title: Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in mice.
abstract: Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders. Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n = 22) and ephrin-A2A5(-/-) (n = 22) mice, the latter possessing visuotopic anomalies. Mice were treated with LI-rTMS or sham (handling control) daily for 14 d, then fluorojade and fluororuby were injected into visual cortex. The distribution of dorsal LGN (dLGN) neurons and corticotectal terminal zones (TZs) was mapped and disorder defined by comparing their actual location with that predicted by injection sites. In the afferent geniculocortical projection, LI-rTMS decreased the abnormally high dispersion of retrogradely labeled neurons in the dLGN of ephrin-A2A5(-/-) mice, indicating geniculocortical map refinement. In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5(-/-) mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5(-/-) mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.
authors.affiliation: Experimental and Regenerative Neuroscience, School of Animal Biology, and.
authors.forename: Kalina
authors.initials: K
authors.lastname: Makowiecki
authors.affiliation: Experimental and Regenerative Neuroscience, School of Animal Biology, and School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia 6009, and.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Harvey
authors.affiliation: Sorbonne Universités, Pierre and Marie Curie University of Paris 06 and Centre National de la Recherche Scientifique, Institut de Biologie Paris Seine, UMR8256 Biological Adaptation and Ageing, F-75005 Paris, France.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Sherrard
authors.affiliation: Experimental and Regenerative Neuroscience, School of Animal Biology, and jennifer.rodger@uwa.edu.au.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rodger
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D001927:Brain Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D036383:Ephrin-A2 / Q000172:deficiency / Q000235:genetics; D036386:Ephrin-A5 / Q000172:deficiency / Q000235:genetics; D005829:Geniculate Bodies / Q000002:abnormalities / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000002:abnormalities / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D050781:Transcranial Magnetic Stimulation; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D014793:Visual Cortex / Q000002:abnormalities*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D036383:Ephrin-A2; D036386:Ephrin-A5; D012333:RNA, Messenger
keywords: LI-rTMS; corticotectal projection; critical period; ephrin-A2A5−/− mice; geniculocortical; plasticity
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