Transcranial magnetic stimulation as a tool to understand genetic conditions associated with epilepsy

Silvennoinen, Katri; Balestrini, Simona; Rothwell, John C.; Sisodiya, Sanjay M.

doi:10.1111/epi.16634

Cited by 9 publications

(6 citation statements)

References 111 publications

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“…SICI was originally described using ISIs of both 2 and 3 ms 15 ; both are commonly reported in studies using TMS in epilepsy‐associated conditions. 19 It is plausible that there is some inter‐individual variability as to which of these ISIs is optimal. Accounting for this, as well as to obtain a single value for SICI, we averaged the ratios for both ISIs to yield the mean SICI (mSICI), an approach described previously.…”

Section: Methodsmentioning

confidence: 99%

“…LICI and SICI were expressed as the ratio of median conditioned MEP amplitude to the median unconditioned MEP amplitude. SICI was originally described using ISIs of both 2 and 3 ms 15 ; both are commonly reported in studies using TMS in epilepsy‐associated conditions 19 . It is plausible that there is some inter‐individual variability as to which of these ISIs is optimal.…”

Section: Methodsmentioning

confidence: 99%

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Short‐ and long‐interval intracortical inhibition in EPM1 is related to genotype

et al. 2022

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Objective Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)–induced long‐interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short‐interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. Methods TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter‐stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. Results The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age‐ and sex‐matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). Significance Our results strengthen the finding of deranged γ‐aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease‐modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Short‐ and long‐interval intracortical inhibition in EPM1 is related to genotype

et al. 2022

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“…As noted in a previous publication [19], rats were given 200 mg/kg nicotine (Beyotime, Shanghai, China) subcutaneously to combat the surrounding cholinergic effect. After 30 minutes, rats were administrated with pilocarpine hydrochloride (Beyotime)‐to induce epilepsy‐ except for control group, accordingly [20]. Rats in the model and Cu Zn‐SOD group exhibited convulsions and fainting.…”

Section: Methodsmentioning

confidence: 99%

Cu‐Zn SOD suppresses epilepsy in pilocarpine‐treated rats and alters SCN2A/Nrf2/HO‐1 expression

Wen

Tan

Xiang

2022

Epileptic Disorders

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Objective. Copper-zinc superoxide dismutase (Cu-Zn SOD) is downregulated in epilepsy, however, the role of Cu-Zn SOD in epilepsy remains unclear. Methods. Based on the pilocarpine hydrochloride-induced rat model of epilepsy, cortical-striatum brain slices of rats were examined based on field excitatory post-synaptic potentials. Pathological changes were observed by transmission electron microscope. Also using SH-SY5Y cells, flow cytometry and TUNEL staining were applied to investigate cell apoptosis, and ELISA was applied to detect SOD activity. In addition, qRT-PCR and western blot were performed to detect SCN2A/Nrf2/HO-1 gene and protein expression levels, respectively. Results. Cu-Zn SOD over-expression suppressed epilepsy in vivo. In addition, Cu-Zn SOD knockdown notably decreased SOD activity and induced apoptosis in SH-SY5Y cells. Moreover, Cu-Zn SOD silencing decreased the levels of SCN2A, Nrf2 and HO-1. Lastly, Cu-Zn SOD was shown to modulate the NaV1.2/ Nrf2/HO-1 axis in rats.Significance. In this model, Cu-Zn SOD attenuated epilepsy and was shown to alter the expression level of proteins of the NaV1.2 /Nrf2/HO-1 signalling pathway, indicating that Cu-Zn SOD might be a target for the treatment of epilepsy.

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“…Ideally, conventional and new models should be integrated and complemented with clinical information extrapolated by deep phenotyping and natural history studies to define the appropriate endpoints to use for the preclinical models [ 51 ]. Deep phenotyping should be pursued through multimodal techniques [ 52 , 53 ] which may help bridge the gap between standard clinical phenotype (i.e. clinical information derived from routine practice) and preclinical information provided by in vitro or in vivo model systems.…”

Section: Steps To Implement Pm In Epilepsymentioning

confidence: 99%

Steps to Improve Precision Medicine in Epilepsy

Balestrini,

Mei,

Sisodiya

et al. 2023

Mol Diagn Ther

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Precision medicine is an old concept, but it is not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision medicine in epilepsy, this has been based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope of precision medicine is to provide effective strategies for treating individual patients with specific agent(s) that are likely to work best based on the causal biological make-up. We provide an overview of the main applications of precision medicine in epilepsy, including the current limitations and pitfalls, and propose potential strategies for implementation and to achieve a higher rate of success in patient care. Such strategies include establishing a definition of precision medicine and its outcomes; learning from past experiences, from failures and from other fields (e.g. oncology); using appropriate precision medicine strategies (e.g. drug repurposing versus traditional drug discovery process); and using adequate methods to assess efficacy (e.g. randomised controlled trials versus alternative trial designs). Although the progress of diagnostic techniques now allows comprehensive characterisation of each individual epilepsy condition from a molecular, biological, structural and clinical perspective, there remain challenges in the integration of individual data in clinical practice to achieve effective applications of precision medicine in this domain.

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Transcranial magnetic stimulation as a tool to understand genetic conditions associated with epilepsy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 9 publications

References 111 publications

Short‐ and long‐interval intracortical inhibition in EPM1 is related to genotype

Short‐ and long‐interval intracortical inhibition in EPM1 is related to genotype

Cu‐Zn SOD suppresses epilepsy in pilocarpine‐treated rats and alters SCN2A/Nrf2/HO‐1 expression

Steps to Improve Precision Medicine in Epilepsy

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