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Background: Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During EMDR, patients make horizontal eye movements (EMs) while simultaneously recalling a traumatic memory, which renders the memory less vivid and emotional when it is later recalled again. Recalling highly emotional autobiographical memories enhances noradrenergic neurotransmission. Noradrenaline (NA) strengthens memory (re)consolidation. However, memories become less vivid after recall+EMs. Therefore, NA might either play no significant role or serve to strengthen memories that are degraded by EMs. The present study was designed to test the latter hypothesis. We predicted that blocking NA would abolish the memory degrading effects of EMs., Methods: Fifty-six healthy participants selected three negative autobiographical memories. One was then recalled while making EMs, one was recalled without EMs, and one was not recalled. Vividness and emotionality of the memories as well as heart rate and skin conductance level during memory retrieval were measured before, directly after, and 24 hours after the EM task. Before the task, participants received a placebo or the noradrenergic β-receptor blocker propranolol (40 mg)., Results: There were no effects of EMs on memory emotionality or psychophysiological measures in the propranolol and placebo groups. However, in the placebo group, but not in the propranolol group, memory vividness significantly decreased from pretest to posttest and follow-up after recall+EMs relative to the control conditions., Conclusions: Blocking NA abolished the effects of EMs on the vividness of emotional memories, indicating that NA is crucial for EMDR effectiveness and possibly strengthens the reconsolidation of the degraded memory., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states., Methods: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat., Results: Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2)., Conclusions: The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Reducing fear when a threat has disappeared protects against a continuously elevated anxiety state. In this study, we investigated the brain mechanism involved in this process., Methods: The threat paradigm consisted of discrete cues that signaled either threat of shock or safety. Healthy participants were tested in two sessions in which eyeblink startle (n = 26) and blood oxygen level dependence (n = 23) were measured to index subjects' defensive state and brain responses respectively., Results: Startle results indicated that subjects could rapidly decrease their defensive state after the offset of shock threat. Functional magnetic resonance imaging data indicated that the termination of threat was associated with the recruitment of lateral and ventromedial prefrontal cortices. An exploratory connectivity analysis showed that activity in these prefrontal regions was linked and was also associated with activity in brain regions typically responding to threat, the right anterior insula and amygdala., Conclusions: These results provide first evidence for a prefrontal mechanism that functions to control anxiety after threat offset, which may be dysfunctional in patients who suffer from excessive sustained anxiety. Moreover, the results support a model in which the lateral prefrontal cortex controls anxiety related limbic activity through connections with ventromedial prefrontal cortex., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Sustained anxiety can be modeled using context conditioning, which can be studied in a virtual reality environment. Unpredictable stressors increase context conditioning in animals. This study examined context conditioning to predictable and unpredictable shocks in humans using behavioral avoidance, potentiated startle, and subjective reports of anxiety., Methods: Subjects were guided through three virtual rooms (no-shock, predictable, unpredictable contexts). Eight-sec duration colored lights served as conditioned stimuli (CS). During acquisition, no shock was administered in the no-shock context. Shocks were paired with the CS in the predictable context and were administered randomly in the unpredictable context. No shock was administered during extinction. Startle stimuli were delivered during CS and between CS to assess cued and context conditioning, respectively. To assess avoidance, subjects freely navigated into two of the three contexts to retrieve money., Results: Startle between CS was potentiated in the unpredictable context compared to the two other contexts. Following acquisition, subjects showed a strong preference for the no-shock context and avoidance of the unpredictable context., Conclusions: Consistent with animal data, context conditioning is increased by unpredictability. These data support virtual reality as a tool to extend research on physiological and behavioral signs of fear and anxiety in humans.

Background: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue., Methods: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions., Results: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam., Conclusions: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.

Background: Brainstem auditory evoked potentials (BAEP) reflect the activation of brainstem nuclei in the first milliseconds after presentation of an auditory stimulus. These electrophysiological correlates of neural processing are highly automatic and not influenced by cognitive factors or task demands; however, data from patients with anxiety disorders suggest deviations in the BAEP. It has been hypothesized that these differences reflect heightened activation of structures involved in defensive states, such as the amygdala and locus coeruleus, projecting to the inferior colliculus, one of the brainstem generators of wave V of the BAEP. The present study investigated this possibility by testing BAEP during experimentally induced anxiety in healthy volunteers., Methods: In this study, BAEP were recorded from healthy normal volunteers under threat of shock, compared with safe conditions., Results: The first experiment (n = 12) showed that shock anticipation increased the amplitude of wave V. A replication experiment (n = 13) confirmed this finding., Conclusions: Although BAEP are highly robust with respect to attentional manipulations, they are affected by transient activation of the fear system due to threat of shock. This finding indicates that some of the electrophysiological brainstem abnormalities observed in anxiety disorders can be replicated in healthy control subjects by inducing a transient state of anxiety.