Cerebral blood flow predicts differential neurotransmitter activity

Juergen Dukart; Štefan Holiga; Christopher Chatham; Peter Hawkins; Anna Forsyth; Rebecca McMillan; Jim Myers; Anne R Lingford-Hughes; David J Nutt; Emilio Merlo-Pich; Celine Risterucci; Lauren Boak; Daniel Umbricht; Scott Schobel; Thomas Liu; Mitul A Mehta; Fernando O Zelaya; Steve C Williams; Gregory Brown; Martin Paulus; Garry D Honey; Suresh Muthukumaraswamy; Joerg Hipp; Alessandro Bertolino; Fabio Sambataro

doi:10.1038/s41598-018-22444-0

Cerebral blood flow predicts differential neurotransmitter activity

Juergen Dukart^*, Štefan Holiga, Christopher Chatham, Peter Hawkins, Anna Forsyth, Rebecca McMillan, Jim Myers, Anne R Lingford-Hughes, David J Nutt, Emilio Merlo-Pich, Celine Risterucci, Lauren Boak, Daniel Umbricht, Scott Schobel, Thomas Liu, Mitul A Mehta, Fernando O Zelaya, Steve C Williams, Gregory Brown, Martin PaulusGarry D Honey, Suresh Muthukumaraswamy, Joerg Hipp, Alessandro Bertolino, Fabio Sambataro

^*Corresponding author for this work

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Abstract

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

Original language	English
Article number	4074
Pages (from-to)	4074
Journal	Scientific Reports
Volume	8
Issue number	1
Early online date	6 Mar 2018
DOIs	https://doi.org/10.1038/s41598-018-22444-0
Publication status	Published - 6 Mar 2018

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Cerebral blood flow predicts_DUKART_Publishedonline6March2018_GOLD VoR (CC BY)Final published version, 3.12 MBLicence: CC BY

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Dukart, J., Holiga, Š., Chatham, C., Hawkins, P., Forsyth, A., McMillan, R., Myers, J., Lingford-Hughes, A. R., Nutt, D. J., Merlo-Pich, E., Risterucci, C., Boak, L., Umbricht, D., Schobel, S., Liu, T., Mehta, M. A., Zelaya, F. O., Williams, S. C., Brown, G., ... Sambataro, F. (2018). Cerebral blood flow predicts differential neurotransmitter activity. Scientific Reports, 8(1), 4074. Article 4074. https://doi.org/10.1038/s41598-018-22444-0

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title = "Cerebral blood flow predicts differential neurotransmitter activity",

abstract = "Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.",

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Dukart, J, Holiga, Š, Chatham, C, Hawkins, P, Forsyth, A, McMillan, R, Myers, J, Lingford-Hughes, AR, Nutt, DJ, Merlo-Pich, E, Risterucci, C, Boak, L, Umbricht, D, Schobel, S, Liu, T, Mehta, MA , Zelaya, FO , Williams, SC, Brown, G, Paulus, M, Honey, GD, Muthukumaraswamy, S, Hipp, J, Bertolino, A & Sambataro, F 2018, 'Cerebral blood flow predicts differential neurotransmitter activity', Scientific Reports, vol. 8, no. 1, 4074, pp. 4074. https://doi.org/10.1038/s41598-018-22444-0

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AU - Dukart, Juergen

AU - Holiga, Štefan

AU - Chatham, Christopher

AU - Hawkins, Peter

AU - Forsyth, Anna

AU - McMillan, Rebecca

AU - Myers, Jim

AU - Lingford-Hughes, Anne R

AU - Nutt, David J

AU - Merlo-Pich, Emilio

AU - Risterucci, Celine

AU - Boak, Lauren

AU - Umbricht, Daniel

AU - Schobel, Scott

AU - Liu, Thomas

AU - Mehta, Mitul A

AU - Zelaya, Fernando O

AU - Williams, Steve C

AU - Brown, Gregory

AU - Paulus, Martin

AU - Honey, Garry D

AU - Muthukumaraswamy, Suresh

AU - Hipp, Joerg

AU - Bertolino, Alessandro

AU - Sambataro, Fabio

PY - 2018/3/6

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AB - Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

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Cerebral blood flow predicts differential neurotransmitter activity

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