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Neural Circuit Repair by Low-Intensity rTMS

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Abstract

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.

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References

  1. Pell GS, Roth Y, Zangen A. Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms. Prog Neurobiol. 2011;93:59–98.

    Article  Google Scholar 

  2. Grimaldi G, Argyropoulos GP, Boehringer A, Celnik P, Edwards MJ, Ferrucci R, Galea JM, Groiss SJ, Hiraoka K, Kassavetis P, et al. Non-invasive cerebellar stimulation–a consensus paper. Cerebellum. 2014;13:121–38.

    Article  CAS  Google Scholar 

  3. Benussi A, Pascual-Leone A, Borroni B. Non-invasive cerebellar stimulation in neurodegenerative ataxia: a literature review. Int J Mol Sci. 2020;21:E1948.

    Article  Google Scholar 

  4. Hatten ME. Adding cognitive connections to the cerebellum. Science. 2020;370:1411–2.

    Article  CAS  Google Scholar 

  5. Rodger J, Mo C, Wilks T, Dunlop SA, Sherrard RM. Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity. FASEB J. 2012;26:1593–606.

    Article  CAS  Google Scholar 

  6. Grehl S, Viola HM, Fuller-Carter PI, Carter KW, Dunlop SA, Hool LC, Sherrard RM, Rodger J. Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies. Brain Stimul. 2015;8:114–23.

    Article  Google Scholar 

  7. Morellini N, Grehl S, Tang A, Rodger J, Mariani J, Lohof AM, Sherrard RM. What Does Low-Intensity rTMS Do to the Cerebellum? Cerebellum 2015;14:23–6. Available at:  https://doi.org/10.1007/s12311-014-0617-9.

  8. Siebner HR, Lang N, Rizzo V, Nitsche MA, Paulus W, Lemon RN, Rothwell JC. Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex. J Neurosci. 2004;24:3379–85.

    Article  CAS  Google Scholar 

  9. Welsh JP, Lang EJ, Suglhara I, Llinás R. Dynamic organization of motor control within the olivocerebellar system. Nature. 1995;374:453–7.

    Article  CAS  Google Scholar 

  10. Dixon KJ, Sherrard RM. Brain-derived neurotrophic factor induces post-lesion transcommissural growth of olivary axons that develop normal climbing fibers on mature Purkinje cells. Exp Neurol. 2006;202:44–56.

    Article  CAS  Google Scholar 

  11. Willson ML, McElnea C, Mariani J, Lohof AM, Sherrard RM. BDNF increases homotypic olivocerebellar reinnervation and associated fine motor and cognitive skill. Brain. 2008;131:1099–112.

  12. Dufor T, Grehl S, Tang AD, Doulazmi M, Traoré M, Debray N et al. Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns. Sci Adv. 2019;5:eaav9847.

  13. Makowiecki K, Harvey AR, Sherrard RM, Rodger J. Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in mice. J Neurosci. 2014;34:10780–92.

    Article  Google Scholar 

  14. Letellier M, Bailly Y, Demais V, Sherrard RM, Mariani J,  Lohof AM. Reinnervation of late postnatal Purkinje cells by climbing fibers: Neosynaptogenesis without transient multi-innervation. J Neurosci. 2007;27:5373–83.

  15. Chédotal A, Bloch-Gallego E, Sotelo C. The embryonic cerebellum contains topographic cues that guide developing inferior olivary axons. Development. 1997;124:861–70.

    Article  Google Scholar 

  16. Letellier M, Wehrlé R, Mariani J, Lohof AM. Synapse elimination in olivo-cerebellar explants occurs during a critical period and leaves an indelible trace in Purkinje cells. Proc Natl Acad Sci USA. 2009;106:14102–7.

    Article  Google Scholar 

  17. Grehl S, Martina D, Goyenvalle C, Deng Z-D, Rodger J, Sherrard RM. In vitro magnetic stimulation: a simple stimulation device to deliver defined low intensity electromagnetic fields. Front Neural Circuits. 2016;10:85.

    Article  Google Scholar 

  18. Santulli G, Nakashima R, Yuan Q, Marks AR. Intracellular calcium release channels: an update. J Physiol. 2017;595:3041–51.

    Article  CAS  Google Scholar 

  19. Görlach A, Bertram K, Hudecova S, Krizanova O. Calcium and ROS: a mutual interplay. Redox Biol. 2015;6:260–71.

    Article  Google Scholar 

  20. Consentino L, Lambert S, Martino C, Jourdan N, Bouchet P-E, Witczak J, Castello P, El-Esawi M, Corbineau F, d’Harlingue A, et al. Blue-light dependent reactive oxygen species formation by Arabidopsis cryptochrome may define a novel evolutionarily conserved signaling mechanism. New Phytol. 2015;206:1450–62.

    Article  CAS  Google Scholar 

  21. Müller P, Ahmad M. Light-activated cryptochrome reacts with molecular oxygen to form a flavin–superoxide radical pair consistent with magnetoreception. J Biol Chem. 2011;286:21033–40.

    Article  Google Scholar 

  22. van Wilderen LJGW, Silkstone G, Mason M, van Thor JJ, Wilson MT. Kinetic studies on the oxidation of semiquinone and hydroquinone forms of Arabidopsis cryptochrome by molecular oxygen. FEBS Open Bio. 2015;5:885–92.

    Article  Google Scholar 

  23. Chaves I, Pokorny R, Byrdin M, Hoang N, Ritz T, Brettel K, Essen L-O, van der Horst GTJ, Batschauer A, Ahmad M. The cryptochromes: blue light photoreceptors in plants and animals. Annu Rev Plant Biol. 2011;62:335–64.

    Article  CAS  Google Scholar 

  24. Wiltschko R, Wiltschko W. Sensing magnetic directions in birds: radical pair processes involving cryptochrome. Biosensors (Basel). 2014;4:221–42.

    Article  Google Scholar 

  25. Foley LE, Gegear RJ, Reppert SM. Human cryptochrome exhibits light-dependent magnetosensitivity. Nat Commun. 2011;2:356.

    Article  Google Scholar 

  26. Sherrard RM, Morellini N, Jourdan N, El-Esawi M, Arthaut L-D, Niessner C et al. Low-intensity electromagnetic fields induce human cryptochrome to modulate intracellular reactive oxygen species. PLoS Biol. 2018;1:e2006229.

  27. van der Horst GTJ, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker APM, van Leenen D, et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature. 1999;398:627–30.

    Article  Google Scholar 

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Funding

The study was supported in part by the Institut de la Recherche sur la Moelle épinière et l’Encéphale and the Agence Nationale de la Recherche, project « BrainMag» (N° ANR-19-CE37-0021).

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Authors and Affiliations

  1. Sorbonne Université and CNRS, IBPS-B2A UMR8256 Biological Adaptation and Ageing, Boite 256, 9 Quai St Bernard, 75005, Paris, France

    A. M. Lohof, T. Dufor & R. M. Sherrard

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  1. A. M. Lohof
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  2. T. Dufor
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  3. R. M. Sherrard
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Correspondence to R. M. Sherrard.

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Lohof, A.M., Dufor, T. & Sherrard, R.M. Neural Circuit Repair by Low-Intensity rTMS. Cerebellum 21, 750–754 (2022). https://doi.org/10.1007/s12311-021-01354-4

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