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Original Investigation |

Identifying Large-Scale Brain Networks in Fragile X Syndrome

Scott S. Hall, PhD1; Heidi Jiang, BS2,3; Allan L. Reiss, MD1,4; Michael D. Greicius, MD2
[+] Author Affiliations
1Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
2Functional Imaging in Neuropsychiatric Disorders Lab, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California
3currently a graduate student in the Northwestern University Interdepartmental Neuroscience Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
4Departments of Radiology and Pediatrics, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California
JAMA Psychiatry. 2013;70(11):1215-1223. doi:10.1001/jamapsychiatry.2013.247.
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Importance  Fragile X syndrome (FXS) is an X-linked neurogenetic disorder characterized by a cognitive and behavioral phenotype resembling features of autism spectrum disorder. Until now, research has focused largely on identifying regional differences in brain structure and function between individuals with FXS and various control groups. Very little is known about the large-scale brain networks that may underlie the cognitive and behavioral symptoms of FXS.

Objective  To identify large-scale, resting-state networks in FXS that differ from control individuals matched on age, IQ, and severity of behavioral and cognitive symptoms.

Design, Setting, and Participants  Cross-sectional, in vivo neuroimaging study conducted in an academic medical center. Participants (aged 10-23 years) included 17 males and females with FXS and 16 males and females serving as controls.

Main Outcomes and Measures  Univariate voxel-based morphometric analyses, fractional amplitude of low-frequency fluctuations (fALFF) analysis, and group-independent component analysis with dual regression.

Results  Patients with FXS showed decreased functional connectivity in the salience, precuneus, left executive control, language, and visuospatial networks compared with controls. Decreased fALFF in the bilateral insular, precuneus, and anterior cingulate cortices also was found in patients with FXS compared with control participants. Furthermore, fALFF in the left insular cortex was significantly positively correlated with IQ in patients with FXS. Decreased gray matter density, resting-state connectivity, and fALFF converged in the left insular cortex in patients with FXS.

Conclusions and Relevance  Fragile X syndrome results in widespread reductions in functional connectivity across multiple cognitive and affective brain networks. Converging structural and functional abnormalities in the left insular cortex, a region also implicated in individuals diagnosed with autism spectrum disorder, suggests that insula integrity and connectivity may be compromised in FXS. This method could prove useful in establishing an imaging biomarker for FXS.

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Figure 1.
Gray Matter Density Differences Between Controls and Patients With FXS Using Voxel-Based Morphometry

All results were obtained with the use of threshold-free cluster enhancement with q < 0.05, false discovery rate corrected. Red-yellow indicates regions of significantly greater gray matter density in patients with fragile X syndrome (FXS) compared with controls, and blue regions show the opposite comparison. Images are displayed in radiologic convention: the left side of the image corresponds to the right side of the brain. Coordinates refer to the x, y, and z dimensions of Montreal Neurological Institute space.

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Figure 2.
Brain Regions Showing Significant Reduction in fALFF in Patients With FXS

A, Analysis of fractional amplitude of low-frequency fluctuations (fALFF) between 0.01 and 0.10 Hz, using threshold-free cluster enhancement (TFCE) with q< 0.05 false discovery rate correction. Blue indicates areas where controls had significantly more fALFF than did patients with fragile X syndrome (FXS). No regions survived multiple comparisons correction for the opposite contrast. B, fALFF difference map for controls > FXS in blue overlaid with FXS fALFF maps positively covaried with IQ in yellow at TFCE with P < .001 uncorrected. A few regions in the cerebellum were negatively covaried with fALFF at TFCE with P < .001 (not pictured, see the Supplement [eTable 3]). C, Scatterplot of correlation between IQ scores and mean fALFF values grouped by sex within the surviving left insula cluster thresholded at P < .001 uncorrected. For additional details, see the Figure 1 caption.

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Figure 3.
Brain Regions Showing Reduced Network Connectivity in Patients With FXS

A, Group-independent component analysis depicting 11 networks coded by color: anterior and ventral default mode network (DMN), left and right executive control network (ECN), language, precuneus, salience, visuospatial, higher visual, primary visual, and sensorimotor. B, Dual regression results, controls > fragile X syndrome (FXS) using threshold-free cluster enhancement (TFCE) with q< 0.05 false discovery rate (FDR) corrected and color coded by network membership. One thalamic cluster in the primary visual network (not pictured) survived TFCE with q< 0.05 FDR correction for the opposing comparison. For additional details, see the Figure 1 caption.

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Figure 4.
Brain Regions Showing Reductions in Between-Group VBM, fALFF, and Functional Connectivity in Patients With FXS

Blue region depicts surviving cluster at intersection of controls > fragile X syndrome (FXS) voxel-based morphometry (VBM), controls > FXS fractional amplitude of low-frequency fluctuations (fALFF), and controls > FXS dual regression within the salience network; threshold-free cluster enhancement with q< 0.05 false discovery rate correction used for each analysis. For additional details, see the Figure 1 caption.

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