Anticipatory Threat Responding: Associations With Anxiety, Development, and Brain Structure

Abstract

Background: While translational theories link neurodevelopmental changes in threat learning to pathological anxiety, findings from studies in patients inconsistently support these theories. This inconsistency may reflect difficulties in studying large patient samples with wide age ranges using consistent methods. A dearth of imaging data in patients further limits translational advances. We address these gaps through a psychophysiology and structural brain imaging study in a large sample of patients across the lifespan.

Methods: A total of 351 participants (8-50 years of age; 209 female subjects; 195 healthy participants and 156 medication-free, treatment-seeking patients with anxiety) completed a differential threat conditioning and extinction paradigm that has been validated in pediatric and adult populations. Skin conductance response indexed psychophysiological response to conditioned (CS+, CS-) and unconditioned threat stimuli. Structural magnetic resonance imaging data were available for 250 participants. Analyses tested anxiety and age associations with psychophysiological response in addition to associations between psychophysiology and brain structure.

Results: Regardless of age, patients and healthy comparison subjects demonstrated comparable differential threat conditioning and extinction. The magnitude of skin conductance response to both conditioned stimulus types differentiated patients from comparison subjects and covaried with dorsal prefrontal cortical thickness; structure-response associations were moderated by anxiety and age in several regions. Unconditioned responding was unrelated to anxiety and brain structure.

Conclusions: Rather than impaired threat learning, pathological anxiety involves heightened skin conductance response to potential but not immediately present threats; this anxiety-related potentiation of anticipatory responding also relates to variation in brain structure. These findings inform theoretical considerations by highlighting anticipatory response to potential threat in anxiety.

Trial registration: ClinicalTrials.gov NCT00018057.

Keywords: Anticipation; Anxiety; Conditioning; Development; Extinction; Threat.

Figure 1.. Schematic representation of the threat conditioning and extinction paradigm.

During conditioning, one face (CS+) was repeatedly paired with a fearful face co-terminating with a scream (UCS); the other face (CS−) was never paired with the UCS. During extinction, both faces were presented in the absence of the UCS. Note: CS = conditioned stimulus; UCS = unconditioned stimulus.

Figure 2.. Conditioned and unconditioned psychophysiological threat response.

A) Conditioned skin conductance responses (SCR) by stimulus type (CS−, CS+) averaged across each phase of the task (pre-conditioning, conditioning, extinction), by anxiety group (healthy, anxious). B) Averaged SCR to the unconditioned stimulus by anxiety group (healthy, anxious). Note: SCR data were square-root-transformed microsiemens units. Pre-cond. = Pre-conditioning, Cond. = Conditioning, n.s. = not significant. Error bars represent one standard error of the mean.

Figure 3.. Brain structure correlates of psychophysiological response to conditioned cues.

Result of analysis predicting individual averaged skin conductance responses to conditioned cues (CS− and CS+) across the task by cortical thickness, anxiety status (healthy, anxious), and age (in years). A) Association between cortical thickness and conditioned response, controlling for anxiety and age. B) Modulation of association between cortical thickness and conditioned response by anxiety. C) Moderation of association between cortical thickness and conditioned response by age. Each surface’s color reflects −log(p-value) of the threshold-free cluster enhancement statistic; brighter colors represent stronger effects (threshold: p_FWE<0.05). Note: L = left; R = right.