Repetitive transcranial magnetic stimulation for protection against delayed neuronal death induced by transient ischemia

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Object. Data in the present study demonstrate that repetitive transcranial magnetic stimulation (rTMS) induces ischemic tolerance against delayed neuronal death (DND) of hippocampal neurons following an otherwise lethal ischemic insult.

Methods. Various regimens of rTMS were delivered to adult gerbils at various times prior to an episode of ischemia induced by transient (5-minute) bilateral common carotid artery (CCA) occlusion. The extent of DND in the CA1 region of the hippocampus was assessed quantitatively 7 days after the transient ischemic episode.

When rTMS was delivered 2 to 5 days prior to bilateral CCA occlusion, DND was substantially attenuated; delivery of rTMS 12 to 24 hours prior to occlusion induced partial tolerance. In the group of animals that had received stimulation 2 days prior to occlusion, neuron density in the CA1 sector was significantly higher (three gerbils, 210.33, 86.01% of normal) than in the group that experienced ischemia only (three gerbils, 10.66, 4.36% of normal). A similar degree of neuron sparing occurred when stimulation was delivered 3, 4, or 5 days prior to occlusion. Note that rTMS was effective when it was delivered at frequencies of 25 and 50 Hz. Stimulation at 25 Hz for 128 seconds (3200 pulses) was more effective than stimulation at 50 Hz for 64 seconds (3200 pulses) or 128 seconds (6400 pulses), however.

Conclusions. Noninvasive rTMS represents an important tool for exploring the mechanisms of ischemic tolerance and preventing ischemic neuronal damage.

Article Information

Address reprint requests to: Minoru Fujiki, M.D., Department of Neurosurgery, School of Medicine, Oita University, 1–1 Idaigaoka, Hazama-machi, Oita 879–5593 Japan. email: fujiki@med.oita-u.ac.jp.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photomicrographs indicating neuron density in the CA1 region of the hippocampus in an animal 7 days after occlusion-induced ischemia (A and B) and in an animal that had undergone rTMS preconditioning 2 days before bilateral CCA occlusion (D). Note the prominent cell loss in CA1 in the animal subjected to ischemia only and the relative absence of neuron loss in the animal that had received rTMS. C: Photomicrograph demonstrating cell density in a sham-operated animal. Bars = 200 µm (A), 100 µm (C), and 50 µm (B and D).

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    Bar graph demonstrating quantitative evaluation of several combinations of stimulus conditions. Neuron density per 1-mm length of the CA1 sector was evaluated 7 days after bilateral CCA occlusion after different combinations of stimulation. The rTMS treatment reduced cell loss when delivered at frequencies of 25 and 50 Hz. Note that stimulation of 25 Hz for 128 seconds (3200 pulses) was more effective than stimulation of 50 Hz for 64 seconds (3200 pulses) or 128 seconds (6400 pulses). High-frequency stimulation at 50 Hz worked less effectively even with the same number of pulses (for 64 seconds) or the same or longer duration (for 128 or 256 seconds). *p < 0.05, compared in each duration; +p < 0.05, compared with 50 Hz; **p < 0.05, compared with control.

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    Graph demonstrating the time course of MSIT. Magnetic stimulation was delivered at different intervals prior to the induction of occlusion, and neuron loss was assessed 7 days following ischemia. Maximal sparing occurred when magnetic stimulation was delivered 2 to 5 days prior to the ischemic challenge. Note that each circle represents a different animal at a different time point. Squares represent the mean values. *p < 0.05, compared with control.

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    Graph demonstrating CBF changes during TMS. There was no significant change (decrease or increase) in CBF before, during, and 90 minutes after rTMS. White squares represent control animals; black squares indicate TMS-treated animals.

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    Photomicrographs demonstrating TUNEL staining in ischemia-only (A) and TMS-treated (B) animals. Note the substantial number of dying cells in the ischemia-only animal (A) and the smaller number in the rTMS-conditioned animal (B). Bar = 50 µm.

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