Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1

Abstract

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits and autism spectrum disorders. As a single gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity MRI (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

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

“…The relative poor performance of functional measures goes rather well with a previous FDG PET study that measured brain metabolism and hence activity in adults with NF1 and that showed only a small cluster of hypoactivity in the thalamus (Apostolova et al, 2015). Our results using indexes of connectivity are also partly in accord with those of Tomson et al (2015) who showed that both modularity (i.e., an index of clustering of neighboring nodes) and longdistance connectivity (in particular antero-posterior) were different between NF1 and TD. Task-evoked functional indexes could be better suited to differentiate between the two groups.…”

“…As for fMRI, NF1 children showed reduced activation in a set of area within the salience network (i.e., inferior occipital gyrus, fusiform gyrus/posterior cerebellum, pre-SMA and inferior frontal gyrus) during a GO-NO GO task (Pride, Korgaonkar, North, Barton, & Payne, 2017). Finally, Tomson et al (2015), have shown abnormal network-related measures in the connectome of children affected by NF1 using graph-theory. Other studies have observed reduced deactivation of the default mode network (DMN) in NF1 subjects relative to controls during low level visual stimulation (Violante et al, 2012a) or spatial working memory task (Ibrahim et al, 2017).…”

“…Interestingly, a previous clinical study showed that the drug lovastatin, that ameliorate cognitive symptoms in NF1 patients, increase long range connectivity within the regions of the DMN. Finally, Tomson et al (2015), have shown abnormal network-related measures in the connectome of children affected by NF1 using graph-theory.…”

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study

“…It is also implicated in spatial representations of numbers (36). The decrease we observed in task-based neural activity within this region has also been observed in the resting state in patients with NF1 (37). Consistent with the directionality of our findings, prior fMRI studies have also found decreased neural activity in patients with NF1 relative to controls within the context of visual processing (37-39), and spatial working memory tasks (7).…”

Computerized cognitive training for children with neurofibromatosis type 1: A pilot resting-state fMRI study

“…Preliminary evidence suggests that resting state (i.e., task-free) BOLD activity patterns in NF1 may be modifiable (e.g., by pharmacological treatment: Chabernaud et al, 2012). Relative to healthy controls, abnormal resting state functional connectivity has also been identified in NF1 (Loitfelder et al, 2015; Tomson et al, 2015). …”