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Communication Dans Un Congrès Année : 2006

Effects of rTMS signals applied on the rat brain: potential genotoxicity and mechanism of an antidepressant effect

Résumé

Objective. Concerning the antidepressant effect of Repetitive Transcranial Magnetic Stimulation (rTMS) a preliminary study did not demonstrate any genotoxic effect (Charlet de Sauvage et al., BioEM05, June 2005, Dublin) of a rTMS single session. Our objective was to evaluate the toxicity of rTMS signals with the full protocol used in clinical trials. Methods. The protocol is the same as that followed by Pr Auriacombe and Pr Tignol at the Charles Perrens hospital (Bordeaux, France) in their clinical trial, including the starting polarity of the rTMS signal. The clinical paradigms published mention rTMS centered on the dorso-prefrontal cortex, on the left side for high frequency stimulation (> 1 Hz) or on the right side for low frequencies. The most serious side effect is the very exceptional occurrence of epileptic seizure (the 8 cases observed since 1985 occurred at high frequencies, between 5 et 25 Hz). To avoid this effect, the clinical team changed to a low frequency paradigm: a daily session of 3 trains of 60 magnetic stimulations at 1 Hz at 110% of motor threshold, during 4 weeks. Consequently, compared with the in vivo experiment reported on rats in Dublin, the number of exposure sessions in the present experiment was increased from one day to 4 weeks (5 days per week). The frequency of the rTMS signal was lowered from 10/s to 1/s and the target was the right prefrontal cortex instead of the left one. Magnetic pulses induced by one-sine currents (duration 340 μs), and with an amplitude reaching 110% of the hind-limb motor threshold were used. Each exposure session consisted in a sequence of 3 trains of 60 magnetic pulses at 1 Hz separated by a resting period of 10 seconds, so that the total duration of a session was 3 min 20 s. A total of 180 pulses per day were delivered to the animals as compared with 2000 for the preliminary experiment. Rats were exposed to the rTMS signal produced by a coil placed on top of the skull but not touching the head, with the coil parallel to the skull and the coil axis passing through the bregma point, as defined in the atlas of Paxinos and Watson (1986). Mapping of the induced electric field, hence of the induced current density, was established for the flat 6.3 cm diameter coil used in this experiment. Eddy currents induced in the rat brain were calculated using a rat head simulation derived from the Brooks model constructed from MRI images in the rat and tissue conductivities estimated from low-frequency literature data. A software designed in the MatLab environment, based on the resolution of node and mesh equations, was used and validated. Peak current densities were estimated at around 5.1 A/m2 in the whole brain (range 0.19 to 14.6 A/m2) and 4.7 A/m2 at the prefrontal cortex. Genotoxicity was evaluated on rat brain cells using the alkaline Comet assay. A total of eight animals per group (sham-exposed and exposed rats) was used. Conclusion and perspectives. The results of the effects of a 4 week daily sequence of rTMS signals on the induction of DNA damages (genotoxicity) will be presented. As part of this project and in order to study the molecular mechanisms of the antidepressant effect of rTMS we plan to investigate the role of serotonin (5-HT), a neurotransmitter the implication of which was suggested by Kanno et al. (J. Pharmacol. Sci., 93 :451-457, 2003). rTMS may suppress depressive symptoms by decreasing the affinity of type 5HT1 receptors for serotonin (Massot et al, Brain Res, 858 : 143-150, 2000). The localisation of the serotonin receptors in the brain will be obtained using an immuno-histochemical technique (autoradiography). The affinity of the receptors will be determined by the binding method in brain slices of rats exposed to rTMS. The period of maximum effect following rTMS exposure can be chosen to localise serotonin in the brain with maximum chances of detection. Also this will be determinant for clinical applications
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Dates et versions

hal-00161910 , version 1 (11-07-2007)

Identifiants

  • HAL Id : hal-00161910 , version 1

Citer

R. Charlet de Sauvage, I. Lagroye, B. Billaudel, Christophe Daudet, M. Auriacombe, et al.. Effects of rTMS signals applied on the rat brain: potential genotoxicity and mechanism of an antidepressant effect. 28th Annual Meeting of the BEMS, Jun 2006, Cancun, Mexico. ⟨hal-00161910⟩
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