BackgroundRecent studies have shown that the well-known effect of multisensory stimulation on body-awareness can be extended to self-recognition. Seeing someone else’s face being touched at the same time as one’s own face elicits changes in the mental representation of the self-face. We sought to further elucidate the underlying mechanisms and the effects of interpersonal multisensory stimulation (IMS) on the mental representation of the self and others.Methodology/Principal FindingsParticipants saw an unfamiliar face being touched synchronously or asynchronously with their own face, as if they were looking in the mirror. Following synchronous, but not asynchronous, IMS, participants assimilated features of the other’s face in the mental representation of their own face as evidenced by the change in the point of subjective equality for morphed pictures of the two faces. Interestingly, synchronous IMS resulted in a unidirectional change in the self-other distinction, affecting recognition of one’s own face, but not recognition of the other’s face. The participants’ autonomic responses to objects approaching the other’s face were higher following synchronous than asynchronous IMS, but this increase was not specific to the pattern of IMS in interaction with the viewed object. Finally, synchronous, as compared to asynchronous, IMS resulted in significant differences in participants’ ratings of their experience, but unlike other bodily illusions, positive changes in subjective experience were related to the perceived physical similarity between the two faces, and not to identification.Conclusions/SignificanceSynchronous IMS produces quantifiable changes in the mental representations of one’s face, as measured behaviorally. Changes in autonomic responses and in the subjective experience of self-identification were broadly consistent with patterns observed in other bodily illusions, but less robust. Overall, shared multisensory experiences between self and other can change the mental representation of one’s identity, and the perceived similarity of others relative to one’s self.

Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes.

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.

Non-invasive brain stimulation (NIBS) by electromagnetic fields appears to benefit human neurological and psychiatric conditions, although the optimal stimulation parameters and underlying mechanisms remain unclear. Although, in vitro studies have begun to elucidate cellular mechanisms, stimulation is delivered by a range of coils (from commercially available human stimulation coils to laboratory-built circuits) so that the electromagnetic fields induced within the tissue to produce the reported effects are ill-defined. Here, we develop a simple in vitro stimulation device with plug-and-play features that allow delivery of a range of stimulation parameters. We chose to test low intensity repetitive magnetic stimulation (LI-rMS) delivered at three frequencies to hindbrain explant cultures containing the olivocerebellar pathway. We used computational modeling to define the parameters of a stimulation circuit and coil that deliver a unidirectional homogeneous magnetic field of known intensity and direction, and therefore a predictable electric field, to the target. We built the coil to be compatible with culture requirements: stimulation within an incubator; a flat surface allowing consistent position and magnetic field direction; location outside the culture plate to maintain sterility and no heating or vibration. Measurements at the explant confirmed the induced magnetic field was homogenous and matched the simulation results. To validate our system we investigated biological effects following LI-rMS at 1 Hz, 10 Hz and biomimetic high frequency, which we have previously shown induces neural circuit reorganization. We found that gene expression was modified by LI-rMS in a frequency-related manner. Four hours after a single 10-min stimulation session, the number of c-fos positive cells increased, indicating that our stimulation activated the tissue. Also, after 14 days of LI-rMS, the expression of genes normally present in the tissue was differentially modified according to the stimulation delivered. Thus we describe a simple magnetic stimulation device that delivers defined stimulation parameters to different neural systems in vitro. Such devices are essential to further understanding of the fundamental effects of magnetic stimulation on biological tissue and optimize therapeutic application of human NIBS.

Mirror self-recognition is a key feature of self-awareness. Do we recognize ourselves in the mirror because we remember how we look like, or because the available multisensory stimuli (eg, felt touch and vision of touch) suggest that the mirror reflection is me? Participants saw an unfamiliar face being touched synchronously or asynchronously with their own face, as if they were looking in the mirror. Following synchronous, but not asynchronous, stimulation, and when asked to judge the identity of morphed pictures of the two faces, participants assimilated features of the other's face in the mental representation of their own face. Importantly, the participants' autonomic system responded to a threatening object approaching the other's face, as one would anticipate a person to respond to her own face being threatened. Shared multisensory experiences between self and other can change representations of one's identity and the perceived similarity of others relative to one's self.

Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology; the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

35Magnetic brain stimulation is a promising treatment in neurology and psychiatry, but clinical 36 outcomes are variable. Unfortunately, mechanisms underlying magnetic stimulation effects 37 are ill-defined, which impedes the development of stimulation protocols appropriate for 38 different neurological conditions. Here we show, in vivo and ex vivo, that repetitive 39 transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and 40 synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with 41 complex patterns being particularly effective, and its mechanism requires the presence of 42 cryptochrome (Cry), a putative magneto-receptor. Effective LI-rTMS patterns altered 43 expression of Cry target genes known to promote neuronal repair. Because LI-rTMS 44 generates electric fields too weak to depolarise neurons, these findings indicate that the 45 magnetic field itself induces the repair. Our data open a new framework for magnetic 46 stimulation -cryptochrome-mediated molecular and structural neuroplasticity. This 47 information suggests new routes to treatments specific for each neurological disease. 48 49 50 Dufor et al 3 Because of our imperfect understanding of the extraordinarily complex human brain, 51 repairing its damage or dysfunction remains one of the major challenges in biomedical 52 science, despite pharmaceutic, stem cell and neuroimaging advances. Non-invasive brain 53 stimulation (NIBS) is increasingly used in neurology and psychiatry in an attempt to trigger 54 intrinsic brain-repair mechanisms. While clinical outcomes are promising, they are variable 55 and underlying mechanisms poorly understood, which hinders therapeutic development 1 . A 56 common NIBS protocol applies magnetic stimulation, which has two forms; (a) repetitive 57 transcranial magnetic stimulation (rTMS) delivering strong magnetic pulses (0.5-2 Tesla, T) 58 to depolarize underlying neurons and trigger activity-dependent plasticity 1 ; or (b) low-59 /pulsed-field magnetic stimulation involving weak pulses (µT-mT) delivered to the whole 60 brain to modulate neuronal function without direct neuronal firing 2-4 . Nevertheless, it is 61 unknown how these weak fields modify brain circuits, which are the structural basis of 62 human behaviour. 63 64 The biological effects of magnetic stimulation depend on stimulation frequency, pattern, 65 duration and number of pulses delivered 1,5 . These are restricted in high intensity rTMS for 66 technical reasons (heating) and safety considerations (pain, seizures) 6 . In contrast, low field 67 stimulation employs a wide range of frequencies and patterns to modulate neuronal 68 excitability 2,7 , neuroplasticity 8-10 , neuron survival 11,12 , gene expression 10 and calcium 69 signalling 10,13 . 70 71 In this study, we moved beyond individual neurons aiming to identify magnetic stimulation 72 parameters that repair a lesioned neural pathway. For this, we developed focal low-intensity 73 (mT range) repetitive transcranial magnetic stimulation ...

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