Freezing revisited: coordinated autonomic and central optimization of threat coping.

Animals have sophisticated mechanisms for coping with danger. Freezing is a unique state that, upon threat detection, allows evidence to be gathered, response possibilities to be previsioned and preparations to be made for worst-case fight or flight. We propose that - rather than reflecting a passive fear state - the particular somatic and cognitive characteristics of freezing help to conceal overt responses, while optimizing sensory processing and action preparation. Critical for these functions are the neurotransmitters noradrenaline and acetylcholine, which modulate neural information processing and also control the sympathetic and parasympathetic branches of the autonomic nervous system. However, the interactions between autonomic systems and the brain during freezing, and the way in which they jointly coordinate responses, remain incompletely explored. We review the joint actions of these systems and offer a novel computational framework to describe their temporally harmonized integration. This reconceptualization of freezing has implications for its role in decision-making under threat and for psychopathology.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Emotion regulation flexibility: EEG/EMG predictors and consequences of switching between reappraisal and distraction strategies.

Flexible use of emotion regulation (ER) strategies is central to mental health. To advance our understanding of what drives adaptive strategy-switching decisions, in this preregistered study, we used event-related potentials (late positive potential, LPP and stimulus preceding negativity, SPN) and facial electromyography (EMG corrugator activity) to test the antecedents and consequences of switching to an alternative ER strategy. Participants (N = 63, Mage = 24.8 years, all female) passively watched and then implemented an instructed ER strategy (reappraisal or distraction) in response to high-intensity negative pictures that were either easy or difficult to reinterpret (high or low reappraisal affordance, respectively). Next, they decided to "switch from" or "maintain" the instructed strategy and subsequently implemented the chosen strategy. Reappraisal affordance manipulations successfully induced switching. Regarding antecedents, switching was predicted by the reduced ER efficacy of the current strategy (corrugator, but not LPP). Switching to distraction was additionally predicted by increased responses to the stimulus during passive viewing (corrugator and LPP) and increased anticipatory effort in implementing reappraisal (SPN). Concerning consequences, switching to distraction improved, whereas switching to reappraisal impaired post-choice ER effects (LPP). However, starting with reappraisal was overall more effective than starting with distraction, irrespective of the subsequent decision (corrugator). Our results suggest that switching between ER strategies occurs in accordance with situational demands (stimulus affordances) and is predicted by reduced peripheral physiological ER efficacy. However, only switching to distraction leads to improved regulatory effects. These insights provide neurocognitively grounded starting points for developing interventions targeting ER flexibility.

Developmental shift in testosterone influence on prefrontal emotion control.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

Coping with COVID: risk and resilience factors for mental health in a German representative panel study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic might affect mental health. Data from population-representative panel surveys with multiple waves including pre-COVID data investigating risk and protective factors are still rare. METHODS: In a stratified random sample of the German household population (n = 6684), we conducted survey-weighted multiple linear regressions to determine the association of various psychological risk and protective factors assessed between 2015 and 2020 with changes in psychological distress [(PD; measured via Patient Health Questionnaire for Depression and Anxiety (PHQ-4)] from pre-pandemic (average of 2016 and 2019) to peri-pandemic (both 2020 and 2021) time points. Control analyses on PD change between two pre-pandemic time points (2016 and 2019) were conducted. Regularized regressions were computed to inform on which factors were statistically most influential in the multicollinear setting. RESULTS: PHQ-4 scores in 2020 (M = 2.45) and 2021 (M = 2.21) were elevated compared to 2019 (M = 1.79). Several risk factors (catastrophizing, neuroticism, and asking for instrumental support) and protective factors (perceived stress recovery, positive reappraisal, and optimism) were identified for the peri-pandemic outcomes. Control analyses revealed that in pre-pandemic times, neuroticism and optimism were predominantly related to PD changes. Regularized regression mostly confirmed the results and highlighted perceived stress recovery as most consistent influential protective factor across peri-pandemic outcomes. CONCLUSIONS: We identified several psychological risk and protective factors related to PD outcomes during the COVID-19 pandemic. A comparison of pre-pandemic data stresses the relevance of longitudinal assessments to potentially reconcile contradictory findings. Implications and suggestions for targeted prevention and intervention programs during highly stressful times such as pandemics are discussed.

Behavioral inhibition, negative parenting, and social withdrawal: Longitudinal associations with loneliness during early, middle, and late adolescence.

Adolescent loneliness can have detrimental effects on physical and mental health, but there is limited understanding of its antecedents in infancy and childhood. A 20-year longitudinal, multi-informant, and multi-methods study (first data collection in 1998) was conducted to examine mechanisms underlying adolescent loneliness (N = 128, 52% boys, Mage_baseline  = 1.23, SD = 0.02, 99% White, recruitment in Dutch urban, healthcare centers). Structural equation modeling showed that high infant behavioral inhibition (BI) was indirectly associated with high loneliness during adolescence via high childhood social withdrawal. This indirect effect was equally strong during early, middle, and late adolescence. Contrary to expectations, infant parenting did not moderate the relation between BI and social withdrawal. The results suggest a developmental cascade with infant BI showing long-lasting indirect effects on adolescent loneliness up to 20 years later via childhood social withdrawal.

Age differences in intertemporal choice among children, adolescents, and adults.

When choosing between sooner-smaller and later-larger rewards (i.e., intertemporal choices), adults typically prefer later-larger rewards more often than children. Intertemporal choice preferences have been implicated in various impulsivity-related psychopathologies, making it important to understand the underlying mechanisms not only in terms of how reward magnitude and delay affect choice but also in terms of how these mechanisms develop across age. We administered an intertemporal choice paradigm to 60 children (8-11 years), 79 adolescents (14-16 years), and 60 young adults (18-23 years). The paradigm systematically varied amounts and delays of the available rewards, allowing us to identify mechanisms underlying age-related differences in patience. Compared with young adults, both children and adolescents made fewer later-larger choices. In terms of underlying mechanisms, variation in delays, absolute reward magnitudes, and relative amount differences affected choice in each age group, indicating that children showed sensitivity to the same choice-relevant factors as young adults. Sensitivity to both absolute reward magnitude and relative amount differences showed a further monotonic age-related increase, whereas no change in delay sensitivity occurred. Lastly, adolescents and young adults weakly displayed a present bias (i.e., overvaluing immediate vs. future rewards; nonsignificant and trend, respectively), whereas children showed a nonsignificant but opposite pattern, possibly indicating that specifically dealing with future rewards changed with age. These findings shed light on the underlying mechanisms that contribute to the development of patience. By decomposing overt choices, our results suggest that the age-related increase in patience may be driven specifically by stronger sensitivity to amount differences with age.

Perceptual control or action-selection? Comment on: a perceptual control theory of emotional action.

The Perceptual Control Theory of Emotional Action provides a compelling view of the synergy between action and perception in the context of emotion. In this invited response, we outline three suggestions to further clarify and concretesise the theory in the hope that it can provide a solid basis for the theoretical, empirical, and clinical fields of emotion and emotion regulation. First, we emphasise the importance of concretesising these ideas in a way that is biologically plausible and testable in terms of its neuronal implementation, which has not been addressed in the main manuscript. Secondly, we highlight the challenges for this account to effectively describe core symptoms in emotional disorders, an essential step if the theory aims to foster the development of better-tuned neurocognitively grounded interventions. Finally, we take a leap on what action-oriented accounts of emotion can mean for the field of emotion regulation.

The association between serotonin transporter availability and the neural correlates of fear bradycardia.

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which-similarly to the human population-mediated the 5-HTT genotype's effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.

Human Lateral Frontal Pole Contributes to Control over Emotional Approach-Avoidance Actions.

Regulation of emotional behavior is essential for human social interactions. Recent work has exposed its cognitive complexity, as well as its unexpected reliance on portions of the anterior PFC (aPFC) also involved in exploration, relational reasoning, and counterfactual choice, rather than on dorsolateral and medial prefrontal areas involved in several forms of cognitive control. This study anatomically qualifies the contribution of aPFC territories to the regulation of prepotent approach-avoidance action tendencies elicited by emotional faces, and explores a possible structural pathway through which this emotional action regulation might be implemented. We provide converging evidence from task-based fMRI, diffusion-weighted imaging, and functional connectivity fingerprints for a novel neural element in emotional regulation. Task-based fMRI in human male participants (N = 40) performing an emotional approach-avoidance task identified aPFC territories involved in the regulation of action tendencies elicited by emotional faces. Connectivity fingerprints, based on diffusion-weighted imaging and resting-state connectivity, localized those task-defined frontal regions to the lateral frontal pole (FPl), an anatomically defined portion of the aPFC that lacks a homologous counterpart in macaque brains. Probabilistic tractography indicated that 10%-20% of interindividual variation in emotional regulation abilities is accounted for by the strength of structural connectivity between FPl and amygdala. Evidence from an independent replication sample (N = 50; 10 females) further substantiated this result. These findings provide novel neuroanatomical evidence for incorporating FPl in models of control over human action tendencies elicited by emotional faces.SIGNIFICANCE STATEMENT Successful regulation of emotional behaviors is a prerequisite for successful participation in human society, as is evidenced by the social isolation and loss of occupational opportunities often encountered by people suffering from emotion regulation disorders, such as social-anxiety disorder and psychopathy. Knowledge about the precise cortical regions and connections supporting this control is crucial for understanding both the nature of computations needed to successfully traverse the space of possible actions in social situations, and the potential interventions that might result in efficient treatment of social-emotional disorders. This study provides evidence for a precise cortical region (lateral frontal pole) and a structural pathway (the ventral amygdalofugal bundle) through which a cognitively complex form of emotional action regulation might be implemented in the human brain.

Patients with Ventromedial Prefrontal Lesions Show an Implicit Approach Bias to Angry Faces.

Damage to the ventromedial PFC (VMPFC) can cause maladaptive social behavior, but the cognitive processes underlying these behavioral changes are still uncertain. Here, we tested whether patients with acquired VMPFC lesions show altered approach-avoidance tendencies to emotional facial expressions. Thirteen patients with focal VMPFC lesions and 31 age- and gender-matched healthy controls performed an implicit approach-avoidance task in which they either pushed or pulled a joystick depending on stimulus color. Whereas controls avoided angry faces, VMPFC patients displayed an incongruent response pattern characterized by both increased approach and reduced avoidance of angry facial expressions. The approach bias was stronger in patients with higher self-reported impulsivity and disinhibition and in those with larger lesions. We further used linear ballistic accumulator modeling to investigate latent parameters underlying approach-avoidance decisions. Controls displayed negative drift rates when approaching angry faces, whereas VMPFC lesions abolished this pattern. In addition, VMPFC patients had weaker response drifts than controls during avoidance. Finally, patients showed reduced drift rate variability and shorter nondecision times, indicating impulsive and rigid decision-making. Our findings thus suggest that VMPFC damage alters the pace of evidence accumulation in response to social signals, eliminating a default, protective avoidant bias and facilitating a dysfunctional approach behavior.

Emotionally Aversive Cues Suppress Neural Systems Underlying Optimal Learning in Socially Anxious Individuals.

Learning and decision-making are modulated by socio-emotional processing and such modulation is implicated in clinically relevant personality traits of social anxiety. The present study elucidates the computational and neural mechanisms by which emotionally aversive cues disrupt learning in socially anxious human individuals. Healthy volunteers with low or high trait social anxiety performed a reversal learning task requiring learning actions in response to angry or happy face cues. Choice data were best captured by a computational model in which learning rate was adjusted according to the history of surprises. High trait socially anxious individuals used a less-dynamic strategy for adjusting their learning rate in trials started with angry face cues and unlike the low social anxiety group, their dorsal anterior cingulate cortex (dACC) activity did not covary with the learning rate. Our results demonstrate that trait social anxiety is accompanied by disruption of optimal learning and dACC activity in threatening situations.SIGNIFICANCE STATEMENT Social anxiety is known to influence a broad range of cognitive functions. This study tests whether and how social anxiety affects human value-based learning as a function of uncertainty in the learning environment. The findings indicate that, in a threatening context evoked by an angry face, socially anxious individuals fail to benefit from a stable learning environment with highly predictable stimulus-response-outcome associations. Under those circumstances, socially anxious individuals failed to use their dorsal anterior cingulate cortex, a region known to adjust learning rate to environmental uncertainty. These findings open the way to modify neurobiological mechanisms of maladaptive learning in anxiety and depressive disorders.

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.

Cortical Oscillatory Mechanisms Supporting the Control of Human Social-Emotional Actions.

The human anterior prefrontal cortex (aPFC) is involved in regulating social-emotional behavior, presumably by modulating effective connectivity with downstream parietal, limbic, and motor cortices. Regulating that connectivity might rely on theta-band oscillations (4-8 Hz), a brain rhythm known to create overlapping periods of excitability between distant regions by temporally releasing neurons from inhibition. Here, we used MEG to understand how aPFC theta-band oscillations implement control over prepotent social-emotional behaviors; that is, the control over automatically elicited approach and avoidance actions. Forty human male participants performed a social approach-avoidance task in which they approached or avoided visually displayed emotional faces (happy or angry) by pulling or pushing a joystick. Approaching angry and avoiding happy faces (incongruent condition) requires rapid application of cognitive control to override prepotent habitual action tendencies to approach appetitive and to avoid aversive situations. In the time window before response delivery, trial-by-trial variations in aPFC theta-band power (6 Hz) predicted reaction time increases during emotional control and were inversely related to beta-band power (14-22 Hz) over parietofrontal cortex. In sensorimotor areas contralateral to the moving hand, premovement gamma-band rhythms (60-90 Hz) were stronger during incongruent than congruent trials, with power increases phase locked to peaks of the aPFC theta-band oscillations. These findings define a mechanistic relation between cortical areas involved in implementing rapid control over human social-emotional behavior. The aPFC may bias neural processing toward rule-driven actions and away from automatic emotional tendencies by coordinating tonic disinhibition and phasic enhancement of parietofrontal circuits involved in action selection.SIGNIFICANCE STATEMENT Being able to control social-emotional behavior is crucial for successful participation in society, as is illustrated by the severe social and occupational difficulties experienced by people suffering from social motivational disorders such as social anxiety. In this study, we show that theta-band oscillations in the anterior prefrontal cortex (aPFC), which are thought to provide temporal organization for neural firing during communication between distant brain areas, facilitate this control by linking aPFC to parietofrontal beta-band and sensorimotor gamma-band oscillations involved in action selection. These results contribute to a mechanistic understanding of cognitive control over automatic social-emotional action and point to frontal theta-band oscillations as a possible target of rhythmic neurostimulation techniques during treatment for social anxiety.

Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation.

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (η p2 = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (η p2 = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

Time ambiguity during intertemporal decision-making is aversive, impacting choice and neural value coding.

We are often presented with choices that differ in their more immediate versus future consequences. Interestingly, in everyday-life, ambiguity about the exact timing of such consequences frequently occurs, yet it remains unknown whether and how time-ambiguity influences decisions and their underlying neural correlates. We developed a novel intertemporal fMRI choice task in which participants make choices between sooner-smaller (SS) versus later-larger (LL) monetary rewards with systematically varying levels of time-ambiguity. Across trials, delay information of the SS, the LL, or both rewards was either exact (e.g., in 5 weeks), of low ambiguity (4 week range: e.g., in 3-7 weeks), or of high ambiguity (8 week range: e.g., in 1-9 weeks). Choice behavior showed that the majority of participants preferred options with exact delays over those with ambiguous delays, indicating time-ambiguity aversion. Consistent with these results, the ventromedial prefrontal cortex showed decreased activation during ambiguous versus exact trials. In contrast, intraparietal sulcus activation increased during ambiguous versus exact trials. Furthermore, exploratory analyses suggest that more time-ambiguity averse participants show more insula and dorsolateral prefrontal cortex activation during subjective value (SV)-coding of ambiguous versus exact trials. Lastly, the best-fitting computational choice models indicate that ambiguity impacts the SV of options via time perception or via an additive ambiguity-related penalty term. Together, these results provide the first behavioral and neural signatures of time-ambiguity, pointing towards a unique profile that is distinct from impatience. Since time-ambiguity is ubiquitous in real-life, it likely contributes to shortsighted decisions above and beyond delay-discounting.

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.