Oxytocin differentially modulates amygdala responses during top-down and bottom-up aversive anticipation

Abstract

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...

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