Neurocognitive Mechanisms of Fear Conditioning and Vulnerability to Anxiety

A commentary on Fear-conditioning mechanisms associated with trait vulnerability to anxiety in human

What is going on around here? Intolerance of uncertainty predicts threat generalization

Attending to stimuli that share perceptual similarity to learned threats is an adaptive strategy. However, prolonged threat generalization to cues signalling safety is considered a core feature of pathological anxiety. One potential factor that may sustain over-generalization is sensitivity to future threat uncertainty. To assess the extent to which Intolerance of Uncertainty (IU) predicts threat generalization, we recorded skin conductance in 54 healthy participants during an associative learning paradigm, where threat and safety cues varied in perceptual similarity. Lower IU was associated with stronger discrimination between threat and safety cues during acquisition and extinction. Higher IU, however, was associated with generalized responding to threat and safety cues during acquisition, and delayed discrimination between threat and safety cues during extinction. These results were specific to IU, over and above other measures of anxious disposition. These findings highlight: (1) a critical role of uncertainty-based mechanisms in threat generalization, and (2) IU as a potential risk factor for anxiety disorder development

States of epistemic curiosity interfere with memory for incidental scholastic facts

Curiosity can be a powerful motivator to learn and retain new information. Evidence shows that high states of curiosity elicited by a specific source (i.e., a trivia question) can promote memory for incidental stimuli (non-target) presented close in time. The spreading effect of curiosity states on memory for other information has potential for educational applications. Specifically, it could provide techniques to improve learning for information that did not spark a sense of curiosity on its own. Here, we investigated how high states of curiosity induced through trivia questions affect memory performance for unrelated scholastic facts (e.g., scientific, English, or historical facts) presented in close temporal proximity to the trivia question. Across three task versions, participants viewed trivia questions closely followed in time by a scholastic fact unrelated to the trivia question, either just prior to or immediately following the answer to the trivia question. Participants then completed a surprise multiple-choice memory test (akin to a pop quiz) for the scholastic material. In all three task versions, memory performance was poorer for scholastic facts presented after trivia questions that had elicited high versus low levels of curiosity. These results contradict previous findings showing curiosity-enhanced memory for incidentally presented visual stimuli and suggest that target information that generates a high-curiosity state interferes with encoding complex and unrelated scholastic facts presented close in time

Executive functions deficits impair extinction of generalization of fear of movement‐related pain

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Background Generalization of fear of movement‐related pain across novel but similar movements can lead to fear responses to movements that are actually not associated with pain. The peak‐shift effect describes a phenomenon whereby particular novel movements elicit even greater fear responses than the original pain‐provoking movement (CS+), because they represent a more extreme version of the CS+. There is great variance in the propensity to generalize as well as the speed of extinction learning when these novel movements are not followed by pain. It can be argued that this variance may be associated with executive function capacity, as individuals may be unable to intentionally inhibit fear responses. This study examined whether executive function capacity contributes to generalization and extinction of generalization as well as peak‐shift of conditioned fear of movement‐related pain and expectancy. Methods Healthy participants performed a proprioceptive fear conditioning task. Executive function tests assessing updating, switching, and inhibition were used to predict changes in (extinction of) fear of movement‐related pain and pain expectancy generalization. Results Low inhibitory capacity was associated with slower extinction of generalized fear of movement‐related pain and pain expectancy. Evidence was found in favor of an area‐shift, rather than a peak‐shift effect, which implies that the peak conditioned fear response extended to, but did not shift to a novel stimulus. Conclusions Participants with low inhibitory capacity may have difficulties withholding fear responses, leading to a slower decrease of generalized fear over time. The findings may be relevant to inform treatments. Significance Low inhibitory capacity is not associated with slower generalization, but extinction of fear generalization. Fear elicited by a novel safe movement, situated outside the CS+/− continuum on the CS+ side, can be as strong as to the original stimulus predicting the pain‐onset

Spontaneous neural synchrony links intrinsic spinal sensory and motor networks during unconsciousness

Non-random functional connectivity during unconsciousness is a defining feature of supraspinal networks. However, its generalizability to intrinsic spinal networks remains incompletely understood. Previously, Barry et al., 2014 used fMRI to reveal bilateral resting state functional connectivity within sensory-dominant and, separately, motor-dominant regions of the spinal cord. Here, we record spike trains from large populations of spinal interneurons in vivo in rats and demonstrate that spontaneous functional connectivity also links sensory- and motor-dominant regions during unconsciousness. The spatiotemporal patterns of connectivity could not be explained by latent afferent activity or by populations of interconnected neurons spiking randomly. We also document connection latencies compatible with mono- and disynaptic interactions and putative excitatory and inhibitory connections. The observed activity is consistent with the hypothesis that salient, experience-dependent patterns of neural transmission introduced during behavior or by injury/disease are reactivated during unconsciousness. Such a spinal replay mechanism could shape circuit-level connectivity and ultimately behavior

Sex differences in discriminating between cues predicting threat and safety

Post-traumatic stress disorder (PTSD) is more prevalent in women than men. PTSD is characterized by overgeneralization of fear to innocuous stimuli and involves impaired inhibition of learned fear by cues that predict safety. While evidence indicates that learned fear inhibition through extinction differs in males and females, less is known about sex differences in fear discrimination and safety learning. Here we examined auditory fear discrimination in male and female rats. In Experiment 1A, rats underwent 1-3 days of discrimination training consisting of one tone predicting threat (CS+; presented with footshock) and another tone predicting safety (CS-; presented alone). Females, but not males, discriminated between the CS+ and CS- after one day of training. After 2-3 days of training, however, males discriminated whereas females generalized between the CS+ and CS-. In Experiment 1B, females showed enhanced anxiety-like behaviour and locomotor activity in the open field, although these results were unlikely to explain the sex differences in fear discrimination. In Experiment 2, we found no differences in shock sensitivity between males and females. In Experiment 3, males and females again discriminated and generalized, respectively, after three days of training. Moreover, fear generalization in females resulted from impaired safety learning, as shown by a retardation test. Whereas subsequent fear conditioning to the previous CS- retarded learning in males, females showed no such retardation. These results suggest that, while females show fear discrimination with limited training, they show fear generalization with extended training due to impaired safety learning

Multiple fear-related stimuli enhance physiological arousal during extinction and reduce physiological arousal to novel stimuli and the threat conditioned stimulus

Highlights•Involved Pavlovian conditioning, extinction, extinction generalization test, and extinction retest.•Compared extinction with CS+ and CS− and generalization stimuli and ‘extinction-as-usual’.•Multiple stimuli increased physiological arousal to both CSs during, and negative CS evaluations, after extinction.•Multiple stimuli reduced physiological arousal to novel stimuli and CS+ after extinction but did not alter negative CS evaluations.•No group differences were observed in subjective anxiety ratings

Cannabidiol regulation of learned fear: implications for treating anxiety-related disorders

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future

Distinct processing of aversive experience in amygdala subregions

Background The amygdala is an anatomically complex medial temporal brain structure whose subregions are considered to serve distinct functions. However, their precise role in mediating human aversive experience remains ill understood. Methods We used functional MRI in 39 healthy volunteers with varying levels of trait anxiety to assess distinct contributions of the basolateral (BLA) and centromedial amygdala (CMA) to anticipation and experience of aversive events. Additionally, we examined the relationship between any identified functional subspecialisation and measures of subjective reported aversion and trait anxiety. Results Our results show that the CMA is responsive to aversive outcomes, but insensitive to predictive aversive cues. In contrast, the BLA encodes an aversive prediction error that quantifies whether cues and outcomes are worse than expected. A neural representation within the BLA for distinct threat levels was mirrored in self-reported subjective anxiety across individuals. Furthermore, trait-anxious individuals were characterised by indiscriminately heightened BLA activity in response to aversive cues, irrespective of actual threat level. Conclusions Our results demonstrate that amygdala subregions are distinctly engaged in processing of aversive experience, with elevated and undifferentiated BLA responses to threat emerging as a potential neurobiological mediator of vulnerability to anxiety disorders

Effect of Tryptophan Depletion on Conditioned Threat Memory Expression: Role of Intolerance of Uncertainty.

BACKGROUND: Responding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occur in many psychiatric disorders, including posttraumatic stress disorder, obsessive-compulsive disorder, and schizophrenia, in which emotional responses can persist pathologically. While there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does lowering serotonin affect memory retention of conditioned threat and safety memory? METHODS: Forty-seven healthy participants underwent conditioning to two stimuli predictive of threat on day 1. One stimulus but not the other was subsequently presented in an extinction session. Emotional responding was assessed by the skin conductance response. On day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind, placebo-controlled, randomized between-groups design. We then tested for the retention of conditioned threat and extinction memory. We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression. RESULTS: The expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion. CONCLUSIONS: These results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology