Rewiring Chronic Pain

Rewiring Chronic Pain: Cognitive & Somatic Therapy Meets Neuroscience

This study examines the effectiveness of a brief psychological intervention for chronic pain treatment, as well as the psychological and neurophysiological mechanisms associated with changes in pain intensity.

Participants with chronic pain will be randomly assigned to one of three groups: two types of brief psychological interventions and a treatment-as-usual control group. Throughout the study, participants will attend a series of therapeutic sessions, complete questionnaires, undergo brain measurements (EEG and MRI), and participate in physiological monitoring using a smartwatch.

The study aims to investigate which cognitive and physiological changes occur during the intervention, and whether early markers can be identified that may predict improvement in pain following this type of treatment. In addition, differences between cognitive and somatic components of the intervention will be examined to better understand which elements contribute to clinical change, and to determine whether knowledge alone is sufficient or whether participants must undergo a bodily experience in order to produce changes in pain levels.

The goal of the study is to improve understanding of the mechanisms underlying chronic pain and responses to psychological treatments, and to contribute to the development of more personalized, effective treatments with minimal side effects in the future.

Study Overview

• Status: Not yet recruiting
• Conditions: Treatment as Usual; Full PRT; Partial PRT (Non Somtic)
• Intervention / Treatment: Other: TAU; Behavioral: Pain Reprocessing Therapy (PRT)

Detailed Description

Chronic pain is estimated to affect 30% of adults and remains poorly managed by pharmacological approaches, which yield only modest pain reductions (~0.7-0.9 points on a 0-10 scale) and carry risks of sedation, misuse, and dependence. Short-term psychological interventions, particularly Pain Reprocessing Therapy (PRT), have shown large effects in randomized trials, yet the mechanisms driving their efficacy, and the specific contributions of cognitive versus somatic components, remain unclear.

Chronic pain has been consistently associated with structural and functional brain alterations in regions supporting sensory, affective, and interoceptive processing, including the ventromedial prefrontal cortex, anterior cingulate cortex, insula, and nucleus accumbens. Contemporary frameworks (e.g., the dynamic pain connectome) conceptualize chronic pain as a disorder of distributed network dysregulation rather than isolated regional dysfunction, motivating whole-brain functional connectivity, gray matter, and white matter analyses. At the electrophysiological level, slow-wave EEG activity, particularly theta (4-8 Hz) and alpha (8-12 Hz) power, has been linked to low-arousal states induced by hypnosis and mindfulness meditation, both of which produce clinical pain reduction. Animal evidence further links theta activity to neuroplasticity. On this basis, we hypothesize that arousal-state shifts indexed by EEG slow-wave activity and HRV coherence during PRT sessions will predict clinical improvement, and that pre-post MRI will reveal corresponding network and structural changes.

The proposed study is a single-blind, three-arm randomized controlled trial that will compare: (1) Full PRT integrating cognitive (psychoeducation) and somatic components (see full protocol at www.painreprocessingtherapy.com/wp-content/uploads/2024/10/PRT-Group-Protocol.pdf); (2) Partial PRT delivering only the cognitive component; and (3) Treatment as Usual (TAU). Both intervention arms will consist of eight 60-minute individual in-person sessions delivered twice weekly by trained providers, with real-time EEG monitoring during each session accessible to the provider to dynamically inform the therapeutic process. Randomization will be stratified by age and medication use, and participants will also be randomly assigned across providers to prevent provider-related confounding. A pilot phase (3-5 participants per intervention arm) will be conducted with EEG but without MRI to refine procedures.

Home practice will be standardized within each arm via a unified 8-10 minute audio recording: somatic tracking for the Full PRT arm, and an external-attention mindfulness exercise (sounds, smells, and visual imagery, deliberately avoiding bodily focus) for the Partial PRT arm, isolating the somatic component. Adherence will be self-reported. Assessment will occur at baseline, mid-treatment (abbreviated battery), post-treatment, and at follow-up (MRI up to 6 months; questionnaires up to 5 years). Twice-daily pain ratings and pre/post-session relaxation and valence ratings (0-10) will be collected throughout treatment.

Multimodal physiological and neural data will be collected as follows. MRI scans (pre- and post-treatment, ~40 min each) will include high-resolution T1-weighted anatomical imaging, resting-state fMRI, diffusion MRI, and 10 minutes of naturalistic audio-guided fMRI (5 min somatic tracking, 5 min neutral book chapter audio, both with eyes-closed via noise-cancelling headphones). EEG will be recorded during every intervention session using the g.tec Unicorn BCI Core-8 (8 channels, flexible montage). Continuous physiological monitoring via Garmin Vivosmart 5 wearables will capture heart rate variability (beat-to-beat intervals), sleep architecture, and daily activity levels for up to 6 weeks. Blood and saliva samples may also be collected.

Analyses will be conducted in Python. Clinical and physiological outcomes will be modeled using Bayesian mixed-effects general linear models to test whether markers of low-arousal states (EEG alpha/theta activity and HRV coherence) predict pain reduction, accounting for repeated measures and covariates. fMRI data will be preprocessed with fMRIPrep and analyzed using parcellation-based connectivity and Network-Based Statistic; structural MRI with FreeSurfer (gray matter volume); diffusion MRI with DIPY (fractional anisotropy); naturalistic fMRI with voxelwise encoding models; and EEG with MNE-Python. Exploratory multivariate prediction of clinical response will use machine learning classifiers.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Or Duek, Ph.D; Phone Number: +972-507606547; Email: ord@bgu.ac.il

Study Locations

• Israel
  • Beersheba, Israel
    • Ben-Gurion University of the Negev
    • Contact: Lital Cohen-Blum, M.A.; Phone Number: +972-522644388; Email: cohelita@post.bgu.ac.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 20-70 years
• Chronic pain lasting over 3 months, including chronic pain conditions such as fibromyalgia and complex regional pain syndrome (CRPS)
• Average pain intensity ≥4 on a 0-10 scale
• Stable medication regimen for at least 4 weeks prior to treatment initiation
• Hebrew language fluency
• Provision of informed consent, including consent for video recordings

Exclusion Criteria:

• Current participation in other pain-related psychotherapy
• Pregnancy
• Substance abuse, including deviations from prescribed medication use
• Change in medication or dosage in the 4 weeks preceding treatment
• Diagnosed active cancer
• Dementia
• Severe depression (BDI-II score > 29)
• Moderate cognitive impairment based on the Montreal Cognitive Assessment (MoCA)
• Current or past diagnosis of schizophrenia, psychosis, bipolar disorder, multiple personality disorder, or dissociative identity disorder
• Inability to undergo MRI as determined by MRI safety screening (e.g., claustrophobia, metal in body such as vascular clips, pacemakers, or certain cochlear implants)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment as Usual; This arm includes receiving the TAU treatment in chronic pain (oral medications and/or physical therapy).	Other: TAU; Participants in this arm will receive treatment as usual.
Experimental: Pain Reprocessing Therapy (PRT); In this condition, the participants will receive pain reprocessing therapy twice a week for four weeks (a total of 8 sessions). This treatment focuses on psychoeducation, cognitive restructuring and somatic elements.	Behavioral: Pain Reprocessing Therapy (PRT); In this full PRT, the participants will receive pain reprocessing therapy twice a week for four weeks (a total of 8 sessions). This treatment focuses on psychoeducation, cognitive restructuring and somatic elements. In the Partial PRT, participants will receive the same intervention, but without the somatic element.; Other Names: PRT; Partial PRT
Experimental: Partial PRT; In this condition, participants will receive partial PRT, which includes psychoeducation and cognitive restructuring.	Behavioral: Pain Reprocessing Therapy (PRT); In this full PRT, the participants will receive pain reprocessing therapy twice a week for four weeks (a total of 8 sessions). This treatment focuses on psychoeducation, cognitive restructuring and somatic elements. In the Partial PRT, participants will receive the same intervention, but without the somatic element.; Other Names: PRT; Partial PRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average pain intensity in the first week post-treatment	Participants will be prompted twice daily via the Labfront app, connected to their wearable, to respond to the following single item from the Brief Pain Inventory (BPI): "Please rate your pain by circling the one number that tells how much pain you have right now," rated on a 0-10 numeric scale (0 = "No pain"; 10 = "Pain as bad as you can imagine"). Prompts will be delivered during 6 weeks, where the primary outcome will be the mean of all valid responses collected during the first week post-treatment.	Twice a day for 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain severity: pre- to post-treatment score difference	Score of pain severity from Brief Pain Inventory- short form (average of items 3-6)	4 weeks of treatment
Pain interference: pre- to post-treatment score difference	Score of pain interference from Brief Pain Inventory- short form (average of items 9A-9G)	4 weeks of treatment
Pain levels (0-10) at up to 6 months follow-up	Participants will complete the Brief Pain Inventory (BPI) questionnaire, which includes the item: "Please rate your pain by circling the one number that best describes your pain on average (in the last week)," rated on a 0-10 numeric scale (0 = "No pain"; 10 = "Pain as bad as you can imagine"). The response to this item will serve as a secondary outcome measure of average pain intensity over the preceding week, assessed at up to 6-month follow-up.	Up to 6 months post-treatment
Anxiety levels: pre- to post-treatment difference	Score of Generalized Anxiety Disorder questionnaire (GAD-7)	4 weeks of treatment
Depression levels: pre- to post-treatment difference	Score of the questionnaire Beck depression inventory || (BDI-II)	4 weeks of treatment
Sleep quality- wearables	Assessing sleep quality using smartwatches	Monitoring will be done for 6 weeks (up to one week before treatment and one week after the end of treatment).
Sleep quality: pre- to post-treatment questionnaire score difference	Difference in scores of Insomnia Severity Index (ISI)	4 weeks of treatment
Self-rated health: pre- to post-treatment questionnaire score difference	Difference in score of the Short Form Survey (SF-12) questionnaire	4 weeks of treatment
Pain catastrophizing: pre- to post-treatment score difference	Difference in score of Pain Catastrophizing Scale (PCL) questionnaire	4 weeks of treatment
Emotional regulation: pre- to post-treatment score difference	Difference in score of the Emotional Regulation Questionnaire (ERQ)	4 weeks of treatment
Causal attribution: change form pre- to post-treatment	Potential shift from words that are associated with body structure and positions to ones that are associated with mind, emotions and cognition.	4 weeks of treatment
Heart Rate Variability (HRV)- wearables	Assessing HRV using smartwatches	Monitoring will be done for 6 weeks (up to one week before treatment and one week after the end of treatment).
Movement- wearables	Assessing movement, including number of steps per day, using smartwatches	Monitoring will be done for 6 weeks (up to one week before treatment and one week after the end of treatment).

Collaborators and Investigators

• Sponsor: Ben-Gurion University of the Negev

Publications and helpful links

General Publications

• Ashar YK, Gordon A, Schubiner H, Uipi C, Knight K, Anderson Z, Carlisle J, Polisky L, Geuter S, Flood TF, Kragel PA, Dimidjian S, Lumley MA, Wager TD. Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: A Randomized Clinical Trial. JAMA Psychiatry. 2022 Jan 1;79(1):13-23. doi: 10.1001/jamapsychiatry.2021.2669.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: June 28, 2026
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 24, 2026

Study Record Updates

• Last Update Posted (Actual): July 24, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: chronic pain; fMRI; functional connectivity; resting-state fMRI; Pain Reprocessing Therapy (PRT); naturalistic neuroimaging; Network Based Statistic (NBS)
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Chronic Pain
• Other Study ID Numbers: SOR-26-0181

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will de-identify the information and allow access to all data elements (except identifying data)
• IPD Sharing Time Frame: 10 months after the end of the study
• IPD Sharing Access Criteria: IPD can be accessed upon request for specific research question
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No