Mapping dynamics in neuronal activation and molecular connectivity with functional PET

The assessment of brain function using PET imaging has recently gained increasing interest due to several technical advancements, including bolus+infusion radiotracer administration protocols combined with hybrid PET/MR or high-sensitive PET/CT scanners. Functional PET (fPET) enables imaging of stimulation-induced changes in glucose metabolism and neurotransmitter action in a single scan as well as computation of molecular connectivity represented by temporal associations of PET signals between brain regions. In addition to methodological considerations, this work aims to highlight key advantages, limitations and future challenges of fPET and applications in multimodal imaging. Regional increases in glucose metabolism largely correspond to those observed with BOLD fMRI across a range of cognitive tasks, whereas divergence within the default mode network during internally directed attention seems to reflect active inhibitory processes. Extensions to radioligands beyond [¹⁸F]FDG demonstrated marked increases in dopamine and serotonin synthesis during reward processing, providing complementary insight into neurotransmitter action. Moreover, image reconstruction in the range of seconds facilitates extraction of moment-to-moment fluctuations in fPET signals for computation of molecular connectivity. The use of large axial field-of-view PET scanners for total-body imaging further enables inference on molecular interactions at the systems level. In sum, fPET imaging, particularly multimodal combinations, offers novel perspectives that cannot be obtained with either of these modalities alone. Future challenges include the detailed characterization of the relationships between neurovascular and neurometabolic coupling as well as the physiological underpinnings of rapid changes in fPET signals and the translation to clinical research settings.