Objective: Neurofibromatosis type 1 (NF1) is a genetic disorder associated with cognitive and behavioral deficits. In NF1, decreased neurofibromin levels attenuate hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) activity, thereby increasing inhibitory interneuron activity and decreasing synaptic plasticity. Lamotrigine, an HCN1-agonist, rescued this electrophysiological phenotype in an NF1 mouse model. We investigated whether lamotrigine can alter cortical inhibition and plasticity in adolescents with NF1 using transcranial magnetic stimulation (TMS).

Methods: We performed an explorative analysis of secondary outcomes in the NF1-EXCEL trial (Clinicaltrials.gov identifier NCT02256124). Thirty-one adolescents with NF1 were randomized to either receive lamotrigine or a placebo. Using TMS, cortical inhibition was assessed with short-interval intracortical inhibition (SICI) and cortical plasticity with paired associative stimulation (PAS) at baseline and after 10 weeks of intervention.

Results: Lamotrigine did not affect baseline cortical excitability. Additionally, no significant effects on either SICI or PAS responses were found after lamotrigine treatment in adolescents with NF1. Finally, lamotrigine did not affect pre-PAS single-pulse cortical excitability measures.

Conclusions: 10-week lamotrigine treatment does not alter cortical inhibition and plasticity in adolescents with NF1. Conclusions: While limited by a small sample size, our study indicates that lamotrigine cannot consistently modulate SICI or PAS in adolescents with NF1, suggesting limited potential for treating the underlying pathophysiological mechanisms.