Search

Background: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states., Methods: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat., Results: Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2)., Conclusions: The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The serotonin transporter (SERT) plays a crucial role in anxiety. Accordingly, variance in SERT functioning appears to constitute an important pathway to individual differences in anxiety. The current study tested the hypothesis that genetic variation in SERT function is associated with variability in the basic reflex physiology of defense. Healthy subjects (N=82) were presented with clearly instructed cues of shock threat and safety to induce robust anxiety reactions. Subjects carrying at least one short allele for the 5-HTTLPR polymorphism showed stronger fear-potentiated startle compared to long allele homozygotes. However, short allele carriers showed no deficit in the downregulation of fear after the offset of threat. These results suggest that natural variation in SERT function affects the magnitude of defensive reactions while not affecting the capacity for fear regulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: Reducing fear when a threat has disappeared protects against a continuously elevated anxiety state. In this study, we investigated the brain mechanism involved in this process., Methods: The threat paradigm consisted of discrete cues that signaled either threat of shock or safety. Healthy participants were tested in two sessions in which eyeblink startle (n = 26) and blood oxygen level dependence (n = 23) were measured to index subjects' defensive state and brain responses respectively., Results: Startle results indicated that subjects could rapidly decrease their defensive state after the offset of shock threat. Functional magnetic resonance imaging data indicated that the termination of threat was associated with the recruitment of lateral and ventromedial prefrontal cortices. An exploratory connectivity analysis showed that activity in these prefrontal regions was linked and was also associated with activity in brain regions typically responding to threat, the right anterior insula and amygdala., Conclusions: These results provide first evidence for a prefrontal mechanism that functions to control anxiety after threat offset, which may be dysfunctional in patients who suffer from excessive sustained anxiety. Moreover, the results support a model in which the lateral prefrontal cortex controls anxiety related limbic activity through connections with ventromedial prefrontal cortex., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Effects of predictability of threat on potentiation of the startle reflex were investigated by presenting participants with predictable and unpredictable electric shocks. Shocks were presented either paired with a visual cue (paired condition) or unrelated to the presentation of the visual cues (unpaired condition). In contrast to previous slower-paced studies, conditions alternated at a rapid rate: each context lasted 8.5 s and within these contexts the visual cues had a duration of 1.5 s. Results replicated previous findings: in the predictable condition, startle responses were augmented by a threat-signaling stimulus, and startle responses in the unpredictable condition were larger than in a neutral condition in which no shocks were presented. In all three conditions, visual stimuli that did not carry information about when a shock could be presented augmented startle reactivity. A control experiment showed that the effects of threat on the startle response could not be ascribed to attention and that the effects of the lead stimuli that did not signal threat are likely to be unrelated to the effects of threat. These results show that the fear system is modulated dynamically as a function of rapidly changing information about threat and emphasize the role of predictability of an aversive stimulus in the distinction between cue-specific and contextual fear.

Background: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue., Methods: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions., Results: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam., Conclusions: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.

Rationale: Fear conditioning reliably increases the startle reflex and stress hormones, yet very little is known about the effect of stress hormones on fear-potentiated startle. Cortisol and the sulfate ester of dehydroepiandrosterone (DHEA-S) are involved in stress and anxiety. Evidence suggests that low cortisol/DHEA-S ratio has a buffering effect on stress and anxiety in preclinical and clinical studies, suggesting that there may be a relationship between fear-potentiated startle and cortisol and DHEA-S activity., Objective: The aim of the study was to examine whether there is a relationship between cortisol/DHEA-S ratio and fear-potentiated startle., Methods: Thirty healthy subjects participated in a differential aversive conditioning experiment during which one of two stimuli (CS+) was paired with a shock, and the other was not (CS-). Conditioned responses were assessed with the startle reflex, defined as startle potentiation during CS+ compared to CS-. DHEA-S and cortisol levels were assayed from blood samples collected in both a baseline and an aversive conditioning session. Subjective state anxiety, arousal, and valence were assessed at various times during testing., Results: Fear-potentiated startle was larger in individuals with high compared to low cortisol/DHEA-S ratio. Multiple regression analyses revealed that fear-potentiated startle was positively associated with cortisol and negatively associated with DHEA-S. There was no significant correlation between DHEA-S and cortisol levels., Conclusion: These data suggest that cortisol and DHEA-S are involved in fear conditioning.

Fear-potentiated startle (FPS) is an increasingly popular psychophysiological method for the objective assessment of fear and anxiety. Studies applying this method often elicit the startle reflex with loud white-noise stimuli. Such intense stimuli may, however, alter psychological processes of interest by creating unintended emotional or attentional artifacts. Additionally, loud acoustic probes may be unsuitable for use with infants, children, the elderly, and those with hearing damage. Past studies have noted robust and reliable startle reflexes elicited by low intensity airpuffs. The current study compares the aversiveness of white-noise (102 dB) and airpuff (3 psi) probes and examines the sensitivity of each probe for the assessment of fear-potentiated startle. Results point to less physiological arousal and self-reported reactivity to airpuff versus white-noise probes. Additionally, both probes elicited equal startle magnitudes, response probabilities, and levels of fear-potentiated startle. Such results support the use of low intensity airpuffs as efficacious and relatively non-aversive startle probes.

This study investigated whether attentional processes contribute to fear-potentiated startle. Ten subjects participated in a threat of shock experiment and an attentional control condition. In the threat of shock experiment, visual cues indicated whether or not an aversive shock might occur. In the attentional control, the shocks were replaced by faint vibrotactile stimuli that had to be counted. The P300 amplitudes of the ERP evoked by the visual cues did not differ under threat and counting, which suggested that both conditions engaged attention to the same extent. In contrast, startle potentiation in the threat condition was an order of magnitude larger than the marginally significant attentional startle facilitation in the counting condition. These results indicate that an attentional contribution to fear-potentiated startle under the present experimental conditions is small. In addition, contextual effects of threat of shock became manifest as baseline startle was facilitated relative to the attention condition. This may reflect a more sustained state of anxiety on which cue-specific fear responses are superimposed.

Rationale: Pre-clinical and clinical investigations have provided a great deal of evidence that the fear-potentiated startle paradigm represents a valid model for the objective assessment of emotional states of anxiety and fear., Objective: The four studies presented in this report sought to further validate the "threat of shock" paradigm as a human analogue to fear-potentiated startle in rats, by examining the effect of benzodiazepine administration on both baseline and fear-potentiated startle., Methods: Three studies, conducted at Utrecht University, evaluated the effects of oxazepam and of diazepam on baseline and fear-potentiated startle, whereas a fourth study, conducted at Yale University, evaluated the effect of diazepam on baseline, contextual and cue-specific fear-potentiated startle. The threat of shock paradigm consisted of verbal instruction about two visual cues (the threat cue predicted the possible administration of electric shock, the other predicted a safe period), followed by a series of presentations of these cues. During these conditions, acoustic startle stimuli were presented in order to elicit startle responses. The magnitude of the startle response was used to index the degree of fear or alarm experienced during the periods of threat and safety. The fourth study examined the effect of IV administration of diazepam in a similar threat of shock paradigm except that there were two additional context manipulations: electrode placement and darkness., Results: None of the drug manipulations affected specific threat-cue potentiation of startle. However, reductions in baseline startle were observed. Further, startle potentiation by darkness was inhibited by diazepam., Conclusions: At least one type of fear-potentiated startle, i.e. potentiation by a cue-specific fear manipulation, is not susceptible to benzodiazepine treatment. In contrast, effects of manipulations more akin to anxiety (darkness, context) appear sensitive to benzodiazepines. Human experimental models differentiating between these cue specific and contextual responses are needed to shed more light on differences in the anatomy and pharmacology of anxiety disorders.