Fear, learning, and the amygdala: a personal reflection in honor of Joseph LeDoux.

In honor of Joseph LeDoux's retirement from an illustrious career in science, I offer a personal reflection on how my graduate training experiences in his lab shaped my subsequent career trajectory and the development of my views on human amygdala function and the scientific enterprise. I discuss the values of openness to scientific exploration and of multi-methodological integration, both of which distinguished his laboratory over the years. I highlight the unique historical context in which the lab's foundational discoveries on the emotional brain occurred and the importance of embracing new technologies to advance an understanding of brain-behavior relationships in affective neuroscience.

Retrieval-induced forgetting of emotional memories.

Long-term memory manages its contents to facilitate adaptive behaviour, amplifying representations of information relevant to current goals and expediting forgetting of information that competes with relevant memory traces. Both mnemonic selection and inhibition maintain congruence between the contents of long-term memory and an organism's priorities. However, the capacity of these processes to modulate affective mnemonic representations remains ambiguous. Three empirical experiments investigated the consequences of mnemonic selection and inhibition on affectively charged and neutral mnemonic representations using an adapted retrieval practice paradigm. Participants encoded neutral cue words and affectively negative or neutral associates and then selectively retrieved a subset of these associates multiple times. The consequences of selection and inhibitory processes engaged during selective retrieval were evaluated on a final memory test in which recall for all studied associates was probed. Analyses of memory recall indicated that both affectively neutral and negative mnemonic representations experienced similar levels of enhancement and impairment following selective retrieval, demonstrating the susceptibility of affectively salient memories to these mnemonic processes. These findings indicate that although affective memories may be more strongly encoded in memory, they remain amenable to inhibition and flexibly adaptable to the evolving needs of the organism.

Reining in regret: emotion regulation modulates regret in decision making.

Whereas the influence of regret on decision making is well-established, it remains unclear whether emotion regulation may modulate both the affective experience of regret and its influence on decisions. To examine this question, participants made decisions about options involving uncertainty using two different, instructed emotion regulation strategies. In one case, they were instructed to treat each choice individually, while in the other they were encouraged to treat a series of decisions as a portfolio. The present experiment demonstrates that approaching a series of decisions as a portfolio led to less extreme affective reactions to outcomes and lowered physiological arousal levels compared to focusing on each decision in isolation. However, the different emotion regulation strategies did not alter the influence of anticipatory regret on choices. The results indicate that these different emotion regulation strategies can be used to alter the experience of regret. These findings support a role for cognitive strategies in mitigating the affective experience of regret and suggest a means to encourage consumer welfare.

Proximal threats promote enhanced acquisition and persistence of reactive fear-learning circuits.

Physical proximity to a traumatic event increases the severity of accompanying stress symptoms, an effect that is reminiscent of evolutionarily configured fear responses based on threat imminence. Despite being widely adopted as a model system for stress and anxiety disorders, fear-conditioning research has not yet characterized how threat proximity impacts the mechanisms of fear acquisition and extinction in the human brain. We used three-dimensional (3D) virtual reality technology to manipulate the egocentric distance of conspecific threats while healthy adult participants navigated virtual worlds during functional magnetic resonance imaging (fMRI). Consistent with theoretical predictions, proximal threats enhanced fear acquisition by shifting conditioned learning from cognitive to reactive fear circuits in the brain and reducing amygdala-cortical connectivity during both fear acquisition and extinction. With an analysis of representational pattern similarity between the acquisition and extinction phases, we further demonstrate that proximal threats impaired extinction efficacy via persistent multivariate representations of conditioned learning in the cerebellum, which predicted susceptibility to later fear reinstatement. These results show that conditioned threats encountered in close proximity are more resistant to extinction learning and suggest that the canonical neural circuitry typically associated with fear learning requires additional consideration of a more reactive neural fear system to fully account for this effect.

The Temporal Dynamics of Spontaneous Emotional Brain States and Their Implications for Mental Health.

Temporal processes play an important role in elaborating and regulating emotional responding during routine mind wandering. However, it is unknown whether the human brain reliably transitions among multiple emotional states at rest and how psychopathology alters these affect dynamics. Here, we combined pattern classification and stochastic process modeling to investigate the chronometry of spontaneous brain activity indicative of six emotions (anger, contentment, fear, happiness, sadness, and surprise) and a neutral state. We modeled the dynamic emergence of these brain states during resting-state fMRI and validated the results across two population cohorts-the Duke Neurogenetics Study and the Nathan Kline Institute Rockland Sample. Our findings indicate that intrinsic emotional brain dynamics are effectively characterized as a discrete-time Markov process, with affective states organized around a neutral hub. The centrality of this network hub is disrupted in individuals with psychopathology, whose brain state transitions exhibit greater inertia and less frequent resetting from emotional to neutral states. These results yield novel insights into how the brain signals spontaneous emotions and how alterations in their temporal dynamics contribute to compromised mental health.

Enhancing Cognitive Restructuring with Concurrent Repetitive Transcranial Magnetic Stimulation: A Transdiagnostic Randomized Controlled Trial.

INTRODUCTION: Emotional dysregulation constitutes a serious public health problem in need of novel transdiagnostic treatments. OBJECTIVE: To this aim, we developed and tested a one-time intervention that integrates behavioral skills training with concurrent repetitive transcranial magnetic stimulation (rTMS). METHODS: Forty-six adults who met criteria for at least one DSM-5 disorder and self-reported low use of cognitive restructuring (CR) were enrolled in a randomized, double-blind, sham-controlled trial that used a between-subjects design. Participants were taught CR and underwent active rTMS applied at 10 Hz over the right (n = 17) or left (n = 14) dorsolateral prefrontal cortex (dlPFC) or sham rTMS (n = 15) while practicing reframing and emotional distancing in response to autobiographical stressors. RESULTS: Those who received active left or active right as opposed to sham rTMS exhibited enhanced regulation (ds = 0.21-0.62) as measured by psychophysiological indices during the intervention (higher high-frequency heart rate variability, lower regulation duration). Those who received active rTMS over the left dlPFC also self-reported reduced distress throughout the intervention (d = 0.30), higher likelihood to use CR, and lower daily distress during the week following the intervention. The procedures were acceptable and feasible with few side effects. CONCLUSIONS: These findings show that engaging frontal circuits simultaneously with cognitive skills training and rTMS may be clinically feasible, well-tolerated and may show promise for the treatment of transdiagnostic emotional dysregulation. Larger follow-up studies are needed to confirm the efficacy of this novel therapeutic approach.

Multivariate Patterns of Posterior Cortical Activity Differentiate Forms of Emotional Distancing.

Distancing is an effective tactic for emotion regulation, which can take several forms depending on the type(s) of psychological distance being manipulated to modify affect. We recently proposed a neurocognitive model of emotional distancing, but it is unknown how its specific forms are instantiated in the brain. Here, we presented healthy young adults (N = 34) with aversive pictures during functional magnetic resonance imaging to directly compare behavioral performance and brain activity across spatial, temporal, and objective forms of distancing. We found emotion regulation performance to be largely comparable across these forms. A conjunction analysis of activity associated with these forms yielded a high degree of overlap, encompassing regions of the default mode and frontoparietal networks as predicted by our model. A multivariate pattern classification further revealed distributed patches of posterior cortical activation that discriminated each form from one another. These findings not only confirm aspects of our overarching model but also elucidate a novel role for cortical regions in and around the parietal lobe in selectively supporting spatial, temporal, and social cognitive processes to distance oneself from an emotional encounter. These regions may provide new targets for brain-based interventions for emotion dysregulation.

Extinction learning alters the neural representation of conditioned fear.

Extinction learning is a primary means by which conditioned associations to threats are controlled and is a model system for emotion dysregulation in anxiety disorders. Recent work has called for new approaches to track extinction-related changes in conditioned stimulus (CS) representations. We applied a multivariate analysis to previously -collected functional magnetic resonance imaging data on extinction learning, in which healthy young adult participants (N = 43; 21 males, 22 females) encountered dynamic snake and spider CSs while passively navigating 3D virtual environments. We used representational similarity analysis to compare voxel-wise activation t-statistic maps for the shock-reinforced CS (CS+) from the late phase of fear acquisition to the early and late phases of extinction learning within subjects. These patterns became more dissimilar from early to late extinction in a priori regions of interest: subgenual and dorsal anterior cingulate gyrus, amygdala and hippocampus. A whole-brain searchlight analysis revealed similar findings in the insula, mid-cingulate cortex, ventrolateral prefrontal cortex, somatosensory cortex, cerebellum, and visual cortex. High state anxiety attenuated extinction-related changes to the CS+ patterning in the amygdala, which suggests an enduring threat representation. None of these effects generalized to an unreinforced control cue, nor were they evident in traditional univariate analyses. Our approach extends previous neuroimaging work by emphasizing how evoked neural patterns change from late acquisition through phases of extinction learning, including those in brain regions not traditionally implicated in animal models. Finally, the findings provide additional support for a role of the amygdala in anxiety-related persistence of conditioned fears.

Examining the Role of Lateral Parietal Cortex in Emotional Distancing Using TMS.

We recently proposed a neurocognitive model of distancing-an emotion regulation tactic-with a focus on the lateral parietal cortex. Although this brain area has been implicated in both cognitive control and self-projection processes during distancing, fMRI work suggests that these processes may be dissociable here. This preregistered (NCT03698591) study tested the contribution of left temporoparietal junction (TPJ) to distancing using repetitive transcranial magnetic stimulation. We hypothesized that inhibiting left TPJ would decrease the efficiency of distancing but not distraction, another regulation tactic with similar cognitive control requirements, thus implicating this region in the self-projection processes unique to distancing. Active and sham continuous theta burst stimulation (cTBS) were applied to 30 healthy adults in a single-session crossover design. Tactic efficiency was measured using online reports of valence and effort. The stimulation target was established from the group TPJ fMRI activation peak in an independent sample using the same distancing task, and anatomical MRI scans were used for individual targeting. Analyses employed both repeated-measures ANOVA and analytic procedures tailored to crossover designs. Irrespective of cTBS, distancing led to greater decreases in negative valence over time relative to distraction, and distancing effort decreased over time while distraction effort remained stable. Exploratory analyses also revealed that active cTBS made distancing more effortful, but not distraction. Thus, left TPJ seems to support self-projection processes in distancing, and these processes may be facilitated by repeated use. These findings help to clarify the role of lateral parietal cortex in distancing and inform applications of distancing and distraction.

Phenomenology of counterfactual thinking is dampened in anxious individuals.

Counterfactual thinking (CFT), or simulating alternative versions of occurred events, is a common psychological strategy people use to process events in their lives. However, CFT is also a core component of ruminative thinking that contributes to psychopathology. Though prior studies have tried to distinguish adaptive from maladaptive CFT, our study provides a novel demonstration that identifies phenomenological differences across CFT in participants with varying levels of trait anxiety. Participants (N = 96) identified negative, regretful memories from the past 5 years and created a better counterfactual alternative (upward CFT), a worse counterfactual alternative (downward CFT), or simply recalled each memory. Participants with high levels of trait anxiety used more negative language when describing their mental simulations, reported lower ratings of composition during upward CFT, and reported more difficulty in imagining the emotion they would have felt had negative events turned out to be better. Additionally, participants with high anxiety thought that upward CFT was less likely to occur relative to individuals with low anxiety. These results help to clarify how mental simulations of aversive life events are altered in anxiety and serve as a stepping stone to future research uncovering the mechanisms of ruminative thought patterns.

Decoding Spontaneous Emotional States in the Human Brain.

Pattern classification of human brain activity provides unique insight into the neural underpinnings of diverse mental states. These multivariate tools have recently been used within the field of affective neuroscience to classify distributed patterns of brain activation evoked during emotion induction procedures. Here we assess whether neural models developed to discriminate among distinct emotion categories exhibit predictive validity in the absence of exteroceptive emotional stimulation. In two experiments, we show that spontaneous fluctuations in human resting-state brain activity can be decoded into categories of experience delineating unique emotional states that exhibit spatiotemporal coherence, covary with individual differences in mood and personality traits, and predict on-line, self-reported feelings. These findings validate objective, brain-based models of emotion and show how emotional states dynamically emerge from the activity of separable neural systems.

The central role of disgust in disorders of food avoidance.

BACKGROUND: Individuals with extreme food avoidance such as Avoidant Restrictive Food Intake Disorder (ARFID) experience impairing physical and mental health consequences from nutrition of insufficient variety or/and quantity. Identifying mechanisms contributing to food avoidance is essential to develop effective interventions. Anxiety figures prominently in theoretical models of food avoidance; however, there is limited evidence that repeated exposures to foods increases approach behavior in ARFID. Studying disgust, and relationships between disgust and anxiety, may offer novel insights, as disgust is functionally associated with avoidance of contamination from pathogens (as may occur via ingestion) and is largely resistant to extinction. METHOD: This exploratory, cross-sectional study included data from 1,644 adults who completed an online questionnaire. Participant responses were used to measure ARFID classification, picky eating, sensory sensitivity, disgust, and anxiety. Structural equation modeling tested a measurement model of latent disgust and anxiety factors as measured by self-reported frequency of disgust and anxiety reactions. Mediational models were used to explore causal ordering. RESULTS: A latent disgust factor was more strongly related to severity of picky eating (B ≈ 0.4) and ARFID classification (B ≈ 0.6) than the latent anxiety factor (B ≈ 0.1). Disgust partially mediated the association between anxiety and picky eating and fully mediated the association between anxiety and ARFID. Models testing the reverse causal ordering demonstrated poorer fit. Findings suggest anxiety may be associated with food avoidance in part due to increased disgust. CONCLUSIONS: Disgust may play a prominent role in food avoidance. Findings may inform novel approaches to treatment.

Neural mechanisms underlying subsequent memory for personal beliefs:An fMRI study.

Many fMRI studies have examined the neural mechanisms supporting emotional memory for stimuli that generate emotion rather automatically (e.g., a picture of a dangerous animal or of appetizing food). However, far fewer studies have examined how memory is influenced by emotion related to social and political issues (e.g., a proposal for large changes in taxation policy), which clearly vary across individuals. In order to investigate the neural substrates of affective and mnemonic processes associated with personal opinions, we employed an fMRI task wherein participants rated the intensity of agreement/disagreement to sociopolitical belief statements paired with neural face pictures. Following the rating phase, participants performed an associative recognition test in which they distinguished identical versus recombined face-statement pairs. The study yielded three main findings: behaviorally, the intensity of agreement ratings was linked to greater subjective emotional arousal as well as enhanced high-confidence subsequent memory. Neurally, statements that elicited strong (vs. weak) agreement or disagreement were associated with greater activation of the amygdala. Finally, a subsequent memory analysis showed that the behavioral memory advantage for statements generating stronger ratings was dependent on the medial prefrontal cortex (mPFC). Together, these results both underscore consistencies in neural systems supporting emotional arousal and suggest a modulation of arousal-related encoding mechanisms when emotion is contingent on referencing personal beliefs.

Smaller hippocampal CA1 subfield volume in posttraumatic stress disorder.

BACKGROUND: Smaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features. METHODS: Case-control cross-sectional studies of U.S. military veterans (n = 282) from the Iraq and Afghanistan era were grouped into PTSD (n = 142) and trauma-exposed controls (n = 140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model. RESULTS: Significantly lower subfield volumes were associated with PTSD in left CA1 (P = 0.01; d = 0.21; uncorrected), CA3 (P = 0.04; d = 0.08; uncorrected), and right CA3 (P = 0.02; d = 0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD (F4, 221  = 3.32, P = 0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD-associated differences in global hippocampal shape were nonsignificant. CONCLUSIONS: The present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.

The Clinical Significance of Posterior Insular Volume in Adolescent Anorexia Nervosa.

OBJECTIVE: The diagnostic criterion disturbance in the experience of the body remains a poorly understood and persistent feature of anorexia nervosa (AN). Increased sophistication in understanding the structure of the insular cortex-a neural structure that receives and integrates visceral sensations with action and meaning-may elucidate the nature of this disturbance. We explored age, weight status, illness severity, and self-reported body dissatisfaction associations with insular cortex volume. METHODS: Structural magnetic resonance imaging data were collected from 21 adolescents with a history of AN and 20 age-, sex-, and body mass index-matched controls. Insular cortical volumes (bilateral anterior and posterior regions) were identified using manual tracing. RESULTS: Volumes of the right posterior insula demonstrated the following: (a) a significant age by clinical status interaction (ß = -0.018 [0.008]; t = 2.32, p = .02) and (b) larger volumes were associated with longer duration of illness (r = 0.48, p < .04). In contrast, smaller volumes of the right anterior insula were associated with longer duration of illness (r = -0.50, p < .03). The associations of insular volume with body dissatisfaction were of moderate effect size and also of opposite direction, but a statistical trend in right posterior (r = 0.40, p < .10 in right posterior; r = -0.49, p < .04 in right anterior). CONCLUSIONS: In this exploratory study, findings of atypical structure of the right posterior insular cortex point to the importance of future work investigating the role of visceral afferent signaling in understanding disturbance in body experience in AN.

Adolescent development of insula-dependent interoceptive regulation.

Adolescence is hypothesized to be a critical period for the maturation of self-regulatory capacities, including those that depend on interoceptive sensitivity, but the neural basis of interoceptive regulation in adolescence is unknown. We used functional magnetic resonance imaging and psychophysiology to study interoceptive regulation in healthy adolescent females. Participants regulated their gut activities in response to a virtual roller coaster by deep breathing aided by visually monitoring their online electrogastrogram (EGG) activity through a virtual thermometer (i.e. gut biofeedback), or without biofeedback. Analyses focused on the insula, given its putative role in interoception. The bilateral posterior insula showed increased activation in the no-biofeedback compared to biofeedback condition, suggesting that the participants relied more on interoceptive input when exteroceptive feedback was unavailable. The bilateral dorsal anterior insula showed activation linearly associated with age during both induction and regulation, and its activation during regulation correlated positively with change of EGG in the tachygastria frequency band from induction to regulation. Induction-related activation in the bilateral ventral anterior insula was nonlinearly associated with age and peaked at mid-adolescence. These results implicate different developmental trajectories of distinct sub-regions of the insula in interoceptive processes, with implications for competing neurobiological theories of female adolescent development.

Distinct medial temporal networks encode surprise during motivation by reward versus punishment.

Adaptive motivated behavior requires predictive internal representations of the environment, and surprising events are indications for encoding new representations of the environment. The medial temporal lobe memory system, including the hippocampus and surrounding cortex, encodes surprising events and is influenced by motivational state. Because behavior reflects the goals of an individual, we investigated whether motivational valence (i.e., pursuing rewards versus avoiding punishments) also impacts neural and mnemonic encoding of surprising events. During functional magnetic resonance imaging (fMRI), participants encountered perceptually unexpected events either during the pursuit of rewards or avoidance of punishments. Despite similar levels of motivation across groups, reward and punishment facilitated the processing of surprising events in different medial temporal lobe regions. Whereas during reward motivation, perceptual surprises enhanced activation in the hippocampus, during punishment motivation surprises instead enhanced activation in parahippocampal cortex. Further, we found that reward motivation facilitated hippocampal coupling with ventromedial PFC, whereas punishment motivation facilitated parahippocampal cortical coupling with orbitofrontal cortex. Behaviorally, post-scan testing revealed that reward, but not punishment, motivation resulted in greater memory selectivity for surprising events encountered during goal pursuit. Together these findings demonstrate that neuromodulatory systems engaged by anticipation of reward and punishment target separate components of the medial temporal lobe, modulating medial temporal lobe sensitivity and connectivity. Thus, reward and punishment motivation yield distinct neural contexts for learning, with distinct consequences for how surprises are incorporated into predictive mnemonic models of the environment.

Medial prefrontal pathways for the contextual regulation of extinguished fear in humans.

The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.

Aversive learning modulates cortical representations of object categories.

Experimental studies of conditioned learning reveal activity changes in the amygdala and unimodal sensory cortex underlying fear acquisition to simple stimuli. However, real-world fears typically involve complex stimuli represented at the category level. A consequence of category-level representations of threat is that aversive experiences with particular category members may lead one to infer that related exemplars likewise pose a threat, despite variations in physical form. Here, we examined the effect of category-level representations of threat on human brain activation using 2 superordinate categories (animals and tools) as conditioned stimuli. Hemodynamic activity in the amygdala and category-selective cortex was modulated by the reinforcement contingency, leading to widespread fear of different exemplars from the reinforced category. Multivariate representational similarity analyses revealed that activity patterns in the amygdala and object-selective cortex were more similar among exemplars from the threat versus safe category. Learning to fear animate objects was additionally characterized by enhanced functional coupling between the amygdala and fusiform gyrus. Finally, hippocampal activity co-varied with object typicality and amygdala activation early during training. These findings provide novel evidence that aversive learning can modulate category-level representations of object concepts, thereby enabling individuals to express fear to a range of related stimuli.

Therapeutic affect reduction, emotion regulation, and emotional memory reconsolidation: A neuroscientific quandary.

Lane et al. emphasize the role of emotional arousal as a precipitating factor for successful psychotherapy. However, as therapy ensues, the arousal diminishes. How can the unfolding therapeutic process generate long-term memories for reconsolidated emotional material without the benefit of arousal? Studies investigating memory for emotionally regulated material provide some clues regarding the neural pathways that may underlie therapy-based memory reconsolidation.