Reduced functional connectivity of the thalamus in schizophrenia.

<p>(A) Statistical significance (t-scores) of decreases in the positive (blue-cyan) and negative (red-yellow) FC of the thalamus in schizophrenia (N  =  69) compared to healthy controls (N  =  74), superimposed on lateral and medial surface views of the cerebrum and anterior and posterior surface views of the cerebellum. (B) Average ROI measures of thalamic FC across subjects for selected ROIs (0.9 mm cubes; 27 voxels) centered at the MNI coordinates listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096176#pone.0096176.s007" target="_blank">Table S3</a>, showing the lower absolute FC for schizophrenia patients than for controls in thalamus (THA), orbitofrontal cortex (OFC; BA 11), posterior lobe of the cerebellum (CBL), posterior cingulum (PCC) (positive connectivity: blue arrows; P < 0.0005), and for superior and middle temporal (STG and MTG; BA 22) and postcentral (PCG; BA 3) gyri and cuneus (BA 19) (negative connectivity: orange arrows; P < 0.0005). MNI coordinates of the bilateral cubic seed (54 voxels) in the thalamus: <i>x</i>  =  ±6 mm; <i>y</i>  =  −3 mm; and <i>z</i>  =  0 mm.</p

Mapping Small-World Properties through Development in the Human Brain: Disruption in Schizophrenia

<div><p>Evidence from imaging studies suggests that the human brain has a small-world network topology that might be disrupted in certain brain disorders. However, current methodology is based on global graph theory measures, such as clustering, <i>C</i>, characteristic path length, <i>L</i>, and small-worldness, <i>S</i>, that lack spatial specificity and are insufficient to identify regional brain abnormalities. Here we propose novel ultra-fast methodology for mapping local properties of brain network topology such as local <i>C</i>, <i>L</i> and <i>S</i> (<i>lC</i>, <i>lL</i> and <i>lS</i>) in the human brain at 3-mm isotropic resolution from ‘resting-state’ magnetic resonance imaging data. Test-retest datasets from 40 healthy children/adolescents were used to demonstrate the overall good reliability of the measures across sessions and computational parameters (intraclass correlation > 0.5 for <i>lC</i> and <i>lL</i>) and their low variability across subjects (< 29%). Whereas regions with high local functional connectivity density (<i>l</i>FCD; local degree) in posterior parietal and occipital cortices demonstrated high <i>lC</i> and short <i>lL</i>, subcortical regions (globus pallidus, thalamus, hippocampus and amygdala), cerebellum (lobes and vermis), cingulum and temporal cortex also had high, <i>lS</i>, demonstrating stronger small-world topology than other hubs. Children/adolescents had stronger <i>l</i>FCD, higher <i>lC</i> and longer <i>lL</i> in most cortical regions and thalamus than 74 healthy adults, consistent with pruning of functional connectivity during maturation. In contrast, <i>l</i>FCD, <i>lC</i> and <i>lL</i> were weaker in thalamus and midbrain, and <i>lL</i> was shorter in frontal cortical regions and cerebellum for 69 schizophrenia patients than for 74 healthy controls, suggesting exaggerated pruning of connectivity in schizophrenia. Follow up correlation analyses for seeds in thalamus and midbrain uncovered lower positive connectivity of these regions in thalamus, putamen, cerebellum and frontal cortex (cingulum, orbitofrontal, inferior frontal) and lower negative connectivity in auditory, visual, motor, premotor and somatosensory cortices for schizophrenia patients than for controls, consistent with prior findings of thalamic disconnection in schizophrenia.</p></div

Reduced clustering, path length and local degree in schizophrenia.

<p>(A) Statistical significance of lower graph theory measures for 69 schizophrenia patients than for 74 healthy controls superimposed on axial views of the human brain. (B) Average values of the graph theory measures in anatomical ROI that demonstrated significant differences in the measures between patients and controls. X-axis labels: Brodmann Areas (number labels), thalamus (THA), putamen (PUT), globus pallidus (GP), amygdala (AMY) and the posterior lobe of the cerebellum (lobe X). Correlation thresholds: <i>R</i>_T1  =  0. 50; <i>R</i>_T2  =  0.65.</p

Voxelwise association between graph-theory measures.

<p>Two-dimensional histograms (probability distributions) corresponding to (non-linear) relationships between voxelwise measures of <i>l</i>FCD, <i>lC</i>, <i>lL</i> and <i>lS</i>, averaged across children (N  =  40), adults (N  =  74) and schizophrenia patients (N  =  69). The color maps (frequency) reflect the number of voxels within each of the 128 × 128 uniform 2d-intervals (bins). Dashed lines reflect the power scaling in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096176#pone-0096176-g003" target="_blank">Fig 3</a>. The dash dot line indicates the boundary of the small-world topology (<i>lS</i>  =  1). Correlation thresholds: <i>R</i>_T1  =  0. 50; <i>R</i>_T2  =  0.65.</p

Statistical significance for differences in graph theory measures between schizophrenia patients and controls.

<p>Sample: 69 patients and 74 matching controls. <i>l</i>C: local clustering; <i>l</i>L: local characteristic path length; <i>l</i>S: local small-worldness; <i>l</i>FCD: local degree. *One way ANOVA: P_FWE < 0.05 cluster-level corrected. SPM8 model: one-way ANOVA with gender, age and motion covariates.</p

Strength, statistical significance and reliability for local measures of degree, clustering (<i>lC</i>) and characteristic path length (<i>lL</i>) at the locations of the functional connectivity density (<i>l</i>FCD) hubs in the brain of children/adolescents.

<p>ICC: two-way mixed single measures intraclass correlation, ICC(3,1).</p><p>T: Student's t-test.</p

Regional measures of absolute graph theory properties.

<p>(A) Average strength of local clustering, <i>lC</i>, characteristic path length, <i>lL</i>, and functional connectivity density (degree), <i>l</i>FCD, of the networks functionally connected to each imaging voxel, superimposed on axial views of the human brain. (B) Maps of two-way mixed single measures intraclass correlation, ICC(3,1) demonstrating the good reliability (ICC > 0.5) of <i>lC</i>, <i>lL</i> and <i>l</i>FCD across sessions and method thresholds. Sample: 3 resting-state sessions from 40 healthy children (WashU dataset), correlation thresholds: <i>R</i>_T1  =  0.40, 0.45 and 0.50; <i>R</i>_T2  =  0.65, 0.70 and 0.75.</p

Strength and statistical significance for local clustering (<i>lC</i>) and characteristic path length (<i>lL</i>), relative to comparable random networks, and for local small-worldness (<i>lS</i>) and degree for the MNI coordinates of <i>l</i>C/<i>l</i>C_rand local maxima from children/adolescents.

<p><i>l</i>FCD: Functional connectivity density. T: Student's t-test. Sample: WashU (40 healthy subjects, 3 ‘resting-state’ MRI sessions). ROI analysis: Average values in 9-mm cubic ROIs (27 voxels) centered at the MNI coordinates of the local maxima.</p

Pruning of functional connectivity during brain maturation.

<p>(A) Statistical significance of higher graph theory measures for 40 children than for 74 adults superimposed on axial views of the human brain. (B) Average values of the graph theory measures in anatomical ROI that demonstrated significant differences in the measures between children and adults. X-axis labels: Brodmann Areas (number labels), thalamus (THA), putamen (PUT), globus pallidus (GP), amygdala (AMY) and the posterior lobe of the cerebellum (lobe X). Correlation thresholds: <i>R</i>_T1  =  0. 50; <i>R</i>_T2  =  0.65.</p

Overlapping hypo connectivity patterns for thalamus and midbrain in schizophrenia.

<p>Overlap and distinct patterns of hypo connectivity with thalamus (red) and SN (blue) for 69 schizophrenia patients versus 74 healthy controls at P < 0.001, superimposed on axial and coronal views of the human brain. The weaker positive (A) and negative (B) connectivity patterns overlap (pink) in thalamus, BAs 2–4, 6, 17–19, 21, 23, 24, 36, 37, 43 and differentiate in ventral striatum, putamen, pallidum (blue), cerebellum, BAs 10, 11, 32, 40 and 44–47 (red).</p