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      Hypervigilance for fear after basolateral amygdala damage in humans

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          Abstract

          Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach–Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety.

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          Most cited references58

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          Serotonin transporter genetic variation and the response of the human amygdala.

          A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
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            Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala.

            Effective mental functioning requires that cognition be protected from emotional conflict due to interference by task-irrelevant emotionally salient stimuli. The neural mechanisms by which the brain detects and resolves emotional conflict are still largely unknown, however. Drawing on the classic Stroop conflict task, we developed a protocol that allowed us to dissociate the generation and monitoring of emotional conflict from its resolution. Using functional magnetic resonance imaging (fMRI), we find that activity in the amygdala and dorsomedial and dorsolateral prefrontal cortices reflects the amount of emotional conflict. By contrast, the resolution of emotional conflict is associated with activation of the rostral anterior cingulate cortex. Activation of the rostral cingulate is predicted by the amount of previous-trial conflict-related neural activity and is accompanied by a simultaneous and correlated reduction of amygdalar activity. These data suggest that emotional conflict is resolved through top-down inhibition of amygdalar activity by the rostral cingulate cortex.
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              Amygdala circuitry mediating reversible and bidirectional control of anxiety.

              Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                May 2012
                15 May 2012
                1 May 2012
                : 2
                : 5
                : e115
                Affiliations
                [1 ]simpleDepartment of Psychology, Utrecht University , Utrecht, The Netherlands
                [2 ]simpleDepartment of Psychiatry and Mental Health, University of Cape Town , Cape Town, South Africa
                [3 ]simpleMRC Medical Imaging Research Unit, Department of Human Biology, University of Cape Town , Cape town, South Africa
                [4 ]simpleDepartment of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University , Durham, NC, USA
                [5 ]simpleDepartment of Psychology, Washington State University , Pullman, WA, USA
                Author notes
                [* ]simpleDepartment of Psychology, Utrecht University , Heidelberglaan 2, Utrecht 3584CS, The Netherlands. E-mail: d.terburg@ 123456uu.nl
                Article
                tp201246
                10.1038/tp.2012.46
                3365265
                22832959
                4f1511be-05a6-4401-b046-5f7ed9352d0c
                Copyright © 2012 Macmillan Publishers Limited
                History
                : 02 March 2012
                : 16 April 2012
                : 16 April 2012
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                fmri,smri,basolateral amygdala,fear vigilance,urbach–wiethe disease,eye tracking

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