title: Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile.
abstract: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK. richard.joules@kcl.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Joules
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: O M
authors.initials: OM
authors.lastname: Doyle
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Schwarz
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: O G
authors.initials: OG
authors.lastname: O'Daly
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: M
authors.initials: M
authors.lastname: Brammer
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: S C
authors.initials: SC
authors.lastname: Williams
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Mehta
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects*; D001931:Brain Mapping; D018592:Cross-Over Studies; D018492:Dopamine Antagonists / Q000494:pharmacology; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D000077213:Lamotrigine; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018967:Risperidone / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D007649:Ketamine; D018967:Risperidone; D000077213:Lamotrigine
keywords: Connection; Drug discrimination; Glutamate; Imaging; NMDA receptor; Schizophrenia; Thalamus; fMRI