Impaired prepulse inhibition and habituation of acoustic startle response in Japanese patients with schizophrenia

Prepulse inhibition (PPI) and habituation of the acoustic startle reflex (ASR) are considered to be candidate endophenotypes of schizophrenia. However, to our knowledge, only one group has investigated these startle measures in Asian patients with schizophrenia. In the present study, we evaluated these startle measures in 51 Japanese patients with schizophrenia and compared them with those of 55 healthy age- and sex-matched Japanese controls. A human startle response monitoring system was used to deliver acoustic startle stimuli, and record and score the electromyographic activity of the orbicularis oculi muscle. The startle measures examined were mean magnitude of ASR to pulse alone trials in initial block (SR), habituation of ASR during the session (HAB), and PPI at prepulse intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90) sound pressure level. SR was not significantly different between the patients and controls. Patients displayed significantly reduced HAB and PPI for all prepulse intensities compared to controls. The greatest statistical difference in PPI between patients and controls was found with PPI86. This did not correlate with any clinical variable in each group. Our results indicate that PPI and habituation of ASR are impaired in Asian patients with schizophrenia.     

Effects of sex and estrous cycle on modulation of the acoustic startle response in mice

Potential sex differences in amplitude, habituation, prepulse inhibition (PPI) and prepulse facilitation (PPF) of the acoustic startle response (ASR) were investigated using male and female mice from the two different inbred mouse strains C57BL/6J (C57) and C3H. Furthermore, the effects of the estrous cycle were tested. The estrous cycle appeared to have no effect on ASR amplitude, habituation, PPF and PPI, the latter being in contrast to results in rats and humans. While sex had no effect on PPI or PPF, males exhibited higher startle amplitudes than females, irrespective of strain, which we discuss to be due to increased male anxiety. In addition, long-term habituation was stronger in C57 males and short-term habituation was weaker in C3H males with respect to females. These results provide evidence for influence of the reproductive hormones on startle reactivity and startle habituation; we therefore conclude that future studies involving genetic influences on behavior using inbred strains are only complete if both sexes are included.     

Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia

Prepulse inhibition (PPI) of acoustic startle reflex has been suggested as a neurophysiologic measure of information processing abnormalities in schizophrenia. However, there has been little information on PPI and related measures in Asian patients with schizophrenia. We examined startle response to acoustic stimuli, its habituation, and PPI in 20 Japanese patients with chronic schizophrenia under antipsychotic medication and 16 healthy controls matched for age and sex. We measured PPI with 115 dB of pulse (40 ms), 82, 86, or 90 dB of prepulse (20 ms) and 30, 60, or 120 ms of lead interval (LI). The startle response to pulse alone trials was significantly smaller in schizophrenics than in controls, which may be due, at least in part, to medication. There was no significant difference in habituation of startle response during the test session between the two groups. PPI differed significantly between the two groups when LI was 120 ms. No significant relationship was found on startle response or PPI with age of onset, number of previous admission, medication dosages, or symptom scores assessed with the Positive and Negative Syndrome Scale (PANSS). Our results confirm impaired PPI in chronic schizophrenia patients compared with controls in Japanese.     

Startle modulation in Caucasian-Americans and Asian-Americans: a prelude to genetic/endophenotypic studies across the 'Pacific Rim'

OBJECTIVES: Deficient prepulse inhibition (PPI) of startle in schizophrenia patients and unaffected family members may be a useful endophenotype in studies seeking to identify vulnerability genes for schizophrenia. Before expanding such studies to include Pacific Rim populations with distinct genetic origins compared with North American Caucasian populations, we examined PPI and related startle measures in normal North American Caucasian and Asian men. METHODS: One hundred and seventy-four consecutive carefully screened right-handed male 18-35 year olds completed tests of startle and PPI using bilateral electromyography measures of orbicularis oculi. Subjects identified their racial background. RESULTS: Startle in Caucasian subjects was of significantly larger magnitude and shorter latency compared with Asian subjects; the percent PPI was significantly greater in Asian versus Caucasian subjects at 60 and 120 ms prepulse intervals. Group differences in PPI but not reflex latency were eliminated when groups were matched for startle magnitude on pulse alone trials. Caucasian-American and Asian-American groups did not differ significantly in resting blink rate, resting electromyography activity, or startle reflex habituation. CONCLUSIONS: Robust phenotypic differences in acoustic startle magnitude and latency between Caucasian-American and Asian-American populations must be considered in studies using startle and PPI as endophenotypes across these populations.     

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.     

Relationship of prepulse inhibition of the startle reflex to attentional and executive mechanisms in man.

Prepulse inhibition (PPI) of the startle reflex at short lead intervals is thought to reflect the operation of a preattentive "sensorimotor gating" mechanism, which suggests that processing of the prepulse stimulus should not be modulated prior to its inhibitory effects on startle. To test this hypothesis, we examined whether PPI is affected following habituation to the prepulse. PPI was measured in two sessions associated with either the presence (habituation condition) or the absence (control condition) of prepulse repetition. There was a trend for prepulse repetition to reduce the effectiveness of that prepulse in inhibiting the startle response. We also explored the relationship of PPI to scores in tests of selective and sustained attention and planning ability. Overall PPI performance was correlated to performance indices of planning ability and there was a trend level correlation with scores in selective but not sustained attention tests. These preliminary results merit further investigation.     

Prepulse inhibition among four strains of mice: effects of type of prepulse and lead time

The effects of the type of prepulse (PP: visual 30 ms and auditory 30 ms) and lead time (50, 100, 200 ms) on the acoustic startle inhibition (prepulse inhibition: PPI) were tested and compared among four strains of inbred mice (BALB/cA, C3H/HeJ, C57BL/6J, and DBA/2N: all n=11). Following 40 trials of habituation using single pulse (white noise: P; 115 dB, 50 ms), the prepulse session made of 36 trials was conducted. In the habituation, the startle amplitude and peak latency were measured. DBA mice showed weaker startle amplitude than the other 3 strains. The peak latency of the BALB mice was faster than the other strains. The PPI by auditory PP was largest in C57BL, followed by C3H, and the least in BALB mice. DBA mice showed no PPI effect. The PPI under visual prepulse condition was observed only in BALB strain. Contrary, DBA mice showed prepulse facilitation in the 50 ms lead time condition.     

Differences in startle reflex and prepulse inhibition in European-Americans and African-Americans

The acoustic startle reflex and its modulation by a prepulse are psychophysiological phenomena that are commonly studied to evaluate various aspects of information processing. Recent reports in human populations suggest that subjects from disparate racial backgrounds may have significant differences in the startle response. To determine if this pattern could be observed in our subject population and whether it extended to prepulse inhibition (PPI), we evaluated baseline startle parameters and PPI in 53 African-Americans (AA) and 38 European-Americans (EA). In AA compared to EA, mean startle magnitude and probability of blink response were lower, with no difference in habituation. PPI was greater in AA than EA when groups were matched on baseline startle magnitude. These findings support the idea of racial differences in startle response. Implications for study design are highlighted, and possible environmental and genetic influences are considered.     

Normal prepulse inhibition and habituation of acoustic startle response in suicidal depressive patients without psychotic symptoms

BACKGROUND: Until now, there is a lack of useful biological markers to predict suicidal behavior in depressive patients. However, it is consistently found that suicidality is associated with a central serotonin deficit. Animal data suggest that prepulse inhibition (PPI) as well as habituation of the acoustic startle response (ASR), which are established as operational measures for sensorimotor gating, decreases after serotonin depletion. Thus, we investigated PPI and habituation of ASR in suicidal patients with depressive disorders as potential biological markers for suicidal behavior. METHODS: PPI and habituation of ASR was measured in 20 depressive patients who had at least one suicide attempt within the last three month. Eighteen healthy matched controls were examined likewise. RESULTS: Suicidal depressive patients did not differ from healthy controls in PPI, startle reactivity and habituation of ASR. Subgroup analyses showed that factors such as severity of depression, impulsiveness, gender, smoking, lethality of the last suicide attempt, number of suicide attempts, and medication had no influence on the results. CONCLUSIONS: These results suggest that neither PPI nor habituation of ASR could serve as useful markers for suicidality.     

Pre- and perinatal predictors of startle eye blink reaction and prepulse inhibition in healthy neonates

The present study examined the startle eye blink reflex and prepulse inhibition (PPI) in 65 healthy term-born neonates. Although the startle eye blink is already present at birth, some relevant neuronal structures are not fully mature. We therefore investigated the relationship between prenatal maturation and perinatal stress experience on startle eye blink and PPI. Eye blinks were evoked by unilaterally presented acoustic broadband white noise (50 ms, 95 dB, prepulse 75 dB). Startle response magnitude and percent PPI were calculated for ipsilateral and contralateral side of stimulation. Neonates exhibited stronger startle responses ipsilaterally than contralaterally, and a significant PPI. Neonates with more prenatal growth and less perinatal stress had greater startle magnitudes. Neonates with more stress had more PPI contralaterally. Results suggest that startle eye blinks may be useful as indicators of prenatal maturation and perinatal stress.     

Prepulse inhibition decreases as startle reactivity habituates

In the present study, I investigated the effect of stimulus repetition on human startle eyeblink reflex inhibition (PPI) by a prepulse. Participants were assigned to one of three groups (n= 14 each). in which they received 18 trials of (a) noise startle stimuli presented alone or preceded by 1000-Hz tone prepulses, (b) startle stimuli presented alone, or (c) prepulses presented alone. All participants then received 18 more trials of startle stimuli presented alone or preceded by 1000-Hz tone prepulses, followed by 6 trials of startle stimuli presented alone or preceded by 2000-Hz tone prepulses. As trials progressed, startle eyeblink electromyogram magnitude habituated and PPI decreased. PPI was not affected by the repeated presentation of the prepulses alone but decreased with the repeated presentation of the startle stimulus alone. Changes in the frequency of the prepulse had no significant effect on PPI. These data suggest that the reduction of PPI that is seen across trials is not due to habituation of the prepulse but is related to startle reactivity in control trials, which is reduced by habituation.     

Low dietary sodium is anxiogenic in rats

Noise exposure during the critical period of postnatal development in rats results in anomalous processing of acoustic stimuli in the adult auditory system. In the present study, the behavioral consequences of an acute acoustic trauma in the critical period are assessed in adult rats using the acoustic startle reflex (ASR) and prepulse inhibition (PPI) of ASR. Rat pups (strain Long-Evans) were exposed to broad-band noise of 125 dB SPL for 8 min on postnatal day 14; at the age of 3-5 months, ASR and PPI of ASR were examined and compared with those obtained in age-matched controls. In addition, hearing thresholds were measured in all animals by means of auditory brainstem responses. The results show that although the hearing thresholds in both groups of animals were not different, a reduced strength of the startle reflex was observed in exposed rats compared with controls. The efficacy of PPI in exposed and control rats was also markedly different. In contrast to control rats, in which an increase in prepulse intensity was accompanied by a consistent increase in the efficacy of PPI, the PPI function in the exposed animals was characterized by a steep increase in inhibitory efficacy at low prepulse intensities of 20-30 dB SPL. A further increase of prepulse intensity up to 60-70 dB SPL caused only a small and insignificant change of PPI. Our findings demonstrate that brief noise exposure in rat pups results in altered behavioral responses to sounds in adulthood, indicating anomalies in intensity coding and loudness perception.     

Developmental stress disrupts habituation but spares prepulse inhibition in young rats

Stress has long been recognized as a factor that contributes to the induction of schizophrenia and results in abnormal sensorimotor functioning and information processing. Patients with schizophrenia show disrupted habituation and prepulse inhibition of the acoustic startle response. This study examined the effects of maternal isolation in rats on the habituation of startle and PPI to assess the potential impact of developmental stress on schizophrenic symptomatology. Evaluation of performance in young adulthood (3-4 months) revealed a disruption of habituation in the isolated group; response amplitude increased over time. PPI was not altered. These results suggest that the disruption of habituation may involve acute effects of elevated stress hormones on neuronal functions. In contrast, disturbance of PPI may require an accrual of neuronal insult and damage to ultimately undermine neurologic function, possibly through impact on N-methyl-D-aspartate-mediated transmission. An analysis of effects at middle age is planned to address this possibility.     

Individual differences in prepulse inhibition of startle as a measure of individual dopamine function

This study investigated whether individual differences in prepulse inhibition (PPI) of the acoustic startle reflex reflect meaningful trait differences in the function of dopaminergic substrates that regulate it. Baseline PPI of individual rats showed strong test-retest reliability across 3 consecutive test days, and there was a significant negative correlation between individual baseline PPI and both disruption of PPI produced by apomorphine and facilitation of PPI by haloperidol. The test-retest reliability and the inverse association between baseline PPI and drug-induced effects were stronger with 8-10 dB prepulses compared with less intense prepulses. These results demonstrate that individual differences in baseline PPI predict individual differences in sensitivity of PPI to drugs that affect the dopamine system and that PPI produced by more intense prepulses may be more representative of these individual differences.     

Impact of stimulus signal-to-noise ratio on prepulse inhibition of acoustic startle

Prepulse inhibition (PPI) of the human acoustic startle response is reduced in the presence of background noise of a sufficient intensity, possibly due to a reduction in signal-to-noise ratio (prepulse intensity relative to background noise). We examined this hypothesis by varying prepulse intensity and background noise intensity in order to hold three different signal-to-noise ratios constant (5, 15, and 25 dB(A) above background noise intensity). The results showed that signal-to-noise ratio proved to be a more important factor than absolute stimulus intensity in determining the degree of PPI of startle eyeblink response magnitude. Therefore, the effectiveness of a prepulse is determined by prepulse salience, not intensity, and this effectiveness is equivalent across a range of physical intensities.     

Automatic and controlled attentional processes in startle eyeblink modification: effects of habituation of the prepulse

The effect of prehabituation of the prepulse on startle eyeblink modification was studied in two experiments. In Experiment 1, college student participants were either prehabituated or nonhabituated to a tone that served as a prepulse in a startle modification passive attention paradigm. Neither short lead interval (60 and 120 ms) prepulse inhibition (PPI) nor long lead interval (2,000 ms) prepulse facilitation (PPF) was affected by the prehabituation procedure. In Experiment 2, participants were presented with an active attention paradigm in which one of two tone prepulses was attended while the other was ignored. One group was prehabituated to the prepulses and the other was not. Unlike the results with the passive paradigm in Experiment 1, prehabituation did significantly diminish attentional modulation of PPI and PPF. These results are consistent with the hypothesis that passive PPI and PPF are primarily automatic processes, whereas attentional modulation involves controlled cognitive processing.     

Effects of background noise on the human startle reflex and prepulse inhibition

Three experiments investigated whether background noise modified the startle blink reflex and prepulse inhibition (PPI). In Experiment 1 background noise was about 28 (ambient), 40, and 60 dB; in Experiments 2 and 3 background noise was ambient and 60 dB. Prepulses were 70-dB tones (Experiments 1 and 3) or a tactile stimulus (Experiment 2). Startle-eliciting stimuli were 94-dB noise (Experiments 1 and 2) or an airpuff to the face (Experiment 3). Prepulses were presented at stimulus onset asynchronies of 30, 60, 120, 240, and 2000 ms relative to the startle-eliciting stimulus. Background noise of 60 dB had no effect on control reflexes, whereas 40-dB background noise increased control reflexes. Background noise decreased PPI, but only when an acoustic stimulus was used as prepulse. In sum, the findings show that background noise reduces the signal-to-noise ratio of acoustic prepulses and decreases their modulatory effect on the startle reflex.     

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.     

Experience increases the prepulse inhibition of the acoustic startle response in mice

The authors have previously shown that inhibition of the acoustic startle response by a prepulse increases when it is repetitively elicited over days. The present experiments show in C3H and C57 mice that this change is caused by an increase in prepulse inhibition (PPI) and not by a decrease in prepulse facilitation. This PPI increase is only evoked if prepulses and startle stimuli are repeatedly given in a temporally paired ("contingent") order, proposing an associative learning process. (Only in C57 mice, PPI was additionally increased by adaptation in the same, but not in a different, context). As an underlying mechanism for this PPI increase by experience, the authors hypothesize Hebbian plasticity of an inhibitory synapse.     

Prepulse Modification of the Acoustic Startle Reaction in Healthy Subjects and Patients with Schizophrenia

The characteristics of prepulse inhibition (PPI) and prepulse facilitation (PPF)of the acoustic startle reaction (ASR) were studied in healthy subjects and patients with schizophrenia. Testing was performed in accordance with the recommendations of the International Schizophrenia Genetics Consortium. Patients showed a deficit in PPI with a prepulse interval of 60 msec and suppression of PPF with an interval of 2500 msec, demonstrating impairments of undirected attention. Differences were seen in the effects of histories of craniocerebral trauma and experience of consumption of psychoactive substances on PPI and PPF in healthy subjects and patients. Correlations between baseline ASR and increases in excitement (PANSS scale P4) and between impairments to PPF and the severity of positive symptomatology were seen. The results obtained here provide evidence that the prepulse ASR modification test can be used in clinical neurophysiology.