Prepulse inhibition and the call alert in emergency medical services.

In emergency medical services, paramedics are informed of an emergency call by a high-intensity acoustic alarm called the "call alert." Sudden, loud sounds like the call alert may cause a startle response and be experienced as aversive. Studies have identified an association between the call alert and adverse health effects in first responders; conceivably, these adverse health effects might be reduced by modifying the call alert to blunt its startling and aversive properties. Here, we assessed whether the call alert causes a startle response and whether its startling and aversive properties are reduced when the call alert is preceded by a weak acoustic "prepulse," a process referred to as "prepulse inhibition" (PPI). Paramedics (n = 50; 34M:13F:3 not reported; ages 20-68) were exposed to four call alerts (two with and two without a prepulse) in counterbalanced order. Responses were measured using electromyography (measuring blink amplitude), visual analog scales (quantifying perceived call alert intensity and aversiveness), and an electrocardiogram (assessing heart rate). Paramedics responded to the call alert with a startle reflex blink and an increased heart rate. Acoustic prepulses significantly reduced the amplitude of the call alert-induced startle blink, the perceived sound intensity, and the perceived "dislike" of the call alert. These findings confirm that the call alert is associated with an acoustic startle response in paramedics; adding a prepulse to the call alert can reduce its startling and aversive properties. Conceivably, such reductions might also diminish adverse health effects associated with the call alert in first responders.

Tobacco withdrawal-induced changes in sensorimotor filtering as a predictor of smoking lapse in trauma-exposed individuals.

Prepulse inhibition (PPI) is a measure of sensorimotor filtering thought to shield the processing of initial weaker auditory stimuli from interruption by a later startle response. Previous studies have shown smoking withdrawal to have a negative impact on sensorimotor filtering, particularly in individuals with psychopathology. Because tobacco use may alleviate sensory and sensorimotor filtering deficits, we examined whether smoking withdrawal-induced changes in PPI were associated with maintenance of smoking abstinence in trauma-exposed individuals with and without PTSD who were attempting to quit smoking. Thirty-eight individuals (n = 24 with current or past PTSD; 14 trauma-exposed healthy controls) made an acute biochemically-verified smoking cessation attempt supported by 8 days of contingency management (CM) and cognitive behavioral therapy (CBT) for smoking. Participants completed a PPI task at the pre-quit baseline, 2 days post-quit, and 5 days post-quit. Post-quit changes in PPI were compared between those who remained abstinent for the first 8-days of the quit attempt and those who lapsed back to smoking. PPI changes induced by biochemically-verified smoking abstinence were associated with maintenance of abstinence across the 8-day CM/CBT-supported quit attempt. As compared to those who maintained tobacco abstinence, participants who lapsed to smoking had significantly lower PPI at 2 and 5 days post-quit relative to baseline. Thus, among trauma-exposed individuals, decreases in PPI during acute smoking cessation supported by CM/CBT are associated with lapse back to smoking. Interventions that improve PPI during early smoking abstinence may facilitate smoking cessation among such individuals who are at high risk for chronic, refractory tobacco use.

Anxiety and initial value dependence in startle habituation.

Studies suggest that deficits in startle reflex habituation occur in trait and clinical anxiety. Measures of habituation are affected by the magnitude of the initial response, with larger initial responses predicting a steeper decline in response over repeated trials. This relationship between initial value and change, commonly called the Law of Initial Value or initial value dependence (IVD), has been partialled out as a covariate in habituation research, but variation in IVD may be informative in itself, reflecting differences in physiological reactivity. The present study explored how trait anxiety and contextual anxiety relate to habituation kinetics of the startle eyeblink response: initial value, linear habituation slope, and the relationship between them (IVD). Participants (n = 31; 15 Control, 16 Contextual Anxiety [CA]) were exposed to two blocks of acoustic startle stimuli, and CA participants were warned that they may receive an electrical shock to the wrist during block 2. Trait anxiety did not predict habituation slope, but it did predict a weaker IVD relationship, meaning that high initial startle magnitude was less predictive of a steep response decline in trait-anxious subjects. Meanwhile, CA did not impact startle habituation or IVD. The results suggest that individual differences in trait anxiety are related to the relationship between initial physiological response magnitude and subsequent change in response. IVD in startle habituation may thus serve as a better biomarker of healthy emotional responding than startle habituation per se.

Effect of facial self-resemblance on the startle response and subjective ratings of erotic stimuli in heterosexual men.

Cues of kinship are predicted to increase prosocial behavior due to the benefits of inclusive fitness, but to decrease approach motivation due to the potential costs of inbreeding. Previous studies have shown that facial resemblance, a putative cue of kinship, increases prosocial behavior. However, the effects of facial resemblance on mating preferences are equivocal, with some studies finding that facial resemblance decreases sexual attractiveness ratings, while other studies show that individuals choose mates partly on the basis of similarity. To further investigate this issue, a psychophysiological measure of affective processing, the startle response, was used in this study, assuming that differences in approach motivation to erotic pictures will modulate startle. Male volunteers (n = 30) viewed 30 pictures of erotic female nudes while startle eyeblink responses were elicited by acoustic noise probes. The female nude pictures were digitally altered so that the face either resembled the male participant or another participant, or were not altered. Non-nude neutral pictures were also included. Importantly, the digital alteration was undetected by the participants. Erotic pictures were rated as being pleasant and clearly reduced startle eyeblink magnitude as compared to neutral pictures. Participants showed greater startle inhibition to self-resembling than to other-resembling or non-manipulated female nude pictures, but subjective pleasure and arousal ratings did not differ among the three erotic picture categories. Our data suggest that visual facial resemblance of opposite-sex nudes increases approach motivation in men, and that this effect was not due to their conscious evaluation of the erotic stimuli.

Effects of stress on human mating preferences: stressed individuals prefer dissimilar mates.

Although humans usually prefer mates that resemble themselves, mating preferences can vary with context. Stress has been shown to alter mating preferences in animals, but the effects of stress on human mating preferences are unknown. Here, we investigated whether stress alters men's preference for self-resembling mates. Participants first underwent a cold-pressor test (stress induction) or a control procedure. Then, participants viewed either neutral pictures or pictures of erotic female nudes whose facial characteristics were computer-modified to resemble either the participant or another participant, or were not modified, while startle eyeblink responses were elicited by noise probes. Erotic pictures were rated as being pleasant, and reduced startle magnitude compared with neutral pictures. In the control group, startle magnitude was smaller during foreground presentation of photographs of self-resembling female nudes compared with other-resembling female nudes and non-manipulated female nudes, indicating a higher approach motivation to self-resembling mates. In the stress group, startle magnitude was larger during foreground presentation of self-resembling female nudes compared with other-resembling female nudes and non-manipulated female nudes, indicating a higher approach motivation to dissimilar mates. Our findings show that stress affects human mating preferences: unstressed individuals showed the expected preference for similar mates, but stressed individuals seem to prefer dissimilar mates.

Accelerated trace eyeblink conditioning after cortisol IV-infusion.

Impairing effects of cortisol on learning performance have been shown in human trace eyeblink conditioning. As the effect is observed from 30 min to hours after administration, a genomic action of cortisol is assumed. Here we report rapid cortisol effects that were observed during the first 10 min after cortisol administration in humans. Young healthy males (n=24) received the cortisol synthesis inhibitor metyrapone (1.5 g per os) to avoid interference of the endogenous pulsatile secretion of cortisol. Next, 2mg cortisol or placebo was infused intravenously, immediately before the trace conditioning task. The probability of the conditioned eyeblink responses was assessed electromyographically during the trace eyeblink conditioning task (unconditioned stimulus: corneal air puff, 10 psi, 50 ms; conditioned stimulus: binaural pure tone, 7 dB, 1000 Hz, 400 ms; empty interval between CS and US: 550 ms). Cortisol resulted in a faster increase of conditioning (p=.02), reaching a comparable level to placebo later on. This result extends the well-known effects of stress on the quality and amount of learning by showing that cortisol also affects the speed of learning. We propose that cortisol accelerates trace eyeblink conditioning via a fast, non-genomic mechanism. This fast action of cortisol is part of the adaptive strategy during the early stress response.

State craving, food availability, and reactivity to preferred snack foods.

The startle response has been shown to be useful in studying reactivity to food cues. Following 6h of food deprivation and exposure to neutral and food cues, we examined the role of state craving combined with both a short and long delay of consumption on affect and startle reflex. Participants completed the PANAS, consumed a controlled early morning meal, and experienced 6h of food deprivation. They then reported back to the laboratory, completed a second baseline PANAS, and had their baseline eyeblink EMG startle responses to 100 dB(A) startle probe assessed. Prior to and following the presentation of cues, startle probes were presented and responses were recorded. The PANAS and state craving were also assessed after each cue. Food cues provoked higher levels of state craving than neutral cues and startle responses failed to habituate as quickly to food cues as they did to neutral cues. In addition, cue exposure created the highest NA among high state cravers in the long delay of consumption group. Startle responses differed from NA in that with long delay startle was high irrespective of state craving scores; in the short delay of consumption condition, startle increased linearly with state craving. These results illustrate that state craving and expectations of food availability are important variables in understanding food-related cue reactivity.

Endogenous cortisol suppression with metyrapone enhances acoustic startle in healthy subjects.

Previous human studies have shown that excess cortisol sufficient to fully occupy central nervous system (CNS) corticosteroid receptors may reduce startle eye blink. The present study tested whether cortisol depletion and the resulting reduction in activity of CNS corticosteroid receptors has the opposite effect. In a single-blind, placebo-controlled, randomized study, eye blink EMG responses to 105 dB acoustic startle stimuli were assessed in 25 healthy subjects who received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. As expected, metyrapone significantly reduced salivary cortisol, indicating effective endogenous cortisol suppression. Startle eye blink responses were significantly increased in the metyrapone group. Short-term habituation of the startle reflex was not different between groups. Our results suggest that startle is enhanced during depletion of cortisol. This effect may be mediated by CNS mechanisms controlling cortisol feedback.

Neonatal exposure to MK801 promotes prepulse-induced delay in startle response time in adult rats.

The acoustic startle reflex in rats can be inhibited if a prepulse stimulus is presented just before the startle stimulus (prepulse inhibition; PPI). When postnatal day 7 (P7) rats are exposed to agents that block the NMDA receptor (NMDAR), robust apoptosis is observed within hours and is thought to be followed at later ages by a significant loss of PPI. To understand these observations further, we exposed rat pups to vehicle or the NMDAR antagonist MK801 (1 mg/kg) at P6, P8, and P10. We then examined animals for PPI at P28 and P56. Compared to vehicle controls, we found no evidence for PPI deficits in the MK801-treated group, although we did observe prepulse-induced delay in response time at P56 (but not at P28). In a parallel study, we also performed histological analysis of brain sections for evidence of the pro-apoptotic marker activated caspase-3, 8 h after vehicle or MK801 injection into P6 animals. We found that there was a robust increase in this marker of cell death in the inferior colliculus of MK801 compared to vehicle-treated animals. Thus, transient blockade of the NMDAR during the postnatal period not only promotes early apoptosis in a brain region critical for acoustic processing but also leads to auditory deficits at a later age, suggesting that injury-induced loss of collicular neurons leads to network reorganization in the auditory system that is progressive in nature.

Cardiac modulation of startle: effects on eye blink and higher cognitive processing.

Cardiac cycle time has been shown to affect pre-attentive brainstem startle processes, such as the magnitude of acoustically evoked reflexive startle eye blinks. These effects were attributed to baro-afferent feedback mechanisms. However, it remains unclear whether cardiac cycle time plays a role in higher startle-related cognitive processes, as well. Twenty-five volunteers responded first by 'fast as possible' button pushes (reaction time, RT), and second, rated perceived intensity of 60 acoustic startle stimuli (85, 95, or 105 dB; 50 ms duration; binaural; instantaneous rise time), which were presented either 230 or 530 ms after the R-wave, and eye blink responses were measured by EMG. RT was divided into evaluation and motor response time according to previous research. Increasing stimulus intensity enhanced startle eye blink, intensity ratings, and RT components. Eye blinks and intensity judgments were lower when startle was elicited at a latency of R+230 ms, but RT components were differentially affected: the evaluative component was attenuated, and the motor component was accelerated when stimuli were presented 230 ms after the R-wave. We conclude that the cardiac cycle affects the attentive processing of acoustic startle stimuli.

Physiologic responses to racial rejection images among young adults from African-American backgrounds.

Physiologic reactivity to racially rejecting images was assessed in 35 young adults (10 males, 25 female) from African-American backgrounds using the startle probe paradigm. In a laboratory setting, participants viewed 16 images depicting racial rejection, racial acceptance, nonracial negative, and nonracial positive themes. While viewing these images, startling bursts of noise were presented and the magnitude of the eyeblink responses were measured. Results supported an attentional mechanism which suggests that, while viewing both racially rejecting and nonracial positive images, individuals may be so absorbed in processing the images that they appear less distracted by the startling noise. However, these patterns were only found for participants low in racial regard. Young adults who felt positively about their racial background did not exhibit differential processing of startle stimuli as a function of slide themes. Race-rejection sensitivity did not moderate startle reactivity. Developmental implications, particularly in light of coping with racial discrimination, are discussed.

Inhibition of cortisol production by metyrapone enhances trace, but not delay, eyeblink conditioning.

RATIONALE: Hypercortisolism [ corrected] impairs trace classical conditioning of the eyeblink response to an air puff but does not affect delay conditioning. OBJECTIVES: The opposite neurohormonal condition, hypocortisolism, may facilitate trace classical conditioning, which might be informative in understanding the role of classical conditioning in stress-sensitive syndromes such as fibromyalgia. MATERIALS AND METHODS: Volunteers (n = 82) were randomized to receive either an inhibitor of cortisol production (metyrapone, 1500 mg) or placebo and to complete a delay or a trace eyeblink conditioning protocol (unconditioned stimulus: corneal air puff, 10 psi, 50 ms; conditioned stimulus: binaural pure tone, 75 dB, 1000 Hz, 400 ms; empty interval in trace conditioning: 600 ms), where conditioned eyeblink response probability was assessed electromyographically. RESULTS: Metyrapone induced hypocortisolism, reflected by a 30% decrease of salivary cortisol levels (p < 0.01), and facilitated trace eyeblink conditioning (p < 0.001), while delay eyeblink conditioning remained unaffected. Moreover, extinction of delay-conditioned eyeblink responses was impaired (p = 0.023), but extinction of trace-conditioned responses remained unaffected. CONCLUSIONS: We conclude that acute mild metyrapone-induced hypocortisolism facilitates hippocampus-mediated classical trace eyeblink conditioning but suppresses the extinction of cerebellum-based delay-conditioned responses. Both results may be of theoretical and clinical significance for the generation and persistence of psychosomatic symptoms in patient groups characterized by relative hypocortisolism (e.g., fibromyalgia and chronic fatigue).

Melatonin reduces arousal and startle responsiveness without influencing startle habituation or affective startle modulation in young women.

Melatonin has been suggested to affect human emotion, but conflicting evidence exists. Therefore, we tested the effect of a single dose of a 4 mg prolonged release formulation of melatonin on a biologically based model of emotional processing. Affective modulation of acoustic white noise startle (103 dB) by emotional slides selected from the International Affective Picture System (IAPS) was assessed in 16 healthy young women twice, in a double-blind, placebo-controlled, balanced cross-over design. Melatonin significantly reduced startle responsiveness, but did not impact affective startle modulation, nor startle habituation. Melatonin significantly reduced arousal ratings and induced a parasympathetically dominated heart rate variability pattern indicative of a non-aroused state. We conclude that melatonin reduces arousal and startle responsiveness. However, no evidence for a direct emotion-modulating effect of melatonin was found in this healthy cohort.

Efficacy of stimulus intensity increases and decreases as inhibitors of the acoustic startle response.

The human startle eyeblink response can be inhibited by a change in the stimulus environment briefly before the startling stimulus; both stimulus presentation (prepulse) and cessation of background sound (gap) can result in startle inhibition. More intense prepulses often result in greater inhibition, and this study (N = 53 college students) examined whether graded decreases in sound energy relative to a steady background noise (a "partial gap") would follow this same pattern of inhibition. Embedded in a 65 dB steady background noise were 100 dB white noise startle stimuli preceded at 120 ms on some trials by stimulus intensity increases or decreases of 5, 10, or 15 dB relative to background. Results showed that startle inhibition was graded by amount of change relative to background, such that greater increases or decreases resulted in greater inhibition. Also, increases were more effective startle inhibitors than decreases at equivalent levels of change from background. These results demonstrate that the neural centers responsible for startle inhibition are responsive to both increases and decreases in stimulus intensity, and are sensitive to amount of change, not simply whether a change occurs. These findings may have implications for the development of a screening method for a hearing disorder called tinnitus.

Effects of prepulse intensity, duration, and bandwidth on perceived intensity of startling acoustic stimuli.

Intense abrupt stimuli can elicit a startle reflex; a weak "prepulse" 30-300 ms earlier can reduce both startle and perceived stimulus intensity. Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to understand brain disorders characterized by gating deficits. Compared to startle, PPI of perceived stimulus intensity (PPIPSI) may provide information that is distinct, and easier to acquire and analyze. To develop this experimental measure, we examined PPIPSI under different stimulus conditions. Both PPI and PPIPSI exhibited a non-linear relationship to prepulse intensity, with prepulses 15 dB(A) above background causing maximal inhibition of both measures. A 50 ms broadband noise prepulse produced maximal PPI and PPIPSI, whereas 5 and 20 ms pure tone prepulses produced maximal PPIPSI and PPI, respectively. PPIPSI is a robust, parametrically sensitive and "low tech" measure of sensory gating that may become a valuable tool for understanding the biology of certain mental disorders.

Filling the gap: Evidence for a spatial differentiation in trace eyeblink conditioning.

Trace eyeblink conditioning is used as a translational model of declarative memory but restricted to the temporal domain. Potential spatial aspects have never been experimentally addressed. We employed a spatiotemporal trace eyeblink conditioning paradigm in which a spatial dimension (application side of the unconditioned stimulus) was differentially coded by tone frequency of the conditioned stimulus and recorded conditioned reactions from both eyes. We found more and stronger conditioned reactions at the side predicted by the conditioned stimulus but only in aware participants. Thus, spatial effects are present in trace eyeblink conditioning and may be differentially conditioned depending on the awareness about the spatial relation between conditioned and unconditioned stimulus.

Enhanced startle reflexivity during presentation of visual nurture cues in young adults who experienced parental divorce in early childhood.

Adverse childhood experiences (ACE) may influence stress and affective processing in adulthood. Animal and human studies show enhanced startle reflexivity in adult participants with ACE. This study examined the impact of one of the most common ACE, parental divorce, on startle reflexivity in adulthood. Affective modulation of acoustically-elicited startle eye blink was assessed in a group of 23 young adults with self-reported history of parental divorce, compared to an age- and sex-matched control group (n=18). Foreground pictures were either aversive (e.g. mutilation and injury), standard appetitive (e.g. erotic, recreational sport), or nurture pictures (e.g. related to early life, parental care), intermixed with neutral pictures (e.g. household objects), and organized in three valence blocks delivered in a balanced, pseudo-randomized sequence. During picture viewing startle eye blinks were elicited by binaural white noise bursts (50ms, 105 dB) via headphones and recorded at the left orbicularis oculi muscle via EMG. A significant interaction of group×picture valence (p=0.01) was observed. Contrast with controls revealed blunted startle responsiveness of the ACE group during presentation of aversive pictures, but enhanced startle during presentation of nurture-related pictures. No group differences were found during presentation of standard appetitive pictures. ACE participants rated nurture pictures as more arousing (p=0.02) than did control participants. Results suggest that divorce in childhood led to altered affective context information processing in early adulthood. When exposed to unpleasant (vs. neutral) pictures participants with ACE showed less startle potentiation than controls. Nurture context, however, potentiated startle in ACE participants, suggesting visual cuing to activate protective behavioral responses.

Background noise decreases both prepulse elicitation and inhibition of acoustic startle blink responding.

Prepulse inhibition of startle (PPI) has proved to be useful in distinguishing between schizophrenia patients and normal controls, although not all studies in this area find such group differences. One reason for this inconsistency may be the fact that some research labs present the startle eliciting and inhibiting stimuli over a steady background noise (70 dB), whereas others present stimuli in ambient noise conditions (30-56 dB). The present study tested the impact of background noise (30, 50, and 70 dB) on PPI in normal college adults, with prepulses at intensities of 75, 80, and 85 dB, and with prepulse rise times of 1 or 10 ms. Background noise decreased the amount of PPI caused by the prepulses, and also decreased the ability of the prepulses to themselves elicit blink responses. We conclude that background noise interferes with the processing of the prepulse, attenuating its effect as both an elicitor and inhibitor of the startle reflex. By elevating the difficulty of prepulse processing, this attenuation may be a necessary condition for observing differences in PPI between patient and control groups.

Prepulse inhibition deficits in women with PTSD.

Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma-exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma-exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed.

Presidential Address 2014: The more-or-less interrupting effects of the startle response.

The startle response can be used to assess differences in a variety of ongoing processes across species, sensory modalities, ages, clinical conditions, and task conditions. Startle serves defensive functions, but it may also interrupt ongoing processes, allowing for a reorientation of resources to potential danger. A wealth of research suggests that prepulse inhibition of startle (PPI) is an indicator of the protection of the processing of the prepulse from interruption by the startle response. However, protection against interruption by suppressing the startle response may extend to many other ongoing processes, including the higher processing of the startle stimulus itself. Proof of protection would require measuring ongoing processing, which has very rarely been reported. The idea that PPI represents the protection of the earliest stages of prepulse processing can be challenged, since those earliest stages are completed by the time the startle response occurs, so they are not threatened by interruption and need not be protected. The conception of low PPI as indicative of a "gating deficit" in schizophrenia should be made with caution, since low PPI is seen in some, but not all studies of schizophrenia, but also in a range of other disorders and conditions. Finally, startle is often used to probe ongoing processes, but the response also modifies those processes, interrupting some processes but perhaps facilitating others. A deeper understanding of the function of startle and PPI might improve the precision of application of these measures in the investigation of a range of research topics.