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Reviews and Overviews   |    
A Translational Neuroscience Approach to Understanding the Development of Social Anxiety Disorder and Its Pathophysiology
Andrew S. Fox, Ph.D.; Ned H. Kalin, M.D.
Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2014.14040449
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Dr. Fox reports no financial relationships with commercial interests. Dr. Kalin has served on scientific advisory boards for Corcept Therapeutics, Neuronetics, CeNeRx BioPharma, and Skyland Trail; is a stockholder with equity options in Corcept Therapeutics and CeNeRx BioPharma; owned Promoter Neurosciences; and holds patents for promoter sequences for corticotropin-releasing factor CRF2alpha and a method of identifying agents that alter the activity of the promoter sequences, promoter sequences for urocortin II and the use thereof, and promoter sequences for corticotropin-releasing factor binding protein and the use thereof.

Supported by NIH Intramural Research Program and extramural grants R21MH91550, R01MH81884, R01MH46729, P50MH84051, MH100031, R21MH09258, the HealthEmotions Research Institute, and Meriter Hospital.

From the Departments of Psychiatry and Psychology, the HealthEmotions Research Institute, and the Waisman Center for Brain Imaging and Behavior, University of Wisconsin, Madison.

Address correspondence to Dr. Kalin (nkalin@wisc.edu).

Copyright © 2014 by the American Psychiatric Association

Received April 04, 2014; Revised June 06, 2014; Accepted June 16, 2014.

Abstract

This review brings together recent research from molecular, neural circuit, animal model, and human studies to help understand the neurodevelopmental mechanisms underlying social anxiety disorder. Social anxiety disorder is common and debilitating, and it often leads to further psychopathology. Numerous studies have demonstrated that extremely behaviorally inhibited and temperamentally anxious young children are at marked risk of developing social anxiety disorder. Recent work in human and nonhuman primates has identified a distributed brain network that underlies early-life anxiety including the central nucleus of the amygdala, the anterior hippocampus, and the orbitofrontal cortex. Studies in nonhuman primates have demonstrated that alterations in this circuit are trait-like in that they are stable over time and across contexts. Notably, the components of this circuit are differentially influenced by heritable and environmental factors, and specific lesion studies have demonstrated a causal role for multiple components of the circuit. Molecular studies in rodents and primates point to disrupted neurodevelopmental and neuroplastic processes within critical components of the early-life dispositional anxiety neural circuit. The possibility of identifying an early-life at-risk phenotype, along with an understanding of its neurobiology, provides an unusual opportunity to conceptualize novel preventive intervention strategies aimed at reducing the suffering of anxious children and preventing them from developing further psychopathology.

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FIGURE 1. Trajectories of Pathological Anxiety and Risk of Psychopathology for Children With Early-Life Anxious Temperament (AT)a

a Extreme AT exists on a continuum with social anxiety disorder (panel A), and many children with high levels of AT go on to experience disabling anxiety. Nearly 50% of children with extreme AT eventually develop social anxiety disorder, while in other children levels of AT remain stable or diminish with experience and maturation (7). During childhood and adolescence (panel B), children with extreme AT are most likely to develop social anxiety disorder, but throughout life individuals with extreme AT remain at a higher risk of developing other disorders that typically become manifest later in life, such as major depressive disorder and substance use disorders (1, 13, 22).

FIGURE 2. Measurement of Anxious Temperament (AT) in Human Children and Young Monkeys by Exposing Them to Potentially Threatening Contextsa

a In panel A, children confronted with a stranger or novel situation respond with varying degrees of behavioral inhibition and physiological activation. In panel B, during the no-eye-contact (NEC) context, an unfamiliar human intruder stands approximately 2.5 m from the monkey and remains still while looking away and presenting his or her profile to the monkey, making sure to make no eye contact. This potentially threatening NEC context specifically elicits robust behavioral inhibition and physiological activation. In contrast, other contexts, such as when a human intruder stares at the monkey, more robustly elicit fight-or-flight responses (36). Depending on the experiment, the NEC context can last 10–30 minutes. The human intruder remains motionless, continuing to present his or her profile throughout the entire test period.

FIGURE 3. Dorsal Amygdala Activation Predicts Variation in Anxious Temperament (AT) in Humans and Monkeysa

a From seven published reports examining the role of the amygdala in individuals with a history of childhood behavioral inhibition, we performed a two-dimensional activation likelihood meta-analysis of the location of activation peaks in the dorsal/ventral and medial/lateral dimensions. As shown in panel A, after dilating each peak with a 4-mm2 sphere, we found that six of the eight amygdala peaks overlapped (yellow) in the dorsal amygdala region (four of the peaks extended into the region shown in red) (AC-PC=anterior commissure-posterior commissure). In panel B, [18F]fluorodeoxyglucose positron emission tomography of 238 rhesus monkeys (41) revealed that metabolism within the anterior temporal lobe predicted AT (yellow). Similar to the human studies, the peak of this region was located in the dorsal amygdala (the peak is shown in white and the 95% spatial confidence interval in red). In both humans (panel C) and monkeys (panel D), the peak activations correspond to the location of the central nucleus of the amygdala (52). Ce=central nucleus; AB=accessory basal nucleus; B=basal nucleus; L=lateral nucleus.

FIGURE 4. Simplified Amygdala-Centric Model of the Brain Systems That Contribute to Monkey Anxious Temperament (AT)a

a Although the full extent of AT’s neural substrates remains unknown, neuroimaging work is beginning to identify regions that are more active in individuals with extreme AT, and lesion work suggests that at least some of these regions are causally involved in the genesis of AT. The most compelling evidence exists for the amygdala, which is a critical component of AT’s neural substrates and is the focus of extensive research that implicates it in fear- and anxiety-related processing. Here we present a simplified diagram of the monkey amygdala and how it fits into the larger set of brain systems that influence AT. The amygdala receives input from AT-related regulatory/evaluative (green), contextual (blue), and sensory (orange) neural systems, each of which is distributed throughout the brain. In general, amygdala information flows from the more ventral basal regions toward the central nucleus of the amygdala and the bed nucleus of the stria terminalis, which, via their projections to brainstem and hypothalamic structures (pink), initiate fear- and anxiety-related physiological and behavioral responses. All images are shown on slices adapted from reference 52. Ce=central nucleus; AB=accessory basal nucleus; B=basal nucleus; L=lateral nucleus; Me=medial nucleus; ICMs=intercalated masses; BST=bed nucleus of stria terminalis; ic=internal capsule; st=stria terminalis; ac=anterior commissure.

FIGURE 5. Mechanisms of Decreased Neuroplasticity Mechanisms in the Maintenance of Early-Life Anxious Temperament (AT)a

a Research suggests that anxious individuals have decreased neurodevelopmental- and neuroplasticity-related gene activation in brain regions underlying AT, such as the central nucleus of the amygdala and the hippocampus (panel A). Within these regions (panel B), genes that encode adhesion molecules (e.g., EPHA4), trk receptors (e.g., NTRK3), intracellular kinase signaling molecules (e.g., IRS2), and intranuclear kinases (e.g., RPS6KA3) are inversely associated with individual differences in AT. These specific genes function to increase neuroplasticity (panel C) through their influences on synaptic plasticity, increasing spine size and creating new synapses, new spines, and new neurons.

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