Connection density affects the behavior of functional brain network metrics

Many neuropsychiatric disorders are associated with alterations in functional brain network (FBN) connectivity. Functional network metrics reveal alterations in FBNs by quantifying changes in network segregation and integration. In general, calculating functional network metrics requires a reasonable thresholding or binarization of the network, which is a challenging task. We observe that the same functional network metric yields conflicting conclusions across different studies: some report higher values in patient groups compared to healthy groups, while others report lower values in patient groups. This paper postulates the hypothesis that arbitrary choices of connection density are responsible for the inconsistency of experimental results.

We investigate the behavior of 16 functional network metrics using three independent datasets that include patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and schizophrenia (SZ). Our analysis covers connection densities from 1% to 99% (in 1% intervals) and examines both binary and weighted networks in time and wavelet domains.

Our results reveal a "reversal phenomenon" in many functional network metrics, where the difference between patient and healthy groups reverses as connection density increases. This provides a plausible explanation for the inconsistent conclusions reported in the literature. We further find that the metrics showing significant differences vary across analytical modes (domain and network type). Moreover, the significant metrics differ across diseases, reflecting disease-related heterogeneity.

To avoid the "reversal phenomenon" and maximize the inter-group differences, we establish optimal connection density ranges for FBN analyses across various neuropsychiatric disorders, thereby improving the consistency and comparability of research results. In addition, we identify a set of metrics that demonstrate robustness across multiple datasets, providing a reliable reference for subsequent analyses. Our work sheds new light into the widespread use of functional network metrics and emphasizes that standardized connection density selection is crucial for achieving consistent results.