title: Corticolimbic hyper-response to emotion and glutamatergic function in people with high schizotypy: a multimodal fMRI-MRS study.
abstract: Animal models and human neuroimaging studies suggest that altered levels of glutamatergic metabolites within a corticolimbic circuit have a major role in the pathophysiology of schizophrenia. Rodent models propose that prefrontal glutamate dysfunction could lead to amygdala hyper-response to environmental stress and underlie hippocampal overdrive in schizophrenia. Here we determine whether changes in brain glutamate are present in individuals with high schizotypy (HS), which refers to the presence of schizophrenia-like characteristics in healthy individuals, and whether glutamate levels are related to altered corticolimbic response to emotion. Twenty-one healthy HS subjects and 22 healthy subjects with low schizotypy (LS) were selected based on their Oxford and Liverpool Inventory of Feelings and Experiences rating. Glutamate levels were measured in the anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, followed by a functional magnetic resonance imaging (fMRI) scan to measure corticolimbic response during emotional processing. fMRI results and fMRI × glutamate interactions were considered significant after voxel-wise P<0.05 family-wise error correction. While viewing emotional pictures, HS individuals showed greater activation than did subjects with LS in the caudate, and marginally in the ACC, hippocampus, medial prefrontal cortex (MPFC) and putamen. Although no between-group differences were found in glutamate concentrations, within the HS group ACC glutamate was negatively correlated with striatal activation (left: z=4.30, P=0.004 and right: z=4.12 P=0.008 caudate; left putamen: z=3.89, P=0.018) and marginally with MPFC (z=3.55, P=0.052) and amygdala (left: z=2.88, P=0.062; right: z=2.79, P=0.079), correlations that were not present in LS subjects. These findings provide, to our knowledge, the first evidence that brain glutamate levels are associated with hyper-responsivity in brain regions thought to be critical in the pathophysiology of psychosis.
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Modinos
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: McLaughlin
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Egerton
authors.affiliation: Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K
authors.initials: K
authors.lastname: McMullen
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Kumari
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Barker
authors.affiliation: Social Brain Laboratory, Netherlands Institute for Neuroscience, Netherlands Academy for Arts and Sciences (KNAW), Amsterdam, The Netherlands.|Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C
authors.identifier: 0000-0002-2845-5467
authors.initials: C
authors.lastname: Keysers
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: S C R
authors.initials: SC
authors.lastname: Williams
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000502:physiology; D004644:Emotions / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008032:Limbic System / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D064847:Multimodal Imaging / Q000379:methods*; D059906:Neuroimaging / Q000379:methods; D017397:Prefrontal Cortex / Q000378:metabolism; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D012569:Schizotypal Personality Disorder / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult
chemical_list: D018698:Glutamic Acid