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.

Study Overview

• Status: Completed
• Conditions: Neurofibromatosis 1
• Intervention / Treatment: Other: Transcranial direct current stimulation

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M13 9QQ
      • University of Manchester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Meets National Institute of Health NF1 diagnostic criteria
2. Children aged 11-17 years
3. Written informed consent/assent

Exclusion Criteria:

1. No history of intracranial pathology other than asymptomatic optic pathway glioma or other asymptomatic and untreated NF1-associated white matter lesion
2. No history of epilepsy or any major mental illness
3. No MRI contraindications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active trancranial direct current stimulation; Active stimulation for 15 minutes	Other: Transcranial direct current stimulation; 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.
Sham Comparator: Sham stimulation; Similar set-up but no actual stimulation	Other: Transcranial direct current stimulation; 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.

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Manchester

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2019
• Primary Completion (Actual): February 19, 2020
• Study Completion (Actual): February 19, 2020

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: July 27, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 27, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
• Other Study ID Numbers: 18/NW/0762

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Collected data will be available to share after publication of study findings
• IPD Sharing Time Frame: The data will be made available upon request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No