo, también se le pasó prueba dos veces a un grupo de control de civiles (n = 85), con aproximadamente 15 meses de diferencia, pero sin estar expuesto frecuentemente a eventos potencialmente traumáticos. Los resultados principales son asociaciones entre (cambios en) los marcadores conductuales, psicofisiológicos, endocrinos y neurales de las respuestas defensivas automáticas y el desarrollo de síntomas relacionados con el trauma después de la exposición al trauma en los reclutas de la policía.Discusión: Este estudio prospectivo en un grupo grande de personal de respuesta a emergencias nos permite distinguir anormalidades neurobiológicas predispuestas y adquiridas en respuestas defensivas automáticas, asociadas con el desarrollo de síntomas relacionados con el trauma. Identificar los correlatos neurobiológicos de (la vulnerabilidad de) la psicopatología relacionada con el trauma puede mejorar en gran medida las pruebas de detección para las personas en riesgo de desarrollar la sintomatología de TEPT y ofrecer objetivos valiosos para intervenciones (preventivas tempranas) para el TEPT. Registrado en el Registro de Holanda: NTR6355.

Ready and waiting: Freezing as active action preparation under threat.

Freezing is a defensive response characterized by rigidity and bradycardia, but it is unclear whether it is a passive versus active preparatory state. We developed a shooting task in which preparation and threat were manipulated independently: Participants were either helpless or able to respond to a possible upcoming attack, and attacks were either associated with an electric shock or not. Essentially, a purely anticipatory preparatory period was used during which no stimuli occurred. Freezing was assessed during this period. In addition to heart rate, body sway was measured, using a stabilometric force platform. The efficacy of the threat manipulation was confirmed via self-report. The ability to prepare led to decreases in heart rate and postural sway, while threat led to decreased heart rate. Further, exploratory analyses suggested that aggressive participants showed reduced initial freezing for threatening opponents, but increased postural freezing when armed. The results suggest that freezing may involve active preparation. Relations to results in passive viewing tasks are discussed.

Amplified Striatal Responses to Near-Miss Outcomes in Pathological Gamblers.

Near-misses in gambling games are losing events that come close to a win. Near-misses were previously shown to recruit reward-related brain regions including the ventral striatum, and to invigorate gambling behavior, supposedly by fostering an illusion of control. Given that pathological gamblers are particularly vulnerable to such cognitive illusions, their persistent gambling behavior might result from an amplified striatal sensitivity to near-misses. In addition, animal studies have shown that behavioral responses to near-miss-like events are sensitive to dopamine, but this dopaminergic influence has not been tested in humans. To investigate these hypotheses, we recruited 22 pathological gamblers and 22 healthy controls who played a slot machine task delivering wins, near-misses and full-misses, inside an fMRI scanner. Each participant played the task twice, once under placebo and once under a dopamine D2 receptor antagonist (sulpiride 400 mg), in a double-blind, counter-balanced design. Participants were asked about their motivation to continue gambling throughout the task. Across all participants, near-misses elicited higher motivation to continue gambling and increased striatal responses compared with full-misses. Crucially, pathological gamblers showed amplified striatal responses to near-misses compared with controls. These group differences were not observed following win outcomes. In contrast to our hypothesis, sulpiride did not induce any reliable modulation of brain responses to near-misses. Together, our results demonstrate that pathological gamblers have amplified brain responses to near-misses, which likely contribute to their persistent gambling behavior. However, there is no evidence that these responses are influenced by dopamine. These results have implications for treatment and gambling regulation.