Diffuse and Localized Functional Dysconnectivity in Schizophrenia: a Bootstrapped Top-Down Approach

Schizophrenia is a brain disorder leading to detached mind's normally integrated processes. Hence, the exploration of the symptoms in relation to functional connectivity (FC) had great relevance in the field. Connectivity can be investigated on different levels, going from global features to single edges between pairs of regions, revealing diffuse and localized dysconnection patterns. In this context, schizophrenia is characterized by a different global integration with reduced connectivity in specific areas of the brain, part of the Default Mode Network (DMN). However, the assessment of FC presents various sources of uncertainty. This study proposes a multi-level approach for more robust group-comparison.FC data between 74 AAL brain areas of 15 healthy controls (HC) and 12 subjects with chronic schizophrenia (SZ) were used. Multi-level analyses were carried out by the previously published SPIDER-NET tool. Graph topological indexes were evaluated to assess global abnormalities. Robustness was augmented by bootstrapped (BOOT) data and the stability was evaluated by removing one (RST1) or two subjects (RST2). The DMN subgraph was extracted and specifically evaluated. Changes relevant to the overall local indexes were also analyzed. Finally, the connection weights were explored to enhance common strongest activations/deactivations.At a global level, expected trends of the indexes were found and the significance of modularity (p = 0:043) was not confirmed by BOOT (p = 0:133). The robustness assessment tests (both RST1 and RST2) highlighted more stable results for BOOT compared to the direct data testing. Conversely, significant results were found in the analysis at lower levels. The DMN highlighted reduced connectivity and strength as well as increased deactivation in the SZ group. At local level, 13 areas were found to be significantly different (p < 0:05) in the groups, highlighting a greater divergence in the frontal lobe. These results were confirmed analyzing the single negative edges, suggesting inverted connectivity between prefronto-temporal areas.In conclusion, multi-level analysis supported by BOOT is highly recommended when analyzing FC, especially when diffuse and localized dysconnections must be investigated in limited samples.