Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies

Rationale: Since the mid-1970s, cross-species translational studies of prep ulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs w hen a relatively weak sensory event (the prepulse) is presented 30-500 ms b efore a strong startle-inducing stimulus. and reduces the magnitude of the startle response. In humans. PPI occurs in a robust, predictable manner whe n the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). Objective: This review covers three areas of interest in human PPI studies. First. we review the normal i nfluences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopath ological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. Methods: All studies identifi ed by a computerized literature search that addressed the three topics of t his review were compiled and evaluated. The principal studies were summariz ed in appropriate tables. Results: The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domai ns are similar across species, supporting the value of PPI studies in trans lational comparisons across species. The most prominent literature describi ng deficits in PPI in psychiatrically defined groups features schizophrenia -spectrum patients and their clinically unaffected relatives. These finding s support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology inv olving cortico-striato-pallidopontine circuits exhibit poor gating of motor , sensory, or cognitive information and corresponding PPI deficits. These g roups include patients with obsessive compulsive disorder, Tourette's syndr ome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and pe rhaps posttraumatic stress disorder (PTSD). Several pharmacological manipul ations have been examined for their effects on PPI in healthy human subject s. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists d isrupt and nicotine increases PPI in at least some human studies. With some other compounds, however. the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-distuptive effects of these compounds in rodents. Conc lusions: Considerable evidence supports a high degree of homology between m easures of PPI in rodents and humans, consistent with the use of PPI as a c ross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive lite rature on clinical populations, much more work is required to clarify the d egree of correspondence between pharmacological effects on PPI in healthy h umans and those reported in animals.