Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy

Abstract

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

Instructions and experiential learning have similar impacts on pain and pain-related brain responses but produce dissociations in value-based reversal learning

“…Bayesian model comparison indicated that the best model included fixed effects of Group, Cue, and Trial, with random intercepts and random slopes for Cue and Trial (see Supplemental Results). Consistent with other studies of expectancy-based pain modulation (Atlas et al, 2010; Wiech et al, 2014; Reicherts et al, 2016; Fazeli and Büchel, 2018; Michalska et al, 2018; Abend et al, 2021), all models indicated that participants reported higher pain when medium heat was preceded by high pain cues than low pain cues (main effect of Cue: see Figure 2B and Table 2). Bayesian modeling indicated that this effect had a 100% probability of being positive (Median = 1.261, 89% CI [0.82, 1.338]), and can be considered practically significant (0% in ROPE).…”

“…We measured whether cue-based expectancy effects on pain and brain responses to noxious heat update dynamically as contingencies change, and whether these relationships vary as a function of whether individuals learn through instruction or experience. All participants demonstrated robust cue-based expectancy effects on pain, consistent with previous work from our group and others (Colloca et al, 2008a; Atlas et al, 2010; Wiech et al, 2014; Fazeli and Büchel, 2018; Jepma et al, 2018; Michalska et al, 2018; Koban et al, 2019; Abend et al, 2021). Here, we provide new evidence that these predictive cue-based expectancy effects on pain update as contingencies change, whether reversals are accompanied by instructions or learned through experience.…”

“…Following conditioning, each cue was paired with stimulation calibrated to elicit ratings of medium pain. This provides a test of cue- based expectancy effects, consistent with our previous work (Atlas et al, 2010, 2013; Johnston et al, 2012; Michalska et al, 2018; Abend et al, 2021). Intermittent reinforcement continued at a 50% reinforcement rate until contingencies reversed.…”

“…In the present analyses, we focused on within-subjects effects and did not examine how these differences vary across individuals as a function of factors such as anxiety, which has previously been shown to impact adaptive learning (Browning et al, 2015). However, we recently examined how instructed reversals impact pain expectations in youth with clinical anxiety and found that youth with and without anxiety showed similar responses to expectancy and instruction, although youth with anxiety showed greater autonomic arousal during pain anticipation (Abend et al, 2021). Future analyses may relate anticipatory responses to the cues themselves with the responses to noxious heat that we focused on here, as well as autonomic responses during anticipation and in response to heat.…”

“…Halfway through runs 2, 4, and 6, the screen displayed instructions to the Instructed Group indicating that contingencies had reversed (see Figure 1C). Immediately following instructions, participants experienced at least one medium heat trial paired with each cue, which provides an immediate test of instructed reversals in the Instructed Group (Atlas et al, 2016; Atlas and Phelps, 2018; Abend et al, 2021). Following the medium heat trials, the new contingencies were reinforced (i.e.…”