Receptor Enriched Functional Connectivity

A PET/fMRI project led by Dr. Ottavia Dipasquale

One of the main limitations of pharmacological fMRI is its lack of molecular specificity. In fact, it relies on the strong assumption that haemodynamic changes can be considered a proxy of altered neurotransmission due to pharmacological agonism or antagonism actions, but the fMRI signal has no intrinsic selectivity to any particular receptor sites.

Supported by the receptor occupancy theory, which states that the magnitude of the drug response is a function of receptor availability and drug binding, REACT offers the possibility to enrich fMRI analysis with the molecular information about target distribution provided by PET and SPECT, a fundamental aspect in drug studies to explore the effects of pharmacological manipulation of brain networks. 

One of the most interesting aspects of this approach is the definition of functional circuits associated to specific neurotransmitters, as this would allow the exploration of those systems that might be impaired in disease and thus a development of innovative and efficacious targeted treatments. Overall, REACT defines the drug-specific topography of brain functional connectivity and may provide an interesting new fingerprint in the characterisation of novel compounds and potentially greater insight to the commonly observed eclectic response to treatment. Some studies have already been conducted in this direction and have showed extremely promising results. 

SOFTWARE AVAILABLE @ https://github.com/ottaviadipasquale/react-fmri

Adapted from DiPasquale et al, 2019

References

Dipasquale, O, Selvaggi, P, Veronese, M, Gabay, AS, Turkheimer, FE & Mehta, MA 2019, ‘Receptor-Enriched Analysis of functional Connectivity by Targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA’, NeuroImage, vol. 195, no. 0, pp. 252-260. https://doi.org/10.1016/j.neuroimage.2019.04.007

Dipasquale, O, Martins, D, Sethi, A, Veronese, M, Hesse, S, Rullmann, M, Sabri, O, Turkheimer, F, Harrison, NA, Mehta, MA& Cercignani, M 2020, ‘Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits’, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 45, no. 9, pp. 1482-1489. https://doi.org/10.1038/s41386-020-0724-x

Mara Cercignani, Ottavia Dipasquale, Iulia Bogdan, Tiziana Carandini, James Scott, Waqar Rashid, Osama Sabri, Swen Hesse, Michael Rullmann, Leonardo Lopiano, Mattia Veronese, Daniel Martins, Marco Bozzali, ‘Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits’, Brain Communications, Volume 3, Issue 2, 2021, fcab023, https://doi.org/10.1093/braincomms/fcab023