Mapping cross-modal functional connectivity of major neurotransmitter systems in the human brain

Abstract

Monoaminergic systems, including serotonin, dopamine, and norepinephrine, are essential for regulating brain activity and facilitating behavioral flexibility. These systems originate from brainstem nuclei and project widely to modulate functions such as mood, attention, memory, and adaptability. Using resting-state functional MRI (rs-fMRI), this study aimed to investigate the connectivity networks of key monoaminergic nuclei in 193 healthy adults and explore their correspondence with molecular imaging maps of neurotransmitter-specific biochemical markers. Functional connectivity (FC) was assessed using seed-based rs-fMRI analyses with seeds placed in the dorsal raphe nucleus (DRN), nucleus centralis superior (NCS), ventral tegmental area (VTA), substantia nigra pars compacta (SNc), and locus coeruleus (LC). Cross-modal analyses using molecular imaging data were performed to correlate these rs-FC maps with the distribution of neurotransmitter-related receptors, transporters, and synthesis enzymes, providing insights into the molecular architecture underlying the FC of monoaminergic systems. Whole-brain FC maps revealed distinct patterns for each nucleus. DRN projections were extensive, connecting to subcortical regions such as the hippocampus and amygdala and cortical areas including the precuneus, cingulate, and medial frontal cortex. NCS projections overlapped partially but uniquely targeted the orbitofrontal and insular cortices. Dopaminergic pathways exhibited connectivity with the striatum, thalamus, and prefrontal cortex, while noradrenergic LC projections displayed lateralized connectivity to occipital, temporal, and frontal regions. Cross-modal correlations with molecular imaging demonstrated significant spatial associations between rs-FC maps and neurotransmitter-specific markers, including 5HTT, DAT, and FDOPA. This study enhances our understanding of neurotransmitter networks, highlighting their relevance in brain function and potential as biomarkers for neuropsychiatric conditions.