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      Prepulse Inhibition of Startle Response: Recent Advances in Human Studies of Psychiatric Disease

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          Prepulse inhibition (PPI) is considered to be one of the most promising neurophysiological indexes for translational research in psychiatry. Impairment of PPI has been reported in several psychiatric diseases, particularly schizophrenia, where PPI is considered a candidate intermediate phenotype (endophenotype) of the disease. Recent findings from a variety of research areas have provided important evidence regarding PPI impairment. Human brain imaging studies have demonstrated the involvement of the striatum, hippocampus, thalamus and frontal and parietal cortical regions in PPI. In addition, several genetic polymorphisms, including variations in the genes coding for Catechol O-methyltransferase, Neuregulin 1, nuclear factor kappa-B subunit 3 and serotonin-2A receptor were related to PPI; and these findings support PPI as a polygenetic trait that involves several neurotransmitter pathways. Early psychosis studies suggest that PPI disruption is present before the onset of psychosis. Also, discrepancy of PPI impairment between children and adults can be found in other psychiatric diseases, such as autistic spectrum disorders and posttraumatic stress disorder, and comprehensive investigation of startle response might contribute to understand the impairment of the neural circuitry in psychiatric diseases. Finally, recent studies with both Asian and Caucasian subjects indicate that patients with schizophrenia exhibit impaired PPI, and impaired sensorimotor gating might be a global common psychophysiological feature of schizophrenia. In conclusion, studies of PPI have successfully contributed to a better understanding of the fundamental neural mechanisms underlying sensorimotor gating and will certainly be most valuable in devising future approaches that aim to investigate the complex pathogenesis of psychiatric diseases.

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

          Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological 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. All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt 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-disruptive effects of these compounds in rodents. Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-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 literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.
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            Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

            Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.
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              Prestimulus effects on human startle reflex in normals and schizophrenics.

               L Bali,  M Geyer,  I Glick (1978)

                Author and article information

                Clin Psychopharmacol Neurosci
                Clin Psychopharmacol Neurosci
                Clinical Psychopharmacology and Neuroscience
                Korean College of Neuropsychopharmacology
                December 2011
                31 December 2011
                : 9
                : 3
                : 102-110
                [1 ]Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
                [2 ]Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
                [3 ]CREST (Core Research for Evolutionary Science and Technology), JST (Japan Science and Technology Agency), Saitama, Japan.
                [4 ]Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Osaka, Japan.
                Author notes
                Address for correspondence: Hidetoshi Takahashi, MD, PhD. Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashicho, Kodaira, Tokyo 1878553, Japan. Tel: +81-42-341-2711, Fax: +81-42-346-1944, htakahashi@
                Copyright© 2011, Korean College of Neuropsychopharmacology

                This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.



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