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

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.