Neural Circuit Repair by Low-Intensity rTMS.

Electromagnetic brain stimulation is a promising treatment in neurology and psychiatry. However, clinical outcomes are variable and underlying mechanisms remain ill-defined, impeding the development of new effective stimulation protocols. There is increasing application of repetitive transcranial magnetic stimulation (rTMS) to the cerebellum to induce forebrain plasticity through its long-distance cerebello-cerebral circuits. To better understand what magnetic stimulation does within the cerebellum, we have developed tools to generate defined low-intensity (LI) magnetic fields and deliver them in vivo, in 3D organotypic culture and in primary cultures, over a range of stimulation parameters. Here we show that low-intensity rTMS (LI-rTMS) to the cerebellum induces axon growth and synapse formation providing olivocerebellar reinnervation. This repair depends on stimulation pattern, with complex biomimetic patterns being most effective, and this requires the presence of a cellular magnetoreceptor, cryptochrome. To explain these reparative changes, we found that repair-promoting LI-rTMS patterns, but not ineffective ones, increased c-fos expression in Purkinje neurons, consistent with the production of reactive oxygen species by activated cryptochrome. Rather than activating neurons via induced electric currents, we propose that weak magnetic fields act through cryptochrome, activating intracellular signals that induce climbing fibre-Purkinje cell reinnervation. This information opens new routes to optimize cerebellar magnetic stimulation and its potential role as an effective treatment for neurological diseases.

Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns.

Although electromagnetic brain stimulation is a promising treatment in neurology and psychiatry, clinical outcomes are variable, and underlying mechanisms are ill-defined, which impedes the development of new effective stimulation protocols. Here, we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex biomimetic patterns being particularly effective, and the presence of cryptochrome, a putative magnetoreceptor. Only repair-promoting LI-rTMS patterns up-regulated genes involved in neuronal repair; almost 40% of were cryptochrome targets. Our data open a new framework to understand the mechanisms underlying structural neuroplasticity induced by electromagnetic stimulation. Rather than neuronal activation by induced electric currents, we propose that weak magnetic fields act through cryptochrome to activate cellular signaling cascades. This information opens new routes to optimize electromagnetic stimulation and develop effective treatments for different neurological diseases.