Late positive potential reveals sustained threat contingencies despite extinction in adolescents but not adults.

BACKGROUND: Major theories link threat learning processes to anxiety symptoms, which typically emerge during adolescence. While this developmental stage is marked by substantial maturation of the neural circuity involved in threat learning, research directly examining adolescence-specific patterns of neural responding during threat learning is scarce. This study compared adolescents and adults in acquisition and extinction of conditioned threat responses assessed at the cognitive, psychophysiological, and neural levels, focusing on the late positive potential (LPP), an event-related potential (ERP) component indexing emotional valence. METHOD: Sixty-five adults and 63 adolescents completed threat acquisition and extinction, 24 h apart, using the bell conditioning paradigm. Self-reported fear, skin conductance responses (SCR), and ERPs were measured. RESULTS: Developmental differences emerged in neural and psychophysiological responses during threat acquisition, with adolescents displaying heightened LPP responses to threat and safety cues as well as heightened threat-specific SCR compared to adults. During extinction, SCR suggested comparable reduction in conditioned threat responses across groups, while LPP revealed incomplete extinction only among adolescents. Finally, age moderated the link between anxiety severity and LPP-assessed extinction, whereby greater anxiety severity was associated with reduced extinction among younger participants. CONCLUSIONS: In line with developmental theories, adolescence is characterized by a specific age-related difficulty adapting to diminishing emotional significance of prior threats, contributing to heightened vulnerability to anxiety symptoms. Further, LPP appears to be sensitive to developmental differences in threat learning and may thus potentially serve as a useful biomarker in research on adolescents, threat learning, and anxiety.

Enhanced late positive potential to conditioned threat cue during delayed extinction in anxious youth.

BACKGROUND: Deficits in threat learning relate to anxiety symptoms. Since several anxiety disorders arise in adolescence, impaired adolescent threat learning could contribute to adolescent changes in risk for anxiety. This study compared threat learning among anxious and non-anxious youth using self-reports, peripheral psychophysiology measures, and event-related potentials. Because exposure therapy, the first-line treatment for anxiety disorders, is largely based on principles of extinction learning, the study also examined the link between extinction learning and treatment outcomes among anxious youth. METHODS: Clinically anxious (n = 28) and non-anxious (n = 33) youth completed differential threat acquisition and immediate extinction. They returned to the lab a week later to complete a threat generalization test and a delayed extinction task. Following these two experimental visits, anxious youth received exposure therapy for 12 weeks. RESULTS: Anxious as compared to non-anxious youth demonstrated elevated cognitive and physiological responses across acquisition and immediate extinction learning, as well as greater threat generalization. In addition, anxious youth showed enhanced late positive potential response to the conditioned threat cue compared to the safety cue during delayed extinction. Finally, aberrant neural response during delayed extinction was associated with poorer treatment outcomes. CONCLUSIONS: The study emphasizes differences between anxious and non-anxious youth in threat learning processes and provides preliminary support for a link between neural processing during delayed extinction and exposure-based treatment outcome in pediatric anxiety.

Functional connectivity between the nucleus accumbens and amygdala underlies avoidance learning during adolescence: Implications for developmental psychopathology.

BACKGROUND: Reward and threat processes work together to support adaptive learning during development. Adolescence is associated with increasing approach behavior (e.g., novelty-seeking, risk-taking) but often also coincides with emerging internalizing symptoms, which are characterized by heightened avoidance behavior. Peaking engagement of the nucleus accumbens (NAcc) during adolescence, often studied in reward paradigms, may also relate to threat mechanisms of adolescent psychopathology. METHODS: 47 typically developing adolescents (9.9-22.9 years) completed an aversive learning task during functional magnetic resonance imaging, wherein visual cues were paired with an aversive sound or no sound. Task blocks involved an escapable aversively reinforced stimulus (CS+r), the same stimulus without reinforcement (CS+nr), or a stimulus that was never reinforced (CS-). Parent-reported internalizing symptoms were measured using Revised Child Anxiety and Depression Scales. RESULTS: Functional connectivity between the NAcc and amygdala differentiated the stimuli, such that connectivity increased for the CS+r (p = .023) but not for the CS+nr and CS-. Adolescents with greater internalizing symptoms demonstrated greater positive functional connectivity for the CS- (p = .041). CONCLUSIONS: Adolescents show heightened NAcc-amygdala functional connectivity during escape from threat. Higher anxiety and depression symptoms are associated with elevated NAcc-amygdala connectivity during safety, which may reflect poor safety versus threat discrimination.

Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity.

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders.

Asymmetric representation of aversive prediction errors in Pavlovian threat conditioning.

Survival in biological environments requires learning associations between predictive sensory cues and threatening outcomes. Such aversive learning may be implemented through reinforcement learning algorithms that are driven by the signed difference between expected and encountered outcomes, termed prediction errors (PEs). While PE-based learning is well established for reward learning, the role of putative PE signals in aversive learning is less clear. Here, we used functional magnetic resonance imaging in humans (21 healthy men and women) to investigate the neural representation of PEs during maintenance of learned aversive associations. Four visual cues, each with a different probability (0, 33, 66, 100%) of being followed by an aversive outcome (electric shock), were repeatedly presented to participants. We found that neural activity at omission (US-) but not occurrence of the aversive outcome (US+) encoded PEs in the medial prefrontal cortex. More expected omission of aversive outcome was associated with lower neural activity. No neural signals fulfilled axiomatic criteria, which specify necessary and sufficient components of PE signals, for signed PE representation in a whole-brain search or in a-priori regions of interest. Our results might suggest that, different from reward learning, aversive learning does not involve signed PE signals that are represented within the same brain region for all conditions.

Large-scale neural network computations and multivariate representations during approach-avoidance conflict decision-making.

Many real-world situations require navigating decisions for both reward and threat. While there has been significant progress in understanding mechanisms of decision-making and mediating neurocircuitry separately for reward and threat, there is limited understanding of situations where reward and threat contingencies compete to create approach-avoidance conflict (AAC). Here, we leverage computational learning models, independent component analysis (ICA), and multivariate pattern analysis (MVPA) approaches to understand decision-making during a novel task that embeds concurrent reward and threat learning and manipulates congruency between reward and threat probabilities. Computational modeling supported a modified reinforcement learning model where participants integrated reward and threat value into a combined total value according to an individually varying policy parameter, which was highly predictive of decisions to approach reward vs avoid threat during trials where the highest reward option was also the highest threat option (i.e., approach-avoidance conflict). ICA analyses demonstrated unique roles for salience, frontoparietal, medial prefrontal, and inferior frontal networks in differential encoding of reward vs threat prediction error and value signals. The left frontoparietal network uniquely encoded degree of conflict between reward and threat value at the time of choice. MVPA demonstrated that delivery of reward and threat could accurately be decoded within salience and inferior frontal networks, respectively, and that decisions to approach reward vs avoid threat were predicted by the relative degree to which these reward vs threat representations were active at the time of choice. This latter result suggests that navigating AAC decisions involves generating mental representations for possible decision outcomes, and relative activation of these representations may bias subsequent decision-making towards approaching reward or avoiding threat accordingly.

Alarm cues and alarmed conspecifics: neural activity during social learning from different cues in Trinidadian guppies.

Learning to respond appropriately to novel dangers is often essential to survival and success, but carries risks. Learning about novel threats from others (social learning) can reduce these risks. Many species, including the Trinidadian guppy (Poecilia reticulata), respond defensively to both conspecific chemical alarm cues and conspecific anti-predator behaviours, and in other fish such social information can lead to a learned aversion to novel threats. However, relatively little is known about the neural substrates underlying social learning and the degree to which different forms of learning share similar neural mechanisms. Here, we explored the neural substrates mediating social learning of novel threats from two different conspecific cues (i.e. social cue-based threat learning). We first demonstrated that guppies rapidly learn about threats paired with either alarm cues or with conspecific threat responses (demonstration). Then, focusing on acquisition rather than recall, we discovered that phospho-S6 expression, a marker of neural activity, was elevated in guppies during learning from alarm cues in the putative homologue of the mammalian lateral septum and the preoptic area. Surprisingly, these changes in neural activity were not observed in fish learning from conspecific demonstration. Together, these results implicate forebrain areas in social learning about threat but raise the possibility that circuits contribute to such learning in a stimulus-specific manner.

Neural mediators of subjective and autonomic responding during threat learning and regulation.

Threat learning elicits robust changes across multiple affective domains, including changes in autonomic indices and subjective reports of fear and anxiety. It has been argued that the underlying causes of such changes may be dissociable at a neural level, but there is currently limited evidence to support this notion. To address this, we examined the neural mediators of trial-by-trial skin conductance responses (SCR), and subjective reports of anxious arousal and valence in participants (n = 27; 17 females) performing a threat reversal task during ultra-high field functional magnetic resonance imaging. This allowed us to identify brain mediators during initial threat learning and subsequent threat reversal. Significant neural mediators of anxious arousal during threat learning included the dorsal anterior cingulate, anterior insula cortex (AIC), and ventromedial prefrontal cortex (vmPFC), subcortical regions including the amygdala, ventral striatum, caudate and putamen, and brain-stem regions including the pons and midbrain. By comparison, autonomic changes (SCR) were mediated by a subset of regions embedded within this broader circuitry that included the caudate, putamen and thalamus, and two distinct clusters within the vmPFC. The neural mediators of subjective negative valence showed prominent effects in posterior cortical regions and, with the exception of the AIC, did not overlap with threat learning task effects. During threat reversal, positive mediators of both subjective anxious arousal and valence mapped to the default mode network; this included the vmPFC, posterior cingulate, temporoparietal junction, and angular gyrus. Decreased SCR during threat reversal was positively mediated by regions including the mid cingulate, AIC, two sub-regions of vmPFC, the thalamus, and the hippocampus. Our findings add novel evidence to support distinct underlying neural processes facilitating autonomic and subjective responding during threat learning and threat reversal. The results suggest that the brain systems engaged in threat learning mostly capture the subjective (anxious arousal) nature of the learning process, and that appropriate responding during threat reversal is facilitated by participants engaging self- and valence-based processes. Autonomic changes (SCR) appear to involve distinct facilitatory and regulatory contributions of vmPFC sub-regions.

Paternal expressed emotion influences psychobiological indicators of threat and safety learning in daughters: A preliminary study.

This preliminary study examined the association of children's anxiety, paternal expressed emotion (EE), and their interaction with psychophysiological indices of children's threat and safety learning. Participants included 24 father-daughter dyads. Daughters (ages 8-13 years, 100% Latina) self-reported their anxiety levels and completed a differential threat conditioning and extinction paradigm, during which psychophysiological responding was collected. Fathers completed a Five-Minute Speech Sample, from which paternal EE (i.e., criticism, emotional overinvolvement) was assessed. Anxiety-dependent associations emerged between paternal EE and individual differences in daughters' psychophysiological responding to safety signals during threat conditioning. Paternal EE was positively associated with psychophysiological responding to safety in daughters with high and mean, but not low, levels of anxiety. Although previous work suggests that chronic harsh maternal parenting is a potential risk factor for children's general threat and safety learning, these preliminary findings implicate milder forms of negative parenting behavior in fathers, particularly for highly anxious children.

Disrupted learning: habitat degradation impairs crucial antipredator responses in naive prey.

Habitat degradation is a global problem and one of the main causes of biodiversity loss. Though widespread, the mechanisms that underlie faunal changes are poorly understood. In tropical marine systems, corals play a crucial role in forming habitat, but coral cover on many reefs is declining sharply. Coral degradation affects the olfactory cues that provide reliable information on the presence and intensity of threat. Here, we show for the first time that the ability of a habitat generalist to learn predators using an efficient and widespread method of predator learning is compromised in degraded coral habitats. Results indicate that chemical alarm cues are no longer indicative of a local threat for the habitat generalist (the damselfish, Pomacentrus amboinensis), and these cues can no longer be used to learn the identity of novel predators in degraded habitats. By contrast, a rubble specialist and congeneric (Pomacentrus coelestis) responded to olfactory threat cues regardless of background environment and could learn the identity of a novel predator using chemical alarm cues. Understanding how some species can cope with or acclimate to the detrimental impacts of habitat degradation on risk assessment abilities will be crucial to defining the scope of resilience in threatened communities.

The Relationship Between Fear Avoidance Belief and Threat Learning in Postoperative Patients After Lung Surgery: An Observational Study.

Background: The role of fear-avoidance beliefs (FAB) in patients with chronic pain has been widely confirmed. However, few conclusions have been drawn about its role in postoperative patients. Objective: To explore the characteristics of FAB in postoperative patients after lung surgery as well as the effect of threat learning on FAB. Methods: Between May and September 2022, this study recruited 150 participants who had undergone thoracoscopic surgery. Variables such as age, gender, education, chronic pain, fear of pain, surgery method, pain intensity, FAB, cough, ambulation and threat learning were collected and subjected to correlation analysis and stepwise regression. Results: The correlation analysis revealed that FAB was associated with age (r = -0.183, p < 0.05), gender (r = -0.256, p < 0.01), and preoperative FOP-9 (r = 0.400, p < 0.01). Postoperative variables such as pain intensity (r = 0.574, p < 0.01), initiation day of ambulation (r = 0.648, p < 0.01), total numbers of ambulation (r = -0.665, p < 0.01), and cough performance (r = -0.688, p < 0.01) were correlated with FAB. Furthermore, FAB was highly correlated with indicators of threat learning: direct (r = 0.556, p < 0.01), observation (r = 0.655, p < 0.01), and instruction (r = 0.671, p < 0.01). The highest variance explanation model of stepwise regression which explained 52.8% of the variance including instruction (B=1.751; p<0.01), direct (B=1.245; p<0.01), observation (B=0.768; p<0.01), age (B=-0.085; p<0.01), and surgery method (B=1.321; p<0.05). Conclusion: Patients commonly experience FAB after lung surgery, which can directly affect their recovery behaviors such as ambulation and active coughing. The formation of FAB is influenced by threat learning, which suggests that controlling threat learning is important in preventing postoperative FAB.

A Brain-To-Brain Mechanism for Social Transmission of Threat Learning.

Survival and adaptation in environments require swift and efficacious learning about what is dangerous. Across species, much of such threat learning is acquired socially, e.g., through the observation of others' ("demonstrators'") defensive behaviors. However, the specific neural mechanisms responsible for the integration of information shared between demonstrators and observers remain largely unknown. This dearth of knowledge is addressed by performing magnetoencephalography (MEG) neuroimaging in demonstrator-observer dyads. A set of stimuli are first shown to a demonstrator whose defensive responses are filmed and later presented to an observer, while neuronal activity is recorded sequentially from both individuals who never interacted directly. These results show that brain-to-brain coupling (BtBC) in the fronto-limbic circuit (including insula, ventromedial, and dorsolateral prefrontal cortex) within demonstrator-observer dyads predict subsequent expressions of learning in the observer. Importantly, the predictive power of BtBC magnifies when a threat is imminent to the demonstrator. Furthermore, BtBC depends on how observers perceive their social status relative to the demonstrator, likely driven by shared attention and emotion, as bolstered by dyadic pupillary coupling. Taken together, this study describes a brain-to-brain mechanism for social threat learning, involving BtBC, which reflects social relationships and predicts adaptive, learned behaviors.

Looking fear in the face: Adults but not adolescents gaze at social threat during observational learning.

Observational threat learning is an indirect pathway to learn about what is safe versus dangerous. Visual gaze patterns may be an important measure to understand the underlying mechanisms of social threat learning. However, little research has considered this type of learning or attention allocation during observational learning, and even less has examined it across development. The study examined visual gaze patterns during observational threat acquisition amongst adolescents and adults. Ninety-three adolescents (13-17 years) and 78 adults (18-34 years) underwent a differential observational acquisition task by watching a video wherein a learning model was presented with colored bells. One bell (conditioned stimulus, CS+) was associated with an electric stimulation to the learning model's arm (social unconditioned stimulus, social US), while the other bell was not (CS-). Eye tracking was used during each trial. First, all participants, regardless of age, fixated longer on the face of the learning model when the CS+ was presented than when the CS- was presented. Second, adolescents averted their gaze from the learning model's face when the learning model received an electrical stimulation, whereas adults fixated more on the learning model's face when the stimulation was administered. Finally, adolescents understood the CS+-US contingency less than adults, stemming from the different gaze pattern for the age groups to the social US. Results replicate previous findings in adults and extend them to adolescents, emphasizing the importance of the learning model's facial expressions in conveying information on what is safe versus dangerous in the environment. Moreover, results showed developmental differences in gaze patterns during observational threat learning; this translated into poorer understanding of the CS+-US association amongst adolescents.

Watch and Learn: Vicarious Threat Learning across Human Development.

Vicarious threat learning is an important pathway in learning about safety and danger in the environment and is therefore critical for survival. It involves learning by observing another person's (the demonstrator) fearful responses to threat and begins as early as infancy. The review discusses the literature on vicarious threat learning and infers how this learning pathway may evolve over human development. We begin by discussing the methods currently being used to study observational threat learning in the laboratory. Next, we focus on the social factors influencing vicarious threat learning; this is followed by a review of vicarious threat learning among children and adolescents. Finally, we examine the neural mechanisms underpinning vicarious threat learning across human development. To conclude, we encourage future research directions that will help elucidate how vicarious threat learning emerges and how it relates to the development of normative fear and pathological anxiety.

Model-based representational similarity analysis of blood-oxygen-level-dependent fMRI captures threat learning in social interactions.

Past research has shown that attributions of intentions to other's actions determine how we experience these actions and their consequences. Yet, it is unknown how such attributions affect our learning and memory. Addressing this question, we combined neuroimaging with an interactive threat learning paradigm in which two interaction partners (confederates) made choices that had either threatening (shock) or safe (no shock) consequences for the participants. Importantly, participants were led to believe that one partner intentionally caused the delivery of shock, whereas the other did not (i.e. unintentional partner). Following intentional versus unintentional shocks, participants reported an inflated number of shocks and a greater increase in anger and vengeance. We applied a model-based representational similarity analysis to blood-oxygen-level-dependent (BOLD)-MRI patterns during learning. Surprisingly, we did not find any effects of intentionality. The threat value of actions, however, was represented as a trial-by-trial increase in representational similarity in the insula and the inferior frontal gyrus. Our findings illustrate how neural pattern formation can be used to study a complex interaction.

The interaction between stress and chronic pain through the lens of threat learning.

Stress and pain are interleaved at multiple levels - interacting and influencing each other. Both are modulated by psychosocial factors including fears, beliefs, and goals, and are served by overlapping neural substrates. One major contributing factor in the development and maintenance of chronic pain is threat learning, with pain as an emotionally-salient threat - or stressor. Here, we argue that threat learning is a central mechanism and contributor, mediating the relationship between stress and chronic pain. We review the state of the art on (mal)adaptive learning in chronic pain, and on effects of stress and particularly cortisol on learning. We then provide a theoretical integration of how stress may affect chronic pain through its effect on threat learning. Prolonged stress, as may be experienced by patients with chronic pain, and its resulting changes in key brain networks modulating stress responses and threat learning, may further exacerbate these impairing effects on threat learning. We provide testable hypotheses and suggestions for how this integration may guide future research and clinical approaches in chronic pain.