Stimulation-specific effects of low intensity repetitive magnetic stimulation on cortical neurons and neural circuit repair in vitro

[Truncated abstract] Electromagnetic fields are widely used to non-invasively stimulate the human brain in clinical treatment and research. Repetitive transcranial magnetic stimulation (rTMS) in humans is applied with maximal high-intensity fields of ~1-2.5 Tesla (T), however the coils used induce currents both at the site of maximum stimulation and in surrounding brain regions, albeit at lower intensities. Importantly, low intensity repetitive transcranial magnetic stimulation in humans (mT range) modifies cortical function, brain oscillations and is beneficial for the treatment of depression. While the effects of magnetic stimulation have been suggested to vary according to frequency and intensity, mechanisms called into action by these parameters and adjacent lowintensity subthreshold stimulation remain unknown.

We investigated the effects of different low intensity repetitive magnetic stimulation (LI-rMS) parameters (10-13 mT) in vitro and describe key aspects of custom tailored LIrMS delivery for the in vitro setting. We applied LI-rMS at different frequencies to primary cortical cultures for 4 days and assessed survival and morphological changes. To understand underlying mechanisms, we measured intracellular calcium flux during LI-rMS and subsequent changes in gene expression. Our results show stimulationspecific effects of LI-rMS. In cortical cultures, straight high frequencies (10 Hz and 100 Hz) affected cell survival, while neuronal outgrowth and branching were inhibited only by 1 Hz stimulation. Moreover, all frequencies induced calcium release from intracellular stores and induced stimulation-specific changes in expression of genes related to apoptosis and neurite outgrowth.