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.

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.

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.

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.

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.

Effects of anxiety sensitivity and expectations on the modulation of the startle eyeblink response during a caffeine challenge.

RATIONALE: The way in which the tendency to fear somatic arousal sensations (anxiety sensitivity), in interaction with the created expectations regarding arousal induction, might affect defensive responding to a symptom provocation challenge is not yet understood. OBJECTIVES: The present study investigated the effect of anxiety sensitivity on autonomic arousal, startle eyeblink responses, and reported arousal and alertness to expected vs. unexpected caffeine consumption. METHODS: To create a match/mismatch of expected and experienced arousal, high and low anxiety sensitive participants received caffeine vs. no drug either mixed in coffee (expectation of arousal induction) or in bitter lemon soda (no expectation of arousal induction) on four separate occasions. Autonomic arousal (heart rate, skin conductance level), respiration (end-tidal CO2, minute ventilation), defensive reflex responses (startle eyeblink), and reported arousal and alertness were recorded prior to, immediately and 30 min after beverage ingestion. RESULTS: Caffeine increased ventilation, autonomic arousal, and startle response magnitudes. Both groups showed comparable levels of autonomic and respiratory responses. The startle eyeblink responses were decreased when caffeine-induced arousal occurred unexpectedly, e.g., after administering caffeine in bitter lemon. This effect was more accentuated in high anxiety sensitive persons. Moreover, in high anxiety sensitive persons, the expectation of arousal (coffee consumption) led to higher subjective alertness when administering caffeine and increased arousal even if no drug was consumed. CONCLUSIONS: Unexpected symptom provocation leads to increased attention allocation toward feared arousal sensations in high anxiety sensitive persons. This finding broadens our understanding of modulatory mechanisms in defensive responding to bodily symptoms.

Startle eye-blink modulation by facial self-resemblance and current mood.

Although salient stimuli are known to modulate startle eye-blink responses, and one's own face is considered of particular salience, effects of facial self-resemblance on startle responsiveness have not been systematically investigated. For the present study, pictures from the FACES database (rated as neutral) were digitally morphed to resemble the participants' (N=37) faces to varying degrees (25-50-75%). Perceptually matched geometrical shapes served as a control condition. At SOAs of either 300ms or 3000ms after picture onset, startle responses were elicited by white noise (50ms, 105dB), and recorded at the orbicularis oculi via EMG. Prior to the experiment, self-reported mood was assessed by means of the PANAS. Relative to non-face stimuli, the presentation of faces reduced startle magnitude at short, but not long, lead intervals. Furthermore, for probes presented at a SOA of 300ms, a linear decrease in startle magnitude with higher levels of self-resemblance was observed, presumably reflecting higher salience of the self-face. The startle modulating effect of self-resembling faces during longer lead intervals was moderated by the participants' current mood: negative affect predicted stronger patterns of attenuation, which might be interpreted as an increase in self-focus resulting from more negative mood.

Effects of a startle stimulus on response speed and inhibition in a go/no-go task.

Two studies examined the interaction of an acoustic startle stimulus and visual go/no-go task stimuli on startle reactivity and task performance. In the first study, an acoustic stimulus (50 ms, 100 dB noise) was presented alone or with a green (go) or red (no-go) circle; in the second study, a prepulse (50 ms, 75 dB noise) was presented alone or 120 ms before the startle stimulus or circle. The startle stimulus speeded responses to the go stimuli and increased the covert false alarm rate in the no-go condition (measured by EMG activity in the hand), although very few overt errors were made in the no-go condition. Startle response magnitude was increased by a circle but decreased by a prepulse. The speeding of go responses caused by a startle stimulus was attenuated by the occurrence of a startle response, suggesting that an intense accessory stimulus can facilitate responding to an imperative stimulus, and that the startle response to that intense stimulus can interfere with that facilitation.

Support for the interruption and protection hypotheses of prepulse inhibition of startle: evidence from a modified Attention Network Test.

The startle response may interrupt information processing (interruption hypothesis), and prepulse inhibition of startle (PPI) may protect that processing from interruption (protection hypothesis). These hypotheses were tested by measuring startle eyeblinks during an Attention Network Test (ANT), a combined flanker and cue reaction time (RT) task that measures the efficiency of multiple attentional networks. ANT trials with and without startle stimuli presented in the interval between the visual cue (prepulse) and target were compared. Results showed that the startle stimulus served as an alerting stimulus, speeding RT in the ANT. However, this reaction time speeding was most pronounced on trials with no startle response (100% PPI). This suggests that the alerting effect of the startle stimulus was attenuated by the startle response, and that PPI decreased the degree of this interference, in support of the interruption and protection hypotheses.

Cortisol, but not intranasal insulin, affects the central processing of visual food cues.

Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative nonreward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.

Rapid cortisol enhancement of psychomotor and startle reactions to side-congruent stimuli in a focused cross-modal choice reaction time paradigm.

The stress hormone cortisol has been shown to affect hemodynamic activity of human brain structures, presumably via a nongenomic mechanism. However, behavioral implications of this finding remain unknown. In a placebo-controlled, blinded, cross-over design the rapid effects of IV hydrocortisone (5mg) on cross-modal integration of simultaneous, unilateral visual and acoustic signals in a challenging startle and reaction time (RT) paradigm were studied. On two separate days 1 week apart, 24 male volunteers responded by button push to either up- or down pointing triangles presented in random sequence in the periphery of one of the visual hemi-fields. Visual targets were accompanied by unilateral acoustic startle noise bursts, presented at the same or opposite side. Saccadic latency, manual RT, and startle eye blink responses were recorded. Faster manual reactions and increased startle eye blink responses were observed 11-20 min after hydrocortisone administration when visual targets and unilateral acoustic startle noises were presented in the same sensory hemi-field, but not when presented in opposite sensory hemi-fields. Our results suggest that a nongenomic, cortisol-sensitive mechanism enhances psychomotor and startle reactions when stimuli occur in the same sensory hemi-field. Such basic cognitive effects of cortisol may serve rapid adaptation and protection against danger stimuli in stressful contexts.

Supertaster, super reactive: oral sensitivity for bitter taste modulates emotional approach and avoidance behavior in the affective startle paradigm.

People differ in both their sensitivity for bitter taste and their tendency to respond to emotional stimuli with approach or avoidance. The present study investigated the relationship between these sensitivities in an affective picture paradigm with startle responding. Emotion-induced changes in arousal and attention (pupil modulation), priming of approach and avoidance behavior (startle reflex modulation), and subjective evaluations (ratings) were examined. Sensitivity for bitter taste was assessed with the 6-n-propylthiouracil (PROP)-sensitivity test, which discriminated individuals who were highly sensitive to PROP compared to NaCl (PROP-tasters) and those who were less sensitive or insensitive to the bitter taste of PROP. Neither pupil responses nor picture ratings differed between the two taster groups. The startle eye blink response, however, significantly differentiated PROP-tasters from PROP-insensitive subjects. Facilitated response priming to emotional stimuli emerged in PROP-tasters but not in PROP-insensitive subjects at shorter startle lead intervals (200-300ms between picture onset and startle stimulus onset). At longer lead intervals (3-4.5s between picture onset and startle stimulus onset) affective startle modulation did not differ between the two taster groups. This implies that in PROP-sensitive individuals action tendencies of approach or avoidance are primed immediately after emotional stimulus exposure. These results suggest a link between PROP taste perception and biologically relevant patterns of emotional responding. Direct perception-action links have been proposed to underlie motivational priming effects of the startle reflex, and the present results extend these to the sensory dimension of taste.

Acoustic startle reactivity while processing reward-related food cues during food deprivation: evidence from women in different menstrual cycle phases and men.

Previous research has shown that food deprivation enhances the acoustic startle reflex when it is elicited during presentation of visual food cues. Frustrative nonreward may explain this effect, since visual food cues are also rated to be more appetitive and arousing during food deprivation. However, the impact of menstrual cycle and sex on this effect remains unclear, and it is also not known whether this effect is influenced by hunger and motivation to eat. According to a within-study design, 20 healthy women in different menstrual cycle phases and 14 healthy men participated twice, in normal and food-deprived conditions. After 18 h of food deprivation, acoustic startle was attenuated by appetitive nonfood foreground pictures, but enhanced by presentation of food pictures. No differences between menstrual cycle phases and sexes appeared. The effect correlated with hunger changes, suggesting that motivational factors play a role.

Startle effects on saccadic responses to emotional target stimuli.

Startle stimuli elicit various physiological and cognitive responses. This study investigated whether acoustic startle stimuli affect saccadic reactions in an emotional pro- or antisaccade task. Startle probes were presented either 500 ms before or simultaneous with an imperative stimulus that indicated whether a saccade towards or away from positive, neutral, or negative peripheral target pictures had to be performed. Valence interacted with saccade direction according to an approach-avoidance pattern of gaze behavior, with delayed prosaccades to negative targets and antisaccades away from positive targets. Acoustic startle stimuli preceding the presentation of peripheral target pictures speeded up the initiation saccades, irrespective of stimulus valence. Results indicate a speeding of cognitive-motor processing by preceding startle stimuli.

For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose-response relationship.

Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.

Effects of ADORA2A gene variation and caffeine on prepulse inhibition: a multi-level risk model of anxiety.

The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety.

Maternal social stress modulates the development of prepulse inhibition of startle in infants.

BACKGROUND: Stress during rearing has negative effects on the maturation of information processing in rodent offspring, but similar evidence in humans is absent. Prepulse inhibition (PPI) of startle is a measure reflecting the integrity of information processing. PPI does not depend on active cooperation, making it a suitable measure for studying newborns and infants. This study investigated whether postnatal development of infant PPI is influenced by self-reported stress in the mother. METHODS: 49 healthy term-born infants were studied twice, four days after birth and again at four months. PPI was assessed by presentation of acoustic startle stimuli (95dB) either alone or preceded (SOA 120ms) by a prepulse (75dB). Mother's social stress levels were assessed with the modified Trier Inventory for the Assessment of Chronic Stress (TICS). Cortisol saliva samples were collected from mothers and their children. RESULTS: ANOVA revealed a different development of PPI in infants whose mothers reported enhanced stress levels due to social isolation and reduced social recognition. Cortisol levels were related to mothers' self-report stress, but not to PPI development in infants. CONCLUSIONS: Maternal stress experience has an impact on the maturation of human infants' information processing in the first four months after birth.