The human brain has been described as a large, sparse, complex network characterized by efficient small-world properties, which assure that the brain generates and integrates information with high efficiency. Many previous neuroimaging studies have provided consistent evidence of 'dysfunctional connectivity' among the brain regions in schizophrenia; however, little is known about whether or not this dysfunctional connectivity causes disruption of the topological properties of brain functional networks. To this end, we investigated the topological properties of human brain functional networks derived from resting-state functional magnetic resonance imaging (fMRI). Data was obtained from 31 schizophrenia patients and 31 healthy subjects; then functional connectivity between 90 cortical and sub-cortical regions was estimated by partial correlation analysis and thresholded to construct a set of undirected graphs. Our findings demonstrated that the brain functional networks had efficient small-world properties in the healthy subjects; whereas these properties were disrupted in the patients with schizophrenia. Brain functional networks have efficient small-world properties which support efficient parallel information transfer at a relatively low cost. More importantly, in patients with schizophrenia the small-world topological properties are significantly altered in many brain regions in the prefrontal, parietal and temporal lobes. These findings are consistent with a hypothesis of dysfunctional integration of the brain in this illness. Specifically, we found that these altered topological measurements correlate with illness duration in schizophrenia. Detection and estimation of these alterations could prove helpful for understanding the pathophysiological mechanism as well as for evaluation of the severity of schizophrenia.

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Using resting-state functional magnetic resonance imaging, we examined the functional connectivity throughout the entire brain in schizophrenia. The abnormalities in functional connectivity were identified by comparing the correlation coefficients of each pair of 116 brain regions between 15 patients and 15 controls. Then, the global distribution of the abnormal functional connectivities was examined. Experimental results indicated, in general, a decreased functional connectivity in schizophrenia during rest, and such abnormalities were widely distributed throughout the entire brain rather than restricted to a few specific brain regions. The results provide a quantitative support for the hypothesis that schizophrenia may arise from the disrupted functional integration of widespread brain areas.

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We used a newly reported regional homogeneity approach to measure the temporal homogeneity of blood oxygen level-dependent signal for exploring the brain activity of schizophrenia in a resting state. The results showed decreased regional homogeneity in schizophrenia, which distributed over the bilateral frontal, temporal, occipital, cerebellar posterior, right parietal and left limbic lobes, similar to the findings reported in previous resting state functional studies. The brain regions that showed decreased regional homogeneity are believed to be involved in the psychopathology and pathophysiology of schizophrenia. Our results indicate that abnormal brain activity of schizophrenia may exist in a resting state and the regional homogeneity may be potentially helpful in understanding the resting state of schizophrenia.

Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in skeletal development. Smad4 is the central intracellular mediator of TGFβ signaling. Our previous studies reveal that Smad4 is required for maintaining the normal development of chondrocytes in the growth plate. However, its biological function during postnatal bone remodeling is largely unknown. To investigate the role of Smad4 in maintaining bone homeostasis, we disrupted the Smad4 gene in differentiated osteoblasts using the Cre-loxP system. The Smad4 mutant mice exhibited lower bone mass up to 6 months of age. The proliferation and function of the mutant osteoblasts were significantly decreased. Bone mineral density, bone volume, bone formation rate and osteoblast numbers were remarkably reduced in Smad4 mutants. Intriguingly, the trabecular bone volume in Smad4 mutant mice older than 7 months was higher than that of controls whereas the calvarial and cortical bone remained thinner than in controls. This correlated with reduced bone resorption possibly caused by downregulation of TGFβ1 and alteration of the ligand receptor activator of NF-κB (RANKL)-osteoprotegerin (OPG) axis. These studies demonstrate essential roles of Smad4-mediated TGFβ signaling in coupling bone formation and bone resorption and maintaining normal postnatal bone homeostasis.

Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.