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      Repetitive Transcranial Magnetic Stimulation Ameliorates Anxiety-Like Behavior and Impaired Sensorimotor Gating in a Rat Model of Post-Traumatic Stress Disorder

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          Abstract

          Background

          Repetitive transcranial magnetic stimulation (rTMS) has been employed for decades as a non-pharmacologic treatment for post-traumatic stress disorder (PTSD). Although a link has been suggested between PTSD and impaired sensorimotor gating (SG), studies assessing the effects of rTMS against PTSD or PTSD with impaired SG are scarce.

          Aim

          To assess the benefit of rTMS in a rat model of PTSD.

          Methods

          Using a modified single prolonged stress (SPS&S) rat model of PTSD, behavioral parameters were acquired using open field test (OFT), elevated plus maze test (EPMT), and prepulse inhibition trial (PPI), with or without 7 days of high frequency (10Hz) rTMS treatment of SPS&S rats.

          Results

          Anxiety-like behavior, impaired SG and increased plasma level of cortisol were observed in SPS&S animals after stress for a prolonged time. Interestingly, rTMS administered immediately after stress prevented those impairment.

          Conclusion

          Stress-induced anxiety-like behavior, increased plasma level of cortisol and impaired PPI occur after stress and high-frequency rTMS has the potential to ameliorate this behavior, suggesting that high frequency rTMS should be further evaluated for its use as a method for preventing PTSD.

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          Most cited references 59

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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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              A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition.

              Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.
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                Author and article information

                Affiliations
                [1 ]Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
                [2 ]Department of Psychiatry, 91 Hospital of P. L. A., Jiaozuo, 454150, China
                University of South Florida, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: Q-RT H-NW Y-HB Z-WP. Performed the experiments: H-NW Y-HB Y-CC R-GZ. Analyzed the data: J-LG. Contributed reagents/materials/analysis tools: Y-HZ. Wrote the paper: H-NW H-HW Y-HZ.

                ‡ These authors contributed equally to this work.

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 February 2015
                2015
                : 10
                : 2
                PONE-D-12-29447
                10.1371/journal.pone.0117189
                4320076
                25659132

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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                Figures: 8, Tables: 0, Pages: 15
                Product
                Funding
                This work was supported by grants from the National Key Technology R & D Program of China (No.2009BA177B09) and the Natural Science Foundation of China (No. 81201041, 81371478 and 81401109). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Research Article

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