Measuring human trace fear conditioning

Jelena, Wehrli,; Xia, Yanfang; Gerster, Samuel; Bach, Dominik R.

doi:10.1111/psyp.14119

Cited by 5 publications

(14 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Secondly, results from parallel methodological work and the current placebo group indicated that our pre-registered and exploratory analyses were unexpectedly underpowered. Effect size to measure trace fear memory retention was smaller in the present placebo group (Cohen's d = 0.31) than in two preceding experiments not involving drugs (Cohen's d = 0.44) (Wehrli et al, 2022).…”

Section: Discussioncontrasting

confidence: 83%

“…These results indicate successful learning and memory retention in our paradigm (see figure 3a, 4a, 3-1 and 4-1). As in our previous work (Wehrli et al, 2022), there was no evidence for a CS+/CS-difference in PSR in the recall test (see figure 4-1).…”

Section: Placebo Group Analysissupporting

confidence: 77%

“…Memory retention was tested one week later, after drug wash-out. Our primary memory measure during the recall test was based on fear-potentiated startle eye-blink response (SEBR), which our previous work had identified as the most sensitive index of fear memory retention in general ( Khemka et al, 2017 ) and in the presently used paradigm in particular ( Wehrli et al, 2022 ). As secondary outcome, we recorded skin conductance responses (SCRs) during the trace interval.…”

Section: Methodsmentioning

confidence: 99%

“…The study was preregistered with a WHO-approved primary registry (German Clinical Trials Register, DRKS00017037) and at the Swiss Federal Complementary Database (Kofam: SNCTP000003485). During recruitment, the analysis protocol was adapted based on ongoing methodological work ( Wehrli et al, 2022 ). The final analysis protocol was preregistered on OSF ( https://osf.io/uqtr5/ ) on December 20, 2020 before unblinding the study medication.…”

Section: Methodsmentioning

confidence: 99%

“…SCR analysis was adapted from the procedure benchmarked in Staib et al (2015): Data were filtered with a 1 st order uni-directional band-pass Butterworth filter (0.0159-5 Hz) and then downsampled to 10 Hz. This modification of filter settings had been validated in our previous methodological work 1 5 (Wehrli et al, 2022). For conditioned response scoring, the standard non-linear model implemented in PsPM was used.…”

Section: Skin Conductance Responsesmentioning

confidence: 99%

See 4 more Smart Citations

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory

Jelena

Xia

Offenhammer

et al. 2023

eNeuro

Self Cite

View full text Add to dashboard Cite

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as post-traumatic stress disorder. Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP) 9 signalling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signalling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomised controlled trial with 101 (50 females) human participants. We find no impact of the drug in our pre-registered analyses. Exploratory post-hoc analyses of memory retention suggested a serum level-dependent effect of doxycycline on trace fear memory retention. However, effect size to distinguish CS+/CS- in the placebo group turned out to be smaller than in previously used delay fear conditioning protocols, which limits the power of statistical tests. Our results suggest that doxycycline effect on trace fear conditioning in healthy individuals is smaller and less robust than anticipated, potentially limiting its clinical application potential.Significance statementThe inhibition of matrix metalloproteinase-9 attenuates memory consolidation and subsequent recall in a delay cue conditioning paradigm. However, it is currently unclear whether this is also the case for other learning scenarios that rely on a different neurocircuitry. We test this hypothesis in human trace fear conditioning which employs remote cues and is additionally dependent on hippocampus involvement. We find that doxycycline does not reduce fear retention in our pre-registered analyses. Exploratory analyse might potentially suggest a weak effect of doxycycline on trace fear memory retention.

show abstract

Section: Discussioncontrasting

confidence: 83%

Section: Placebo Group Analysissupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Skin Conductance Responsesmentioning

confidence: 99%

See 3 more Smart Citations

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory

Jelena

Xia

Offenhammer

et al. 2023

eNeuro

Self Cite

View full text Add to dashboard Cite

show abstract

The impact of doxycycline on human contextual fear memory

Wehrli,

Xia,

Abivardi

et al. 2024

Psychopharmacology

Self Cite

View full text Add to dashboard Cite

Rationale Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown. Methods Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants. Results Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group. Conclusion Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.

show abstract

Measuring human context fear conditioning and retention after consolidation

et al. 2023

Self Cite

View full text Add to dashboard Cite

Fear conditioning is a laboratory paradigm commonly used to investigate aversive learning and memory. In context fear conditioning, a configuration of elemental cues (conditioned stimulus [CTX]) predicts an aversive event (unconditioned stimulus [US]). To quantify context fear acquisition in humans, previous work has used startle eyeblink responses (SEBRs), skin conductance responses (SCRs), and verbal reports, but different quantification methods have rarely been compared. Moreover, preclinical intervention studies mandate recall tests several days after acquisition, and it is unclear how to induce and measure context fear memory retention over such a time interval. First, we used a semi-immersive virtual reality paradigm. In two experiments (N= 23 andN= 28), we found successful declarative learning and memory retention over 7 d but no evidence of other conditioned responses. Next, we used a configural fear conditioning paradigm with five static room images as CTXs in two experiments (N= 29 andN= 24). Besides successful declarative learning and memory retention after 7 d, SCR and pupil dilation in response to CTX onset differentiated CTX+/CTX−during acquisition training, and SEBR and pupil dilation differentiated CTX+/CTX−during the recall test, with medium to large effect sizes for the most sensitive indices (SEBR: Hedge'sg= 0.56 andg= 0.69; pupil dilation: Hedge'sg= 0.99 andg= 0.88). Our results demonstrate that with a configural learning paradigm, context fear memory retention can be demonstrated over 7 d, and we provide robust and replicable measurement methods to this end.

show abstract

Measuring human trace fear conditioning

Cited by 5 publications

References 52 publications

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory

The impact of doxycycline on human contextual fear memory

Measuring human context fear conditioning and retention after consolidation

Contact Info

Product

Resources

About