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 ).…”

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 ).…”

Influences of RASopathies on Neuroanatomical Variation in Children

“…To investigate this further, the syndrome level provides further context to understand the divergent effect on subcortical volumes. Consistent with previously reported findings within individuals with NS, decreased subcortical volumes were observed, ( 9 , 11 , 12 ), whereas NF1 had increased subcortical volumes compared to TD ( 13 , 14 ). Children with NS show decreased volumes compared to children with TD in the caudate, pallidum, and putamen, which is consistent with previous findings indicating that NS has decreased striatal volumes ( 9 ), and has been linked to inattentiveness, hyperactivity, and inhibition control ( 9 , 11 , 43 ).…”

GABA deficiency in NF1

“…GABA A receptor density was also found to be reduced in patients in discrete locations: parieto-occipital cortex, midbrain, and thalamus. Alterations in the parieto-occipital cortex are in agreement with functional 27 , 28 and anatomical 29 , 30 abnormalities reported in NF1. Likewise, thalamic metabolic 31 – 33 and volumetric alterations 30 have been previously reported.…”

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 ).…”

Influences of RASopathies on Neuroanatomical Variation in Children

“…To investigate this further, the syndrome level provides further context to understand the divergent effect on subcortical volumes. Consistent with previously reported findings within individuals with NS, decreased subcortical volumes were observed, ( 9 , 11 , 12 ), whereas NF1 had increased subcortical volumes compared to TD ( 13 , 14 ). Children with NS show decreased volumes compared to children with TD in the caudate, pallidum, and putamen, which is consistent with previous findings indicating that NS has decreased striatal volumes ( 9 ), and has been linked to inattentiveness, hyperactivity, and inhibition control ( 9 , 11 , 43 ).…”

GABA deficiency in NF1

“…GABA A receptor density was also found to be reduced in patients in discrete locations: parieto-occipital cortex, midbrain, and thalamus. Alterations in the parieto-occipital cortex are in agreement with functional 27 , 28 and anatomical 29 , 30 abnormalities reported in NF1. Likewise, thalamic metabolic 31 – 33 and volumetric alterations 30 have been previously reported.…”

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 ).…”

Influences of RASopathies on Neuroanatomical Variation in Children

“…To investigate this further, the syndrome level provides further context to understand the divergent effect on subcortical volumes. Consistent with previously reported findings within individuals with NS, decreased subcortical volumes were observed, ( 9 , 11 , 12 ), whereas NF1 had increased subcortical volumes compared to TD ( 13 , 14 ). Children with NS show decreased volumes compared to children with TD in the caudate, pallidum, and putamen, which is consistent with previous findings indicating that NS has decreased striatal volumes ( 9 ), and has been linked to inattentiveness, hyperactivity, and inhibition control ( 9 , 11 , 43 ).…”

GABA deficiency in NF1

“…GABA A receptor density was also found to be reduced in patients in discrete locations: parieto-occipital cortex, midbrain, and thalamus. Alterations in the parieto-occipital cortex are in agreement with functional 27 , 28 and anatomical 29 , 30 abnormalities reported in NF1. Likewise, thalamic metabolic 31 – 33 and volumetric alterations 30 have been previously reported.…”