Chemoarchitectural influences on the cortical connectome confer resilience in aging

Abstract

The macroscale signaling of the brain emerges from the integration of connected areas, orchestrated by microscale, regional molecular processes. Despite growing multimodal neuroimaging data resources, the role of cortical chemoarchitecture in shaping inter-regional functional connectivity remains poorly understood. Here, we examine whether brain regions that share a chemoarchitectural signature exhibit strong frequency-resolved functional connectivity, and whether aging moderates this neurochemical-functional alignment. Using magnetoencephalography data from across the healthy adult lifespan (n = 569), we identify a frequency-dependent organization of functional connectivity by slow neuromodulator systems, with low-frequency bands ({theta}-) shaped most strongly by noradrenergic systems, and faster ({beta}) alignment dependent on serotonergic chemoarchitecture. Aging strengthens the influence of neurochemistry on inter-regional connectivity, with frequency-specific implications for age-related cognitive performance. Neurochemical influences on{theta} -band connectivity were associated with worse cognition in older adults, while the opposite was true for the low-{gamma} ({gamma}{downarrow}) band. This suggests that neuromodulatory preservation of high-frequency dynamics in older adults may reflect neural resilience. Together, our findings indicate that neurochemical-functional alignment is frequency-dependent, distinguishing between maladaptive and resilient modes of brain organization.