Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner.

Response inhibition in Attention deficit disorder and neurofibromatosis type 1 – clinically similar, neurophysiologically different

“…the level of possible ADD symptoms was not assessed and the age range of patients was broader. Another explanation for the difference in behavioural findings is that the paradigm used by Riberio et al 22. was more difficult, because only one out of nine stimuli was a Nogo stimulus and all stimuli were presented at equal frequency.…”

“…There are explanations for this. Firstly, in the study by Riberio et al 22. the level of possible ADD symptoms was not assessed and the age range of patients was broader.…”

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

“…Although transcranial simulation and magnetic resonance spectroscopy studies have initiated this evidence base, identification of biomarkers linking neurofibromin expression to cognitive outcomes is still required. 25,26 Validated markers would enable pilot studies to demonstrate proof of principle and dose refinement of promising treatments to optimize clinical trial design, and they could prove useful in identifying young children at risk of cognitive problems, which might allow earlier treatment when the brain is potentially more responsive to change.…”

Discriminating between neurofibromatosis‐1 and typically developing children by means of multimodal MRI and multivariate analyses

“…The same group combined high-density EEG during a GO/NO GO task and MRS to study the relationship between the GABAergic system, neurophysiology and impulsivity in NF1. They confirmed reduced GABA+ in the medial frontal and occipital cortex and found an abnormal correlation between GABA+ level in the medial frontal cortex and response style in the GO/NO GO task relative to controls (Ribeiro et al, 2015). This same group also combined a rhythmic motor task with EEG and fMRI finding behavioral, oscillatory and brain activation (i.e., greater recruitment of extra-pyramidal system) differences between NF1 adults and matched controls .…”