Quantifying the influence of biophysical factors in shaping brain communication through remnant functional networks

Abstract Functional connectivity (FC) reflects brain-wide communication essential for cognition, yet the role of underlying biophysical factors in shaping FC remains unclear. We quantify the influence of physical factors—structural connectivity (SC) and Euclidean distance (DC), which capture anatomical wiring and regional distance—and molecular factors—gene expression similarity (GC), and neuroreceptor congruence (RC), representing neurobiological similarity—on resting-state FC. We assess how these factors impact graph-theoretic and gradient features, capturing pairwise and higher-order interactions. By generating remnant functional networks after selectively removing connections tied to specific factors, we show that molecular factors, particularly RC, dominate graph-theoretic features, while gradient features are shaped by a mix of molecular and physical factors, especially GC and DC. SC has a surprisingly minor role. We also link FC alterations to biophysical factors in schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD), with physical factors differentiating these groups. These insights are key for understanding FC across various applications, including task performance, development, and clinical conditions.