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.

Fig. 1

Threat-anticipation task. Timeline of a single trial in the task (top) and corresponding measures of interest used in the analyses (bottom), which included SCR to index cue-based pain anticipation and SCR and subjective pain ratings to index responses to experienced pain. SCR = skin conductance response.

Fig. 2

Psychophysiological response: pain anticipation. Mean skin conductance response (square-root-transformed μS) by cue (low pain, high pain) and group (healthy, anxious). Error bars denote 1 standard error of the mean. **p < 0.01, ***p < 0.001.

Fig. 3

Brain structure: pain anticipation and experience. Left: Significant association between left-hemisphere cortical thickness and mean skin conductance response during pain anticipation (averaged response to low and high pain cues). This analysis was conducted on vertices in a region of interest defined by previous work that tested a similar effect. Right: Significant association between left-hemisphere cortical thickness and mean skin conductance response during pain (averaged response across all temperatures delivered). This result was derived from a whole-brain analysis. All results are for analyses using a cluster-forming threshold of p = 0.005 and a cluster-extent threshold of p_FWE = 0.05. Colours reflect p_FWE of the cluster.

Fig. 4

Response to heat pain. (A) Participants’ mean skin conductance response to heat (square-root-transformed μS) by trial type (LL, LM, HM, HH). (B) Participants’ mean pain ratings of the heat by trial type. Error bars denote one standard error of the mean. Results reflect means across the anxious and healthy groups; see Appendix 1 for means by group. *p < 0.05; **p < 0.01; ***p < 0.001 (Bonferroni-corrected). HH = high-pain cue + high-pain temperature; HM = high-pain cue + medium-pain temperature; LM = low-pain cue + medium-pain temperature; LL = low-pain cue + low-pain temperature.