Rationale
3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these ...effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA’s broad pharmacological profile, further investigation is warranted before moving to a complex clinical population.
Objectives
We aimed to inform clinical research by providing a translational model of MDMA’s effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction.
Methods
We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training.
Results
MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA’s effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA’s effect by 5-HTT inhibition also downregulated 5-HT
2A
-mediated behavior, and 5-HT
2A
antagonism disrupted MDMA’s effect on extinction.
Conclusions
We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT
2A
receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Fear of heights is evolutionarily important for survival, yet it is unclear how and which brain regions process such height threats. Given the importance of the basolateral amygdala (BLA) in ...mediating both learned and innate fear, we investigated how BLA neurons may respond to high-place exposure in freely behaving male mice. We found that a discrete set of BLA neurons exhibited robust firing increases when the mouse was either exploring or placed on a high place, accompanied by increased heart rate and freezing. Importantly, these high-place fear neurons were only activated under height threats, but not looming, acoustic startle, predatory odor, or mild anxiogenic conditions. Furthermore, after a fear-conditioning procedure, these high-place fear neurons developed conditioned responses to the context, but not the cue, indicating a convergence in processing of dangerous/risky contextual information. Our results provide insights into the neuronal representation of the fear of heights and may have implications for the treatment of excessive fear disorders.
Fear can be innate or learned, as innate fear does not require any associative learning or experiences. Previous research mainly focused on studying the neural mechanism of learned fear, often using an associative conditioning procedure such as pairing a tone with a footshock. Only recently scientists started to investigate the neural circuits of innate fear, including the fear of predator odors and looming visual threats; however, how the brain processes the innate fear of heights is unclear. Here we provide direct evidence that the basolateral amygdala (BLA) is involved in representing the fear of heights. A subpopulation of BLA neurons exhibits a selective response to height and contextual threats, but not to other fear-related sensory or anxiogenic stimuli.
Background
The emergence of the COVID-19 and its consequences has led to fears, worries, and anxiety among individuals worldwide. The present study developed the Fear of COVID-19 Scale (FCV-19S) to ...complement the clinical efforts in preventing the spread and treating of COVID-19 cases.
Methods
The sample comprised 717 Iranian participants. The items of the FCV-19S were constructed based on extensive review of existing scales on fears, expert evaluations, and participant interviews. Several psychometric tests were conducted to ascertain its reliability and validity properties.
Results
After panel review and corrected item-total correlation testing, seven items with acceptable corrected item-total correlation (0.47 to 0.56) were retained and further confirmed by significant and strong factor loadings (0.66 to 0.74). Also, other properties evaluated using both classical test theory and Rasch model were satisfactory on the seven-item scale. More specifically, reliability values such as internal consistency (
α
= .82) and test–retest reliability (ICC = .72) were acceptable. Concurrent validity was supported by the Hospital Anxiety and Depression Scale (with depression,
r
= 0.425 and anxiety,
r
= 0.511) and the Perceived Vulnerability to Disease Scale (with perceived infectability,
r
= 0.483 and germ aversion, r = 0.459).
Conclusion
The Fear of COVID-19 Scale, a seven-item scale, has robust psychometric properties. It is reliable and valid in assessing fear of COVID-19 among the general population and will also be useful in allaying COVID-19 fears among individuals.
Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for ...identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-d-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory.
•Individual differences in novelty seeking in rats predict rate of fear extinction.•High novelty seeking rats show faster fear extinction than low novelty seeking rats.•Ketamine impairs reconsolidation of contextual fear memory.•Ketamine’s effects are associated with early growth response 1 down-regulation in CA1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Measuring human trace fear conditioning Wehrli, Jelena M.; Xia, Yanfang; Gerster, Samuel ...
Psychophysiology,
December 2022, Volume:
59, Issue:
12
Journal Article
Peer reviewed
Open access
Trace fear conditioning is an important research paradigm to model aversive learning in biological or clinical scenarios, where predictors (conditioned stimuli, CS) and aversive outcomes ...(unconditioned stimuli, US) are separated in time. The optimal measurement of human trace fear conditioning, and in particular of memory retention after consolidation, is currently unclear. We conducted two identical experiments (N1 = 28, N2 = 28) with a 15‐s trace interval and a recall test 1 week after acquisition, while recording several psychophysiological observables. In a calibration approach, we explored which learning and memory measures distinguished CS+ and CS− in the first experiment and confirmed the most sensitive measures in the second experiment. We found that in the recall test without reinforcement, only fear‐potentiated startle but not skin conductance, pupil size, heart period, or respiration amplitude, differentiated CS+ and CS−. During acquisition without startle probes, skin conductance responses and pupil size responses but not heart period or respiration amplitude differentiated CS+ and CS−. As a side finding, there was no evidence for extinction of fear‐potentiated startle over 30 trials without reinforcement. These results may be useful to inform future substantive research using human trace fear conditioning protocols.
Our report generates new insights into the psychophysiology of trace fear conditioning using long trace intervals (15 s) in humans. By employing a strong explorative/confirmative strategy and comparing multiple psychophysiological measurements we identify skin conductance and pupil size responses to reflect fear acquisition and in agreement with previous research on delay fear conditioning show startle eye‐blink responses to reflect fear retention even a week later.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Fear-conditioning experiments in the anxiety disorders focus almost exclusively on passive-emotional, Pavlovian conditioning, rather than active-behavioral, instrumental conditioning. Paradigms ...eliciting both types of conditioning are needed to study maladaptive, instrumental behaviors resulting from Pavlovian abnormalities found in clinical anxiety. One such Pavlovian abnormality is generalization of fear from a conditioned danger-cue (CS+) to resembling stimuli. Though lab-based findings repeatedly link overgeneralized Pavlovian-fear to clinical anxiety, no study assesses the degree to which Pavlovian overgeneralization corresponds with maladaptive, overgeneralized instrumental-avoidance. The current effort fills this gap by validating a novel fear-potentiated startle paradigm including Pavlovian and instrumental components. The paradigm is embedded in a computer game during which shapes appear on the screen. One shape paired with electric-shock serves as CS+, and other resembling shapes, presented in the absence of shock, serve as generalization stimuli (GSs). During the game, participants choose whether to behaviorally avoid shock at the cost of poorer performance. Avoidance during CS+ is considered adaptive because shock is a real possibility. By contrast, avoidance during GSs is considered maladaptive because shock is not a realistic prospect and thus unnecessarily compromises performance. Results indicate significant Pavlovian-instrumental relations, with greater generalization of Pavlovian fear associated with overgeneralization of maladaptive instrumental-avoidance.
•A novel paradigm assessing Pavlovian and instrumental fear-generalization is validated.•Maladaptive behavioral consequences of Pavlovian fear-generalization are identified.•Increases in generalized fear-potentiated startle are associated with increased instrumental avoidance.•The presented paradigm represents a novel lab-based means to study maladaptive avoidance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This article is part of a Special Issue “SBN 2014”.
Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature ...on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account.
•Women are more vulnerable to anxiety and fear-related disorders than men.•Estrogen levels can modulate fear and stress responses in women and female rodents.•Stress affects the critical nodes of fear circuitry.•Interactions between sex hormones, stress, and fear should be further examined.•Treatment for anxiety and fear-based disorders should account for hormone status.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Overgeneralization (i.e., the transfer of fear to stimuli not related to an aversive event) is part of alterations in associative fear learning in mental disorders. In the present experimental study, ...we investigated whether this holds true for post‐traumatic stress disorder (PTSD) related to childhood abuse. We expected that fear generalization under experimental conditions reflects generalization of aversive stimuli to different social domains in real life. Sixty‐four women with PTSD after childhood abuse and 30 healthy participants (HC) underwent a differential fear conditioning and generalization paradigm. Online risk ratings, reaction time, and fear‐potentiated startle served as dependent variables. Based on the subjectively assessed generalization of triggered intrusions across different domains of life, PTSD participants were split into two groups reporting low (low‐GEN) and high (high‐GEN) generalization. PTSD patients reported a higher expectation of an aversive event. During fear conditioning, they assessed the risk of danger related to a safety cue slower and showed a blunted fear‐potentiated startle toward the danger cue. During generalization testing, reaction time increased in the high‐GEN patients and decreased in the HC group with increasing similarity of a stimulus with the conditioned safety cue. Alterations of fear learning in PTSD suggest impaired defensive responses in case of a high threat probability. Moreover, our findings bridge the gap between the generalization of aversive cues during everyday life and laboratory‐based experimental parameters: impairments in the processing of cues signaling safety generalize particularly in those patients who report a spreading of PTSD symptoms across different domains of everyday life.
Up to 75% of individuals who experienced physical and sexual abuse during childhood develop a post‐traumatic stress disorder (PTSD). The present experimental study contributes to the understanding of this disorder by revealing a complex picture of impairments in cognitive and emotional fear learning. A blunted fear‐potentiated startle revealed impaired defensive responses linked to the intensity and frequency of avoidance symptoms. Moreover, this is the first study that links overgeneralization of fear under experimental conditions to overgeneralization of aversive stimuli to different social domains in PTSD patients' real life.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Unconditioned responding (UCR) to a naturally aversive stimulus is associated with defensive responding to a conditioned threat cue (CS+) and a conditioned safety cue (CS−) in trauma‐exposed ...individuals during fear acquisition. However, the relationships of UCR with defensive responses during extinction training, posttraumatic stress disorder (PTSD) symptom severity, and fearful traits in trauma‐exposed individuals are not known. In a sample of 100 trauma‐exposed adults with a continuum of PTSD severity, we recorded startle responses and skin conductance responses (SCR) during fear acquisition and extinction training using a 140 psi, 250‐ms air blast to the larynx as the unconditioned stimulus. We explored dimensional associations of two different measures of UCR (unconditioned startle and unconditioned SCR) with conditioned defensive responding to CS+ and CS−, conditioned fear (CS+ minus CS−), PTSD symptom severity, and a measure of fearful traits (composite of fear survey schedule, anxiety sensitivity index, and Connor‐Davidson resilience scale). Unconditioned startle was positively associated with startle potentiation to the threat cue and the safety cue across both learning phases (CS+ Acquisition, CS− Acquisition, CS+ Extinction Training, CS− Extinction Training) and with fearful traits. Unconditioned SCR was positively associated with SCR to the CS+ and CS− and SCR difference score during Acquisition. Neither type of UCR was associated with PTSD symptom severity. Our findings suggest that UCR, particularly unconditioned startle to a naturally aversive stimulus, may inform research on biomarkers and treatment targets for symptoms of pervasive and persistent fear in trauma‐exposed individuals.
Our study adds evidence that unconditioned aversive responding is associated with persistent defensive responding to conditioned threat and safety cues and with trait‐level fear in daily life, in trauma‐exposed adults. We complement previous evidence that unconditioned responding (UCR) is associated with defensive responding during fear acquisition and provide empirical support for the theory that UCR may inform research on biomarkers and treatment targets for symptoms of pervasive and persistent fear in trauma‐exposed individuals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (CGRP
neurons) relay sensory signals that contribute to satiation ...and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most CGRP
neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRP
neurons prevent overeating. CGRP
neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of CGRP
neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRP
neurons promote affective-behavioural states that limit harm in response to potential threats.
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KISLJ, NUK, SBMB, UL, UM, UPUK
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