Status epilepticus (SE) is often the triggering event for epileptogenesis, a sequence of neuronal changes that lead to abnormal excitation and ultimately to epilepsy. Epileptogenesis is dependent in large part on lasting enhancement of excitatory synaptic strength that is similar to the long-term potentiation (LTP) seen with experimental high frequency repetitive neuronal stimulation. In this regard, we propose to investigate the anti-epileptogenic potential of transcranial magnetic stimulation (IMS), a noninvasive method for repetitive neuronal activation that is coming to attention as a new therapeutic tool in epilepsy. The attractive properties of TMS are its ability to 1) terminate seizures and to 2) produce a lasting decrease in synaptic strength. The latter effect may be similar to the long-term depression (LTD) that is LTP's inhibitory counterpart. Accordingly, our overall hypothesis is that the anticonvulsive and LTD-like effects of low frequency repetitive (rTMS) can interfere with SE-triggered epileptogenesis and prevent the expression of epilepsy. TMS is based on the principle of electromagnetic induction where intracranial stimulating currents are generated by a strong extracranial magnetic field. TMS is safe, painless and inexpensive. Its anticonvulsive capacity is demonstrated in a small number of human trials showing a reduction seizure frequency reduction in epileptic patients treated with rTMS. However, its mechanism of action is poorly understood. Therefore, this developing field would benefit from animal model research for elucidation of basic TMS physiology, and for evaluation of its therapeutic potential. We recently developed methods for simultaneous TMS and electroencephalography (EEG) in seizing rats, and identified new potent anti-convulsive effect. We now propose to use the rat kainate (KA) SE model to test the capacity of TMS to 1) stop SE and prevent the seizure-associate neuronal injury, and 2) prevent SE-triggered epileptogenesis. Further, to evaluate the TMS-related cellular and molecular mechanisms of action, we will test whether low frequency rTMS can induce LTD by extending our methods to in vitro hippocampal slice recording. To achieve these overall goals, we will extend our studies to include in vitro and ex vivo hippocampal slice recordings.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Fureman, Brandy E
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Children's Hospital Boston
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Muller, Paul A; Dhamne, Sameer C; Vahabzadeh-Hagh, Andrew M et al. (2014) Suppression of motor cortical excitability in anesthetized rats by low frequency repetitive transcranial magnetic stimulation. PLoS One 9:e91065
Vahabzadeh-Hagh, Andrew M; Muller, Paul A; Gersner, Roman et al. (2012) Translational neuromodulation: approximating human transcranial magnetic stimulation protocols in rats. Neuromodulation 15:296-305
Kabakov, Anatoli Y; Muller, Paul A; Pascual-Leone, Alvaro et al. (2012) Contribution of axonal orientation to pathway-dependent modulation of excitatory transmission by direct current stimulation in isolated rat hippocampus. J Neurophysiol 107:1881-9
Hsieh, Tsung-Hsun; Dhamne, Sameer C; Chen, Jia-Jin J et al. (2012) A new measure of cortical inhibition by mechanomyography and paired-pulse transcranial magnetic stimulation in unanesthetized rats. J Neurophysiol 107:966-72
Vahabzadeh-Hagh, Andrew M; Muller, Paul A; Pascual-Leone, Alvaro et al. (2011) Measures of cortical inhibition by paired-pulse transcranial magnetic stimulation in anesthetized rats. J Neurophysiol 105:615-24
Rotenberg, Alexander; Muller, Paul A; Vahabzadeh-Hagh, Andrew M et al. (2010) Lateralization of forelimb motor evoked potentials by transcranial magnetic stimulation in rats. Clin Neurophysiol 121:104-8
Rotenberg, Alexander; Muller, Paul; Birnbaum, Daniel et al. (2008) Seizure suppression by EEG-guided repetitive transcranial magnetic stimulation in the rat. Clin Neurophysiol 119:2697-702