The Connectomic Blueprint of Schizophrenia

Abstract

The foundation for the studies comprising this thesis is the notion that schizophrenia's symptoms stem from faulty integration of neural information due to disruptions in the brain's anatomical connections. This theory is by no means new; it can be traced back to visionary neuroscientists in the late 19th century era of Brain Psychiatry, but - lacking the proper methodological tools - scientists were long unable to support it with neurobiological evidence. It wasn't until the late 20th century development of neuroimaging techniques allowing the examination of functional interaction between brain regions and their anatomical connections that the first evidence for aberrant connectivity in schizophrenia started to emerge. More recently, the application of the mathematical framework of graph theory to the brain's wiring diagram as a whole heralded what might be called the era of Brain Complexity, with an unprecedented interest in studying the brain as the complex network it is. These advances have permeated investigations of neuropsychiatric disorders, and discoveries of an altered organization of the brain's wiring pattern in schizophrenia patients have led to the hypothesis that schizophrenia might best be regarded as a brain network disorder. This thesis contributes to this development, by examining how brain network abnormalities in schizophrenia relate to symptoms, familial predisposition, patterns of brain network development, specificity to the disorder, and functional outcome. Our findings support the notion that schizophrenia affects the organization of the brain’s wiring diagram, particularly impacting central brain hubs and their mutual rich club connections, thereby reducing the brain’s potential for integrative processing. We propose that this deficit may result from a deviant pattern of connectome development, related to familial risk for schizophrenia. As hub and rich club connectivity were found not to be affected in bipolar I disorder, rich club disconnectivity may be relatively specific to schizophrenia. In addition, our finding that connectome organization is predictive of functional outcome highlights the potential of connectomics in someday informing clinical practice in psychiatry.