Review
Update: Studies of prepulse inhibition of startle, with particular relevance to the pathophysiology or treatment of Tourette Syndrome

https://doi.org/10.1016/j.neubiorev.2012.09.002Get rights and content

Abstract

Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating, in which the motor response to an abrupt, intense stimulus is inhibited by a weak lead stimulus. PPI is reduced in several brain disorders, including Tourette Syndrome (TS); it is regulated by forebrain circuitry, including portions of the basal ganglia implicated in the pathophysiology of TS, and is also heritable and under strong genetic control. PPI has been the focus of numerous translational models, because it is expressed by most mammalian species, with remarkable conservation of response characteristics and underlying neural circuitry between rodents and primates. Several of these models have recently explored causative factors in TS – from genes to specific basal ganglia perturbations – as well as potential TS therapeutics, including novel pharmacological and neurosurgical interventions. With the focus on Comprehensive Behavioral Interventions for Tics (CBIT) in the evolving treatment model for TS, future studies might apply PPI as a predictive measure for CBIT response, or for identifying medications that might augment CBIT efficacy. In the end, a measure based on a simple pontine-based reflex will have limitations in its ability to explicate any complex behavioral phenotype.

Highlights

► We review the cross-species utility of prepulse inhibtion (PPI) as an operational measure of sensorimotor gating. ► PPI deficits in Tourette Syndrome (TS) and in other neurodevelopmental brain disorders are discussed. ► The neurobiological regulation of PPI by forebrain circuitry implicated in the pathophysiology of TS is described. ► A conceptual linkage is noted between deficient sensorimotor gating and intrusive sensory phenomena now recognized as a core feature of TS. ► An update of recent findings relevant to the relationship of PPI to TS is provided.

Introduction

The startle reflex is a constellation of responses to sudden, relatively intense stimuli. In humans, the blink reflex component of startle is measured using electromyography of orbicularis oculi; in laboratory animals, whole-body startle is quantified by assessing the downward force resulting from the contraction of the skeletal muscles. Prepulse inhibition (PPI) occurs when a weak prestimulus 30–500 ms prior to the startling stimulus inhibits the startle response; this inhibition is an operational measure of sensorimotor gating (Graham, 1975). While the inhibitory effect of the prepulse on the startle reflex is exerted in the pons, studies have described the limbic forebrain circuitry and descending pontine projections that regulate the inhibitory “tone” within the pons and determine the degree to which the prepulse inhibits the subsequent motor response (cf. Swerdlow et al., 2001a, Swerdlow et al., 2008). PPI thus appears to reflect the activation of “hard-wired”, centrally mediated behavioral inhibitory processes that are regulated by forebrain neural circuitry.

PPI is a useful experimental measure for understanding brain mechanisms for a number of reasons. It is tested in an automated apparatus, under tight stimulus control, and stimulus parameters can be easily modified by the experimenter to elicit optimal response characteristics for studying a number of different aspects of this measure. Because PPI is a form of startle plasticity, it is measured using a “fight-or-flight” behavior that is simple, robust, and exhibited across all mammalian species tested to date. Of relevance to the present discussion, PPI is easily studied in animal models, including mice (Carter et al., 1999, Francis et al., 2003, Frankland et al., 2004), rats (Swerdlow et al., 2001a), guinea pigs (Vaillancourt and Boksa, 2000), pigs (Lind et al., 2004), and infrahuman primates (Linn et al., 2003), using stimulus parameters and equipment for stimulus delivery and response acquisition that are similar or identical to what are used in humans. While there appear to be differences in the neurochemical regulation of PPI across species (cf. Swerdlow et al., 2008), the basic parametric properties of PPI exhibit striking similarities from rodents to humans (e.g. Swerdlow et al., 1994), and PPI is under significant genetic control in both rodents (Francis et al., 2003) and humans (Greenwood et al., 2007).

This review focuses specifically on the results of studies of PPI in Tourette Syndrome, related clinical conditions, and relevant animal models. Broader reviews of PPI have appeared in this journal (e.g. Li et al., 2009), and more comprehensive analyses of our current understanding of TS pathophysiology can be found in accompanying articles in this special issue.

Section snippets

PPI and Tourette Syndrome

Despite its advantages as a laboratory measure of simple brain processes, PPI would likely be a scientific footnote were it not for the fact that it is reduced in a number of different brain disorders. Compared with matched controls, PPI is deficient in patients with schizophrenia (e.g., Braff et al., 1978, Swerdlow et al., 2006b), Huntington's Disease (Swerdlow et al., 1995, Valls-Sole et al., 2004), Obsessive Compulsive Disorder (OCD) (Swerdlow et al., 1993, Hoenig et al., 2005, Ahmari et

Update of recent PPI findings of relevance to TS

A number of past reviews have described PPI and its applications toward understanding TS (e.g. Swerdlow and Sutherland, 2005, Swerdlow and Sutherland, 2006). More recent developments in this field have come from several novel uses of PPI in TS-related models; these studies share a common measure (PPI) and target disorder (TS), but otherwise cover a range of different topics:

  • A.

    Striatal regulation of PPI in mice: Based on the ability to easily study molecular manipulations in mice, they are the

Acknowledgments

NRS is supported by R01-MH059803, R34-MH093453, R01-MH065571, R01-MH042228 and the VA San Diego Healthcare System, VISN22 Mental Illness Research, Education & Clinical Center (MIRECC).

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