Effect of Tryptophan Depletion on Conditioned Threat Memory Expression: Role of Intolerance of Uncertainty

Abstract

Background Responding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occur in many psychiatric disorders, including posttraumatic stress disorder, obsessive-compulsive disorder, and schizophrenia, in which emotional responses can persist pathologically. While there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does lowering serotonin affect memory retention of conditioned threat and safety memory? Methods Forty-seven healthy participants underwent conditioning to two stimuli predictive of threat on day 1. One stimulus but not the other was subsequently presented in an extinction session. Emotional responding was assessed by the skin conductance response. On day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind, placebo-controlled, randomized between-groups design. We then tested for the retention of conditioned threat and extinction memory. We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression. Results The expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion. Conclusions These results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.

Evidence for different roles of inhibitory and prospective intolerance of uncertainty during threat discrimination learning

“…The literature on the impact of IU on threat learning processes is decidedly mixed. Although the majority of the studies point to no effects of IU on threat acquisition, several positive findings (including those from the present study) remain to be explained (Chin et al, 2016;Kanen et al, 2021;Morriss, Macdonald, et al, 2016;Klingelhöfer-Jens et al, 2022;Lipp et al, 2022;Mertens et al, 2022;Sjouwerman et al, 2020;Starita et al, 2019). Possible explanations for disparities across studies is differences in experimental design and outcome measurements (e.g., SCR vs.…”

“…startle; CS response or US omission response). The present study, and most others finding IUspecific effects during acquisition, used within-participant designs featuring multiple cues and startle probes (Chin et al, 2016;Kanen et al, 2021;Morriss, Macdonald, et al, 2016;Sjouwerman et al, 2020), which increases the ambiguity of the experimental situation relative to simpler designs. Indeed, it has been argued that the experimental design can be optimized to capture individual difference effects.…”

“…used a fear generalization paradigm to show that high IU was associated with higher threat generalization from threat to safety cues during acquisition. Kanen et al (2021) showed higher IU was linked to poorer discrimination between two CS+s and a CSduring acquisition, as indexed by SCR. Sjouwerman et al (2020) showed higher auditory startle to the CS-during acquisition for individuals with higher IU scores.…”

“…One possible explanation for the disparity in results is methodological differences. That is, many studies showing IU-related acquisition effects have used a within-subjects design with multiple CS+s and/or included additional startle probes (Chin et al, 2016;Kanen et al, 2021;Klingelhöfer-Jens et al, 2022;Mertens et al, 2022;Morriss, Macdonald, et al, 2016;Sjouwerman et al, 2020), which may have created an extra layer of uncertainty compared to the studies not showing these effects, which have mostly used a single CS+ and no startle probes (Morriss, Zuj, et al, 2021). It could be that IU-related effects on threat discrimination are more likely to emerge when a suprathreshold level of uncertainty or complexity is reached during the learning session.…”

I Doubt It Is Safe: A Meta-analysis of Self-reported Intolerance of Uncertainty and Threat Extinction Training

“…Next, the authors of eligible published studies were contacted regarding their willingness to share details on their design and their individual-level data (i.e., SCR, self-reported IU scores, and any additional self-reported trait anxiety scores). Based on the literature search, call for data on social media, and emailing of experts in the field, 16 records ( 15 , 35 , 36 , 37 , 39 , 40 , 51 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ) (S. Steinman Ph.D., et al , unpublished data, September 2020; R. Sjouwerman, Ph.D., and T.B. Lonsdorf, Ph.D., unpublished data, September 2020) met the inclusion criteria and were available for the meta-analysis (14 published and 2 unpublished records; 18 experiments; sample N = 1006) ( Tables S1 and S2 ).…”