Comments on the use of the startle reflex in psychopharmacological challenges: impact of baseline startle on measurement of fear-potentiated startle.

A large body of experimental literature indicates that thestartle reflex is a sensitive measure of fear and anxiety. Inboth humans and animals, the startle reflex is increasedwhen the startle-eliciting stimulus is presented in thepresence of a cue that signals an aversive event, such as ashock (Davis and Astrachan 1978; Grillon et al. 1991). Inanimals, drugs that reduce anxiety in humans, such asdiazepam and buspirone, reduce this so-called fear-potentiated startle effect (Davis et al. 1993). This findingsuggests that the fear-potentiated startle methodology is auseful procedure to investigate the anxiolytic properties ofdrugs in humans. However, the emerging literature on theeffects of benzodiazepines on fear-potentiated startle tothreat in humans has been contradictory. Benzodiazepineshave been shown to reduce fear-potentiated startle insome studies (Bitsios et al. 1999; Riba et al. 2001), but notin others (Riba et al. 1999; Baas et al. 2002). In all thesestudies, fear-potentiated startle was expressed as adifference score between startle amplitude in the threatcondition minus startle amplitude in a no threat controlcondition. The objective of this paper is to call attentionto the issue that difference scores may not always beappropriate to express fear-potentiated startle. A problemwith difference scores is that they may be dependent onbaseline startle levels, which are themselves affected(reduced) by the sedative side-effect of benzodiazepines(Rodriguez-Fornells et al. 1999). Possibly, a reduction ofabsolute fear-potentiated startle by benzodiazepines couldbe due to a non-specific (i.e. non-anxiolytic) effect onbaseline startle reactivity.The concern that differences in baseline levels mayaffect fear-potentiated startle has been raised in theanimal literature (Davis 1992; Walker and Davis 2000). Apossible solution to equate baseline levels across drugconditions was proposed, namely using different startleprobe intensities (Davis 1992). An additional concern iswhether the dynamics of the startle system changes at theextremes of the scale (cf. floor and ceiling effects). Forthese reasons, one should be cautious in drawing defin-itive conclusions on the modulation of fear-potentiatedstartle by a pharmacological challenge that alters baselinestartle levels. In this report, we illustrate how differencesin baseline levels can affect fear-potentiated startle.Consequently, decisions on how to express fear-potenti-ated startle (e.g. difference score versus ratio) criticallyimpact the results.Little is known about the relationship between baselinestartle and fear-potentiated startle. It is likely that changesin baseline values arise from a variety of factors that mayor may not affect the expression of fear-potentiatedstartle. Approaches based on difference scores are basedon the critical assumption that fear-potentiated startle isadditive rather than multiplicative with respect to baselinestartle levels. In other words, a given absolute differencehas the same significance across levels of the scale (forinstance, the difference between 50 and 60 V is the sameas the difference between 200 and 210 V). The datapresented here show that this may not always be true.The way in which different factors interact to modulatestartle is not a statistical question, but an empirical one.Fear-potentiated startle may be additive or multiplicative,depending on the factors that cause the change in baselinestartle. Only empirical studies can provide us with anunderstanding of the underlying mechanisms that affectbaseline startle and its modulation. To illustrate this point,we reanalyzed data from a previous study. More specif-ically, we compared the impact of changes in baselinestartle levels on fear-potentiated startle. Different baselinestartle levels were obtained by 1) dividing subjects into alow startle and a high startle group and 2) examining theeffect of habituation.