Background: Stress-related disorders are a growing public health concern. While stress is a natural and adaptive process, chronic exposure to stressors can lead to dysregulation and take a cumulative toll on physical and mental well-being. One approach to coping with stress and building resilience is through Mindfulness-Based Stress Reduction (MBSR). By understanding the neural mechanisms of MBSR, we can gain insight into how it reduces stress and what drives individual differences in treatment outcomes. This study aims to establish the clinical effects of MBSR on stress regulation in a population that is susceptible to develop stress-related disorders (i.e., university students with mild to high self-reported stress), to assess the role of large-scale brain networks in stress regulation changes induced by MBSR, and to identify who may benefit most from MBSR. Methods: This study is a longitudinal two-arm randomised, wait-list controlled trial to investigate the effects of MBSR on a preselected, Dutch university student population with elevated stress levels. Clinical symptoms are measured at baseline, post-treatment, and three months after training. Our primary clinical symptom is perceived stress, with additional measures of depressive and anxiety symptoms, alcohol use, stress resilience, positive mental health, and stress reactivity in daily life. We investigate the effects of MBSR on stress regulation in terms of behaviour, self-report measures, physiology, and brain activity. Repetitive negative thinking, cognitive reactivity, emotional allowance, mindfulness skills, and self-compassion will be tested as potential mediating factors for the clinical effects of MBSR. Childhood trauma, personality traits and baseline brain activity patterns will be tested as potential moderators of the clinical outcomes. Discussion: This study aims to provide valuable insights into the effectiveness of MBSR in reducing stress-related symptoms in a susceptible student population and crucially, to investigate its effects on stress regulation, and to identify who may benefit most from the intervention. Trial registration: Registered on September 15, 2022, at clinicaltrials.gov, NCT05541263. https://clinicaltrials.gov/ct2/show/study/NCT05541263 Key words: Mindfulness Based Stress Reduction, MBSR, randomized controlled trial, stress

The authors have declared no competing interest.

NCT05541263

This trial is funded by an internal Donders Centre for Medical Neuroscience junior researcher grant from Radboud University Medical Center. The grant proposal procedure underwent an extensive external peer review process with the final assessment made by an international committee. This funding source is not directly involved in any aspect of design, execution, or analysis of the study, or in the decision to publish potential findings.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The local medical ethics committee, METC Oost-Nederland gave ethical approval for the MindRest study (number: NL74345.091.20).

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Scripts used for stimulus presentation, analysis scripts, and non-sensitive pseudonymised data such as questionnaire data, behavioural data, pre-processed physiology data, and group-level MR data will be openly available in the Open Science Framework at https://osf.io. Pseudonymised MR images will be saved on the Donders Repository at https://data.donders.ru.nl and will be made available upon request to the corresponding author. Raw MR images will not be available due to privacy restrictions. Trial results will be disseminated in relevant peer-reviewed journals and scientific conferences.