Melissa Tsuboyama1, Harper L Kaye2, Alexander Rotenberg3. 1. Neuromodulation Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, MA, USA. 2. Behavioral Neuroscience Program, Boston University School of Medicine, Boston, MA, USA. 3. Neuromodulation Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: Alexander.Rotenberg@childrens.harvard.edu.
Abstract
PURPOSE: Despite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures. METHODS: A focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures. FINDINGS: Studies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results. IMPLICATIONS: TMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug-device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics.
PURPOSE: Despite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures. METHODS: A focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures. FINDINGS: Studies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results. IMPLICATIONS: TMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug-device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics.
Authors: Keith Starnes; Jeffrey W Britton; David B Burkholder; Iffat A Suchita; Nicholas M Gregg; Bryan T Klassen; Brian Nils Lundstrom Journal: Front Neurosci Date: 2022-06-10 Impact factor: 5.152
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