Phasic and sustained fear in humans elicits distinct patterns of brain activity

Abstract

Aversive events are typically more debilitating when they occur unpredictably than predictably. Studies in humans and animals indicate that predictable and unpredictable aversive events can induce phasic and sustained fear, respectively. Research in rodents suggests that anatomically related but distinct neural circuits may mediate phasic and sustained fear. We explored this issue in humans by examining threat predictability in three virtual reality contexts, one in which electric shocks were predictably signaled by a cue, a second in which shocks occurred unpredictably but never paired with a cue, and a third in which no shocks were delivered. Evidence of threat-induced phasic and sustained fear was presented using fear ratings and skin conductance. Utilizing recent advances in functional magnetic resonance imaging (fMRI), we were able to conduct whole-brain fMRI at relatively high spatial resolution and still have enough sensitivity to detect transient and sustained signal changes in the basal forebrain. We found that both predictable and unpredictable threat evoked transient activity in the dorsal amygdala, but that only unpredictable threat produced sustained activity in a forebrain region corresponding to the bed nucleus of the stria terminalis complex. Consistent with animal models hypothesizing a role for the cortex in generating sustained fear, sustained signal increases to unpredictable threat were also found in anterior insula and a frontoparietal cortical network associated with hypervigilance. In addition, unpredictable threat led to transient activity in the ventral amygdala–hippocampal area and pregenual anterior cingulate cortex, as well as transient activation and subsequent deactivation of subgenual anterior cingulate cortex, limbic structures that have been implicated in the regulation of emotional behavior and stress responses. In line with basic findings in rodents, these results provide evidence that phasic and sustained fear in humans may manifest similar signs of distress, but appear to be associated with different patterns of neural activity in the human basal forebrain.

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

“…There is now substantial evidence of BNST activation during evoked anxiety in humans (i.e., from imaging studies [Hasler et al 2007;Straube et al 2007;Somerville et al 2010Somerville et al , 2013Alvarez et al 2011;Yassa et al 2012]), and compelling evidence that electrical stimulation of a brain area lying at the junction of the anterior capsule, anterior commissure, and posterior ventral striatum-an area which corresponds very closely to the area targeted by our cannula-markedly reduces anxiety and depression in patients with otherwise intractable obsessive-compulsive disorder (Greenberg et al 2010). That pharmacological modulation of BNST might also prove therapeutic is an exciting prospect.…”

Micro-Positron Emission Tomography Imaging of Rat Brain Metabolism during Expression of Contextual Conditioning

“…An fMRI study in healthy participants concluded that the BST indexes hypervigilant threat monitoring (Somerville et al, 2010). Another fMRI study in healthy participants found BST activity when comparing unpredictable threat with no threat using virtual reality contexts (Alvarez et al, 2011).…”

Using the Threat Probability Task to Assess Anxiety and Fear During Uncertain and Certain Threat

“…Much of this work uses potentiation of the acoustic startle response as a primary dependent measure 13 , which is the same dependent measure used in the Threat Probability Task. The neurobiological substrates of the startle response circuit have been extensively studied with the discovery of clear connections to the brain structures active in responses to uncertain and certain threats 19,20 . The startle response can be assessed in numerous species which provides a powerful translational tool to study emotions.…”