Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.
Ontology highlight
ABSTRACT:
SUBMITTER: Indovina I
PROVIDER: S-EPMC3047792 | biostudies-literature | 2011 Feb
REPOSITORIES: biostudies-literature
Publications
Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.
Indovina Iole I Robbins Trevor W TW Núñez-Elizalde Anwar O AO Dunn Barnaby D BD Bishop Sonia J SJ
Neuron 20110201 3
Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimen ...[more]
Similar Datasets
Project description:In fear conditioning, training with typical category exemplars has been shown to promote fear generalization to novel exemplars of the same category, whereas training with atypical category exemplars supports limited if any generalization to other category members, amounting to a typicality asymmetry in fear generalization. The present study sought to examine how trait anxiety bears on typicality asymmetry in fear generalization. Participants in one condition were presented with typical exemplars during fear acquisition and atypical exemplars of the same category in the subsequent generalization test (typical condition), whereas in the other group, atypical and typical exemplars were presented during fear acquisition and generalization test, respectively (atypical condition). We observed a typicality asymmetry in fear generalization in self-reported expectancy ratings in low trait anxious individuals only. High trait anxious individuals showed a similar degree of fear generalization in both conditions. The current results help illuminate why some individuals are at risk for exhibiting broad fear generalization after exposure to an aversive event.
| S-EPMC7116627 | biostudies-literature
Project description:Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans.
| S-EPMC6869800 | biostudies-literature
Project description:Both animal and human studies have identified a critical role of the hippocampus in contextual fear conditioning. In humans mainly functional magnetic resonance imaging has been used. To extend these findings to volumetric properties, 58 healthy participants underwent structural magnetic resonance imaging and participated in a differential fear conditioning paradigm with contextual stimuli. Ratings of emotional valence, arousal, and contingency as well as skin conductance responses (SCRs) were used as indicators of conditioning. Twenty-nine participants with the smallest hippocampal volumes were compared with 29 persons with the largest hippocampal volumes. Persons with larger hippocampal volume (especially on the right side) learned to discriminate between two conditioned contexts, whereas those with small hippocampal volumes did not, as indicated by SCRs. Further analyses showed that these results could not be explained by amygdalar volumes. In contrast, the participant answers on the self-report measures were not significantly influenced by hippocampal or amygdalar, but by total brain volume, suggesting a role of cortical structures in these more cognitive evaluation processes. Reanalysis of the self-report data using partial hippocampal volumes revealed a significant influence of the posterior but not anterior subvolumes, which is in accordance with theories and empirical findings on hippocampal functioning. This study shows the relevance of hippocampal volume for contextual fear conditioning in healthy volunteers and may have important implications for anxiety disorders.
| S-EPMC6870016 | biostudies-literature
Project description:The brain-derived neurotrophic factor (BDNF) is critically involved in neuroplasticity, as well as the acquisition, consolidation, and retention of hippocampal- and amygdala-dependent learning. A common functional A-->G single nucleotide polymorphism (BDNFval66met) in the prodomain of the human BDNF gene is associated with abnormal intracellular trafficking and reduced activity-dependent BDNF release. We studied the effect of BDNFval66met in an aversive differential fear conditioning, and a delayed extinction paradigm in 57 healthy participants. Pictures of male faces were used as stimuli and fear learning was quantified by fear potentiated startle (FPS) and skin conductance responses (SCR). Aware BDNF met-carriers show a deficit in amygdala-dependent fear conditioning as indicated by an absence of FPS responses in the last acquisition block. This deficit was maintained in the first block of extinction. No genotype differences were found in conditioned SCR discrimination. These data provide evidence for the involvement of BDNF signaling in human amygdala-dependent learning. We suggest that the BDNF met-allele may have a protective effect for the development of affective pathologies that may be mediated via reduced synaptic plasticity induced by negative experience.
| S-EPMC2862474 | biostudies-literature
Project description:These data are from the brains (amygdala and hippocampus) of mice originally derived from a cross between C57BL/6J and DBA/2J inbred strains. We used short-term selection to produce outbred mouse lines with differences in contextual fear conditioning, which is a measure of fear learning. We selected for a total of 4 generations. Fear learning differed in the selected lines and this difference was stronger with each successive generation of selection. These mice also showed differences for measures of anxiety-like behavior, but were not different for tests of non-fear motivated learning, suggesting that selection altered alleles that are specifically involved in emotional behaviors. We identified several QTLs for the selection response. We used Affymetrix microarrays to identify differentially expressed genes in the amygdala and hippocampus of mice from the final generation of selection. Amygdala and hippocampus samples were rapidly dissected out of experimentally naïve mice f rom each selected line. Three samples were pooled and hybridized to each array. Experimentally naïve mice were used because the behavior of the mice can be reliably anticipated due to their lineage. Thus, these gene expression differences are not due to the response to human handling, foot shock or fear-inducing conditioned stimuli. We have a second similar study that focuses on a different selected population that was based on C57BL/6J and A/J mice (see GES4034).
2006-01-13 | GSE4035 | GEO
Project description:Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [11C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [11C]raclopride PET scans per participant. We contrasted baseline [11C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [11C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.SIGNIFICANCE STATEMENT It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.
| S-EPMC6445999 | biostudies-literature
Project description:Fear extinction is a powerful model of adaptive and anxiety-related maladaptive fear inhibition. This learning process is dependent upon plastic interactions between the amygdala, the anterior midcingulate cortex (aMCC), the hippocampus, and the ventromedial prefrontal cortex (vmPFC). With regard to the amygdala, the basolateral (BLA) and centromedial amygdala (CMA) serve unique roles in fear extinction. In a large sample (N = 91), the current study examined pre- to post-extinction changes in resting state functional connectivity (RSFC) of fear inhibition and expression pathways. We also examined how trait anxiety and extinction performance were associated with extinction-related changes within these neural pathways. We found stronger pre- to post-extinction RSFC in pathways known to play a role in the down-regulation of fear responses (BLA-hippocampus, aMCC-hippocampus, CMA-hippocampus, CMA-aMCC). We also found that trait anxiety was associated with strengthening of a BLA-aMCC circuit supporting fear expression following extinction learning. Furthermore, we found that physiological indices of poorer extinction learning were linked to weaker pre- to post-extinction RSFC of a BLA-hippocampus pathway important for fear extinction consolidation. Our results highlight the network changes that occur during extinction, the separable role of CMA and BLA-based circuitry and a key pathway linked to risk for anxiety pathology.
| S-EPMC6204483 | biostudies-literature
Project description:Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.
| S-EPMC3327848 | biostudies-literature
Project description:Very preterm birth is associated with an increased risk for anxiety disorders. Abnormal brain development may result in disordered fear learning processes, which may be exacerbated by environmental risk factors and persist in adulthood. We tested the hypotheses that very preterm-born young adults displayed higher levels of fear conditioning, less differentiation between threat (CS+) and safety (CS-) signals, and stronger resistance to extinction relative to term-born controls. A group of 37 very preterm-born young adults and 31 age- and sex-matched term-born controls performed a differential fear conditioning paradigm on two consecutive days. Acquisition and extinction training were performed on day 1. Recall and reinstatement were tested on day 2. Preterm-born participants showed significantly higher levels of anxiety in the Depression-Anxiety-Stress-Scale-21 questionnaire. The fear conditioning outcome measures, skin conductance response amplitudes and anxiety ratings, were overall higher in the preterm-born group compared to controls. Awareness of CS-US contingencies was mildly reduced in preterms. Acquisition, extinction, recall and reinstatement of differential conditioned fear responses (CS+ > CS-), however, were not significantly different between the groups. There were no significant group by stimulus type interactions. The finding of largely preserved associative fear learning in very preterm-born young adults was unexpected and needs to be confirmed in future studies.
| S-EPMC10344879 | biostudies-literature
Project description:ImportanceThe fear conditioning and extinction neurocircuitry has been extensively studied in healthy and clinical populations, with a particular focus on posttraumatic stress disorder. Despite significant overlap of symptoms between posttraumatic stress disorder and anxiety disorders, the latter has received less attention. Given that dysregulated fear levels characterize anxiety disorders, examining the neural correlates of fear and extinction learning may shed light on the pathogenesis of underlying anxiety disorders.ObjectivesTo investigate the psychophysiological and neural correlates of fear conditioning and extinction recall in anxiety disorders and to document how these features differ as a function of multiple diagnoses or anxiety severity.Design, setting, and participantsThis investigation was a cross-sectional, case-control, functional magnetic resonance imaging study at an academic medical center. Participants were healthy controls and individuals with at least 1 of the following anxiety disorders: generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. The study dates were between March 2013 and May 2015.ExposuresTwo-day fear conditioning and extinction paradigm.Main outcomes and measuresSkin conductance responses, blood oxygenation level-dependent responses, trait anxiety scores from the State Trait Anxiety Inventory-Trait Form, and functional connectivity.ResultsThis study included 21 healthy controls (10 women) and 61 individuals with anxiety disorders (36 women). P values reported for the neuroimaging results are all familywise error corrected. Skin conductance responses during extinction recall did not differ between individuals with anxiety disorders and healthy controls (ηp2 = 0.001, P = .79), where ηp2 is partial eta squared. The anxiety group had lower activation of the ventromedial prefrontal cortex (vmPFC) during extinction recall (ηp2 = 0.178, P = .02). A similar hypoactive pattern was found during early conditioning (ηp2 = 0.106, P = .009). The vmPFC hypoactivation was associated with anxiety symptom severity (r = -0.420, P = .01 for conditioning and r = -0.464, P = .004 for extinction recall) and the number of co-occuring anxiety disorders diagnosed (ηp2 = 0.137, P = .009 for conditioning and ηp2 = 0.227, P = .004 for extinction recall). Psychophysiological interaction analyses revealed that the fear network connectivity differed between healthy controls and the anxiety group during fear learning (ηp2 range between 0.088 and 0.176 and P range between 0.02 and 0.003) and extinction recall (ηp2 range between 0.111 and 0.235 and P range between 0.02 and 0.002).Conclusions and relevanceDespite no skin conductance response group differences during extinction recall, brain activation patterns between anxious and healthy individuals differed. These findings encourage future studies to examine the conditions longitudinally and in the context of treatment trials to improve and guide therapeutics via advanced neurobiological understanding of each disorder.
| S-EPMC5539837 | biostudies-literature