The scn1a-ploymorphism and carbamazepine-effects on cortical excitability in healthy adults in a tms-study in the epicure-consortium

Abstract

Purpose: SCN1A encodes a voltage-gated sodium channel and acts in neuronal depolarization. Mutations lead to various epilepsy syndromes. Studies revealed a correlation between genotype of SCN1A-polymorphism (IVS5N+5 G->A; dbSNP: rs3812718) and pharmacoresponse to Carbamazepine (CBZ) Transcranial magnetic stimulation (TMS) measures drug induced cortical excitability changes. Purpose: SNP- effect on cortical excitability as measured by baseline/CBZTMS Method: Genotyping: 272 volunteers, 140 homozygotic (AA: 53.5%, GG: 46.5%). Whole TMS- samples of 92. TMS-parameter: motor evoked potentials in RMT, interstimulus intervals, cortical silent period (CSP). Offline Analysis. Design: double-blind, randomized, cross-over; two visits (TMS at baseline & 5 hours after 400mg CBZ or Placebo p.o.). Result: No age or sex differences. CBZ (medium level: 4.53 mg/ml) resulted in higher excitability threshold (p=0.001). Genotypes did neither differ in baseline cortical excitability (p=0.290) nor in response to CBZ (p=0.154) as measured by RMT. However, CSP was prolonged after CBZ for GG and not AA (p=0.015) Conclusion: We did not find significant baseline differences for the genotypes. Differential reaction to CBZ was apparent only in CSP; GG was associated with a higher increase in CSP duration than AA. CSP reflects the function of GABAergic interneurons, which are disturbed in functional SCN1A disorders. The study shows that pharmacogenetic group differences can be proven by TMS.