title: Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.
abstract: A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: N V
authors.initials: NV
authors.lastname: Kraguljac
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Frölich
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tran
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: White
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nichols
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barton-McArdle
authors.affiliation: Department of Electrical and Computer Engineering, MRI Research Center, Auburn University, Auburn, AL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Reid
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Bolding
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Lahti
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D064368:Healthy Volunteers; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D007649:Ketamine / Q000378:metabolism / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D009448:Neurochemistry; D059906:Neuroimaging; D017397:Prefrontal Cortex / Q000503:physiopathology; D012146:Rest; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine