ReviewUpdate: Studies of prepulse inhibition of startle, with particular relevance to the pathophysiology or treatment of Tourette Syndrome
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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2020, Journal of Psychiatric ResearchCitation Excerpt :Forebrain substrates of the CSTC loops, including the medial prefrontal cortex, orbitofrontal cortex, basolateral amygdala and nucleus accumbens regulate the inhibitory tone of PPI (Miller et al., 2010; Saint Marie et al., 2010; Swerdlow et al., 1992; Wan and Swerdlow, 1997). Tics as well as obsessive-compulsive symptoms are hypothesized to represent deficits in central inhibitory functioning and early filter processing (Swerdlow, 2012; Morein-Zamir, 2010). Thus, deficient PPI shares overlapping psychophysiological as well as neural substrates with OCD and TS.
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2019, Behavioural Brain ResearchCitation Excerpt :Conceptually, PPI is considered a form of feedforward inhibition that aids the undisrupted processing of sensory information by potentially disrupting stimuli [2]. Importantly, in human, deficits in PPI are associated with a number of disorders associated with information processing disruptions such as schizophrenia, Tourette’s syndrome, Huntington’s disease, obsessive-compulsive and post-traumatic stress disorder [3–9] as well as anxiety disorders [10,11]. The mechanisms and neurotransmitters involved in PPI have been investigated in human [5,12], rodent [13–18], fish [19–23], bird [24], mollusk [25–27] and other invertebrates [28], thereby underscoring the importance of PPI as a comparative operational measure of information processing in the CNS.
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2018, NeuropharmacologyCitation Excerpt :Attenuated PPI is thought to reflect an underlying abnormality in the brain's process of gating excessive environmental stimulus. Deficits in PPI are found in patients with several neuropsychiatric disturbances (Braff et al., 2001) including schizophrenia (Feifel et al., 2016), autism (Perry et al., 2007), obsessive-compulsive disorders and Tourette's Syndrome (Swerdlow, 2013). The experimental apparatus (Med Associates Inc.