What does the magnetic field do? Neural changes beyond induction of an electric field

Symposium title: Mechanisms underlying magnetic stimulation: the need for animal studies Symposium description: Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique, which shows promise for treating a range of neuropsychiatric disorders. However, to improve clinical treatment, we need to answer questions about how TMS interacts with the brain and identify its underlying mechanisms. Such fundamental studies are effectively not possible in humans and thus require a range of experiments in different animal species to gain insights into TMS function on the cellular and circuit level. In this symposium, we bring together new results from animal experiments from organotypic rodent cultures to in vivo rat and primate physiology that explore the mechanisms of TMS and rTMS in more detail. The symposium will give new insights into what TMS, at low or high intensity, does to single neurons and their circuits in the brain. Our new data indicate that magnetic pulses modify more than synaptic activity, even altering the intrinsic properties of stimulated neurons and circuits. Such changes to neuronal excitability are usually recorded as EEG or ECoG potentials, which are a summation from many cells in different cortical layers as well as contaminating sensory afferents that are inadvertently stimulated by the magnetic pulses. We show how much of this activity is the direct effect of TMS on the cortical neurons. Furthermore, we also demonstrate how modulation of circuit activity is directly reflected in clinically relevant measures, such as MEPs. To these cortical changes, we go deeper towards underlying mechanisms; adding subcellular signaling cascades that give insights into why rTMS effects continue beyond the stimulation period. Abstract Repetitive transcranial magnetic stimulation, rTMS, is increasingly used in neurology and psychiatry, aiming to trigger intrinsic brain-repair mechanisms. To optimize stimulation protocols, we need more complete understanding of the mechanisms underlying rTMS. As the stimulation-induced structural changes to neurons and their networks are difficult to visualize in the living human brain, animal models become essential. To better understand what magnetic stimulation does within the brain, we have developed tools to generate defined low intensity (LI) magnetic fields (10 mT) and deliver them to neural tissue in vivo, in 3D organotypic culture and in primary cultures, over a range of stimulation parameters. We have shown that low-intensity rTMS (LI-rTMS) can remove aberrant connections, induce reinnervation of denervated neurons and change neuronal morphology in a stimulation-pattern specific manner. In addition to effects of magnetic pulses on neuronal activity, we have also identified potential mechanisms to explain these reparative changes. LI-rTMS requires the presence of a cellular magneto-receptor, cryptochrome, to induce structural changes in neurons. We also show that it modulates intracellular reactive oxygen species (ROS) and increases intracellular calcium and expression of neuroplasticity-related genes. By providing a greater understanding of the cellular effects of magnetic stimulation, these data some of the information necessary to open the range of possible new and personalized treatment strategies. Research Category and Technology and Methods Basic Research: 22. Neuroplasticity Keywords: LI-rTMS, radical oxygen species, transcriptome, mouse