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      Amygdala-Cortical Connectivity: Associations with Anxiety, Development, and Threat : 2015 ADAA Scientific Research Symposium: Anxiety, Development, and Connectivity

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d5267306e179">Background</h5> <p id="P1">Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al., 2013). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d5267306e184">Methods</h5> <p id="P2">Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically-defined amygdala seed regions differed across anxiety and age groups. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d5267306e189">Results</h5> <p id="P3">Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: −16, 31, −6 and 1, 36, −4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d5267306e194">Conclusions</h5> <p id="P4">In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdala-vmPFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations. </p> </div>

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          Most cited references54

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          Neurons in medial prefrontal cortex signal memory for fear extinction.

          Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.
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            Neural mechanisms of extinction learning and retrieval.

            Emotional learning is necessary for individuals to survive and prosper. Once acquired, however, emotional associations are not always expressed. Indeed, the regulation of emotional expression under varying environmental conditions is essential for mental health. The simplest form of emotional regulation is extinction, in which conditioned responding to a stimulus decreases when the reinforcer is omitted. Two decades of research on the neural mechanisms of fear conditioning have laid the groundwork for understanding extinction. In this review, we summarize recent work on the neural mechanisms of extinction learning. Like other forms of learning, extinction occurs in three phases: acquisition, consolidation, and retrieval, each of which depends on specific structures (amygdala, prefrontal cortex, hippocampus) and molecular mechanisms (receptors and signaling pathways). Pharmacological methods to facilitate consolidation and retrieval of extinction, for both aversive and appetitive conditioning, are setting the stage for novel treatments for anxiety disorders and addictions.
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              Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.

              A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD control subjects underwent a 2-day fear conditioning and extinction protocol in a 3-T functional magnetic resonance imaging scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. The SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of functional magnetic resonance imaging data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC and greater activation in dACC were observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.
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                Author and article information

                Journal
                Depression and Anxiety
                Depress Anxiety
                Wiley
                10914269
                October 2016
                October 2016
                October 03 2016
                : 33
                : 10
                : 917-926
                Affiliations
                [1 ]Emotion and Development Branch; National Institute of Mental Health, National Institutes of Health; Bethesda Maryland
                [2 ]Department of Psychology; University of Haifa; Israel
                [3 ]Department of Psychology; Rutgers University; New Brunswick New Jersey
                [4 ]Department of Psychology; University of Miami; Coral Gables Florida
                Article
                10.1002/da.22470
                5096647
                27699940
                d89721b4-01b5-4f89-867d-772923cd4e7d
                © 2016

                http://doi.wiley.com/10.1002/tdm_license_1.1

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