Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I

Abstract

Neurofibromatosis type 1 (NF1) has regularly been associated with cognitive, social, and behavioral problems. The fact that many different cognitive and behavioral impairments have been observed in NF1 suggests that networks of brain regions are involved rather than specific brain regions. Here, we examined whether functional connectivity was different in NF1 and, if so, whether associations were present with cognitive, social, and behavioral outcomes. Fourteen NF1 patients (8 male, age: M = 12.49, SD = 2.65) and 30 healthy controls (HC; 23 male, age: M = 12.30, SD = 2.94; p = 0.835) were included. Functional connectivity was assessed using functional restingstate scanning. We analyzed brain regions that have been associated with cognitive and social functions: the bilateral ventral anterior cingulate cortex (vACC), the bilateral amygdala, the bilateral orbitofrontal cortex (OFC), and the posterior cingulate cortex (PCC). For NF1 patients, connection strengths between brain regions showing HC-NF1 differences were correlated with parent reports of cognitive, social, and behavioral functioning. Compared to HC, patients showed differences in functional connectivity between the left vACC and the frontal cortex, insula, and subcortical areas (caudate, putamen), between the left amygdala and the frontal cortex, insula, supramarginal gyrus, and PCC/precuneus, and between the left OFC and frontal and subcortical areas (caudate, pallidum). In patients, indications were found for associations between increased frontofrontal and temporofrontal functional connectivity with cognitive, social, and behavioral deficits (r-range = 0.536-0.851). NF1 patients showed differences in functional connectivity between areas associated with cognitive and social functioning when compared to controls. This, plus the fact that connectivity strengths in these networks were associated with worse cognitive, social, and behavioral outcomes, suggests a neuropathological basis for the widespread deficits observed in NF1.

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

“…This result does not allow for causal inference but supports the hypothesis that in addition to the amygdala (Molosh et al ), alterations in PFC in Nf1 +/− mice (and also in NF1 patients) contribute to the social deficits of these mice. This finding is consistent with a recent human study in NF1 patients, suggesting an important role for the frontal cortex in social cognition performance (Loitfelder et al ).…”

“…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 ).…”

“…Intellectual disabilities occur in up to 50% of NF1 children; they may manifest as cognitive slowing, memory disturbances, difficulties in solving strategic problems, visuospatial impairments, deficits in motor coordination, mental flexibility and affective disorders (Diggs-Andrews & Gutmann 2013;Ribeiro et al 2012;Silva et al 1997;Violante et al 2013;Zöller et al 1997). Recent evidence suggests that social cognitive deficits are common in NF1 and that this condition qualifies as an autism spectrum disorder (Lehtonen et al 2013;Loitfelder et al 2015;Plasschaert et al 2015;Pride et al 2013Pride et al , 2014Walsh et al 2013).…”

Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1

“…The observed intra-module clustering pattern suggests that NF1 networks have stronger between-module connectivity and weaker within-module connectivity than controls. These findings are in line with the two prior resting state functional MRI studies of NF1, in which (using seed-based approaches) the investigators find altered short-range connectivity patterns in NF1 participants compared to controls [Chabernaud et al, 2012;Loitfelder et al, 2015]. Together, these data indicate less tightly organized clustering of visual and default mode networks and potentially impaired intramodular affiliation.…”

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). …”