Mechanistic Study of Personalized rTMS in Chronic Pain

This study builds directly on previous clinical findings identifying four cortical targets-primary motor cortex (M1), anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and the posterior insula (PSI)-as exhibiting neurophysiological properties potentially useful for guiding individualized repetitive transcranial magnetic stimulation (rTMS) target selection. Earlier results demonstrated that chronic pain patients with low alpha-band intertrial coherence (ITC) over M1 were more likely to respond to stimulation of M1, whereas patients with high alpha-band ITC showed a greater likelihood of responding to stimulation of PSI, ACC or DLPFC. These findings suggest that specific electroencephalography (EEG) connectivity markers may help predict the cortical target most likely to provide therapeutic benefit for an individual patient.

Building on this evidence, the present trial will classify participants according to their pre-treatment transcranial magnetic stimulation-electroencephalography (TMS-EEG) connectivity profiles and assign treatment to the cortical region with the highest predicted probability of clinical response.

A total of 90 patients with chronic pain will be enrolled in a double-blind, randomized, two-parallel-arm clinical trial comparing the analgesic effects of individualized target selection with those of the standard rTMS protocol. Participants will be randomized 1:1 to:

• Individualized targeting, in which the rTMS site is selected based on each participant's TMS-EEG connectivity profile
• Standard stimulation, representing the conventional rTMS approach for pain relief.

At baseline, participants will complete standardized questionnaires and undergo neurophysiological assessments, including single-pulse TMS-EEG for target classification. The induction phase will then begin, consisting of five consecutive daily rTMS sessions delivered Monday through Friday. Each session lasts 30 minutes, including 15 minutes of active stimulation.

The induction phase will be followed by a 7-week maintenance phase, during which participants receive one rTMS session per week (seven sessions in total). At the end of the maintenance phase, all outcome measures will be reassessed to evaluate treatment efficacy.

Inclusion criteria

• Presence of chronic pain (present most of the days for more than 3 months).
• Pain with a mean pain intensity between 3-9 on a 0-10 pain scale (where 0 means no pain and 10 means the worst pain imaginable).
• Speak and understand English or Danish

Exclusion criteria

• Pregnant or breastfeeding
• Current uncontrolled major depression as the main diagnosis
• Current history of substance abuse
• Lack of ability to cooperate, to fully understand the protocol or any difficulty in filling out questionnaires (e.g., due to language or cognitive problems)
• Formal contraindications to TMS application (presence of epilepsy, cranial implanted ferromagnetic devices, e.g., intracranial neurostimulator or cochlear implants, tattoos with metal ink on the face or permanent make up with metal in the face )
• Unable to answer the "Transcranial Magnetic Stimulation Adult Safety Screen" screening questionnaire.
• Participation in other research protocols within 1 month before the inclusion.