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- enting, schizophrenia, endophenotypic marker S tartle eyeblink modification (SEM) is a powerful tool for studying information processing by examining how a star- tle eyeblink is modified by a preceding, nonstartling stim- ulus (prepulse). When the prepulse precedes the startle pulse by a short interval (known as the lead interval), for example, less than 500 msec, the startle eyeblink is inhibited, a phenomenon known as prepulse inhibition (PPI). When the lead interval is longer, for example, greater than 1000 msec, the startle eyeblink is facilitated, particularly if the prepulse and startle stimulus are in the same sensory modality, a phenomenon known as prepulse facilitation (PPF). Investigators have used SEM to study informa- tion processing deficits in schizophrenia for many years (Braff et al 1978; Cadenhead et al 1997; Dawson et al 1993; Hazlett et al 1998). More recently, PPI has been used with schizotypal indi- viduals (Cadenhead et al 1993) and first-degree relatives of schizophrenics (Cadenhead et al 2000) as a possible endophe- notypic marker. This article examines both PPI and PPF in schizophrenia patients, their first-degree relatives (siblings), and normal control subjects. It is thought that PPI and PPF reflect two separate mecha- nisms: PPI is believed to index an automatic sensorimotor gating mechanism or a protection of processing mechanism (Braff et al 1992; Graham 1980) whereby the processing of the prepulse gates out the sensory information of the startle stimulus. Deficits in PPI could theoretically lead to cognitive overload and frag- mentation, traits exhibited by some pathologic populations such as schizophrenia patients (Braff and Geyer 1990). In contrast, PPF in a passive attention paradigm is thought to reflect a classical activating effect (Graham 1975), indicating alerting or attention or automatically elicited generalized orienting (as op- posed to specific orienting during a task that requires attention to be paid to specific stimuli; Graham and Hackley 1991). Prepulses appear to cause subjects to orient to incoming information, thus enhancing the subsequent amount of eyeblink to the startle burst, if the prepulse and startle burst are in the same modality (Graham 1980). Deficits in orienting have been related to deficits in allocation of processing resources to external stimuli and a reduction in available processing resources, traits also exhibited by schizophrenia patients (for a review, see Nuechterlein and Dawson 1984). Moreover, deficits in orienting have been shown to be stable trait markers for schizophrenia patients (Dawson et al 1994; Spohn et al 1989) and at-risk populations (Simons 1981). Although PPI is thought to be automatic, several studies have shown that by directing attention toward the prepulse, PPI and PPF can be enhanced (Dawson et al 1993; Filion et al 1993, 1994; Hawk et al 2002; Hazlett et al 1998; Schell et al 2000). Some investigators (e.g., Braff et al 1992; Cadenhead et al 2000) interpret the PPI deficits exhibited by schizophrenia patients as reflecting automatic sensorimotor gating deficits during a passive attention task. Others (e.g., Dawson et al 1993, 2000) suggest that PPI deficits exhibited by schizophrenia patients are in the controlled attentional modulation of PPI during an active atten- tion task; however, differences in the methods used to elicit PPI and PPF can have substantial impact on the results. The methods used in our study differ in several ways from those of laboratories that consistently find absolute PPI deficits in schizophrenia 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. This study addressed one parameter that could lead to differences in findings across laboratories. Specifically, laborato- ries that find deficits in absolute, automatic PPI in a passive attention paradigm in schizophrenia patients and at-risk subjects use discrete white noise prepulses (which begin and end before startle onset), whereas those that find deficits only in attentional modulation of PPI and PPF use continuous pure-tone prepulses (which begin and continue up to and beyond startle onset) in an From the Department of Psychiatry and Biobehavioral Sciences (JKW, MM, DS, MFG), University of California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (JKW, MM, DS, MFG); Department of Psychology (MED), University of Southern California; and Department of Psychology (AMS), Occidental College, Los Angeles, California. Address reprint requests to Jonathan K. Wynn, Ph.D., Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd. (MIRECC 210A), Building 210, Los Angeles, CA 90073. Received March 28, 2003; revised August 26, 2003; accepted October 24, 2003. BIOL PSYCHIATRY 2004;55:518 –523 0006-3223/04/$30.00 doi:10.1016/j.biopsych.2003.10.018 © 2004 Society of Biological Psychiatry