Non-Invasive Brain Stimulation Modulates GABAergic Activity In Neurofibromatosis 1

Abstract BackgroundNeurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive phenotypes common to neurodevelopmental conditions such as Autism Spectrum Disorder (ASD) & Attention Deficit Hyperactivity Disorder (ADHD). GABAergic dysregulation underlies working memory impairments seen in NF1. This mechanistic experimental study investigates how inter-individual differences in GABA relate to working memory and whether application of anodal transcranial direct current stimulation (atDCS) can modulate of GABA and working memory.Methods31 adolescents with NF1 were recruited to a single-blind, sham-controlled cross-over trial. Baseline assessments included detailed working memory tests and parent reported measures. Each participant had two study visits, one with atDCS and another with sham intervention applied to the left Dorsolateral Prefrontal Cortex (DLPFC) inside the scanner. Magnetic Resonance Spectroscopy was collected before and after aTDCS/sham intervention in the left DLPFC and occipital cortex.ResultsHigher baseline GABA was associated with faster response times (RT) on verbal and visuospatial working memory measures. No correlation was observed between baseline GABA and working memory accuracy. AtDCS was associated with significantly greater reduction in GABA, as compared to sham in the left DLPFC. There was no effect of atDCS on Glx in left DLPFC and no significant effect of atDCS on GABA or Glx in the occipital cortex. There was no effect of atDCS on behavioural measures of working memory.LimitationsLimitations of this study include use of brief behavioural outcome measures post tDCS chosen to reduce participant burden and the lack of a healthy control group. The GABA levels measured in this study will contain contributions from co-edited macromolecule signal (so-called GABA+), but the relative contribution of these macromolecular signals are thought to be constant unlikely to account for within participant/session GABA changes. ConclusionsThis first such study in adolescents with NF1, showed that atDCS modulates inhibitory activity in the DLPFC. This focussed mechanism trial presents a highly promising approach to understanding complex neural pathology in neurodevelopmental disorders. Given the strong evidence linking GABA abnormalities to cognitive deficits across neurodevelopmental conditions such as ASD, modulation of GABA using atDCS offers a promising novel therapeutic approach. ClinicalTrials.gov Identifier: NCT0499142. Registered 5th August 2021; retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04991428