A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms
Introduction
Sensorimotor gating is a preattentive, automatic process, involving control of motor responses to sensory stimuli, by which excess or trivial stimuli are screened or “gated out” of awareness, allowing for efficient processing of relevant information (Braff and Geyer, 1990). Prepulse inhibition (PPI) is an operational measure of this inhibitory function, defined as an attenuation of the startle reflex when the startle-eliciting stimulus, the pulse, is preceded by a weaker sensory stimulus, the prepulse (Graham, 1975). Oversensitivity to sensory stimulation theoretically correlates with stimulus overload and may lead to cognitive fragmentation (Braff and Geyer, 1990).
PPI deficits in schizophrenia were first reported by Braff and colleagues (Braff et al., 1978), and subsequently replicated by numerous studies across various ethnicities (Braff et al., 2001), including our own with a Japanese population (Kunugi et al., 2007). Further studies have also found such deficits in unaffected first-degree relatives of schizophrenia patients and in subjects with schizotypal personality disorder (Cadenhead et al., 2000, Kumari et al., 2005), which suggests that these deficits are a genetically transmitted fundamental trait, in other words, a promising endophenotype of schizophrenia (Braff and Light, 2005, Light et al., 2012).
A growing number of reports in the literature, however, have shown that PPI deficits in schizophrenia patients may be, at least partially, ameliorated by antipsychotic medication (Aggernaes et al., 2010, Kumari et al., 2002, Kumari et al., 1999, Leumann et al., 2002, Oranje et al., 2002, Quednow et al., 2006, Swerdlow et al., 2014, Swerdlow et al., 2006, Wynn et al., 2007). Interestingly, the difference in PPI between the medicated and unmedicated schizophrenia patients was no longer significant when the severity of the positive syndrome was entered as a covariate (Weike et al., 2000). This finding was corroborated by a longitudinal study which reported that PPI deficits in medicated patients were observed in acute illness, but not in an improved clinical state, suggesting that PPI deficits may be state dependent (Meincke et al., 2004b). Another within-subject study suggested that improvements in sensorimotor gating may be related to antipsychotic-related symptom reduction, rather than the antipsychotic medication itself (Minassian et al., 2007). The effects of antipsychotics on PPI were not evident when patients with schizophrenia were acutely symptomatic (Xue et al., 2012).
So far, evidence linking PPI deficits to schizophrenia symptoms has been inconsistent (Braff et al., 2001). PPI deficits have been related to positive symptoms (Braff et al., 1999, Wang et al., 2013, Weike et al., 2000, Xue et al., 2012), negative symptoms (Braff et al., 1999, Xue et al., 2012), distractibility (Karper et al., 1996), thought disorder (Perry and Braff, 1994, Perry et al., 1999), formal thought disorder and bizarre behavior (Meincke et al., 2004b), psychological discomfort (Duncan et al., 2006), and general psychopathology (Martinez-Gras et al., 2009, Xue et al., 2012). Conversely, large cohort studies of schizophrenia patients (the Consortium on the Genetics of Schizophrenia: COGS) have found no association between PPI deficits and positive or negative symptoms (Swerdlow et al., 2014, Swerdlow et al., 2006). However, subjects in these studies were on either limited to or dominantly males.
Sexual dimorphism of PPI in healthy adult subjects has been well documented, with men exhibiting higher PPI than women in the majority of studies (Abel et al., 1998, Swerdlow et al., 1999, Swerdlow et al., 1993). However, fewer studies have examined the sex differences in schizophrenia patients, producing inconsistent findings. One study found no effect of sex on PPI (Ludewig et al., 2002), while another study reported that PPI deficits were detected only in men with schizophrenia (Kumari et al., 2004). On the contrary, there are also studies reporting significant PPI deficits in schizophrenia women compared with healthy women (Braff et al., 2005), and significantly lower PPI in schizophrenia women than men (Swerdlow et al., 2014, Swerdlow et al., 2006).
Swerdlow and colleagues suggested that such “variability in the relationship between these clinical variables and PPI across studies may reflect site differences in patient characteristics or PPI methodology, and the intrinsic heterogeneity of schizophrenia” (Swerdlow et al., 2014). Indeed, most studies included various ethnicities that may have influenced the outcome, since ethnic differences in startle magnitude and PPI were reported (Swerdlow et al., 2014, Swerdlow et al., 2007, Swerdlow et al., 2005). Therefore, this single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia. The advantages of this study are that all subjects were of a single ethnicity (Japanese), and that tests were administered with the same equipment in the same measurement room. Furthermore, in order to eliminate the factors that might have influenced PPI, diagnostic groups were matched for sex and age, and separate analyses were made on men and women. This is a replication of our preliminary study, where we employed a small independent sample and demonstrated PPI deficits in schizophrenia patients for the first time in Asian subjects (Kunugi et al., 2007). More specifically, we had two questions: 1) whether reduced startle reflex, habituation, and PPI were present in the patient group as a whole, and separately in men and women when compared with their respective healthy counterparts, and 2) whether PPI deficits were related to any schizophrenia symptoms/subgroups. We hypothesized that reduced startle measures would be observed in the patient group, in both men and women, and PPI deficits would be related to certain symptoms/subgroups.
Section snippets
Subjects
The subjects comprised 181 patients with schizophrenia and 250 healthy controls aged 18–64 years, matched for sex and age. All subjects were biologically unrelated Japanese individuals. Demographic and clinical data are presented in Table 1, Table 2, respectively. They were recruited over 6 years (2009–2015) by our research team at the National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan, through notices posted in the NCNP Hospital, website announcements, or advertisements in a
Difference in startle measurements by diagnostic group and sex
Diagnostic comparison of each startle measurement is shown in Fig. 1 and Supplementary Table 1. The ratio of non-responder was significantly higher in patients (25%) than in controls (11%) (χ2(1) = 13.9, p < 0.001). BSR magnitude was significantly reduced in patients (U = 16,358.5, p < 0.001, Fig. 1a), but separate analysis found that this was present only in female patients (U = 3465.5, p < 0.001). Habituation was significantly lower in patients than in controls (U = 11,814.0, p = 0.001, Fig. 1
Discussion
To our knowledge, this is the largest PPI study of schizophrenia patients of a single ethnicity (Japanese) from a single facility, compared with controls matched for age and sex, which enabled stratified analysis by sex without the potential confounding effect of ethnicity. Our major findings were the following two points. First, as hypothesized, significantly reduced BSR magnitude, habituation, PPI60ms_90dB and PPI120ms_90dB were observed in the patient group when compared with controls.
Role of funding source
This study was supported by Health and Labour Sciences Research Grants (Comprehensive Research on Disability, Health, and Welfare; H21-Kokoro-002 for H.K.), and Intramural Research Grant for Neurological and Psychiatric Disorders at National Center of Neurology and Psychiatry (24-11, 26-11, and 27-1 for H.K.). These agencies had no role in study designing, acquisition and interpretation of the data or writing the report.
Contributors
J.M. made statistical analysis, managed literature search, interpreted the data, and wrote the draft of the manuscript. M.O. and S.H. analyzed the EMG data. M.O., S.H., T.T., and H.H. conducted clinical interviews. J.M., M.H. and I.I. contributed for data collection. H.K. supervised the entire project, and H.K. and H.H. gave critical comments on the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare no conflict of interest that could influence their work.
Acknowledgements
We thank the volunteers for their participation. We also thank Yukiko Kinoshita, Yumiko Kawamoto, and Anna Nagashima for data collection.
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