The adaptive threat bias in anxiety: Amygdala–dorsomedial prefrontal cortex coupling and aversive amplification

Abstract

Functionally, anxiety serves to increase vigilance towards aversive stimuli and improve the ability to detect and avoid danger. We have recently shown, for instance, that anxiety increases the ability to a) detect and b) instigate defensive responses towards aversive and not appetitive face stimuli in healthy individuals. This is arguably the key adaptive function of anxiety, yet the neural circuitry underlying this valence-specific effect is unknown. In the present translational study, we sought evidence for the proposition that dorsomedial regions of the prefrontal (DMPFC) and cingulate cortex constitute the human homologue of the rodent prelimbic and are thus associated with increased amygdala responding during this adaptive threat bias in anxiety. To this end, we applied a novel functional connectivity analysis to healthy subjects (N = 20) identifying the emotion of fearful and happy faces in an fMRI scanner under anxious (threat of unpredictable foot shock) and non-anxious (safe) conditions. We showed that anxiety significantly increased positive DMPFC–amygdala connectivity during the processing of fearful faces. This effect was a) valence-specific (it was not seen for happy faces), b) paralleled by faster behavioral response to fearful faces, and c) correlated positively with trait anxiety. As such we provide the first experimental support for an anxiety-mediated, valence-specific, DMPFC–amygdala aversive amplification mechanism in healthy humans. This may be homologous to the rodent prelimbic–amygdala circuit and may, given the relationship with trait anxiety, underlie vulnerability to anxiety disorders. This study thus pinpoints a key neural mechanism in adaptive anxiety and highlights its potential link to maladaptive anxiety.

Introduction

Anxiety is adaptive; its functional role is to facilitate sensory processing and prompt rapid activation of defense mechanisms (Baas et al., 2006, Cornwell et al., 2007); especially in response to threatening stimuli (Blanchard et al., 2011, Davis et al., 2009, Grillon, 2008). We have recently shown, for instance, that threat of shock-induced anxiety selectively increases a) detection of (Robinson et al., 2011a) and b) psychophysiological defense responses towards (Grillon and Charney 2011) fearful faces while at the same time having no effect on detection or response to happy faces. This affective bias can significantly improve survival chances. For instance, when anxiously walking home at night, this bias might improve the ability to detect and respond to a mugger waiting in the dark. It is arguable, in fact, that this bias towards threat is the key adaptive function of anxiety. Yet the neural circuitry underlying this crucial effect is unknown. The present study thus aims to clarify the functional connectivity underlying the threat-specific affective bias in anxiety.

Recent research in rodents has highlighted a medial prefrontal cortical (prelimbic)–amygdala circuit which can increase behavioral responses to threat (Sierra-Mercado et al., 2011). More specifically, stimulation of the prelimbic region increases, via excitatory top–down neurons, activity within the amygdala and subsequent behavioral fear responses (Sierra-Mercado et al., 2011, Vidal-Gonzalez et al., 2006). A human homologue of this top–down aversive amplification mechanism could thus plausibly drive the selective bias towards fearful faces in anxiety. Milad et al. have demonstrated, on the basis of regions critical for fear conditioning in healthy individuals and in PTSD, that dorsal regions of the cingulate and medial-prefrontal cortex in humans are functionally equivalent to the rodent's prelimbic (Milad et al., 2007, Milad et al., 2009). This is consistent with the observation that dorsal regions of the prefrontal cortex and cingulate show positive connectivity with the amygdala (Etkin et al., 2011) and with the observation that the same dorsal regions (specifically the dorsomedial prefrontal cortex; DMPFC) are most consistently activated by induced anxiety in healthy individuals (Mechias et al., 2010). However, the functional connectivity between these regions during anxiety and, specifically, their relationship with the adaptive threat bias is unknown. We thus sought evidence for the proposition that DMPFC–amygdala connectivity can promote a bias towards threat in anxious, healthy, humans.

We adapted the task used in our prior behavioral and psychophysiological studies for fMRI. Healthy volunteers identified fearful and happy faces while they experienced anxiety induced via threat of unpredictable foot-shock. We predicted an enhanced behavioral response to fearful, but not happy, faces during threat (Robinson et al., 2011a). Moreover, as stimulation of the prelimbic in rodents underlies an increase in amygdala-mediated aversive behavior during anxiety, we expected to see positive coupling between the DMPFC (Mechias et al., 2010, Milad et al., 2007) and the amygdala in a functional connectivity analysis (Etkin et al., 2011, Vidal-Gonzalez et al., 2006) and, more specifically, increased positive coupling between the DMPFC and the amygdala during processing of fearful faces under induced anxiety (Robinson et al., 2011a).