Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients

The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health.The neuropeptide oxytocin (OXT) acts as important modulator of emotion regulation, as reflected by reduced amygdala responses but increased amygdala-prefrontal cortex (PFC) functional connectivity in response to threatening stimuli. The present randomized, between-subject, placebo (PLC)controlled pharmacological study combined intranasal administration of OXT with functional MRI during an explicit (cognitive) emotion regulation (i.e. distancing reappraisal) paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom-up and top-down emotion regulation. OXT attenuated the activation in posterior insular cortex and amygdala during anticipation of top-down regulation of predictable threat stimuli in participants with high trait anxiety, providing evidence to support the anxiolytic action of OXT. In contrast, OXT enhanced amygdala activity during bottom-up anticipation of an unpredictable threat stimulus in participants with low trait anxiety. OXT may thus facilitate top-down goal-directed attention by attenuating amygdala activity in high anxiety individuals, while promote bottom-up attention/vigilance to unexpected threat by enhancing anticipatory amygdala activity in low anxiety individuals. The opposite effects of OXT on anticipatory amygdala activation in high versus low anxiety individuals may suggest a baseline anxiety level dependent mechanism via which OXT promotes optimal levels of amygdala activation during the anticipation of an imminent threat. OXT may thus have the potential to promote an adaptive balance between bottom-up and top-down attention systems depending on individual levels of pre-treatment trait anxiety levels. 2017; Zilverstand et al., 2017). Behavioral interventions (Campbell-Sills and Barlow, 2007; Gross et al., 2006; Jazaieri et al., 2015), neurofeedback targeting the amygdala-prefrontal circuits (Cohen Kadosh et al., 2016; Zhao et al., 2019) and pharmacological agents primarily targeting serotonergic and GABAergic neurotransmission (Farach et al., 2012; Singewald et al., 2015) can facilitate the regulation of negative emotions, including anxiety and fear. However, not all patients respond adequately to the currently available treatment strategies and the pharmacological interventions may induce negative side-effects which often limit compliance with the treatment protocols, thus novel strategies to improve emotion regulation are urgently needed.Emotion generation and regulation involves the interaction of intrinsic/automatic bottom-up processes and controlled/deliberately top-down processes (Ochsner and Gross, 2005;Ochsner and Gross, 2007;Suri et al., 2013). Bottom-up processes are stimulus-driven and initiated by salient stimuli in the environment. In contrast, top-down processes are goal-driven and context-dependent (Beck and Kastner, 2009;Desimone and Duncan, 1995;Sussman et al., 2016a). During both the (pre-stimulus) anticipation and adven...

Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.

BackgroundSocial anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD.MethodsParticipants (n = 110; age, 9.2 – 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated.ResultsOur data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate ‐ to‐moderately high heritability in the right hippocampus.ConclusionThe present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD.