Renewal of fear and avoidance in humans to escalating threat: Implications for translational research on anxiety disorders.

Exposure-based treatment for threat avoidance in anxiety disorders often results in fear renewal. However, little is known about renewal of avoidance. This multimodal laboratory-based treatment study used an ABA renewal design and an approach-avoidance (AP-AV) task to examine renewal of fear/threat and avoidance in twenty adults. In Context A, 9 visual cues paired with increases in probabilistic money loss (escalating threats) produced increases in ratings of feeling threatened and loss expectancies and skin-conductance responses (SCR). During the AP-AV task, a monetary reinforcer was available concurrently with threats. Approach produced the reinforcer or probabilistic loss, while avoidance prevented loss and forfeited reinforcement. Escalating threat produced increasing avoidance and ratings. In Context B with Pavlovian extinction, threats signaled no money loss and SCR declined. During the AP-AV task, avoidance and ratings also declined. In a return to Context A with Pavlovian threat extinction in effect during the AP-AV task, renewal was observed. Escalating threat was associated with increasing ratings and avoidance in most participants. SCR did not show renewal. These are the first translational findings to highlight renewal of avoidance in humans. Further research should identify individual difference variables and altered neural mechanisms that may confer increased risk of avoidance renewal.

The tipping point: Value differences and parallel dorsal-ventral frontal circuits gating human approach-avoidance behavior.

Excessive avoidance and diminished approach behavior are both prominent features of anxiety, trauma and stress related disorders. Despite this, little is known about the neuronal mechanisms supporting gating of human approach-avoidance behavior. Here, we used functional magnetic resonance imaging (fMRI) to track dorsal anterior cingulate and medial prefrontal (dACC/dmPFC) activation along an approach-avoidance continuum to assess sensitivity to competing appetitive and aversive contingencies and correspondence with behavior change. Behavioral and fMRI experiments were conducted using a novel approach-avoidance task where a monetary reward appeared in the presence of a conditioned stimulus (CS), or threat, that signaled increasing probability of unconditioned stimulus (US) delivery. Approach produced the reward or probabilistic US, while avoidance prevented US delivery, and across trials, reward remained fixed while the CS threat level varied unpredictably. Increasing the CS threat level (i.e., US probability) produced the desired approach-avoidance transition and inverted U-shaped changes in decision times, electrodermal activity and activation in pregenual ACC, dACC/dmPFC, striatum, anterior insula and inferior frontal regions. Conversely, U-shaped changes in activation were observed in dorsolateral and ventromedial prefrontal cortex and bimodal changes in the orbitofrontal and ventral hippocampus. These new results show parallel dorsal-ventral frontal circuits support gating of human approach-avoidance behavior where dACC/dmPFC signals inversely correlate with value differences between approach and avoidance contingencies while ventral frontal signals correlate with the value of predictable outcomes. Our findings provide an important bridge between basic research on brain mechanisms of value-guided decision-making and value-focused clinical theories of anxiety and related interventions.