Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse

Abstract

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1^+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1^+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1^+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

Keywords: ADHD; Autism; Mouse model; Neurofibromatosis type 1; Pediatric patients; fMRI.

Fig. 1.

Pediatric NF1 participants demonstrate disrupted association network organization. (A) A global similarity-based clustering parcellation to seven networks of two age- and gender-matched typically developing children (TDC) comparison groups, TDC1 group (left) matched for participant motion and TDC2 group (middle) matched for MRI repetition time. Network parcellation of the NF1 group (right) demonstrates a notable lack of long-distance connectivity. (B) Network overlap estimated with Sørensen–Dice index (similarity coefficient) between the two control groups (all > 0.75; left) reveals close agreement between left and right hemispheres. The similarity coefficient between TDC1 and NF1 groups (middle) and TDC2 and NF1 groups (right) is virtually equivalent for the Visual, Ventral Attention (VA) and Somatomotor (SM), but low for Limbic, Dorsal Attention (DA), Frontoparietal (FP) and Default networks. (C) Consistent with the similarity coefficient, spatial extent is conserved for the Visual network and is similar to the adult form (not shown; cf. Yeo et al., 2011). Putative SM and VA networks are similar across TDC2 and NF1 but differ relative to adults. The DA, FP, Default and Limbic networks differ between TDC2 and NF1 although the spatial extent of the two networks is similar when considered together.

Fig. 2.

Reduced posterior-anterior connectivity along the cingulate cortex in NF1 children. (A) Seed-based analysis for the posterior cingulate cortex in TDC 1(top) and NF1 (bottom) groups demonstrates reduced long-range functional connectivity in the NF1 group (p < .0001, uncorrected). (B) Connectivity profiles between the posterior cingulate cortex and a series of seeds along the anterior cingulate cortex. These profiles were submitted to a repeated-measures ANOVA, which revealed significant main effect of Group and an interaction between Group and Longitudinal axis of the cingulate cortex, indicating distance-dependent reduced connectivity in NF1 children.

Fig. 3.

Corticostriatal functional connectivity in NF1 and typically developing children (TDC). (A) Seed locations in the human cortex and striatum. (B) Three polar plots display corticostriatal functional connectivity of the three striatal sub-regions (frontoparietal, default and limbic). Polar scales ranges from z(r) of −0.2 to 0.6 in0.2 increments. (C) Bar plots depict average corticostrital connectivity between each cortical network and the different striatal seeds. Error bars indicate standard errors of the mean. (D) Quantification of the interaction between pairs of Cortical Network and Group (repeated-measures ANOVA), *p < .05, corrected for multiple comparisons using the Bonferroni correction.

Fig. 4.

Reduced posterior-anterior connectivity along the cingulate cortex in NF1 mice. (A) Seed-based analysis for the retrosplenial cortex in WT (top) and NF1 (bottom) mice demonstrates posterior-anterior functional connectivity only in the WT group (p < .001, uncorrected). (B) Connectivity profiles between the retrosplenial cortex and a series of seeds along the anterior cingulate area. These profiles were submitted to a repeated-measures ANOVA, which revealed significant main effect of Group and an interaction between Group and Longitudinal axis of the cingulate cortex, indicating distance-dependent reduced connectivity in NF1 mice. ACA – anterior cingulate cortex; AUDv/Tea – ventral auditory/temporal association cortices; MO – motor cortex; PL – prelimbic cortex; PTLp – posterior parietal association cortex; RSP – retrosplenial cortex.

Fig. 5.

Functional and anatomical corticostriatal connectivity in the mouse brain. Qualitative comparisons between optical density maps (green) representing anatomical connectivity, and statistical parametric maps (p < .0001, voxel extent ≥ 5, uncorrected) representing positive functional connectivity correlations in WT (blue-light blue) and NF1 (red-yellow) mice, are presented for four cortical regions. Overlapping corticocortical and corticostriatal connections can be observed in WT but to a lesser extent in NF1. The parametric maps are overlaid on a downsampled version of the Allen Mouse Brain Atlas that matches at the original fMRI resolution. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6.

Alterartion of corticostriatal functional connectivity in NF1 mice. (A) Seed locations in the mouse cortex and striatum. (B) Three polar plots display corticostriatal functional connectivity of the three striatal subregions (frontal, somatomotor and auditory). Polar scales range from z(r) of −0.05 to 0.2 in 0.05 increments.(C) Bar plots depict average corticostrital connectivity between each cortical network and the different striatal seeds. Error bars indicate standard errors of the mean(D) Quantification of the interaction between pairs of Cortical Network and Group (repeated-measured ANOVA, frontal [FR], somatomotor [SM] and auditory [AUD]), **p < .01, ***p < .001, corrected for multiple comparisons using the Bonferroni correction. AUD – auditory cortex: dorsal (d), primary (p), ventral (v); MO – motor cortex: primary (p), secondary (s); ORBm – medial orbitofrontal cortex; PL – prelimbic cortex; PTLp – posterior parietal association cortex; RSP – retrosplenial cortex; SSp-bfd – barrel-related primary somatosensory cortex; SSs – secondary somatosensory cortex; VIS – visual cortex: anteromedial (am), primary (p).