Behavioral Neurobiology of Schizophrenia and Its Treatment (Current Topics in Behavioral Neurosciences) by Neal R. Swerdlow

Author:Neal R. Swerdlow
Language: eng
Format: mobi
Publisher: Springer
Published: 2010-08-18T21:00:00+00:00

Prepulse Inhibition of the Startle Reflex

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Number of Papers re. PPI

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Fig. 1 Dramatic increase in PubMed PPI citations over time

Fig. 2 The basic, neutral, uninstructed PPI paradigm

PubMed search found over 550 papers for the key words “PPI þ schizophrenia” in

the past 8 years, reflecting the importance of this measure in schizophrenia research.

In the PPI paradigm, the first weak sensory event (the prepulse) inhibits or

“gates” the motor response to a startling stimulus; hence, we use the term “sensori-

motor gating” to describe the construct measured by PPI (as opposed to a purely

sensory paradigm such as P50 or N100 suppression) (see Fig. 2).

PPI is a common, lawfully mediated, and robust mammalian phenomenon that

occurs when the prepulse and startling stimuli are in the same or different sensory

modalities (Blumenthal and Gescheider 1987; Graham 1980; Hoffman and Ison

1980). It occurs in all mammals tested to date, and it is not a form of conditioning,

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D.L. Braff

because it occurs on the first exposure to the combination of weak prepulse

and strong startling stimuli (Blumenthal et al. 1996). PPI (unlike startle itself)

does not exhibit habituation or extinction over multiple trials and is a relatively

stable neurobiological marker: PPI measurements repeated at 1-month intervals for

3 months yielded intraclass correlations of 0.94 (Cadenhead et al. 1999). Neuro-

biologically, the prepulse has inhibitory influences that can be regulated by con-

nections between limbic, cortical, basal ganglia, and pontine circuitry (cf. Lee et al.

1996; Swerdlow and Koob 1987; Swerdlow et al. 1992). Thus, PPI reflects the

activation of behavioral gating processes that are regulated by forebrain neural

circuitry. This circuitry exerts a “down-stream tonic” regulatory or modulating

influence, but the signal of the prepulse need not traverse or be transmitted across

forebrain circuitry in order to produce PPI (Davis and Gendelman 1977). The

forebrain regulation of PPI has been the target of many mammalian neurobiological

and psychopathology studies (Swerdlow et al. 2001d).

In order to elicit PPI, a weak prepulse stimulus activates brain-based processes

that blunt responsivity to sensory events during a subsequent relatively brief

temporal window. The temporal limits of the time period of “gating” attributed

to the prepulse are empirically determined to be approximately 30–500 ms in

duration, in both humans and rodents (Graham 1975; Hoffman and Searle 1968).

Prepulse-to-pulse intervals of 30–240 ms are typically utilized in human PPI

experiments, with maximal amplitude inhibition generally occurring with intervals

of approximately 120 ms. Compared to amplitude inhibition, startle latency reduc-

tion (“latency facilitation”) typically occurs at briefer prepulse-to-pulse intervals

(e.g., 30 ms). The period of reduced reflex responsivity after the prepulse presenta-

tion has been hypothesized to transiently “protect” information contained in the

weak stimulus, so that maximal information can be processed from the prepulse

stimulus, without interference from subsequent strong or disrupting startling stimuli

(Blumenthal et al. 1996; Braff et al. 1978, 2001a, b; Swerdlow et al. 1999).

PPI is studied in the laboratory, but under “natural” circumstances, the process

of sensorimotor gating is conceptualized as helping the organism to regulate

environmental inputs in order to navigate successfully in a stimulus-laden world

full of supernumerary and nonsalient stimuli, and to selectively allocate attentional

resources to salient stimuli (Braff et al. 1978, 1992, 1999; Grillon et al.

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