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

Schizophrenia (SZ) 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. FC can be investigated on different levels, going from global features to single edges between regions, revealing diffuse and localized dysconnection patterns. In this context, SZ is characterized by a diverse global integration with reduced connectivity in specific areas 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 between 74 AAL brain areas of 15 healthy controls (HC) and 12 SZ subjects were used. Multi-level analyses and graph topological indexes evaluation were carried out by the previously published SPIDER-NET tool. Robustness was augmented by bootstrapped (BOOT) data and the stability was evaluated by removing one (RST1) or two subjects (RST2). The DMN subgraph was evaluated, toegether with overall local indexes and connection weights to enhance common activations/deactivations. At a global level, expected trends were found. The robustness assessment tests 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 ($p<0.05$), highlighting a greater divergence in the frontal lobe. These results were confirmed analyzing the negative edges, suggesting inverted connectivity between prefronto-temporal areas. In conclusion, multi-level analysis supported by BOOT is highly recommended, especially when diffuse and localized dysconnections must be investigated in limited samples.