BACKGROUND: Schizophrenia manifests as a constellation of both psychotic symptoms (eg. hallucinations, delusions) and so-called negative symptoms. The latter includes anhedonia, avolition, amotivation and they are the strongest predictors of disability. Resting state fMRI (rsfMRI) has demonstrated that the brain is organized into low-dimensional number (7-17) brain networks and this allowed visualization of the relationship between symptom severity and large-scale brain network organization. Traditional rsfMRI analyses have assumed that the spatial organization of these networks are spatially invariant between individuals. This dogma has recently been overturned with the observation that the spatial organization of these brain networks shows significant variation between individuals. We sought to determine if previously observed relationships between symptom severity and network connectivity are actually due to individual differences in spatial organization. METHODS: 44 participants diagnosed with schizophrenia underwent rsfMRI scans and clinical assessment. A multivariate pattern analysis was used to examine how each participant’s whole brain functional connectivity correlates with ‘negative’ symptom severity. RESULTS: Brain connectivity to a region of the right dorso-lateral pre-frontal cortex (r DLPFC) correlates with symptom severity. The result is explained by the individual differences in the topographic distribution of two brain networks: the default mode network (DMN) and the task positive network (TPN). Both networks demonstrate strong (r~0.49) and significant (p<0.001) relationships between topography and symptom severity. For individuals with low symptom severity, this critical region is a part of the DMN. In highly symptomatic individuals, this region is a part of the TPN. CONCLUSIONS: Previously overlooked individual variation in brain organization is tightly linked to individual variation in schizophrenia symptom severity. The recognition of critical links between network topology and pathological symptomology may serve as a guide for future interventions aimed at establishing causal relationships between certain critical regions of the brain and cognitive and behavioral phenotypes. Thus, fMRI and network topology may be translated to a clinical setting as a viable, individual-centered treatment option. / 2020-06-17T00:00:00Z