Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation and Expressive Writing for Post-Traumatic Stress

Objective: To evaluate the efficacy and safety of a combined intervention consisting of repetitive transcranial magnetic stimulation (rTMS) and emotional re-experiencing through expressive writing, as well as to analyze the influence of the timing of rTMS application on clinical outcomes in adults with post-traumatic stress symptomatology.

Design: A randomized controlled superiority trial with three parallel groups: (1) rTMS administered 10 minutes prior to emotional re-experiencing via expressive writing, (2) rTMS administered 10 minutes after emotional re-experiencing, and (3) sham stimulation with an equivalent temporal structure. Assessments will be conducted at baseline, post-intervention, and at one-month follow-up.

Study setting: University Institute of Neurosciences (IUNE), University of La Laguna (ULL), located in San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain.

Participants: Community-dwelling adults aged 18 to 65 years, exposed to at least one traumatic or highly stressful event, presenting post-traumatic stress symptomatology defined by a score ≥ 24 on the Revised Impact of Event Scale (IES-R). A total sample size of 45 participants is anticipated, distributed across three groups of 15 participants each.

Measures: Post-traumatic stress symptomatology will be assessed using the IES-R; anxiety symptoms using the GAD-7; and depressive symptoms using the PHQ-9. Affect will be assessed with the PANAS. Physiological arousal will be recorded via heart rate and skin conductance using a polygraph. rTMS will be delivered using a Magstim Rapid2 stimulator with a figure-of-eight coil, guided by BrainSight neuronavigation. Emotional re-experiencing will be induced through expressive writing.

Outcomes: The primary outcome will be the change in post-traumatic stress symptomatology. Secondary outcomes will include safety, measured by the frequency and type of adverse events and serious adverse events; changes in anxiety and depressive symptomatology; and situational changes in affect and physiological arousal during expressive writing sessions.

Data analysis: Baseline characteristics of each group will be presented in a descriptive table. Continuous variables will be summarized using means and standard deviations, whereas categorical variables will be reported as absolute and relative frequencies. Between-group differences at baseline will be explored using analysis of variance (ANOVA) for continuous variables and chi-square tests of independence for categorical variables. Assumptions of normality and homogeneity of variances will be assessed beforehand. When these assumptions are violated, non-parametric alternatives will be used, including the Kruskal-Wallis test for continuous variables and Fisher's exact test for categorical variables.

Intervention effects will be analyzed using linear mixed-effects models and, as a complementary approach, repeated-measures ANOVA. Main effects of group (sequential 1, sequential 2, and sham) and time (baseline, post-intervention, and one-month follow-up), as well as the group × time interaction, will be examined for the primary outcome (post-traumatic stress symptomatology) and secondary outcomes (anxiety symptoms, depressive symptoms, and situational changes).

Analyses will be conducted under both an intention-to-treat (ITT) and per-protocol (PP) framework. The ITT population will include all randomized participants who have received at least one rTMS session, consistent with previous research (Philip et al., 2019). The PP population will include participants who completed the assigned treatment without substantial protocol deviations.

For ITT analyses, missing data will be handled using linear mixed-effects models estimated via maximum likelihood, allowing the use of all available data under the assumption that missingness is at random (MAR). If evidence suggests that missing data may depend on unobserved variables (not missing at random, NMAR), sensitivity analyses will be conducted using pattern-mixture models or selection models to assess the robustness of the findings.

Subgroup analyses are not planned. Results will be reported in tables with descriptive statistics by group and time point. Effect sizes (Cohen's d and partial eta squared) will be reported along with 95% confidence intervals. The statistical significance threshold will be set at α = .05, with Bonferroni correction applied when appropriate for multiple comparisons. All analyses will be performed using R statistical software (R Core Team, 2025).