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

Study Overview
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Brief Summary
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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.

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

Conditions
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Neurofibromatosis 1

Intervention / Treatment
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* Other: Transcranial direct current stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets National Institute of Health NF1 diagnostic criteria Children aged 11-17 years Written informed consent/assent Exclusion Criteria: No history of intracranial pathology other than asymptomatic optic pathway glioma or other asymptomatic and untreated NF1-associated white matter lesion No history of epilepsy or any major mental illness No MRI contraindications.

Ages Eligible for Study
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Minimum Age: 11 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Single-blind cross over experimental trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active trancranial direct current stimulation<br>Active stimulation for 15 minutes | Other: Transcranial direct current stimulation<br>* tDCS is a form of non-invasive brain stimulation. tDCS is an established research tool for non-invasive modulation of neuroplasticity. It uses low-intensity DC currents to modulate spontaneous neuronal network activity by altering the resting membrane potential. Anodal tDCS has been shown to increase cortical excitability, reduce regional levels of GABA enhance LTP and synaptic plasticity.<br>|
| Sham Comparator: Sham stimulation<br>Similar set-up but no actual stimulation | Other: Transcranial direct current stimulation<br>* tDCS is a form of non-invasive brain stimulation. tDCS is an established research tool for non-invasive modulation of neuroplasticity. It uses low-intensity DC currents to modulate spontaneous neuronal network activity by altering the resting membrane potential. Anodal tDCS has been shown to increase cortical excitability, reduce regional levels of GABA enhance LTP and synaptic plasticity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Corsi Block task | memory span task | immediately after the intervention |