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Efficacy of maintenance repetitive transcranial magnetic stimulation (rTMS) treatment in reducing auditory verbal hallucinations (AVH) with high frequency and neuronavigation guidance. A double-blind, randomized and multicentric study

Repetitive transcranial magnetic stimulation (rTMS) can alleviate persistent auditory verbal hallucinations (AVH) in schizophrenic patients, but the classical procedure with low-frequency stimulation for several weeks upon the left temporoparietal junction have shown modest therapeutic effects, and there is currently no robust predictive factor to the response of the treatment. In a previous multicentric, randomized, and double-blind controlled study, we demonstrated that a high-frequency (20 Hz) rTMS over an anatomical target can rapidly affect AVHs. We used an intensification of the classical procedure delivering 20-Hz rTMS over a 2-day period, in addition to a personalized anatomical stimulation target and neuronavigation guidance as shown in the following figure.

Localization of the treatment target (yellow circle) defined on MRI at the crossing between the projection of the ascending branch of the left lateral sulcus (LS; in red) and the left STS (in green)

Besides the significant efficacy of the procedure, we observed that the efficacy was maximal at two weeks after the end of the treatment (Dollfus et al., Schizophr Bull., 2018).

Percentage of Responders at Day 2, 7, 14, 21 and 28. Placebo group in black. Active group in red

In the present project, we hypothesize that the two-day cure could benefit from maintenance rTMS sessions every week for one month and then every two weeks for 3 months to provide an optimal strategy for a long-lasting AVH reduction. To investigate the clinical efficacy of a 4-month maintenance procedure of rTMS in AVH reduction, we propose a multicenter, controlled, double-blind study enrolling 120 patients randomly assigned in two groups. The active group will receive active rTMS with a two-day intense procedure (consisting in 4 20-Hz rTMS sessions within two days) and a maintenance phase with a two-rTMS session every week for one month and then every two weeks the next 3 months. The individual target will be personalized and guided by neuronavigation as described above. The placebo group will benefit from the exact same procedure but with sham rTMS instead of active rTMS. Patients will be carried out during 5 months and we will study what distinguishes responders from non-responders. We will also investigate variables that can predict an efficacy. First, we will focus on the BDNF serum levels as a reflect of the individual neural plasticity. Second, we will measure the scalp-to-cortex distance (SCD) to the target since we previously demonstrated a significant relationship between the reduction of AVH after 20 rTMS and the SCD as shown in the following figure (Nathou et al., Brain Stimul., 2015)

MainstimStudy is financed by the Health French Ministry (PHRC-N)