Neurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive phenotypes common to neurodevelopmental conditions such as autism. GABAergic dysregulation underlies working memory impairments seen in NF1. This mechanistic experimental study investigates whether application of anodal transcranial direct current stimulation (atDCS) can modulate GABA and working memory in NF1. Thirty-one NF1 adolescents 11–18 years, were recruited to this single-blind sham-controlled cross-over randomized trial. AtDCS or sham stimulation was applied to the left Dorsolateral Prefrontal Cortex (DLPFC) and MR Spectroscopy was collected before and after intervention in the left DLPFC and occipital cortex. Task-related functional MRI was collected before, during, and after stimulation. Higher baseline GABA+ in the left DLPFC was associated with faster response times on baseline working memory measures. AtDCS was seen to significantly reduced GABA+ and increase brain activation in the left DLPFC as compared to sham stimulation. Task performance was worse in the aTDCS group during stimulation but no group differences in behavioural outcomes were observed at the end of stimulation. Although our study suggests aTDCS modulates inhibitory activity in the DLPFC, further work is needed to determine whether repeated sessions of atDCS and strategies such as alternating current stimulation offer a better therapeutic approach.
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
Neurofibromatosis 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 whether application of anodal transcranial direct current stimulation (atDCS) can modulate GABA and working memory in NF1. 31 adolescents with NF1 were recruited to this single-blind sham-controlled cross-over randomized trial. Active or sham tDCS was applied to the left Dorsolateral Prefrontal Cortex (DLPFC) and Magnetic Resonance Spectroscopy was collected before and after intervention in the left DLPFC and occipital cortex. Higher baseline GABA in the left DLPFC was associated with faster response times (RT) on baseline working memory measures. AtDCS was seen to significantly reduced GABA as compared to sham stimulation in the left DLPFC. There was no effect of atDCS on Glutamate/glutamine (Glx) in the left DLPFC or on GABA/Glx in the occipital cortex. This first such study in adolescents with NF1, showed that atDCS modulates inhibitory activity in the DLPFC. Given the strong evidence linking GABA abnormalities to cognitive deficits across neurodevelopmental conditions such as ASD, modulation of GABA using atDCS offers a promising therapeutic approach.ClinicalTrials.gov Identifier: NCT0499142. Registered 05/08/2021; retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04991428
Background: Neurofibromatosis 1 (NF1) is a single-gene neurodevelopmental disorder associated with cognitive and behavioural impairments, particularly with deficits in working memory. This study investigates the cerebral volumetric differences in adolescents with NF1 as compared to typically developing controls and how working memory task performance is associated with these differences. Methods: 31 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed multimodal measurement of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter(GM) volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Finally, we examined how the components derived from PCA correlated with the changes in GM volume in the NF1 group, after adjusting for age, sex and total intracranial volume. Results: The NF1 cohort showed increased GM volumes in the thalamus, globus pallidus, caudate, putamen, dorsal midbrain and cerebellum bilaterally as compared to controls. The PCA yielded three independent behavioural components reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of the inferior lateral parietal cortex was associated with poorer performance on the high working memory load tasks. Increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks. Discussion: This is the first study to examine the neuroanatomical correlates of working memory in NF1 adolescents. Consistent with prior literature we show larger subcortical brain volumes in in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports previously suggested hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.
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