Over the Edge: Extending the duration of a reconsolidation intervention for spider fear

The study investigates whether the duration of a memory reactivation procedure determines whether reconsolidation, limbo, or extinction processes are engaged in a naturalistic fear (spider fear). Prior work shows that disrupting reconsolidation after a brief tarantula exposure plus propranolol can produce abrupt, durable fear reduction, but the reconsolidation window is narrow and may be missed. In laboratory fear-conditioning, prediction error is necessary for reconsolidation; too much prediction error can induce extinction, while intermediate levels can create a limbo state insensitive to amnesic agents. The learning history (age/strength of memory) and the reactivation conditions jointly determine outcomes. Translating these principles to clinical fears is challenging because prediction error is hard to quantify and learning histories are unknown. This study focuses on reactivation duration as a practical proxy for the amount of prediction error, aiming to identify a behaviorally controlled boundary condition in spider-fearful individuals by comparing brief (~3 min) versus extended (~14 min) reactivation procedures prior to propranolol administration.

Evidence from Pavlovian fear conditioning shows that after reactivation, memories may undergo reconsolidation (requiring protein synthesis), become insensitive in a limbo state, or undergo extinction, with prediction error modulating which process occurs. Reconsolidation is triggered by limited prediction error; extensive prediction error yields extinction; intermediate amounts produce limbo. Neurobiological markers in animals (e.g., calcineurin in basolateral amygdala) distinguish these states, but such markers are not accessible in humans. Laboratory manipulations of prediction error include increasing the number of unreinforced CS presentations or extending unreinforced exposure duration. Boundary conditions depend on learning history: stronger/older memories may require different reactivation parameters and may even widen the reconsolidation window. Translational studies targeting naturalistic fears have shown mixed results, with variability in reactivation procedures and inconsistent replication of drug effects on reconsolidation. A prior arachnophobia study using ~2–3 min tarantula exposure plus 40 mg propranolol produced near-binary improvements in approach and reduced self-reported distress, with sustained benefits. However, without a direct marker during reactivation, clinical translation relies on retrospective outcomes. This motivated testing reactivation duration as a proxy for prediction error to delineate boundary conditions.

Design: Pre-registered, stratified-randomized, parallel-group study comparing brief (~2–5 min; target ~3 min) versus extended (~13–15 min; target ~14 min) tarantula reactivation procedures followed by 40 mg oral propranolol. Primary outcome was tarantula Behavioral Approach Task (BAT) step at post-assessment (t2). Bayesian analyses were pre-registered, with insulated sequential stopping rules. Participants: Spider-fearful adults recruited via university channels. Strict inclusion criteria (e.g., SPQ >17; at least one early high SUDS ≥65 during reactivation; not more afraid of house spiders than tarantulas; fear > disgust). Medical exclusions applied (e.g., low BP/HR). Sequential analysis stopping rules: (1) Bayesian Mann–Whitney U test BF≥10 for/against hypothesis of higher tarantula BAT in brief vs extended; (2) <50% in brief touched tarantula at t2; (3) N=50 max. Data collection stopped at criterion (2) with n=43 analyzed: brief n=23 (20 female; mean age 22.04±3.74), extended n=20 (17 female; mean age 21.60±4.60). Procedure and timeline: t0 (Day 1): medical screen; questionnaires (SPQ, FSQ, PHQ-9, STAI-T, ASI); house-spider BAT (no tarantula BAT at baseline to preserve novelty at treatment). t1 (Day 5–7): STAI-S, medical checks; pre-treatment spider fear interview; imagined treatment SUDs; spider self-efficacy; reactivation procedure (brief or extended) in front of the same tarantula used for later BAT; oral propranolol 40 mg within 3 min of reactivation; 90-min rest to reach peak levels; post-pill vitals and STAI-S. t2 (Day 7–9): imagined treatment SUDs, spider self-efficacy; tarantula BAT; SPQ/FSQ; house-spider BAT. t3 (Day 8–10): SPQ/FSQ online. t4 (~Day 90): SPQ/FSQ online. t5 (~1 year): SPQ/FSQ online. Reactivation procedures: Conducted in same room/with same adult Grammostola porteri (~15 cm leg span). Participants stood with hands on a glass box directly in front of the open terrarium to heighten expectancy that the spider might approach. The brief protocol lasted ~3 min, with a warning and a single spray to provoke movement; the extended protocol lasted ~14 min and included multiple spray warnings and sprays at set intervals (increasing the number of potential prediction error events). SUDS ratings and prompts about feelings and bodily sensations were interleaved at fixed time points. Interventions and measures: Propranolol HCl 40 mg (Accord Healthcare; provided by Huygens Apothecary). BATs: Tarantula BAT steps 1–8 (from standing 50 cm from closed terrarium to placing a hand inside and closing eyes while the tarantula is sprayed). House-spider BAT steps 1–9 (from sitting near closed jar to spider walking on bare hand). SUDS at each completed step. Questionnaires: SPQ (0–31), FSQ (0–186), plus PHQ-9, STAI, ASI. Single items: imagined BAT SUDS; imagined treatment SUDS; spider self-efficacy (0–100); treatment credibility. Blinding and randomization: Randomization stratified by t0 scores, performed by independent researchers. Assessors at t0 and t2 were blind to condition; the t1 experimenter was unblinded only upon entering the reactivation room. An independent researcher conducted insulated sequential analyses, keeping the team blind to interim results. Statistical analysis: Bayesian framework. Primary confirmatory test: one-sided Bayesian Mann–Whitney U for tarantula BAT step (brief>extended). Additional confirmatory tests included distress (SUDS) at final tarantula BAT step, house-spider BAT ordinal regression (brms), and repeated-measures ANOVAs for SUDS and questionnaires. Default priors in JASP unless specified; details and code in OSF.

- Manipulation checks: Propranolol was physiologically active. Heart rate and blood pressure decreased from pre- to 90 min post-pill in both groups (BF_inclusion_Time ≥ 474.26), with no Group×Time interaction (BF_inclusion_Group*Time ≤ 2.23). Effect sizes across t1: η²_Systolic ≈ 0.431, η²_Diastolic ≈ 0.346, η²_HeartRate ≈ 0.797. - Primary outcome (t2 tarantula BAT step): No evidence that brief > extended. One-sided Bayesian Mann–Whitney U: BF01 = 4.80 (evidence for no group difference). Final SUDS at tarantula BAT also showed some evidence against the predicted lower distress in brief group (BF = 2.91). - House-spider BAT: Strong evidence of improved approach from t0 to t2 (0% approached less; strong BF for Time effect), with no Group or Group×Time effects (BF10 ≤ 2.40 and ≤ 1.71, respectively). SUDS at final completed step dropped markedly from t0 to t2 (BF_inclusion_Time = 7.73e7). - Questionnaires: SPQ and FSQ decreased robustly over time with no evidence that changes depended on reactivation duration (SPQ BF_inclusion_Time = ∞; BF_Exclusion_Condition*Time = 9.51. FSQ BF_inclusion_Time = 3.00e15; BF_Exclusion_Condition*Time = 16.28). From t0 to t2, abrupt decreases: SPQ BF = 4.39e7; FSQ BF = 3.43e7. Long-term: SPQ further decreased from t2 to t5 (BF = 3.11); FSQ remained broadly stable from t2 to t5 (BF = 2.25). At final follow-up, 7% had a minimal increase (e.g., SPQ +1), with mean SPQ scores below the inclusion threshold from t2 through t5. - Overall: Both groups showed substantial and enduring reductions in behavioural avoidance and self-reported fear, maintained at 1-year follow-up, with no differential effect of reactivation duration.

The study aimed to behaviorally demarcate boundary conditions for reconsolidation in a naturalistic fear by manipulating reactivation duration. Contrary to predictions, extending reactivation from ~3 to ~14 minutes did not diminish treatment efficacy; both durations followed by propranolol were associated with marked and sustained reductions in spider fear, including improved approach to a generalization stimulus and sharp declines in questionnaire scores by two days post-treatment. Several interpretations are considered: (A) Neither reactivation duration triggered reconsolidation, and alternative mechanisms (e.g., expectancy/appraisal effects, increased engagement due to certainty of taking an active drug, enhanced self-efficacy) produced improvements; (B) Reconsolidation occurred in one group (likely brief), while other processes in the extended group yielded equivalent outcomes; (C) Reconsolidation occurred in both groups, potentially because the number or salience of prediction error events did not differ meaningfully between protocols or because stronger, older memories have a wider reconsolidation window than laboratory-conditioned fears suggest. The alignment of immediate behavioral and self-report changes (unlike some lab findings where cognitive changes lag) and the lack of placebo control complicate mechanism attribution. Standardized reactivation may not have been optimal for all individuals, and slight baseline differences (e.g., clinical status proportions) could have obscured subtle effects. Nonetheless, the findings suggest that brief, single-session reactivation combined with pharmacologic intervention can achieve robust, durable improvements in naturalistic fears.

Extending the reactivation procedure from ~3 to ~14 minutes did not differentially affect outcomes of a propranolol-based reconsolidation intervention for spider fear; both durations yielded rapid and lasting reductions in fear behavior and self-reported fear up to one year. This suggests either that reconsolidation’s boundary conditions in naturalistic fears are wider than in laboratory paradigms or that alternative mechanisms (e.g., placebo/appraisal, self-efficacy changes) can produce substantial benefits when combined with a single reactivation and active drug. Future work should include placebo-controlled designs and test other behaviorally controlled parameters to manipulate prediction error (e.g., repeated discrete approach episodes such as repeatedly placing hands on the box, or leaving and re-entering the room) to clarify mechanisms and refine boundary conditions for effective clinical translation.

- No placebo control group, limiting causal attribution to reconsolidation versus alternative mechanisms. - Lack of non-invasive, independent markers of reconsolidation or prediction error in humans necessitated retrospective inference. - The extended protocol differed not only in duration but also in number of spray provocations, potentially conflating prediction error quantity with other procedural factors. - Standardized reactivation may not have matched individual learning histories; stringent inclusion criteria may limit generalizability and may have excluded individuals who could benefit from tailored clinical procedures. - Slight imbalance in clinical status at baseline between groups could obscure small effects. - No baseline tarantula BAT to preserve novelty limits direct pre-post comparison on the primary behavioral outcome.