The neuroreceptors and transporters underlying spontaneous brain activity

Understanding the neuromodulatory drivers of brain activity is essential for elucidating cognition and neuropathology. Neuromodulators act through neuroreceptors in a coordinated manner, yet most studies focus on isolated neuromodulators, overlooking their holistic interactions. To address this, we developed a neuroreceptor-based framework that integrates cortical density maps of 19 neuroreceptors and transporters from Positron Emission Tomography (PET) to model the BOLD signal and functional connectivity. Across four datasets (Ntotal = 314), this framework reveals a network architecture capturing dynamic interactions between neuroreceptors, transporters, and brain activity. The BOLD signal emerges from two neuroreceptor modules reflecting either higher-order associative or action-driven functions. Validation in independent datasets links the framework to LSD binding profiles and Modafinil mechanism of action. Extending these findings, we uncover mechanistic links between neuroreceptors, transporters, and altered brain activity in neuropsychiatric disorders. Furthermore, the neuroreceptor-based framework outperforms anatomical-based models in reconstructing brain activity, demonstrating its predictive power. These findings underscore the potential of a neuroreceptor-based framework to advance our understanding of neuromodulatory mechanisms across diverse brain states and conditions.