aiTBS and rTMS in Neuropathic Pain and Prediction of Response

This study evaluates the analgesic benefit of two non-invasive brain stimulation techniques: high frequency repetitive transcranial magnetic stimulation (rTMS) and accelerated intermittent theta burst stimulation (aiTBS) - compared to sham stimulation, in patients with chronic neuropathic pain lasting at least 6 months. Transcranial magnetic stimulation, which is delivered by a coil positioned on the scalp over the motor cortex, generates a low-intensity, submotor-threshold electromagnetic field that noninvasively activates targeted brain regions involved in pain perception. The procedure is painless and non-invasive. Sham stimulation uses the inactive face of the same coil and produces an identical sound, ensuring that neither patients nor investigators know which stimulation is being delivered. Conventional rTMS has demonstrated moderate analgesic efficacy in neuropathic pain, but its effect is delayed and requires at least 5 treatment sessions. iTBS delivers the same total stimulation dose in a much shorter time (approximately 8 minutes per session versus 30 minutes for conventional rTMS) and enables accelerated protocols with multiple sessions per day, which have shown promising results in depression. This study compares aiTBS, rTMS and sham by a randomized controlled trial (RCT) with a crossover design: participants are randomized in a 2:1 ratio to receive either active stimulation (both techniques in sequence) or sham stimulation (both techniques in sequence). Each treatment phase consists of either 5 consecutive daily rTMS sessions or 5 aiTBS sessions delivered on a single day (with a 45-min pause between sessions). The cross-over will take place after a 4 to 6-week washout period between the two active or sham treatments. The total study duration per participant is from 10 to 12 weeks, with 11-12 in-person visits. Assessments include self-reported pain diaries numeric pain rating scale (NPRS), validated pain, psychosocial, and quality-of-life questionnaires, resting-state Electroencephalography (EEG) recordings, and transcranial magnetic stimulation (TMS) based measures of intracortical excitability and inhibition. The exploratory aim is to identify neurophysiological and clinical predictors of treatment response, to better personalize the treatment in chronic pain population.

Inclusion Criteria: 1. Age over 18 years and less than 80 years 2. Average pain intensity ≥ 4/10 on the numerical scale of the Brief Pain Inventory at screening and randomization 3. Pain present for at least 4 days per week 4. Persistent pain for at least 6 months 5. Stable pharmacological treatment for pain for at least 1 month prior to the study. 6. Peripheral or central neuropathic pain (postherpetic neuralgia, painful neuropathies, nerve lesions, radiculopathy, trigeminal neuralgia, stabilized multiple sclerosis, spinal cord lesion or stroke) fulfilling criteria for probable or definite neuropathic pain; and scoring ≥ 4 out of 10 on the DN4 questionnaire 7. Informed consent 8. Patients who can be followed for the whole duration of the study 9. Patients affiliated to social security in France Exclusion Criteria: 1. Ongoing litigation 2. Contraindication to rTMS : * implanted electronic devices and/or conductive objects near the coil: patients with an active implanted device activated or controlled by physiological signals (e.g. pacemakers, implanted cardioverter defibrillators \[ICD\], vagus nerve stimulators \[VNS\] and portable cardioverter defibrillators \[WCD\], ocular implants, deep 16 brain stimulation, drug chambers/pumps, intracardiac leads) even if the device has been removed. * Non-removable metal objects near the coil: Patients with a conductive implant, ferromagnetic or made of any other metal sensitive to magnetic fields, in the head or at a distance of less than 30 cm from the coil (e.g. cochlear implant, implanted electrodes/pacemakers, aneurysm clips or coils, stents and bullet fragments). 3. Current drug or psychoactive substance abuse (DSM V) 4. Pregnancy or lactation 5. Epilepsia or past epilepsia 6. Progressive unsable pathology (eg cancer) 7. Current psychosis according to DSM V criteria 8. Presence of other pain more severe than that justifying inclusion 9. Lack of correct completion of pain self-assessment diaries between inclusion and randomisation (at least 4 weekly pain scores over 7 days), 10. Subject unable to understand informed consent, under guardianship or curatorship 11. Patients participating in another research protocol within 30 days prior to inclusion. 12. Patient who has already received a treatment with rTMS