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

Abstract

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.

The Regenerative Effect of Trans-spinal Magnetic Stimulation After Spinal Cord Injury: Mechanisms and Pathways Underlying the Effect

“…Our findings have strengthened the theories from previous studies that rTMS influences a wide variety of cells without direct activations of neuronal firing [58] including glial cells [20]. Indeed, Cullen et al showed that rTMS increases the number of newborn oligodendrocytes in the adult mouse cortex and their survival and enhances myelination [51].…”

Human Cryptochrome Mediates Oxidative Stress Responses Modulated by Static and Electromagnetic Fields in Doxorubicin-Treated Cells

“…Furthermore, some recent experiments revealed that radical pair formation in the mammalian-type CRYs can occurs during magnetosensitivity by molecular oxygen and is not dependent to light [60][61][62] . CRYs can implicate to reinnervation and repairing of nervous systems in the mammalian brain as light-independent magnetosensor by an external low intensity EMF stimulations 63 . However, magnetosensitivity property requires the light in the ies, birds, etc.…”

“…MFs exposure on the cell behaviors and neural activities 63,69 . Redox cycling of CRYs participates the formation of radical pair and singlet/triplet interconversion in the FAD¯° that triggers the transfer electron form CRYs to MagR and magnetic susceptibility in MagR proteins 16 .…”

In Vitro Study of Neurochemical Changes Following Low-Intensity Magnetic Stimulation

“…There is evidence that LIMS can modulate brain function in humans [12] and in animal models [24]; however, the cellular and molecular mechanisms underlying the therapeutic effects of LIMS remain poorly understood. A few in vitro and ex vivo studies have demonstrated that LIMS alters gene expression [25], intracellular calcium concentrations in non-neuronal cells [26] [27] [28] and neuronal cells [29], neurobiological changes [30], neuronal excitability [31], and cellular metabolic and biochemical profiles [32]. However, it is still unknown whether LIMS provides facilitation or suppression effects depending on the stimulation protocol.…”