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      Preventing PTSD with oxytocin: effects of oxytocin administration on fear neurocircuitry and PTSD symptom development in recently trauma-exposed individuals

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      a , *
      European Journal of Psychotraumatology
      Taylor & Francis
      PTSD, early intervention, prevention, oxytocin, amygdala, fMRI

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          ABSTRACT

          Background: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which develops in approximately 10% of trauma-exposed individuals. Currently, there are few early preventive interventions available for PTSD. Intranasal oxytocin administration early posttrauma may prevent PTSD symptom development, as oxytocin administration was previously found to beneficially impact neurobiological (e.g. amygdala reactivity) and socio-emotional PTSD vulnerability factors.

          Objective: The overall aim of this dissertation was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD.

          Methods: We performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry – consisting of the amygdala and (pre)frontal brain regions – in recently trauma-exposed emergency department patients (range = 37–41). In addition, we performed a multicentre randomized double-blind placebo-controlled clinical trial (RCT) to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development up to six months posttrauma ( = 107).

          Results: In our fMRI experiments we observed acutely increased amygdala reactivity to fearful faces and attenuated amygdala-ventromedial and ventrolateral prefrontal cortex functional connectivity after a single oxytocin administration in recently trauma-exposed individuals. However, in our RCT we found that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms.

          Conclusions: These findings indicate that repeated intranasal oxytocin is a promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity. Administration frequency dependent effects of oxytocin or the effects of oxytocin administration on salience processing may serve as explanatory frameworks for the contrasting oxytocin effects on anxiety-related measures in our clinical and neuroimaging studies.

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          Most cited references75

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          Dissociable intrinsic connectivity networks for salience processing and executive control.

          Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.
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            Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.

            Estimates of 12-month and lifetime prevalence and of lifetime morbid risk (LMR) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) anxiety and mood disorders are presented based on US epidemiological surveys among people aged 13+. The presentation is designed for use in the upcoming DSM-5 manual to provide more coherent estimates than would otherwise be available. Prevalence estimates are presented for the age groups proposed by DSM-5 workgroups as the most useful to consider for policy planning purposes. The LMR/12-month prevalence estimates ranked by frequency are as follows: major depressive episode: 29.9%/8.6%; specific phobia: 18.4/12.1%; social phobia: 13.0/7.4%; post-traumatic stress disorder: 10.1/3.7%; generalized anxiety disorder: 9.0/2.0%; separation anxiety disorder: 8.7/1.2%; panic disorder: 6.8%/2.4%; bipolar disorder: 4.1/1.8%; agoraphobia: 3.7/1.7%; obsessive-compulsive disorder: 2.7/1.2. Four broad patterns of results are most noteworthy: first, that the most common (lifetime prevalence/morbid risk) lifetime anxiety-mood disorders in the United States are major depression (16.6/29.9%), specific phobia (15.6/18.4%), and social phobia (10.7/13.0%) and the least common are agoraphobia (2.5/3.7%) and obsessive-compulsive disorder (2.3/2.7%); second, that the anxiety-mood disorders with the earlier median ages-of-onset are phobias and separation anxiety disorder (ages 15-17) and those with the latest are panic disorder, major depression, and generalized anxiety disorder (ages 23-30); third, that LMR is considerably higher than lifetime prevalence for most anxiety-mood disorders, although the magnitude of this difference is much higher for disorders with later than earlier ages-of-onset; and fourth, that the ratio of 12-month to lifetime prevalence, roughly characterizing persistence, varies meaningfully in ways consistent with independent evidence about differential persistence of these disorders. Copyright © 2012 John Wiley & Sons, Ltd.
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              Oxytocin modulates neural circuitry for social cognition and fear in humans.

              In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.
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                Author and article information

                Journal
                Eur J Psychotraumatol
                Eur J Psychotraumatol
                ZEPT
                zept20
                European Journal of Psychotraumatology
                Taylor & Francis
                2000-8066
                2017
                11 April 2017
                : 8
                : 1
                : 1302652
                Affiliations
                [ a ]Department of Psychiatry, Academic Medical Center, University of Amsterdam , Amsterdam, the Netherlands
                Author notes
                CONTACT Jessie L. Frijling J.L.Frijling@ 123456amc.uva.nl Department of Psychiatry, Academic Medical Center, University of Amsterdam , Amsterdam, the Netherlands

                Mentors

                Miranda Olff (Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. Arq Psychotrauma Expert Group, Diemen, the Netherlands)

                Dick J. Veltman (Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands)

                Mirjam van Zuiden (Academic Medical Centre, University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands)

                Article
                1302652
                10.1080/20008198.2017.1302652
                5400019
                28451068
                f8b2c087-d496-4cf7-9df6-b17dfc0eb560
                © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 February 2017
                : 15 February 2017
                : 1 March 2017
                Page count
                References: 99, Pages: 14
                Funding
                Funded by: Academic Medical Center Research Council
                Award ID: 110614
                Funded by: ZonMw 10.13039/501100001826
                Award ID: 91210041
                This work was supported by the Academic Medical Centre Research Council [110614]; ZonMw [91210041].
                Categories
                Other
                PhD Summary

                Clinical Psychology & Psychiatry
                ptsd,early intervention,prevention,oxytocin,amygdala,fmri
                Clinical Psychology & Psychiatry
                ptsd, early intervention, prevention, oxytocin, amygdala, fmri

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