The Neurocircuitry of Fear, Stress, and Anxiety Disorders

Department of Psychology, Tufts University, Medford, MA 02155, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 08/2009; 35(1):169-91. DOI: 10.1038/npp.2009.83
Source: PubMed


Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

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    • "The maturation of neural structures involved in the circuitry involved in fear processing may play a crucial role. Animal and human neuroimaging studies have highlighted the role of the amygdala, the prefrontal cortex (PFC), and the hippocampus in fear learning (LeDoux, 2000; Shin & Liberzon, 2010). These regions are characterized by different trajectories throughout developmental stages (Casey, Jones, & Hare, 2008), with prefrontal regions maturing later than subcortical limbic structures. "
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    ABSTRACT: Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 9999: 1-11, 2016.
    No preview · Article · Jan 2016 · Developmental Psychobiology
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    • "Lastly, we began to investigate biological correlates of PTSD-related symptoms by evaluating protein expression changes of GABAergic factors in selected limbic brain areas four weeks after UWT. Accumulative data from animals (Jacobson-Pick et al., 2008; Jacobson-Pick and Richter-Levin, 2012; Tzanoulinou et al., 2014) and humans (Lydiard, 2003; Shin and Liberzon, 2010) suggests an involvement of the GABAergic system in stress-related psychopathologies. Stress exposure is expected to induce an abundance of expression changes which contribute to stress resilience and vulnerability. "
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    ABSTRACT: Diagnosis of psychiatric disorders in humans is based on comparing individuals to the normal population. However, many animal models analyze averaged group effects, thus compromising their translational power. This discrepancy is particularly relevant in posttraumatic stress disorder (PTSD), where only a minority develop the disorder following a traumatic experience. In our PTSD rat model, we utilize a novel behavioral profiling approach that allows the classification of affected and unaffected individuals in a trauma-exposed population. Rats were exposed to underwater trauma (UWT) and four weeks later their individual performances in the open field and elevated plus maze were compared to those of the control group, allowing the identification of affected and resilient UWT-exposed rats. Behavioral profiling revealed that only a subset of the UWT-exposed rats developed long-lasting behavioral symptoms. The proportion of affected rats was further enhanced by pre-exposure to juvenile stress, a well-described risk factor of PTSD. For a biochemical proof of concept we analyzed the expression levels of the GABAA receptor subunits α1 and α2 in the ventral, dorsal hippocampus and basolateral amygdala. Increased expression, mainly of α1, was observed in ventral but not dorsal hippocampus of exposed animals, which would traditionally be interpreted as being associated with the exposure-resultant psychopathology. However, behavioral profiling revealed that this increased expression was confined to exposed-unaffected individuals, suggesting a resilience-associated expression regulation. The results provide evidence for the importance of employing behavioral profiling in animal models of PTSD, in order to better understand the neural basis of stress vulnerability and resilience.
    Full-text · Article · Jan 2016 · Neurobiology of Disease
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    • "Multimodal imaging of the amygdaloid complex may provide complementary information and novel insights on PTSD pathophysiology, which otherwise would only be partially revealed by each modality separately. Based on earlier work implicating amygdala-centered network dysfunction in abnormal fear processing and excessive fear responses [Barbas, 2007; Brown et al., 2014; Cisler et al., 2014; Etkin et al., 2009; Jovanovic and Ressler, 2010; LeDoux, 2007; Pessoa and Adolphs, 2010; Roy et al., 2013; Sah et al., 2003; Shin and Liberzon, 2010], we hypothesized adolescents with PTSD to show diminished BLA connectivity with regulatory prefrontal regions, such as the medial prefrontal and anterior cingulate cortices. Moreover, we hypothesized adolescents with PTSD to show increased CMA connectivity with regions involved in fear expression. "
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    ABSTRACT: Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. Hum Brain Mapp, 2016.
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