Insufficient sleep can initiate or exacerbate anxiety by triggering excessive fear generalization. In this study, a de novo paradigm was developed and used to examine the neural mechanisms governing the effects of sleep deprivation on processing perceptual and concept-based fear generalizations. A between-subject design was adopted, wherein a control group (who had a typical night\'s sleep) and a one-night sleep deprivation group completed a fear acquisition task at 9:00 PM on the first day and underwent a generalization test the following morning at 7:00 AM. In the fear acquisition task, navy blue and olive green were used as perceptual cues (P+ and P-, respectively), while animals and furniture items were used as conceptual cues (C+ and C-, respectively). Generalization was tested for four novel generalized categories (C+P+, C+P-, C-P+, and C-P-). Shock expectancy ratings, skin conductance responses, and functional near-infrared spectroscopy were recorded during the fear acquisition and generalization processes. Compared with the group who had a typical night\'s sleep, the sleep deprived group showed higher shock expectancy ratings (especially for P+ and C-), increased oxygenated hemoglobin in the dorsolateral prefrontal cortex, and increased activation in the triangular inferior frontal gyrus during the generalization test. These findings suggest that sleep deprivation increases the generalization of threat memories, thus providing insights into the overgeneralization characteristics of anxiety and fear-related disorders.

Individuals with anxiety disorders frequently display heightened fear responses, even in situations where there is no imminent danger. We hypothesize that these irrational fear responses are related to automatic processing of fear generalization. The initial automatic detection of stimuli often operates at a non-conscious level. However, whether fear generalization can occur when the cues are not perceived consciously remains unclear. The current study investigated the neurocognitive mechanisms underlying fear conditioning and its non-conscious and conscious generalization using a backward masking paradigm, combined with analysis of event-related potentials from electroencephalographic recordings. Behaviorally, participants showed heightened shock expectancy in response to non-conscious perceived generalization stimuli compared to those perceived consciously. Nonetheless, participants could not consciously distinguish between danger and safe cues in non-conscious trials. Physiologically, danger cues evoked larger frontal N1 amplitudes than safety cues in non-conscious trials, suggesting enhanced attention vigilance towards danger cues in the early sensory processing stage. Meanwhile, when fear generalization was conscious, it was accompanied by a larger P2 amplitude, indicating attention orientation or stimulus evaluation. In addition, fear conditioning was associated with sustained discrimination on P2, P3, and LPP. These findings collectively suggest that non-conscious fear generalization occurs at the neural level, yet additional control conditions are required to confirm this phenomenon on the US expectancy. Thus, non-consciously fear generalization may represent a mechanism that could trigger automatic irrational fear, highlighting the need for further research to explore therapeutic targets in anxiety disorders.

UNASSIGNED: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory.
UNASSIGNED: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25).
UNASSIGNED: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, p = .037).
UNASSIGNED: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.
Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Short-chain fatty acids (SCFAs) are produced in the colon following bacterial fermentation of dietary fiber and are important microbiota-gut-brain messengers. However, their mechanistic role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is scarcely studied in humans. We have previously shown that colonic administration of a SCFA mixture (acetate, propionate, butyrate) lowers the cortisol response to stress in healthy participants, but does not impact fear conditioning and extinction. To disentangle the effects of the three main SCFAs, we examined whether butyrate alone would similarly modulate these psychobiological responses in a randomized, triple-blind, placebo-controlled intervention study in 71 healthy male participants (Mage = 25.2, MBMI = 22.7 [n = 35 butyrate group, n = 36 placebo group]). Colon-delivery capsules with pH-dependent coating were used to administer 5.28 g of butyrate or placebo daily for one week. Butyrate administration significantly increased serum butyrate concentrations without modulating serum acetate or propionate, nor fecal SCFAs. Butyrate administration also significantly modulated fear memory at the subjective but not physiological levels. Contrary to expectations, no changes in subjective nor neuroendocrine responses to acute stress were evident between the treatment groups from pre- to post-intervention. We conclude that colonic butyrate administration alone is not sufficient to modulate psychobiological stress responses, unlike administration of a SCFA mixture. The influence of colonic and systemic butyrate on fear memory and the persistence of fear extinction should be further systematically investigated in future studies.

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Benzodiazepines (BZDs) are anxiolytic drugs that act on GABAa receptors and are used to treat anxiety disorders. However, these drugs come with the detrimental side effect of anterograde amnesia, or the inability to form new memories. In this review we discuss, behavioral paradigms, sex differences and hormonal influences affecting BZD-induced amnesia, molecular manipulations, including the knockout of GABAa receptor subunits, and regional studies utilizing lesion and microinjection techniques targeted to the hippocampus and amygdala. Additionally, the relationship between BZD use and cognitive decline related to Alzheimer\'s disease is addressed, as there is a lack of consensus on whether these drugs are involved in inducing or accelerating pathological cognitive deficits. This review aims to inspire new research directions, as there is a gap in knowledge in understanding the cellular and molecular mechanisms behind BZD-induced amnesia. Understanding these mechanisms will allow for the development of alternative treatments and potentially allow BZDs to be used as a novel tool to study Alzheimer\'s disease.

UNASSIGNED: Exposure therapy is at the core of the treatment of pathological anxiety. While the inhibitory learning model proposes a framework for the mechanisms underlying exposure therapy, in particular expectancy violation, causal evidence for its assumptions remains elusive. Therefore, the aim of the current study was to provide evidence for the influence of expectancy violation on extinction retention by manipulating the magnitude of expectancy violation during extinction learning.
UNASSIGNED: In total, 101 individuals completed a web-based fear conditioning protocol, consisting of a fear acquisition and extinction phase, as well as a spontaneous recovery and fear reinstatement test 24h later. To experimentally manipulate expectancy violation, participants were presented only with states of the conditioned stimulus that either weakly or strongly predicted the aversive outcome. Consequently, the absence of any aversive outcomes in the extinction phase resulted in low or high expectancy violation, respectively.
UNASSIGNED: We found successful fear acquisition and manipulation of expectancy violation, which was associated with reduced threat ratings for the high compared to the low expectancy violation group directly after extinction learning. On Day 2, inhibitory CS-noUS associations could be retrieved for expectancy ratings, whereas there were no substantial group differences for threat ratings.
UNASSIGNED: These findings indicate that the magnitude of expectancy violation is related to the retrieval of conscious threat expectancies, but it is unclear how these changes translate to affective components (i.e., threat ratings) of the fear response and to symptoms of pathological anxiety.

Exposure-based therapies for anxiety and related disorders are believed to depend on fear extinction learning and corresponding changes in extinction circuitry. Frontopolar multifocal transcranial direct current stimulation (tDCS) has been shown to improve therapeutic safety learning during in vivo exposure and may modulate functional connectivity of networks implicated in fear processing and inhibition. A pilot randomized controlled trial was completed to determine the effects of frontopolar tDCS on extinction learning and memory. Community volunteers (n = 35) completed a 3-day fear extinction paradigm with measurement of electrodermal activity. Participants were randomized (single-blind) to 20-min of sham (n = 17, 30 s. ramp in/out) or active (n = 18) frontopolar (anode over Fpz, 10-10 EEG) multifocal tDCS (20-min, 1.5 mA) prior to extinction training. Mixed ANOVAs revealed a significant group*trial effect on skin conductance response (SCR) to the conditioned stimulus (CS + ) during extinction training (p = 0.007, Cohen\'s d = 0.55). The effects of frontopolar tDCS were greatest during the first two extinction trials, suggesting that tDCS may have promoted fear inhibition prior to safety learning. Return of fear to the CS + during tests were comparable across conditions (ps > 0.50). These findings suggest that frontopolar tDCS may modulate the processing of threat cues and associated circuitry or promote the inhibition of fear. This has clear implications for the treatment of anxiety and related disorders with therapeutic exposure.

A major constraint of the behavioral epidemiological models is the assumption that human behavior is static; however, it is highly dynamic, especially in uncertain circumstances during a pandemic. To incorporate the dynamicity of human nature in the existing epidemiological models, we propose a population-wide multi-time-scale theoretical framework that assimilates neuronal plasticity as the basis of altering human emotions and behavior. For that, variable connection weights between different brain regions and their firing frequencies are coupled with a compartmental susceptible-infected-recovered model to incorporate the intrinsic dynamicity in the contact transmission rate ( β ). As an illustration, a model of fear conditioning in conjunction with awareness campaigns is developed and simulated. Results indicate that in the presence of fear conditioning, there exists an optimum duration of daily broadcast time during which awareness campaigns are most effective in mitigating the pandemic. Further, global sensitivity analysis using the Morris method highlighted that the learning rate and firing frequency of the unconditioned circuit are crucial regulators in modulating the emergent pandemic waves. The present study makes a case for incorporating neuronal dynamics as a basis of behavioral immune response and has further implications in designing awareness campaigns.

Fear generalization is pivotal for the survival-promoting avoidance of potential danger, but, if too pronounced, it promotes pathological anxiety. Similar to adult patients with anxiety disorders, healthy children tend to show overgeneralized fear responses.
This study aims to investigate neuro-developmental aspects of fear generalization in adolescence - a critical age for the development of anxiety disorders.
We compared healthy adolescents (14-17 years) with healthy adults (19-34 years) regarding their fear responses towards tilted Gabor gratings (conditioned stimuli, CS; and slightly differently titled generalization stimuli, GS). In the conditioning phase, CS were paired (CS+) or remained unpaired (CS-) with an aversive stimulus (unconditioned stimuli, US). In the test phase, behavioral, peripheral and neural responses to CS and GS were captured by fear- and UCS expectancy ratings, a perceptual discrimination task, pupil dilation and source estimations of event-related magnetic fields.
Closely resembling adults, adolescents showed robust generalization gradients of fear ratings, pupil dilation, and estimated neural source activity. However, in the UCS expectancy ratings, adolescents revealed shallower generalization gradients indicating overgeneralization. Moreover, adolescents showed stronger visual cortical activity after as compared to before conditioning to all stimuli.
Various aspects of fear learning and generalization appear to be mature in healthy adolescents. Yet, cognitive aspects might show a slower course of development.