Accelerated Theta Burst in Chronic Pain: A Biomarker Study

Study Overview
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Brief Summary
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This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for chronic pain. In this double blind, randomized control study, participants will be randomized to the treatment group to receive accelerated theta-burst stimulation or to a control group. All participants will be offered the open-label, active treatment 4 week prior to completing the initial 5 days of treatment.

Detailed Description
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Repetitive transcranial magnetic stimulation (rTMS) is an established technology as therapy for treatment-resistant depression and has been utilized to treat persons suffering from chronic pain. The approved method for treatment is 10Hz stimulation for 40 min over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been very successful in real world situations. The limitations of this approach include the duration of the treatment (approximately 40 minutes per treatment session). Recently, researchers have aggressively pursued modifying the treatment parameters to reduce treatment times with some preliminary success. This study intends to further modify the parameters to create a more rapid form of the treatment and look at the change in neuroimaging biomarkers.

Official Title
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Accelerated Theta Burst in Chronic Pain: A Biomarker Study

Conditions
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Chronic Pain

Intervention / Treatment
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* Device: Intermittent Theta Burst Stimulation (iTBS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients need to meet at least a 4/10 on a clinical pain rating scale and/or fulfill fibromyalgia diagnostic criteria on the 2010 Fibromyalgia Diagnostic Criteria (Wolfe et al., 2010) Age 18 - 70 Right-handed Agree to having fMRI scans as well as rTMS sessions Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and treatment Women of childbearing potential must agree to use adequate contraception prior to study entry and continue this for the duration of the study Participants may continue antidepressant regimen, but must be stable for 6 weeks prior to enrollment in the study. Antidepressant must be of the SSRI class only (if currently on a different antidepressant, patients will be switched to an SSRI). They must maintain that same antidepressant regimen throughout the study duration. Exclusion Criteria: History of MI, CABG, CHF, or other cardiac history. Any condition that would contraindicate MRI (such as ferromagnetic metal in the body) Pregnancy or breastfeeding Any neurological condition, history of epilepsy, history of rTMS failure with FDA approved rTMS parameters, history of any implanted device or psychosurgery for depression, history of receiving ECT. OCD, narcolepsy or any additional significant neurological disorder as determined by the PI. Autism spectrum disorder Inability to stop taking medication contraindicated with treatment Any significant psychiatric disorder as identified on the Mini International Neuropsychiatric Interview and determined by the PI A positive urine toxicology screen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Blinded, randomized control
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: iTBS over L-DLPFC to dACC<br>Participants will receive iTBS (intermittent theta burst stimulation) to the left dorsal lateral prefrontal cortex (L-DLPFC) with high connectivity to the dorsal anterior cingulate cortex (dACC). The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of resting motor threshold adjust to the skull to cortical surface distance. Stimulation will be delivered to L-DLPFC using the MagPRo stimulator. | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* Participants will receive active or sham transcranial magnetic stimulation delivered to the L-DLPFC.<br>* Other names: Repetitive Transcranial Magnetic Stimulation (rTMS);|
| Active Comparator: iTBS over L-DLPFC to sgACC<br>Participants will receive iTBS (intermittent theta burst stimulation) to the left dorsal lateral prefrontal cortex (L-DLPFC) with high connectivity to the subgenual cingulate cortex (sgACC). The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of resting motor threshold adjust to the skull to cortical surface distance. Stimulation will be delivered to L-DLPFC using the MagPRo stimulator. | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* Participants will receive active or sham transcranial magnetic stimulation delivered to the L-DLPFC.<br>* Other names: Repetitive Transcranial Magnetic Stimulation (rTMS);|
| Sham Comparator: Sham iTBS over L-DLPFC<br>Participants will receive sham iTBS (intermittent theta burst stimulation) to the left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Sham stimulation will be delivered to L-DLPFC using the MagPRo stimulator. | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* Participants will receive active or sham transcranial magnetic stimulation delivered to the L-DLPFC.<br>* Other names: Repetitive Transcranial Magnetic Stimulation (rTMS);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Brief Pain Inventory (BPI) score | A self-report measure designed to enable investigators to easily obtain sensitive measures of the degree of depression and individual is experiencing. Scoring: Pain Severity Score: This is calculated by adding the scores for questions 2, 3, 4 and 5 and then dividing by 4. This gives a severity score out of 10. Pain Interference Score: This is calculated by adding the scores for questions 8a, b, c, d, e, f and g and then dividing by 7. This gives an interference score out of 10. | Pre-treatment, immediately post-treatment | 
| Change in the McGill Pain Questionnaire score | A self-report questionnaire that allows individuals that assesses the quality and intensity of pain that is experienced. The pain rating index has 2 subscales: sensory subscale with 11 words, and affective subscale with 4 words. These items are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate and 3 = severe. There's also one item for present pain intensity and one item for a 10cm visual analogue scale for average pain. | Pre-treatment, immediately post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Montgomery Asberg Depression Rating Scale (MADRS) score | A ten item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60; 0 to 6 - normal, symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; >34 - severe depression. | Pre-treatment, immediately post-treatment, 2 weeks post-treatment, 4 weeks post-treatment | 
| Change in teh Hamilton Rating Scale for Depression (HAM-17) score | A provider administered questionnaire used to assess remission and recovery from depression. in general the higher the total score the more severe the depression. HAM-D score level of depression: 10-13 mild; 14-17 mild to moderate; >17 moderate to severe. | Pre-treatment, immediately post-treatment, 2 weeks post-treatment, 4 weeks post-treatment | 
| Change in the Pain Catastrophizing Scale (PCS) score | A self-report measure, consisting of 13 items scored from 0 to 4, resulting in a total possible score of 52 that measures a person's catastrophizing of pain. A higher score indicates a higher level of pain catastrophizing. | Pre-treatment, immediately post-treatment, 2 weeks post-treatment, 4 weeks post-treatment | 
| Change in functional connectivity as measured by Functional Magnetic Resonance Imaging (fMRI) | Participants will have fMRI scans both before the first treatment (baseline) and after the aiTBS course. The MRI scans will be used to identify potential biomarkers for antidepressant response and pain response, as well as identify aiTBS-induced changes in functional connectivity. | Pre-treatment, immediately post-treatment, 4 weeks post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Pain, Repetitive Transcranial Magnetic Stimulation (rTMS), Accelerated Theta Burst Stimulation (aTBS), Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)