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nf1 seeds

Manual assertion inferred from combination of experimental and computational evidence i

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Manual assertion based on experiment in i

Molecule processing

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

Nf1 seeds

40 mm 3 sphere located in the posterior cingulate cortex in which seed-based Fisher’s Z transformed r correlation maps submitted to a one-way t-tests (SPM, Wellcome Department of Cognitive Neurology, London, UK). In addition, seed-to-seed analysis examined the connectivity between the posterior and anterior cingulate cortex. A similar seed-to-seed approach was used to characterize corticostriatal connectivity by calculating the Z transformed r correlation between striatal seeds (in volume space) and cortical seeds (in surface space), as previously described (Choi et al., 2012).

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.

2.3. Human data preprocessing

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.

B.S., E.B., S.C., and I.K. designed research; B.S. E.B., G.Z., J.A, A.K., R.J.P., L.G.V., M.T.A. performed research; B.S., E.B., G.Z., and I.K. analyzed data; and B.S., E.B., G.Z., N.B., F.X.C., L.B.-S., R.J.P, L.G.V., S.C., M.T.A., and I.K. wrote the paper.

2.6. Experimental design and statistical analysis

Here, we report a cross-species comparative analysis of the functional organization of the NF1 brain in both humans and mice. In typically developing children, we characterized the organization of large-scale cortical functional networks and formation of corticostriatal functional connectivity in this age group for the first time and identified alterations in functional organization associated with NF1. We then applied the same functional imaging method in a mouse model of NF1 and found similar alterations in corticocortical and corticostriatal connectivity.