Gyrification, cortical and subcortical morphometry in neurofibromatosis type 1: an uneven profile of developmental abnormalities

Abstract

BackgroundNeurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with NF1. Previous studies have reported contradictory findings and have focused only on volumetric measurements. Here, we investigated the volumes of subcortical structures and the composite dimensions of the cortex through analysis of cortical volume, cortical thickness, cortical surface area and gyrification.MethodsWe studied 14 children with NF1 and 14 typically developing children matched for age, gender, IQ and right/left-handedness. Regional subcortical volumes and cortical gyral measurements were obtained using the FreeSurfer software. Between-group differences were evaluated while controlling for the increase in total intracranial volume observed in NF1.ResultsSubcortical analysis revealed disproportionately larger thalami, right caudate and middle corpus callosum in patients with NF1. Cortical analyses on volume, thickness and surface area were however not indicative of significant alterations in patients. Interestingly, patients with NF1 had significantly lower gyrification indices than typically developing children primarily in the frontal and temporal lobes, but also affecting the insula, cingulate cortex, parietal and occipital regions.ConclusionsThe neuroanatomic abnormalities observed were localized to specific brain regions, indicating that particular areas might constitute selective targets for NF1 gene mutations. Furthermore, the lower gyrification indices were accompanied by a disproportionate increase in brain size without the corresponding increase in folding in patients with NF1. Taken together these findings suggest that specific neurodevelopmental processes, such as gyrification, are more vulnerable to NF1 dysfunction than others. The identified changes in brain organization are consistent with the patterns of cognitive dysfunction in the NF1 phenotype.

Brain and behaviour phenotyping of a mouse model of neurofibromatosis type‐1: an MRI/DTI study on social cognition

“…No major axonal disorganization or disruption seems to be present in Nf1 +/− mice brains, and the MD and FA differences could be a consequence of increased spacing between axons. This notion is also consistent with a study in NF1 patients by Violante et al (). Moreover, inter‐hemispheric differences in MD were also observed, which a pattern often found in neurodevelopmental disorders due to their slightly distinct developmental trajectory (Table ).…”

“…In this study, featuring a structure–function correlation approach, we found indications for an important role of the PFC in the social cognition deficits in the Nf1 +/− mouse model. The PFC and CPu were chosen as regions of interest for analyses because previous human studies had already shown impairments in these structures (Cutting et al ; Duarte et al ; Greenwood et al ; Karlsgodt et al ; Loitfelder et al ; Shilyansky et al ,b; Steen et al ; Violante et al ). Despite their correlational (non‐causal) nature, these results are interesting because they point to an important role of high‐level structures such as the PFC in social cognition, in addition to the amygdala (Molosh et al ).…”

Emerging genotype–phenotype relationships in patients with large NF1 deletions

“…The negative effects of OMgp haploinsufficiency on synaptic plasticity could be additive in relation to the consequences of the loss of the NF1 gene product neurofibromin, an important regulator of Ras signalling in the brain. At least 50% of the patients with intragenic NF1 mutations suffer from intellectual disabilities manifesting as cognitive slowing, memory disturbances, difficulties in solving strategic problems, visuospatial impairment and deficits in motor coordination (Diggs-Andrews and Gutmann 2013; Violante et al 2013). These symptoms are further aggravated in patients with NF1 microdeletions who exhibit a significantly lower mean FSIQ than patients with intragenic NF1 mutations (Descheemaeker et al.…”

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

“…In particular, NF1 affects the structure, function and neurochemistry of the central nervous system, leading to learning impairments (Payne, Moharir, Webster, & North, 2010; Violante, Ribeiro, Edden, et al, 2013). Individuals with NF1 present increased white matter volume, particularly within the frontal lobe and the corpus callosum, as well as increased grey matter volume, particularly in the thalamus and right caudate nucleus (Duarte et al, 2014; Payne et al, 2010; Violante, Ribeiro, Silva, & Castelo-Branco, 2013). Reduced integrity of white matter microstructure is also found in NF1, suggesting a reduction in effective structural connectivity (Karlsgodt et al, 2012).…”