Fear conditioning is preserved in very preterm-born young adults despite increased anxiety levels

Abstract

Very preterm birth is associated with an increased risk for anxiety disorders. Abnormal brain development may result in disordered fear learning processes, which may be exacerbated by environmental risk factors and persist in adulthood. We tested the hypotheses that very preterm-born young adults displayed higher levels of fear conditioning, less differentiation between threat (CS+) and safety (CS-) signals, and stronger resistance to extinction relative to term-born controls. A group of 37 very preterm-born young adults and 31 age- and sex-matched term-born controls performed a differential fear conditioning paradigm on two consecutive days. Acquisition and extinction training were performed on day 1. Recall and reinstatement were tested on day 2. Preterm-born participants showed significantly higher levels of anxiety in the Depression-Anxiety-Stress-Scale-21 questionnaire. The fear conditioning outcome measures, skin conductance response amplitudes and anxiety ratings, were overall higher in the preterm-born group compared to controls. Awareness of CS-US contingencies was mildly reduced in preterms. Acquisition, extinction, recall and reinstatement of differential conditioned fear responses (CS+ > CS-), however, were not significantly different between the groups. There were no significant group by stimulus type interactions. The finding of largely preserved associative fear learning in very preterm-born young adults was unexpected and needs to be confirmed in future studies.

Figure 1

Depression-Anxiety-Stress-Scale-21 (DASS-21) questionnaire. Median scores and interquartile range (IQR) in the preterm and control groups. Dots represent individual scores. Normal range: depression score: 0–9, anxiety score: 0–7, stress score: 0–14; maximum possible score: 42.

Figure 2

(A) Skin conductance response amplitudes and (B) respective relative treatment effect (RTE) estimates. (A) Colored bars represent group mean (log-transformed) values for habituation phase and early and late blocks of acquisition training, extinction training, recall and reinstatement phases. Error bars indicate S.E.M. (B) Horizontal lines denote median RTEs and whiskers denote 95% confidence intervals. Blue colors = controls, red colors = preterms. Dark colors: CS + E and CS + U, light colors: CS-.

Figure 3

Median ratings regarding (A) valence, (B) arousal, (C) fear and (D) US expectancy on a Likert-scale of 1 (“very pleasant”/“very calm”/“not afraid”, “US not expected”, respectively) to 9 (“very unpleasant”/“very nervious”/“very afraid”, “US expected”, respectively). Horizontal lines denote median values. Whiskers range from the first to the third quartile. Blue colors = controls, red colors = preterms. Dark colors: CS + E and CS + U, light colors: CS−. Gray background = fear acquisition training. For respective relative treatment effects see Fig. S2 in Supplementary data.

Figure 4

CS-US contingency assessed after the acquisition training. (A) Group median reported CS-US contingency and individual data. Horizontal line represents median value, whiskers range from the first to the third quartile. (B) Group mean compound contingency scores and individual data. Horizontal line represents mean value, error bars indicate 95% confidence intervals. Dots represent individual data. Blue color = controls, red color = preterms.

Figure 5

Experimental paradigm and event blocking scheme. Habituation and acquisition were performed in context A. Extinction, recall and reinstatement were performed in context B. Contexts were represented by a photography of either a desk (“office”) or a bookshelf (“library”). The CSs were represented by the same desk lamp shining either in blue, red or yellow color. For further details see text. Experimental paradigm according to Milad et al..