Personalized Pain Treatment by Transcranial Magnetic Stimulation in Patients With Chronic Pain: a Study on Mechanisms

This project aims to test if the effects of non-pharmacological, non-invasive pain treatment can be enhanced by employing brain connectivity information to guide the application of repetitive transcranial magnetic stimulation (rTMS). Previous efficacy and safety trials have supported that rTMS for pain relief is applied to four main cortical areas: primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and posterosuperior insular (PSI). However, some patients respond to rTMS to one of these targets but not to the others. Since there is no current strategy to know which patient will respond to each treatment target, patients with chronic pain end up undergoing trial and error strategies, which delay their improvement. This is actually not different from challenges related to pharmacological treatment, where each medication only relieves pain in 30-40% of patients, and the choice of each medication is based on "trial-and-error basis".

Several strategies currently aim to provide a more individualized strategy for choosing analgesic interventions based on patient-related information. In order to allow for the design of efficacy trials in the future, the present project is based on a proof-of-concept, mechanistic design. It will employ rTMS stimulation for pain control, but the choice of each of the stimulation targets will be made based on each individual's brain signals as read by EEG recorded before the start of the treatment. Therefore, before receiving a full rTMS treatment, patients will undergo a neurophysiological screening session using single-pulseTMS-EEG. Single-pulseTMS and EEG have been routinely used in the clinic as a part of the neurophysiological assessment of patients for decades but have not yet been used in the association as an attempt to try to guide the choice of treatment. In the screening session, single pulses TMS will be applied to each of the primary network hubs used in therapeutic rTMS: M1, DLPFC, ACC, and PSI. Concomitantly, the EEG oscillatory activity of these four cortical areas will be recorded, and the brain connectivity state will be assessed. By using information derived from a patient´s brain connectivity state using transcranial magnetic stimulation with electroencephalography (TMS-EEG), the most appropriate of the four classic targets will be selected and used in rTMS on an individualized basis. It is hypothesized that the brain regions with low local-to-global connectivity will provide better pain relief compared to non-personalized treatment approaches and compared to targets with optimized local-to-global connectivity status.

A total of 90 subjects with chronic pain will be included in a double-blind, randomized three parallel-arm study comparing the analgesic effect of the therapeutic rTMS target chosen based on TMS-EEG:

1. target area presenting the lowest local-to-global connectivity
2. target area presenting the highest local-to-global connectivity
3. classic M1 stimulation.

The subjects will be allocated in a 1:1:1 ratio to one of three arms (30 subjects per arm). The protocol is designed as an adaptive study, incorporating interim analyses after enrolling 30 and 60 subjects. These evaluations, conducted by a blinded specialist statistician panel, will assess the efficacy of the target selection strategy for each arm, focusing on the primary outcome's progression.