Pharmacological manipulation of memory reconsolidation opens up promising new avenues for anxiety disorder treatment. However, few studies have directly investigated reconsolidation-based approaches in subclinical or clinical populations, leaving optimal means of fear memory reactivation unknown. We conducted a systematic pilot study to assess whether a reconsolidation-based treatment could tackle public speaking anxiety in a subclinical sample (N = 60). As lab studies indicate that the duration of reactivation may be important for inducing reconsolidation, we investigated several speech lengths to help inform further translational efforts. Participants underwent a stressinducing speech task composed of 3-min preparation, and from 0 to 9 min of public speaking, in 1-min increments. They then received either 40 mg of propranolol (n = 40) or placebo (n = 20), double-blind, allocated 4:2 for each speech duration. Participants performed a second speech 1 week post treatment, and were followed up with questionnaires 1-and 3 months later. Both self-reported speech distress and questionnaire measures of public speaking anxiety showed clear reductions following treatment. However, propranolol did not reliably outperform placebo, regardless of speech duration at treatment. Physiological responses (heart rate and salivary cortisol) to the public speaking task remained stable from treatment to test. These findings highlight the challenges facing the translation of laboratory research on memory reconsolidation into clinical interventions. Lack of explicit controls for factors beyond duration, such as 'prediction error', could explain these null findings, but positive results in clinical interventions are needed to demonstrate that taking such factors into account can deliver the promises of reconsolidation-based therapy.

Pharmacological manipulation of memory reconsolidation opens up promising new avenues for anxiety disorder treatment. However, few studies have directly investigated reconsolidation-based approaches in subclinical or clinical populations, leaving optimal means of fear memory reactivation unknown. We conducted a systematic pilot study to assess whether a reconsolidation-based treatment could tackle public speaking anxiety in a subclinical sample (N = 60). As lab studies indicate that duration of reactivation may be important for inducing reconsolidation, we investigated several speech lengths to help inform further translational efforts. Participants underwent a stress-inducing speech task composed of three minutes preparation, and from 0-9 minutes of public speaking, in one minute increments. They then received either 40mg propranolol (n = 40) or placebo (n = 20), double-blind, allocated 4:2 for each speech duration. Participants performed a second speech one week post-treatment, and were followed up with questionnaires one- and three months later. Both self-reported speech distress and questionnaire measures of public speaking anxiety showed clear reductions following treatment. However, propranolol did not reliably outperform placebo, regardless of speech duration at treatment. Physiological responses (heart rate and salivary cortisol) to the public speaking task remained stable from treatment to test. These findings highlight the challenges facing the translation of laboratory research on memory reconsolidation into clinical interventions. Lack of explicit controls for factors beyond duration, such as ‘prediction error’, could explain these null findings, but positive results in clinical interventions are needed to demonstrate that taking such factors into account can deliver the promises of reconsolidation-based therapy. This is a pre-print of an article published in the open access journal Translational Psychiatry https://doi.org/10.1038/s41398-020-0857-z

Sequential testing enables researchers to monitor and analyze data as it arrives, and decide whether or not to continue data collection depending on the results. Although there are approaches that can mitigate many statistical issues with sequential testing, we suggest that current discussions of the topic are limited by focusing almost entirely on the mathematical underpinnings of analytic approaches. An important but largely neglected assumption of sequential testing is that the data generating process under investigation remains constant across the experimental cycle. Without care, psychological factors may result in violations of this assumption when sequential testing is used: researchers’ behavior may be changed by the observation of incoming data, in turn influencing the process under investigation. We argue for the consideration of an ‘insulated’ sequential testing approach, in which research personnel remain blind to the results of interim analyses. We discuss different ways of achieving this, from automation to collaborative inter-lab approaches. As a practical supplement to the issues we raise, we introduce an evolving resource aimed at helping researchers navigate both the statistical and psychological pitfalls of sequential testing: the Sequential Testing Hub (www.sequentialtesting.com). The site includes a guide for involving an independent analyst in a sequential testing pipeline, an annotated bibliography of relevant articles covering statistical aspects of sequential testing, links to tools and tutorials centered around how to actually implement a sequential analysis in practice, and space for suggestions to help develop this resource further. We aim to show that although unfettered use of sequential testing may raise problems, carefully designed procedures can limit the pitfalls arising from its use, allowing researchers to capitalize on the benefits it provides.

Pharmacologically disrupting fear memory reconsolidation dramatically reduces fear behaviour. For example, 2–3 min of tarantula exposure followed by 40 mg of propranolol HCl (i.e., a reconsolidation intervention) abruptly decreased spider avoidance, an effect that persisted one year later. However, the success of reconsolidation interventions is not guaranteed: Pavlovian fear-conditioning research shows that the window to target memory reconsolidation is small and easy to miss. If exposure is too long to trigger reconsolidation, but too short for extinction learning, an inactive transitional limbo state occurs, rendering the fear memory unchanged and insensitive to amnesic agents. In this pre-registered study, we aimed to find this behaviourally-controlled boundary condition. Spider-fearful participants underwent a ~3 min (n = 23) or ~14 min (n = 20) exposure to a tarantula, intended to trigger reconsolidation or the limbo state respectively, followed by 40 mg of propranolol. We expected greater spider fear reduction after 3 than 14 min of exposure. Unexpectedly, there were no group differences on any outcome measures. In both groups, Bayesian analysis revealed a marked reduction in fear behaviour towards a generalisation stimulus (a house spider) accompanied by lower self-reported distress, with a sharp decline in spider fear scores two days after treatment that persisted one year later. Possible explanations include that the boundary conditions of reconsolidation are wider in older and stronger memories than experimentally-induced fears, or that alternative processes caused the treatment effects. Although the mechanism is unclear, these results carry a tentative promising message for the potential of brief reconsolidation-targeting interventions to mitigate irrational fears.