The connectomics of schizophrenia
Neuroimaging studies show impaired structural and functional connectivity in individuals diagnosed with schizophrenia (39–41). The dysconnection between different brain regions of GM and the WM circuits that connect them are consistent with reduced functional connectivity revealed in both resting state and task-based functional (fMRI) studies (32, 41). Recent advances in the use of MRI and in particular diffusion-weighted imaging (DTI) have brought insight into the extent of structural WM dysconnectivity and alterations in the macro-scale neuronal wiring in schizophrenia. Most studies have investigated fractional anisotropy (FA), a neuroimaging marker that indexes the constraint of the direction of water diffusion in WM and can be a measure of an abnormality in the integrity of myelin microstructure or axonal integrity or differences in the orientation of how axonal fibers are organized. White matter in the frontal and temporal lobes have been the most frequently reported with reduced FA integrity in DTI studies of those with schizophrenia (39–41). Meta-analyses of voxel-based DTI studies in schizophrenia have found significant decreases in two main brain regions, the left frontal deep WM and left temporal deep WM (42), with overlapping GM and WM structural abnormalities (43). A more recent meta-analysis that included 29 independent international studies found global WM microstructural disruptions throughout the entire brain (44).
Consistent with these findings, an additional imaging study found significant decreases in WM FA to not only involve the fronto-temporal regions, but also to be widespread throughout each lobe of the brain, including the cerebellum. Major fiber bundles that connect the cortical lobes including the corpus callosum, cingulum and thalamic radiations exhibited the most severe pathology. More than 50% of the cortico-cortical and cortico-subcortical WM fibers that provide the connections between those hub regions that contribute to the “rich club” in the brain were affected (45) and network hubs located in association cortex particularly affected (20, 21). These significant structural disturbances may be responsible for the widespread disruption of cortical information processing and integration of information across multiple regions of the brain in schizophrenia.
Functional MRI studies have also suggested abnormalities in the connectivity of brain networks in schizophrenia and relate to the structural disturbances that interconnect them. While reduced functional connectivity is a replicated finding among many studies (32, 41, 46, 47), there have also been reports of increase in functional connectivity in the illness (48, 49). The discrepancy may simply be related to non-uniform changes in brain connectivity, such as hyper-synchrony of neuronal ensembles vs. dysregulated networks, fMRI preprocessing errors, or abnormalities in neuronal wiring and oscillatory firing and compensatory hyper-connectivity of important hubs within the association cortex as a consequence of the illness (50).