Non-invasive brain stimulation modulates GABAergic activity in neurofibromatosis 1

Abstract

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.

Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?

“…The rationale came from evidence on patients with schizophrenia and bipolar disorder with catatonia (Haroche et al, 2022 ) and was grounded in the neurobiological hypothesis of PMS, involving haploinsufficiency of SHANK3 associated with NMDA receptor hypofunctionality and catatonia (Kohlenberg et al, 2020 ). Even in the study on NF1 (Garg et al, 2022 ), the rationale of tDCS application was grounded in the neurobiological hypothesis of the condition. Anodal tDCS was applied to left dorsolateral prefrontal cortex (DLPFC) to reduce GABA and to improve performance on working memory (WM) tasks, increasing brain activation in the targeted area, since NF1 is characterized by GABAergic over activity and impairment in synaptic plasticity (Costa et al, 2002 ; Cui et al, 2008 ; Molosh et al, 2014 ).…”

“…-HT, -idrossitriptamina; ADHD, attention deficit/ hyperactivity disorder; AMPA, Ammino--idrossi--Metil--isossazol- Given that the atypically developing brain has anatomical and functional differences compared to mature and typically developing brain, it is reasonable to consider that it may respond differently to external stimuli, such as session of stimulation (Garg et al, 2022). Combining pre-clinical research and experimental studies involving participants with DS represents the most effective approach for investigating the potential of tDCS as a treatment tool for cognitive improvement in this population.…”

Excitation-Inhibition Imbalance in Migraine: From Neurotransmitters to Brain Oscillations

“…Additionally, neurostimulation may also affect neurotransmitter levels, for example, anodal tDCS reduced GABA+ concentration in the dorsolateral prefrontal cortex [ 257 ] and motor cortex [ 258 ]. Therefore, this could represent a second mode of action for neurostimulation in migraine, either by changing the oscillations or by changing the neurotransmitter levels, or possibly both.…”