Potentiation Of Startle Response Research Articles

Manipulating expectancy violations to strengthen the efficacy of human fear extinction

Recent theoretical and clinical articles have emphasized a role for expectancy violations in improving the effectiveness of exposure therapy. Expectancy violations are critical to extinction learning and strengthening these violations has been suggested to improve the formation and retention of extinction memories, which should result in lasting symptom reductions after treatment. However, more detailed mechanistic insights in this process are needed to better inform clinical interventions. In two separate fear-conditioning experiments, we investigated whether stronger expectancy violations (Exp1) or fostering awareness of expectancy violations (Exp2) during extinction could reduce the subsequent return of fear. We measured fear potentiated startle (FPS) and skin conductance responses (SCR) as physiological indices of fear, and US expectancy ratings to assess our manipulations. While we successfully created stronger expectancy violations in Exp1, we found no evidence that these stronger violations reduced the return of fear at test. Interestingly, fostering awareness of violations (Exp2) reduced differential SCRs, but not FPS responses. These findings provide novel insights into the effect of US expectancies on fear extinction in the lab, but they also illustrate the complexity of capturing clinically relevant processes of change with fear-conditioning studies.

In search of the behavioral effects of fear: A paradigm to assess conditioned suppression in humans.

Conditioned fear can substantially reduce the likelihood that an individual will engage in reward‐related behavior––a phenomenon coined conditioned suppression. Despite the unmistakable relevance of conditioned suppression for excessive fears and their adverse consequences, the phenomenon has primarily been observed in animal models and is not yet well understood. Here, we aimed to develop a conditioned suppression paradigm that enables a robust quantification of the effect of Pavlovian fear on subsequent reward‐related behavior in humans and assess its potential relation to physiological measures of fear. In phase 1, an instrumental response was incentivized with monetary rewards. In phase 2, one of two conditioned stimuli (CS+) was reinforced with an aversive unconditioned stimulus (US, i.e., electric stimulus). During Pavlovian fear learning we assessed differential skin conductance (SCR) and fear‐ potentiated startle responses (FPS). Lastly, we tested the effect of the fear conditioned CS+ on the response rate of the instrumental response in a transfer phase. Despite strong Pavlovian fear conditioning, as indicated by large effect sizes in differential SCR and FPS, we did not find any evidence for conditioned suppression: that is, there was no significant reduction of instrumental responding in the presence of the CS+ compared to a new control stimulus. This lack of conditioned suppression is in line with previous studies that reported difficulties inducing conditioned suppression and points toward a general challenge in investigating conditioned suppression in humans. Implications and directions for future research on the highly relevant behavioral effects of fear and anxiety are discussed.

Physiological and neural correlates of worry and rumination: Support for the contrast avoidance model of worry.

The current experiments tested neural and physiological correlates of worry and rumination in comparison to thinking about neutral events. According to the avoidance model-stating that worry is a strategy to reduce intense emotions-physiological and neurobiological activity during worried thinking should not differ from activation during neutral thinking. According to the contrast avoidance model-stating that worry is a strategy to reduce abrupt shifts of emotions-activity should be increased. To test these competing models, we induced worry and neutral thinking in healthy participants using personal topics. A rumination condition was added to investigate the specificity of changes induced by the mental process. Two experiments were conducted assessing the effects on different response levels: (1) neural activation using fMRI, and (2) physiological response mobilization using startle and autonomic measures. During worry, participants showed a potentiated startle response and BOLD activity indicative of emotional network activation. These data partly support the contrast avoidance model of worry. Both mental processes showed elevated activity in a common network referred to as default network indicating self-referential activity.

Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction

Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear-potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research.

Generalization of Contextual Fear in Humans

Enhanced fear responses to cues, which were not associated with the threat but share perceptual characteristics with the threat signal, indicate generalization of conditioned fear. Here, we investigated for the first time generalization processes in contextual fear conditioning. Thirty-two participants were guided through two virtual offices (acquisition phases). Mildly painful electric shocks (unconditioned stimulus, US) were unpredictably delivered in one office (anxiety context, CTX+), but never in the other office (safety context, CTX-). During the generalization test, participants were guided through CTX+, CTX-, and the generalization context (G-CTX), which contained features of both the CTX+ and the CTX-, but no US was delivered. We found successful contextual fear conditioning (i.e., the CTX+ compared to the CTX- elicited potentiated startle responses and was rated with more negative valence, higher arousal and higher anxiety). Importantly, implicit and explicit responses dissociated in the generalization test. Thus, participants rated the G-CTX as more arousing and anxiogenic than the CTX- indicating anxiety generalization, but they showed enhanced startle responses to the CTX+ only, while the G-CTX and the CTX- did not differ. In summary, healthy participants on an explicit level responded to the generalization context like to the anxiety context, but on an implicit level responded to the generalization context like to the safety context. Possibly, this dissociation suggests distinct and specific generalization processes underlying contextual fear.

Resting heart rate variability and the startle reflex to briefly presented affective pictures

We have previously shown that persons with low HRV showed potentiated startle responses to neutral stimuli. In the present study we replicated our prior findings and extended them to examine the effects of HRV on the startle magnitude to pictures that were presented outside of conscious awareness. A total of 85 male and female students were stratified via median split on their resting HRV. They were presented pictures for 6s or for 30ms. Results indicated that the high HRV group showed the context appropriate startle magnitude increase to unpleasant foreground. The low HRV group showed startle magnitude increase from pleasant to neutral pictures but no difference between the neutral and unpleasant pictures. This pattern of results was similar for the 30ms and the 6s conditions. These results suggest that having high HRV may allow persons to more efficiently process emotional stimuli and to better recognize threat and safety signals.

Modulation of the startle response in verbal aggressors: Differences among stimuli with distinct affective social content.

emotional response to socially affective stimuli is an important variable to understand aggression. Research is lacking on the psychophysiological basis of verbal aggressiveness that would allow the identification of these emotional responses. The aim of the present study was to investigate modulation of the startle response in verbal aggressors during the presentation of visual stimuli with different affective social content. Acoustic startle probes were administered to 29 verbal aggressors and 28 non-verbal aggressors while viewing slides from the International Affective Picture System, which contains sexual, filial, neutral, unpleasant, and suffering of others pictures. Verbal aggressors showed a low startle response to sexual pictures compared with non-verbal aggressors and a potentiated startle response to neutral pictures compared with unpleasant, filial, and suffering of others pictures. These differences were observed among women. Based on previous studies, the present results may be explained by high testosterone levels, low cortisol levels, and moral disengagement exhibited by verbally aggressive women.

Fear-potentiated startle response is unrelated to social or emotional functioning in adolescents with autism spectrum disorders.

It has been suggested that atypical amygdala function contributes to the social impairments characteristic of autism spectrum disorders (ASDs). Previous research has demonstrated that adolescents and adults with ASD generate normal response during a fear-potentiated startle paradigm, suggesting this aspect of amygdala function is intact and may not account for the social dysfunction associated with the condition. The amygdala also plays a crucial role in the expression of anxiety and may contribute to high rates of reported anxiety in individuals with ASD. The present study partially replicates prior work by examining the fear-potentiated startle response in adolescents with ASD, and extends this to investigate the relationship between startle response and anxiety. Eyeblink magnitude and latency (electromyographic activity; EMG) were collected from 20 adolescents with ASD and 19 typically developing (TD) age-matched adolescents during a fear-potentiated startle paradigm. Parent-report and self-report of anxiety and additional psychiatric symptoms were collected. Parental reports indicated higher rates of associated psychopathology in adolescents with ASD compared with TD adolescents. Consistent with previous results, both groups showed normal potentiated startle response, and no group differences in EMG were found. Symptoms of anxiety and level of social impairment were unrelated to startle response. These findings held for all levels of anxiety, suggesting that within the context of the fear-potentiated startle paradigm, amygdala response is not associated with degree of atypical social or emotional functioning in ASD.

Combined NK1 antagonism and serotonin reuptake inhibition: effects on emotional processing in humans

Synergistic effects of NK₁ receptor antagonism combined with serotonin reuptake inhibition have been reported in preclinical models. GSK424887 is a selective competitive antagonist of the human NK₁ receptor and inhibitor of the serotonin transporter. However, its actions in human models of depression have not been assessed. This study explored the effects of acute administration of GSK424887 compared to placebo in healthy male volunteers. The selective serotonin reuptake inhibitor (SSRI) citalopram was used as a positive control. A battery of emotional processing tasks was given at the peak time of drug effect. GSK424887 enhanced attentional vigilance in the dot-probe task to both positive and negative stimuli. By contrast, citalopram enhanced perception of angry, sad and happy facial expressions and increased positive bias in the facial expression recognition task. Neither drug significantly affected emotion potentiated startle responses or emotional memory. These results suggest that acute administration of GSK424887 modulated some aspects of emotional processing but these effects were not similar to those seen previously with antidepressant agents. This was the first use of the battery of emotional processing tasks in a Phase 1 study. Repeated administration of the test and active control drugs may be needed to reliably characterise their effects.

Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle

The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.

Fear conditioning in psychopaths: Event-related potentials and peripheral measures

Aversive pavlovian delay conditioning was investigated in a sample of 11 criminal psychopaths as identified by using the Psychopathy Checklist-Revised and 11 matched healthy controls. A painful electric stimulus served as unconditioned stimulus and neutral faces as conditioned stimuli. Event-related potentials, startle response potentiation, skin conductance response, corrugator activity, and heart rate were assessed, along with valence, arousal, and contingency ratings of the CS and US. Compared to healthy controls, psychopathic subjects failed to differentiate between the CS+/CS− as shown by an absence of a conditioned response in startle potentiation and skin conductance measures. Through use of a fear-eliciting US, these data confirm previous findings of a deficient capacity to form associations between neutral and aversive events in psychopathy that appears unrelated to cognitive deficits and is consistent with hypothesized frontolimbic deficits in the disorder.

Fear Extinction in Traumatized Civilians with Posttraumatic Stress Disorder: Relation to Symptom Severity

The symptoms of posttraumatic stress disorder (PTSD) can be explained, at least in part, as an inability to inhibit learned fear during conditions of safety. Our group has shown that fear inhibition is impaired in both combat and civilian PTSD populations. On the basis of our earlier findings, we employed an established fear extinction paradigm to further explore fear dysregulation in a civilian traumatized population. Fear-potentiated startle (FPS) was examined in 127 trauma-exposed individuals with and without PTSD. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, [CS+]) that was paired with an aversive air blast to the larynx (unconditioned stimulus) and a different colored shape that was not paired to the air blast (nonreinforced condition stimulus). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement. Both groups demonstrated successful fear conditioning on the basis of startle and unconditioned stimulus-expectancy ratings; however, participants with PTSD displayed greater FPS responses to the CS+ and nonreinforced conditioned stimulus compared with the group without PTSD. During fear extinction, the PTSD group showed elevated FPS responses to the previously reinforced CS+ during the early and middle stages of extinction. During the acquisition and extinction phases, PTSD participants with higher levels of reexperiencing symptoms exhibited greater potentiated startle responses to the CS+ compared with PTSD participants with lower reexperiencing symptoms. These results suggest that PTSD is associated with enhanced fear learning and a greater "fear load" to extinguish after conditioned fear is acquired.

Genetic variation in brain‐derived neurotrophic factor and human fear conditioning

Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS +/- 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning--evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

Anxiety and defensiveness: individual differences in affective startle modulation

Anxious individuals selectively attend to threatening information, and defensiveness may influence the experience and expression of anxiety. Fifty-eight undergraduates scoring high and low on measures of anxiety and defensiveness viewed pleasant, neutral, and unpleasant pictures. Acoustic startle probes were presented 60, 240, or 2,000 ms after picture onset. At 60 ms and 240 ms, repressors (low anxiety, high defensiveness) showed weaker blinks during both pleasant and unpleasant compared to neutral pictures, suggesting enhanced early attention to affective stimuli, regardless of valence. At 2,000 ms, high-anxious but not low anxious participants showed potentiated startle responses during unpleasant compared to pleasant pictures. Although this result replicated previous research on anxiety and valence modulation of startle, exploratory analyses suggested that the valence effect was restricted to trait anxious individuals tending toward a defensive coping style. Across probe conditions, defensiveness was associated with heightened startle reactivity independent of self-reported anxiety and foreground stimulus characteristics.

Differential effects of hypocretins on noise-alone versus potentiated startle responses

Hypocretins are recently discovered neuropeptides, synthesized exclusively in the hypothalamus with excitatory efferents to noradrenergic, serotonergic, and GABAergic (gamma-aminobutyric acid) neurons. Hypocretins also increase corticotropin releasing hormone (CRH) secretion. These actions suggest a possible role for hypocretins in the neurobiology of anxiety, fear, or startle mechanisms. We examined the effects of intracerebroventricular (ICV) administration of hypocretin-A and hypocretin-B on behavior in the Startle Potentiated Startle (SPS) paradigm, a repeated measures, non-shock animal model for studying the classically conditioned enhancement of acoustic startle in the rat. SPS has been used to study effects of anxiolytic treatments. Male Sprague–Dawley rats were tested using the SPS paradigm for 3 days (M–W–F). Following training, rats were anesthetized and 26 gauge stainless cannulae were permanently implanted into the lateral ventricle for intracerebroventricular (ICV) infusions. Following 6–9 days of recovery period, the M–W–F SPS testing was resumed. ICV infusion of both Hypocretin-A (1 and 3 nM) and Hypocretin-B (3 and 10 nM) produced significant reduction in Noise Alone Startle amplitude compared to pre-infusion baseline, whereas infusion with vehicle did not affect Noise Alone Startle. The effect of Hypocretin-B was brief (first 10 min post-infusion), whereas the effect of Hypocretin-A persisted across much of the 50 min post-infusion period. Neither Hypocretin-A nor Hypocretin-B significantly altered the magnitude of the SPS response. Contrary to our expectations, hypocretins seems to possess anxiolytic rather than pro-anxiogenic properties, as indicated by decrease in Noise Alone Startle.

Neurovisceral integration, emotions and health: An update

In the present paper we describe a model of neurovisceral integration in which a set of neural structures involved in cognitive, affective and autonomic regulation are related to heart rate variability (HRV) and health. We show that autonomic imbalance is associated with increased morbidity and mortality. We also provide evidence that this autonomic imbalance can be indexed by HRV. We then provide pharmacological and neuroimaging data in support of the neural structures linking the central nervous system to HRV. Next, in an experiment investigating emotional regulation we showed that resting levels of HRV were related to emotion modulated startle responses such that those with higher HRV produced context appropriate responses compared with those with low HRV. We then show that stimuli presented outside of conscious awareness lead to potentiated startle responses and undifferentiated phasic HR responses. These results suggest that the prefrontal cortex may modulate responses to threat via a top-down regulation of sympathoexcitatory circuits. We propose that these findings have important implications for the understanding of the two-way communication between the heart and the brain, and provide a connection among negative emotions and negative health consequences via the common mechanism of autonomic imbalance and low parasympathetic activity.

Individuals with Autism Spectrum Disorder Show Normal Responses to a Fear Potential Startle Paradigm

The present study utilized a fear potentiated startle paradigm to examine amygdala function in individuals with autism spectrum disorder. Two competing hypotheses regarding amygdala dysfunction in autism have been proposed: (1) The amygdala is under-responsive, in which case it would be predicted that, in a fear potentiated startle experiment, individuals with autism would exhibit decreased fear conditioning and/or potentiation, and (2) The amygdala is over responsive, in which case an exaggerated potentiation of the startle response would be predicted. Fourteen adolescents and adults diagnosed with autism spectrum disorder and 14 age, gender, IQ, and anxiety level-matched typical adolescents and adults participated. Both participants with autism and typical participants potentiated the startle response following fear conditioning and no group differences in the latency or amplitude of the potentiated startle response were found. These results suggest that this aspect of amygdala function, namely fear conditioning and potentiation of the startle response, is intact in individuals with autism.

Latent inhibition of conditioned odor potentiation of startle: a developmental analysis.

We conducted a two-part study of age and latent inhibition in the rat. In the first part of the study, rats given odor-shock pairings at 23 or 75 days of age exhibited a potentiated startle response in the presence of the odor the following day. This effect did not occur in rats trained at 16 or 20 days of age. Odor pre-exposure on the day prior to conditioning markedly reduced the odor potentiation of startle effect in 23- and 75-day-old rats but had no effect in 16 and 20-day-olds. In the second part of the study, rats were pre-exposed to the odor at 16 or 20 days of age and then conditioned at 23 days of age. When tested the day after conditioning, these pre-exposed rats exhibited a disruption in the odor potentiation of startle effect. We compare our results with other studies of latent inhibition, and with recent studies on whether conditioned responses are appropriate to the animal's age at training or their age at test.

Aversive Pavlovian conditioning in psychopaths: Peripheral and central correlates

Differential aversive Pavlovian conditioning with a foul odor as unconditioned stimulus (US) and neutral faces as conditioned stimuli (CS) was compared between 9 noncriminal psychopaths as defined by the Hare Psychopathy Checklist Revised and 12 healthy controls. Event-related potentials (ERP), heart rate, skin conductance response, corrugator EMG, and startle response potentiation as well as valence, arousal, and contingency of the CS were assessed. Whereas the healthy controls (HC) showed significant CS +/CS- differentiation, the psychopaths (PP) failed to exhibit a conditioned response although unconditioned responses were comparable between the groups. N100, P200, and P300 to the CSs revealed that psychopaths were not deficient in information processing and showed even better anticipatory responding than the HC group indicated by the terminal contingent negative variation (tCNV), that lacked, however, CS+ and CS- differentiation. These data indicate a deficit in association formation in psychopaths that may be related to deficient interaction of limbic-subcortical and cortical structures.

Acoustic Startle Eyeblink Response After Acute Exercise

The acoustic startle eyeblink response (ASER) is a useful probe for investigating central nervous system activity associated with emotional responses to aversive and appetitive stimuli. Though the ASER is sensitive to change in emotional arousal, the effect of acute physical exertion on ASER has not been reported. We examined changes in ASER amplitude and latency in 26 healthy young men (24 ± 5 yr) after 20 min of cycling at light and hard intensities (40% and 75% VO2peak) and after 20 min of quiet rest. Mixed model ANCOVA, controlling precondition scores, indicated no effects for ASER amplitude or latency in either sedentary or active participants (p >. 10). Our findings indicate that possible effects of acute exercise on potentiated startle or ASER responses elicited by positive or negative foreground stimuli should not be expected to be confounded by an altered baseline acoustic startle eyeblink response when measured in healthy young men.