title: Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis.
abstract: The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral 'limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal 'associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.
authors.affiliation: 1] Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia [2] Monash Clinical and Imaging Neuroscience Laboratory, School of Psychology and Psychiatry, Monash University, Clayton, VIC, Australia.
authors.forename: Orwa
authors.initials: O
authors.lastname: Dandash
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Harrison
authors.affiliation: 1] Division of Anaesthesia, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Ram
authors.initials: R
authors.lastname: Adapa
authors.affiliation: 1] Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S894, Paris, France [2] Centre Hospitalier Sainte-Anne, Department of Psychiatry, Service Hospitalo-Universitaire, Paris, France [3] INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S894, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gaillard
authors.affiliation: Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giorlando
authors.affiliation: 1] Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia [2] School of Psychology, University of Birmingham, Birmingham, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wood
authors.affiliation: Department of Psychiatry, Brain Mapping Unit and Behavioural and Clinical Neurosciences Institute, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Fletcher
authors.affiliation: 1] Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia [2] Monash Clinical and Imaging Neuroscience Laboratory, School of Psychology and Psychiatry, Monash University, Clayton, VIC, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Fornito
mesh_terms: D000328:Adult; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology*; D004311:Double-Blind Method; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D059907:Functional Neuroimaging; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects* / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects; D011605:Psychoses, Substance-Induced / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013788:Thalamus / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine