Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia - PubMed (original) (raw)

Multicenter Study

. 2007 May;92(1-3):237-51.

doi: 10.1016/j.schres.2007.01.012. Epub 2007 Mar 8.

Joyce Sprock, Gregory A Light, Kristin Cadenhead, Monica E Calkins, Dorcas J Dobie, Robert Freedman, Michael F Green, Tiffany A Greenwood, Raquel E Gur, Jim Mintz, Ann Olincy, Keith H Nuechterlein, Allen D Radant, Nicholas J Schork, Larry J Seidman, Larry J Siever, Jeremy M Silverman, William S Stone, Debbie W Tsuang, Ming T Tsuang, Bruce I Turetsky, David L Braff

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Multicenter Study

Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia

Neal R Swerdlow et al. Schizophr Res. 2007 May.

Abstract

Background: Startle and its inhibition by weak lead stimuli ("prepulse inhibition": PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies.

Methods: Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the "PPI site" (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI.

Results: Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural "drift", which may be particularly relevant to multi-site studies using these measures.

Conclusion: With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

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Figures

Figure 1

Figure 1

Consortium on the Genetics of Schizophrenia (COGS) structure and interactions. Figure from Calkins et al. (2006), with permission of author. Data were uploaded to a central Data Core website, managed by the UCLA site. Files were accepted only if they met specific size and format criteria. Individual data files were downloaded by the QA site (UCSD), blind to diagnosis and other demographic variables.

Figure 2

Figure 2

Schematic representation of startle trial types (top) and session design (below). The startle test session included 74 active and 18 blank “no-stim” trials (interspersed throughout the session), and lasted 23.5 min, beginning with a 5-min acclimation period with 70-dB(A) SPL white noise that continued throughout the session. Startle stimuli were 40-msec 115-dB(A) SPL noise bursts (near-instantaneous rise time, est. 1 ms). Prepulses were 20 ms noise bursts 15-dB above a 70-dB(A) SPL white noise background, with prepulse onset 30, 60 or 120 ms prior to pulse onset; using slightly more intense 16 dB prepulses with this startle system, prepulse-associated EMG activity is <0.5 % of startle stimulus-induced levels. Five startle stimuli were presented at the beginning (Block 1) and end of the session (Block 4) to assess habituation. In Blocks 2-3, pulse alone and each of the 3 prepulse trial-types was pseudo-randomly intermixed (9 trials per condition per blocks; inter-trial intervals 11-19 s (mean=15 s)). In 18 blank “no-stim” trials, data were recorded without stimulus presentation, to assess basal EMG activity. Subjects were excluded for mean block 2 startle magnitude <10 startle units; this threshold was established to identify the lowest 10% of a normal distribution of startle magnitude values from >200 adult CCS tested at UCSD, using the present stimulus parameters. Applied to the present sample, it identified the lowest 11.7%.

Figure 3

Figure 3

Mean (SEM) values (A) and individual distributions (B) for startle magnitude during session blocks 2 and 3, when PPI is measured, at the 7 COGS test sites (A-G). 1 startle unit = 1.31 μV. The focus of this study was the comparison of startle measures across test sites, and thus separate analyses of each startle variable at each site are not described. Nonetheless, of the primary startle measures that involve a within-subject comparison -- habituation (startle magnitude in block 1 vs. 4), prepulse facilitation of latency (reduction of onset and peak latency on prepulse trials compared to pulse alone trials), and PPI (reduction of startle magnitude on prepulse + pulse trials compared to pulse alone trials) -- all are highly significant at each individual site.

Figure 4

Figure 4

Startle habituation, shown as mean (SEM) startle magnitude during blocks 1 and 4 (A), and as a percent score (B), across the 7 COGS sites. 1 startle unit = 1.31 μV. * = p < 0.05, B vs. A, E and F

Figure 5

Figure 5

Peak startle latency (ms (SEM)), on PA trials (0 ms prepulse intervals), and 30, 60 and 120 ms prepulse+pulse trials, across the 7 COGS sites. Inset shows distinct patterns of peak reflex latency modulation in women vs. men. Despite the lack of significant site × trial type interaction for peak latency, inspection of the data revealed some inter-site variability in the patterns of latency facilitation across the different prepulse intervals. For example, peak latency for 120 ms prepulse trials was significantly slower than for 30 and 60 ms trials for some sites (A,B,C,G) but not others (D,F), and fastest latencies were detected with 30 ms prepulse trials at some sites, and with 60 ms prepulse trials at others. Neither hearing threshold nor electrode impedance correlated significantly with reflex latency on PA or any prepulse trials (all r's<0.13). No significant relationships were detected between reflex latency and either WRAT scores or ethnicity. Ambient noise levels also did not correlate significantly with mean peak latency for each site on PA (rs= -0.03, p=0.93) or on any prepulse trials (rs's= -0.24 - (-0.01); p's=0.54 - 0.97). ANOVA across all sites revealed a significant interaction of gender × trial type (F=3.33, df 3,447, p<0.02). As seen in the inset, this interaction is reflected in patterns of reflex latency across sites: sites testing predominantly men (e.g. site F) exhibited latency patterns characteristic of males in the present study (minimal difference in latency across prepulse intervals), and those testing predominantly women (e.g. site A) exhibited latency patterns characteristic of females in the present study (less facilitation with 120 vs. 60 ms prepulse intervals).

Figure 6

Figure 6

A. Mean %PPI (SEM) with 30, 60 and 120 ms prepulse+pulse trials across the 7 COGS sites. B. %PPI in men and women, shown in test orders A and B. * = p < 0.0003, significant effect of test order in men; # = p < 0.015, men > women, test order A, after significant interaction of sex × test order, p < 0.02.

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