Reproducible human reward imaging phenotypes exhibit differential sensitivity to dopamine D2 receptor antagonism
Abstract
Abstract Human reward processing varies along cue-centric and outcome-centric axes, but a reproducible mechanistic account of individual variation in incentive salience attribution has been lacking. Using fMRI across five cohorts (N-total=1,251; N1=890; N2=245; N3=34; N4=48; N5=34), we identified two robust imaging phenotypes mirroring sign- and goal-tracking (ST-like, GT-like). ST-like individuals showed dominant ventral striatal responses to reward-anticipation cues and sustained incentive salience attribution; GT-like individuals showed heightened responses to reward outcomes. This distinction was replicable across sites and independent samples. Single-dose and repeated-dose D 2 /D 3 antagonism (risperidone, haloperidol, amisulpride) selectively reduced anticipatory ventral striatal activity in ST, with single-dose antagonism additionally producing a parallel drop in self-reported energy. Instead, D 2 /D 3 partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D 2 affinity was associated with blunted anticipatory signals and higher negative symptom burden, offering a neuroimaging-driven basis for stratifying patients and predicting response to dopaminergic agents.
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Authors: Nicola Sambuco, Antonella Lupo, Peter Hawkins, Pierluigi Selvaggi, Linda A. Antonucci, Alessandro Bertolino, Giuseppe Blasi, Piegiuseppe Di Palo, Luigi Grassi, D. Grasso, Philipp Homan, GianMarco Leggio, Francesco Massari, Alessio Maria Monteleone, Martin Osugo, Roberta Passiatore, Alessandra Raio, Antonio Rampino, Tobias Banaschewski, Gareth Barker, Arun LW Bokde, Ruediger Bruehl, Sylvane Desrivières, Herta Flor, Hugh Garavan, Penny Anne Gowland, Antoine Grigis, A. Heinz, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, luise Poustka, Michael N Smolka, Nathalie Holz, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, Apulian Network On Risk For Psychosis, Oliver Howes, Mitul A Mehta, Giulio Pergola
Institutions: University of Bari Aldo Moro, Johns Hopkins University, Charité - Universitätsmedizin Berlin, Imperial College London, Fudan University, University of Nottingham, Ludwig-Maximilians-Universität München, Inserm, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Heidelberg University, University Hospital Heidelberg, University of Tübingen, Sorbonne Université, University of Vermont, Centre National de la Recherche Scientifique, Johns Hopkins Medicine, Humboldt-Universität zu Berlin, Lieber Institute for Brain Development, University of Zurich, University Hospital Zurich, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, University of Campania "Luigi Vanvitelli", Université Paris-Saclay, CEA Paris-Saclay, Casa Sollievo della Sofferenza, University Psychiatric Hospital, King's College London, University of Catania, University of Ferrara, University of Mannheim, Technische Universität Dresden, Trinity College Dublin, South London and Maudsley NHS Foundation Trust, Shanghai Center for Brain Science and Brain-Inspired Technology, Central Institute of Mental Health, German Center for Diabetes Research, European Telecommunications Standards Institute, Physikalisch-Technische Bundesanstalt, MRC London Institute of Medical Sciences, Centre Borelli