Mechanism of Action of Transcranial Direct Current Stimulation in Neurofibromatosis Type 1

Intellectual impairment, particularly working memory deficits are a significant cause of morbidity in children with Neurofibromatosis type (NF1) with long-term implications on academic and occupational functioning. Whilst significant discoveries have been made in Nf1 animal models in trying to find treatments for these conditions, human translational studies have not been successful. This mechanistic experimental study will investigate the neural mechanisms underlying working memory deficits in NF1. In particular, we will investigate how individual differences in inhibitory neurotransmitter GABA relate to performance on working memory tests. Further, we will investigate the use of a novel, experimental intervention called transcranial Direct Current Stimulation (tDCS);known to modulate GABA. Using a randomized, crossover design in a cohort of 30 adolescents aged 11-17 years, we will apply real or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). State-of-art real time imaging techniques such as Magnetic Resonance Spectroscopy (MRS) and task based functional MRI (fMRI) will be used to investigate the effect of tDCS on GABA concentration, changes in functional plasticity and working memory. We expect that results from this study will help elucidate the neural mechanisms underlying working memory deficits in people with NF1 and show biologic activity for a novel, low-cost intervention that can be used for cognitive remediation in NF1. This kind of focused mechanism trial method is a highly promising approach to understanding the complex neural system pathology in a multifactorial neurodevelopmental condition like NF1.