Relationship between prepulse inhibition of acoustic startle response and schizotypy in healthy Japanese subjects

Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the most common psychophysiological index of sensorimotor gating. Several studies have investigated the relationship of PPI of ASR to schizotypy in Caucasians. However, little has been reported on this relationship in Asians. We investigated a possible relationship between PPI of ASR and schizotypy in 79 healthy Japanese subjects. Schizotypy was assessed by the Schizotypal personality Questionnaire (SPQ). PPI was evaluated at signal‐to‐noise ratios (SnRs: difference between background noise intensity and prepulse intensity) of +12, +16, and +20 dB. The total SPQ score, cognitive/perceptual score, and interpersonal score correlated negatively with PPI at SnR of +16 and +20 dB. We conclude that PPI is associated with the trait of schizotypy in healthy Asian subjects.     

Acoustic startle and prepulse inhibition in the Mongolian gerbil

The acoustic startle response has been studied in great detail in rodents, however almost only in rats and mice, two very similar, domesticated animals. The Mongolian gerbil (Meriones unguiculatus) is an established animal model for auditory research with good low-frequency hearing that covers most of the human audiogram. Gerbils have also been used to investigate the influence of domestication on auditory-related behavior. We characterized the acoustic startle response in gerbils and determined the influence of domestication by directly comparing animals from a domesticated with a wild-type strain. Mongolian gerbils showed a strong and reliable acoustic startle response to noise bursts above a threshold of 77–80 dB SPL which levels out above 115 dB SPL. Only domesticated gerbils showed short-term habituation to repetitive stimulation while the responses in wild-type animals remained at about the same level. Prepulse inhibition of the acoustic startle response by noise burst or gap-in-noise prepulses in gerbils was strong, maximum prepulse inhibition induced by noise bursts was between 67% (wild-types) and 90% (domesticated). Differences between domesticated and wild-type gerbils were even more pronounced for gap-prepulse inhibition. For a gap duration of 50 ms with a lead time of 100 ms, percent inhibition in domesticated gerbils (80%) was almost double the inhibition in wild-types. Such strong prepulse inhibition can be very useful as a basis for efficient audiometric measurements in gerbils.     

Attenuation of the prepulse inhibition of the acoustic startle response within and between sessions

Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are widely used biological markers in the study of psychiatric disorders and have been shown to be homologous across species. Previous studies in humans suggested that PPI is a stable and reliable measure between test sessions, but that PPI decreases within sessions. The purpose of this study was to explore the short- and long-term decrease in PPI as a potential confound in the measurement and interpretation of PPI. We investigated the progression of PPI and habituation of ASR in three test sessions spaced 4 weeks apart in a group of 20 healthy participants. Analysis revealed a significant decrease in the percent PPI within and between the test sessions. Nevertheless, PPI was reliable across three test sessions, indicating that the significant attenuation of PPI over time was a consistent phenomenon. These results suggest that PPI exhibits short- and long-term attenuation.     

The relationship between prepulse detection and prepulse inhibition of the acoustic startle reflex

Prepulse inhibition (PPI) of the startle reflex is defined as the attenuation of the startle response to a startling stimulus (pulse), when such a stimulus is briefly preceded by a stimulus of subthreshold intensity (prepulse). PPI is thought to be neither learned nor due to conscious response inhibition, as it occurs at stimulus onset asynchronies (SOAs) too short to enable the activation of a volitional response. The present study explored the latter of these assertions by investigating (a) the degree to which human subjects are able to detect prepulses at SOAs of 30, 60 and 120 ms, and (b) whether such detection is related to inhibition. Startle eyeblink reflex and detection were measured in 39 participants subjected to an acoustic startle paradigm. Results revealed a significant trend in prepulse detection according to SOA, with highest detection rates at the 120-ms SOA (75%). However, trials on which detection occurred did not differ from trials without detection on measures of startle inhibition. This suggests that PPI is independent of awareness of the prepulse.     

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle

There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI.     

Relationship of prepulse inhibition to temperament and character in healthy Japanese subjects

Prepulse inhibition (PPI) of acoustic startle reflex (ASR) and personality, such as temperament and character, are considered candidate endophenotypes of schizophrenia. Gene polymorphism studies have provided evidence that both PPI and self-transcendence (ST) are polygenetic traits that involve several neurotransmitters, including the serotonin and dopamine signaling pathways. However, the relationship between PPI and temperament/character has not been properly addressed to date. Here, we investigated the link between PPI and temperament/character in 169 healthy Japanese subjects. A human startle response monitoring system was used to deliver acoustic startle stimuli and to record and score the electromyographic activity of the orbicularis oculi muscle. PPI was evaluated at signal-to-noise ratios (SnRs: intensity difference between background noise and prepulse) of +12, +16, and +20 dB. The lead interval (from prepulse onset to pulse onset) was 120 ms, and Temperament and Character Inventory was used in both groups. Significant correlations at SnR of +16 and +20 dB to ST were identified. Our results suggest that impaired sensorimotor gating, evaluated as lower PPI of ASR, of healthy subjects is correlated with self transcendence, the character which is closely related with schizophrenia and schizotypy.     

Iron deficiency affects acoustic startle response and latency, but not prepulse inhibition in young adult rats

Iron deficiency is associated with alterations in dopamine and serotonin transporters as well as changes in dopamine receptor (DR) density, monoamine concentrations, and in vivo extracellular contents of monoamines in terminal fields. Human infants with iron deficiency have both delayed maturation as well as lengthened central conduction times in auditory evoked potential studies. The current study utilizes the magnitude of the acoustic startle response (ASR), prepulse inhibition (PPI), and mean latency to maximum startle response (T(max)), to examine the functional integrity of response to environmental cues. Male and female rats consumed iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. ID rats of both sexes had 20-60% reductions in ASR when compared to CN rats but there was no effect on PPI. T(max) was significantly longer by 10-20% in females, but not males. Dopamine transporter density was significantly lower in putamen, nucleus accumbens, and olfactory tubercle in males, but not female rats while the serotonin transporter was significantly different from control animal density in five of 14 brain regions. Norepinephrine transporter density was lower in the locus ceruleus of ID male rats but was unaffected in ID female rats. Regression modeling of ASR with brain monoamine transporters and receptors showed hematocrit, norepinephrine transporter (NET) in dentate gyrus, and D1R in the nucleus accumbens account for nearly 49% of the variance in ASR. T(max) was not significantly associated with any of the independent variables. We conclude that iron deficiency affects the startle response, but not the inhibitory circuits involved in prepulse inhibition. Importantly, sex also strongly influenced these behavioral responses. Future studies, perhaps pharmacologic in nature, are necessary to ascertain whether iron deficiency modifies the contribution of monoaminergic systems to responses to environmental stimuli.     

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.     

P50 and acoustic startle gating are not related in healthy participants

Although P50 event-related potential (ERP) suppression and acoustic startle prepulse inhibition are conceptualized as measures of sensory and sensorimotor gating, respectively, the relationship between these measures is unclear. In the present study, P50 and prepulse inhibition trials were interleaved in a single testing session to determine their relationship. Thirty-one healthy participants were presented with startle- and P50-eliciting stimuli across six trial blocks. Lead stimuli (i.e., the prepulse to the acoustic startle and the first click in the dual click ERP paradigm) resulted in significant gating, or amplitude attenuation, of responses to the startle probe and second paired click. There were no meaningful correlations between the P50 and prepulse inhibition variables, indicating that P50 suppression and acoustic startle prepulse inhibition measure distinct neural mechanisms. The implications of these findings for operationally defining the psychological construct of gating with these psychophysiological measures are discussed.     

Sex-related differences in prepulse inhibition of startle in irritable bowel syndrome (IBS)

Alterations in central networks involved in the regulation of arousal, attention, and cognition may be critical for irritable bowel syndrome (IBS) symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest that different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients.     

Prepulse inhibition of the startle response with chronic schizophrenia: A replication study

Prepulse inhibition (PPI) deficit, the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90). ASR was significantly different between schizophrenic patients and controls. HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. In addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90 dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR, HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients.     

Prepulse inhibition of startle and its moderation by schizotypy and smoking

Abstract The influences of smoking status and schizotypy on prepulse inhibition (PPI) of the startle eye-blink response were assessed in 71 healthy volunteers, across a wide range of prepulse-to-pulse intervals (50-2020 ms). Multiple regression analyses revealed that nonsmoking participants high in cognitive disorganization showed reduced PPI between 50 and 260 ms, whereas at prepulse intervals of 80 and 140 ms individuals high in introvertive anhedonia had greater PPI compared to their low-scoring counterparts. Moreover, there were positive associations in nonsmokers between introvertive anhedonia and latencies to onset and peak response. In contrast, for those individuals who smoked these associations were attenuated or abolished. The results suggest that PPI is altered differentially in psychosis-prone populations who display different symptom profiles, and that these relationships are moderated by smoking status.     

Role of phospholipase A2 in prepulse inhibition of the auditory startle reflex in rats

High levels of calcium-independent phospholipase A₂ (iPLA₂) are present in the striatum and cerebral cortex [W.Y. Ong, J.F. Yeo, S.F. Ling, A.A. Farooqui, Distribution of calcium-independent phospholipase A₂ (iPLA₂) in monkey brain, J. Neurocytol. 34 (2005) 447–458], and several clinical investigations have suggested a possible role of altered iPLA₂ activity in neurodegenerative and psychiatric disorders. The present study was carried out to elucidate a possible effect of PLA₂ on prepulse inhibition (PPI) of the acoustic startle reflex. Rats that received intraperitoneal injection of the non-specific PLA₂ inhibitor, quinacrine, showed significantly decreased PPI at 76, 80, and 84 dB, compared to saline injected controls. In addition, rats that received intrastriatal injection of antisense oligonucleotide to iPLA₂ showed significant reduction in PPI at prepulse intensities of 76 and 84 dB compared to scrambled sense injected controls. Together, these findings point to a role of PLA₂ in PPI of the auditory startle reflex and sensorimotor gating.     

Cholinergic neurons in the pedunculopontine tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat

The amplitude of the acoustic startle response (ASR) is markedly reduced when the startle eliciting pulse is preceded by a weak, non-startling stimulus at an appropriate lead time, usually about 100 ms. This phenomenon is termed prepulse inhibition (PPI) and has received considerable attention in recent years as a model of sensorimotor gating. We report here on experiments which were undertaken in order to investigate some of the neural mechanisms of PPI. We focused on the characterization of the cholinergic innervation of the pontine reticular nucleus, caudal part (PnC), an obligatory relay station in the primary startle pathway. The combination of retrograde tracing with choline acetyltransferase-immunocytochemistry revealed a cholinergic projection from the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) to the PnC. Extracellular recording from single PnC units, combined with microiontophoretic application of the acetylcholine (ACh) agonists acetyl--methylcholine (AMCH) and carbachol revealed that ACh inhibits the majority of acoustically responsive PnC neurons. Neurotoxic lesions of the cholinergic neurons of the PPTg significantly reduced PPI without affecting the ASR amplitude in the absence of prepulses. No effect on long-term habituation of the ASR was observed. The present data indicate that the pathway mediating PPI impinges upon the primary acoustic startle circuit through an inhibitory cholinergic projection from the PPTg to the PnC.     

On the mechanism of prepulse inhibition

Prepulse inhibition of the acoustic startle response in rats was studied in normal or sham-operated animals or animals with bilateral lesions in the frontal poles, dorsal hippocampus and overlying parietal cortex, parietal cortex alone, or bilateral electrolytic lesions in the motor nuclei of the fifth and seventh cranial nerves which control the activity of the middle ear muscles (m. tensor tympani and m. stapedius). Lesions in the frontal poles had no effect on prepulse inhibition. Lesions of parietal cortex produced some impairment of prepulse inhibition at short interstimulus intervals (1 and 2 sec) while lesions of the motor nuclei of the fifth and seventh cranial nerves markedly reduced prepulse inhibition at all intervals tested. The hypothesis is suggested that reflexive contraction of the middle ear muscles may produce prepulse inhibition of the acoustic startle response.     

Attentional modification of short-lead prepulse inhibition and long-lead prepulse facilitation of acoustic startle among preadolescent boys

In adults, short-lead prepulse inhibition and long-lead prepulse facilitation of startle are greater during attended than ignored prestimuli. To examine these phenomena in children, fourteen 9- to 12-year-old boys completed a tone discrimination task in two sessions separated by 1 week. During each tone series, participants attended to one pitch and ignored the other. Startle probes (102 dB) were presented 120, 240, 2,000 or 4,500 ms following the onset of two-thirds of tones, and during one-third of intertrial intervals. Eyeblink EMG startle was recorded. Percent prepulse inhibition at 120 ms was greater for attended than ignored stimuli in Session 1 but not Session 2. Long-lead prepulse facilitation was marginally greater for attended than ignored tones and did not vary across sessions. Test-retest reliability was moderate during attended prestimuli but was modest during ignored prestimuli. Reliability of attentional modification was poorest at 120 ms and strongest at 4,500 ms. Overall, this study extended prior work in adults and provided a basis for further study of controlled attentional modification of startle in children.     

Influence of a monetary incentive upon attentional modification of short-lead prepulse inhibition and long-lead prepulse facilitation of acoustic startle

Short-lead prepulse inhibition and long-lead prepulse facilitation of startle are greater during attended than ignored prestimuli. The present work examined whether this attentional modification is influenced by monetary incentive. Participants (43 college students) were randomly assigned to receive a small performance-based monetary incentive or were instructed to try their best. The task was to judge the duration of tones of one of two pitches during a series of 48 tones. Prepulse inhibition of startle eyeblink EMG was assessed at 60, 120, and 240 ms, and prepulse facilitation was assessed at 4,500 ms following tone onset. Short-lead percent prepulse inhibition was greater during attended than ignored prestimuli only at 120 ms among paid participants. Long-lead prepulse facilitation was greater for attended than ignored tones, but this effect did not vary with incentive condition. This study demonstrates that attentional modification of short-lead prepulse inhibition is sensitive to a monetary incentive and provides a basis for further examination of motivational effects on early attentional processing.     

Effects of acute systemic 3-nitropropionic acid administration on rat activity and acoustic startle

Spontaneous activity, acoustic startle, and prepulse inhibition (PPI) of acoustic startle were measured in male Sprague–Dawley rats 3–5 h after 0, 10, 15, or 20 mg/kg i.p. 3-nitropropionic acid (3-NP), a mitochondrial toxin. Mean activity was significantly influenced by the 3-NP dose due to decreased activity for 20 mg/kg. Mean startle amplitude was not significantly affected by the 3-NP dose. Means of PPI for prepulses 6 and 12 dBA above background were smaller than means for respective 0 mg/kg doses, but the main effect of 3-NP dose did not reach statistical significance in ANOVA. The changes in measured exploratory-type activity and, possibly, in startle PPI parallel the occurrence of clinical signs exhibited at 3–5 h after 3-NP injection. Neural processing involved in these quantitative behavioral endpoints seems to be affected as energy stores are depleted and degenerative processes are beginning.     

The effects of prepulse inhibition timing on the startle reflex and reaction time

A loud acoustic stimulus has been shown to provoke a reflexive startle response and accelerate simple reaction times. However, an auditory prepulse presented in advance of a startling stimulus can reduce the effect of the startling stimulus. The current study examined the effect of the timing of the prepulse on startle-induced reaction times and the startle reflex. The task was to perform a 30° arm extension movement in response to a visual "go" stimulus. On selected trials, an auditory prepulse (80dB) was presented either 100ms, 500ms or 1000ms prior to the "go" signal. In addition, an auditory startling stimulus (124dB) was presented in conjunction with the "go" signal on some trials. Our results indicated that an auditory prepulse presented 100ms, and to a lesser extent 500ms, significantly decreased the amplitude of the startle reflex; however, the reaction time acceleration associated with the startling acoustic stimulus (SAS) was unaffected. The differential effect of the prepulse on the startle reflex and reaction time acceleration confirm different neural pathways for these effects while the differential effect of the prepulse on the control and startle RTs suggest different mechanisms for movement initiation.     

Independence of valence modulation and prepulse inhibition of startle

This study sought to determine whether prepulse inhibition and valence modulation of startle are independent, both within and across individuals. Acoustic probes (105 dB) were delivered as 68 undergraduate s viewed pleasant, neutral, and unpleasant pictures. Weak acoustic stimuli (8 dB above background) preceded half of the probes by 120 ms. As expected, startles were larger during unpleasant than during pleasant pictures, and smaller on prepulse than no-prepulse trials. In general, valence modulation and prepulse inhibition of startle were unrelated. That is, prepulse inhibition was consistent across affective states, valence modulation did not differ between no-prepulse and prepulse trials, and valence modulation and prepulse inhibition effects were uncorrelated across individuals. Analysis of raw and percent modification scores generally led to similar conclusions. It is concluded that valence modulation and prepulse inhibition are independent startle modulatory phenomena, although this conclusion is tempered by a finding of poor internal consistency reliability for valence modulation.