Prepulse Facilitation and Prepulse Inhibition in Schizophrenia Patients and Their Unaffected Siblings Jonathan K. Wynn, Michael E. Dawson, Anne M. Schell, Mark McGee, Dustin Salveson, and Michael F. Green Background: Deficits in schizophrenia patients and their first-degree relatives have been reported in prepulse inhibition (PPI), a phenomenon that measures an early stage of information processing (sensorimotor gating). It is less clear whether these information processing deficits extend to prepulse facilitation (PPF), which measures a later stage of generalized alerting or orienting. Methods: This study examined three separate issues: first, whether schizophrenia patients have deficits in PPI and PPF; second, whether the siblings of patients show deficits in these processes; and third, whether prepulse duration influences the degree of the deficits. These issues were examined in 76 schizophrenia patients, 36 of their siblings, and 41 normal control subjects. Results: Patients and siblings did not differ from control subjects in PPI, perhaps due to the use of different procedural parameters compared with other laboratories that have consistently found PPI deficits in schizophrenia patients. Patients and their siblings produced significantly less PPF than control subjects. For both PPI and PPF, prepulse duration was not a significant factor. Conclusions: These results imply that PPF deficits reveal a generalized alerting or orienting deficit that is present in both schizophrenia patients and their siblings, suggesting that this deficit may be tapping an endophenotypic vulnerability factor. Key Words: Startle, prepulse inhibition, prepulse facilitation, ori- PPF in a passive attention paradigm is thought to reflect a classical activating effect (Graham 1975), indicating alerting or enting, schizophrenia, endophenotypic marker attention or automatically elicited generalized orienting (as op- tartle eyeblink modification (SEM) is a powerful tool for posed to specific orienting during a task that requires attention to be paid to specific stimuli; Graham and Hackley 1991). Prepulses studying information processing by examining how a star- appear to cause subjects to orient to incoming information, thus tle eyeblink is modified by a preceding, nonstartling stim- S enhancing the subsequent amount of eyeblink to the startle ulus (prepulse). When the prepulse precedes the startle pulse by burst, if the prepulse and startle burst are in the same modality a short interval (known as the lead interval), for example, less (Graham 1980). Deficits in orienting have been related to deficits than 500 msec, the startle eyeblink is inhibited, a phenomenon in allocation of processing resources to external stimuli and a known as prepulse inhibition (PPI). When the lead interval is reduction in available processing resources, traits also exhibited longer, for example, greater than 1000 msec, the startle eyeblink by schizophrenia patients (for a review, see Nuechterlein and is facilitated, particularly if the prepulse and startle stimulus are in Dawson 1984). Moreover, deficits in orienting have been shown the same sensory modality, a phenomenon known as prepulse to be stable trait markers for schizophrenia patients (Dawson et facilitation (PPF). Investigators have used SEM to study informa- al 1994; Spohn et al 1989) and at-risk populations (Simons 1981). tion processing deficits in schizophrenia for many years (Braff et Although PPI is thought to be automatic, several studies have al 1978; Cadenhead et al 1997; Dawson et al 1993; Hazlett et al shown that by directing attention toward the prepulse, PPI and 1998). More recently, PPI has been used with schizotypal indi- PPF can be enhanced (Dawson et al 1993; Filion et al 1993, 1994; viduals (Cadenhead et al 1993) and first-degree relatives of Hawk et al 2002; Hazlett et al 1998; Schell et al 2000). Some schizophrenics (Cadenhead et al 2000) as a possible endophe- investigators (e.g., Braff et al 1992; Cadenhead et al 2000) notypic marker. This article examines both PPI and PPF in interpret the PPI deficits exhibited by schizophrenia patients as schizophrenia patients, their first-degree relatives (siblings), and reflecting automatic sensorimotor gating deficits during a passive normal control subjects. It is thought that PPI and PPF reflect two separate mecha- attention task. Others (e.g., Dawson et al 1993, 2000) suggest that nisms: PPI is believed to index an automatic sensorimotor gating PPI deficits exhibited by schizophrenia patients are in the mechanism or a protection of processing mechanism (Braff et al controlled attentional modulation of PPI during an active atten- 1992; Graham 1980) whereby the processing of the prepulse tion task; however, differences in the methods used to elicit PPI gates out the sensory information of the startle stimulus. Deficits and PPF can have substantial impact on the results. The methods in PPI could theoretically lead to cognitive overload and frag- used in our study differ in several ways from those of laboratories mentation, traits exhibited by some pathologic populations such that consistently find absolute PPI deficits in schizophrenia as schizophrenia patients (Braff and Geyer 1990). In contrast, patients, for example, differences in level of background noise (which makes the prepulse less easily detectable), recording electromyogram (EMG) from the right eye, and the use of different types of prepulses. From the Department of Psychiatry and Biobehavioral Sciences (JKW, MM, DS, MFG), University of California, Los Angeles; Veterans Affairs Greater This study addressed one parameter that could lead to Los Angeles Healthcare System (JKW, MM, DS, MFG); Department of differences in findings across laboratories. Specifically, laborato- Psychology (MED), University of Southern California; and Department of ries that find deficits in absolute, automatic PPI in a passive Psychology (AMS), Occidental College, Los Angeles, California. attention paradigm in schizophrenia patients and at-risk subjects Address reprint requests to Jonathan K. Wynn, Ph.D., Veterans Affairs use discrete white noise prepulses (which begin and end before Greater Los Angeles Healthcare System, 11301 Wilshire Blvd. (MIRECC startle onset), whereas those that find deficits only in attentional 210A), Building 210, Los Angeles, CA 90073. modulation of PPI and PPF use continuous pure-tone prepulses Received March 28, 2003; revised August 26, 2003; accepted October 24, 2003. (which begin and continue up to and beyond startle onset) in an 0006-3223/04/$30.00 BIOL PSYCHIATRY 2004;55:518–523 doi:10.1016/j.biopsych.2003.10.018 © 2004 Society of Biological Psychiatry J.K. Wynn et al BIOL PSYCHIATRY 2004;55:518–523 519 active attention paradigm. Our study included both types of Table 1. Demographic Data prepulses in a passive attention paradigm. In passive attention paradigms, PPI has been proposed as a Schizophrenia Siblings Controls vulnerability indicator for schizophrenia. Those presumably at n 76 36 41 risk for developing schizophrenia (psychometrically defined; Age (years)a 42.70 (8.46) 38.23 (9.61) 35.64 (7.96) e.g., Simons and Giardina 1992) and those diagnosed with Range 20–55 18–55 21–50 schizotypal personality disorder (Cadenhead et al 1993) have Sex (M:F)b 74:2 17:19 19:21 exhibited PPI deficits. Only one published study, to our knowl- Antipsychotic Medicationc 22:43 edge, examined PPI in first-degree relatives of schizophrenia (typical:atypical) patients (Cadenhead et al 2000). In this study, deficient PPI in BPRS first-degree relatives was found under a specific condition— Total 47.78 (10.67) namely, measuring PPI from the right (but not left) eye at a Thinking Disturbance 2.95 (1.15) 30-msec lead interval, but not at lead intervals of 60 or 120 msec. Withdrawal-Retardation 2.30 (1.10) Although there have been numerous studies on PPI in Baseline Startle (␮V) 17.34 (28.82) 20.12 (22.34) 12.89 (14.43) schizophrenia, schizophrenia-spectrum populations, and at-risk Data are Mean (SD). populations, the literature concerning PPF deficits is sparse. M, male; F, female; BPRS, Brief Psychiatric Rating Scale. There is only one published study, to our knowledge, that aSchizophrenia patients significantly older than controls, p Ͻ .001. examined PPF in a passive paradigm in schizophrenia. Braff et al bLarger proportion of males in the schizophrenia group, p Ͻ .001. c (1978) examined both PPI and PPF in schizophrenia patients. For patients on known medications. Although the patients were deficient in PPI, they did not show any PPF differences from normal control subjects. Other studies schizophrenia based on the Structured Clinical Interview for have found PPF attentional modulation deficits during an active DSM-IV (SCID; First et al 1996b). All patients with useable startle attention task (i.e., failure to produce more PPF during a eyeblink data (see Subject Exclusions) were receiving antipsy- to-be-attended prepulse) in both schizophrenia patients (Daw- chotic medication at the time of testing: 43 were on atypical son et al 1993, 2000) and subjects putatively at risk based on the antipsychotics, 22 were on typical antipsychotics, and 11 were on Chapman scales (Schell et al 1995). mixed or unknown (e.g., blinded) antipsychotics. Our research examined three separate issues. First, we tested Psychiatric symptoms were assessed in the patient group whether schizophrenia patients have deficits in PPI and PPF with using the 24-item Brief Psychiatric Rating Scale (BPRS; Ventura et the parameters used in