title: Hypofrontality and Posterior Hyperactivity in Early Schizophrenia: Imaging and Behavior in a Preclinical Model.
abstract: Schizophrenia is a debilitating neuropsychiatric disorder typically diagnosed from late adolescence to adulthood. Subthreshold behavioral symptoms (e.g., cognitive deficits and substance abuse) often precede the clinical diagnosis of schizophrenia. However, these prodromal symptoms have not been consistently associated with structural and functional brain biomarkers, limiting the chance of early diagnosis of schizophrenia.
  
  
  
  Using an extensively multimodal range of magnetic resonance methods (for anatomy, metabolism, and function), we screened early biomarkers in a methylazoxymethanol acetate (MAM) rat model of schizophrenia and saline-treated control (SHAM) rats, in conjunction with immunohistochemistry, myelin staining, and a novel three-choice, reversal-learning task to identify early behavioral markers corresponding the subthreshold symptoms.
  
  
  
  MAM (vs. SHAM) rats had lower/higher structural connectivity in anterior/posterior corpus callosum. The orbitofrontal cortex of MAM rats showed lower resting-state functional magnetic resonance imaging functional connectivity in conjunction with lower neuronal density, lower glucose oxidation, and attenuated neurotransmission (hypofrontality). In contrast, these measures were all higher in visual cortex of MAM rats (posterior hyperactivity), which might parallel perceptual problems in schizophrenia. In behavioral studies, MAM (vs. SHAM) rats displayed abnormal orbitofrontal cortex-mediated decision-making processes, resulting in a novel reward-sensitive hyperflexible phenotype, which might reflect vulnerability of prodromal patients to substance abuse.
  
  
  
  We identified two novel biomarkers of early schizophrenia in a preclinical rat model: hypofrontality associated with the hyperflexible phenotype, and posterior hyperactivity. Because each of these magnetic resonance methods is clinically translatable, these markers could contribute to early diagnosis and the development of novel therapies of schizophrenia.
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Gen
authors.initials: G
authors.lastname: Kaneko
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Basavaraju G
authors.initials: BG
authors.lastname: Sanganahalli
authors.affiliation: Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Groman
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Helen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coman
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Rao
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Peter
authors.initials: P
authors.lastname: Herman
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Lihong
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Katherine
authors.initials: K
authors.lastname: Rich
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut; Department of Biomedical Engineering, and, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Robin A
authors.initials: RA
authors.lastname: de Graaf
authors.affiliation: Department of Psychiatry, Yale University, Yale University, New Haven, Connecticut.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
authors.affiliation: Magnetic Resonance Research Center, Yale University, Yale University, New Haven, Connecticut; Department of Diagnostic Radiology, Yale University, Yale University, New Haven, Connecticut; Department of Biomedical Engineering, and, Yale University, Yale University, New Haven, Connecticut. Electronic address: fahmeed.hyder@yale.edu.
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D003657:Decision Making / Q000502:physiology; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008746:Methylazoxymethanol Acetate; D064847:Multimodal Imaging; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012193:Reversal Learning / Q000502:physiology; D012201:Reward; D012559:Schizophrenia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D012565:Schizophrenic Psychology
chemical_list: D015415:Biomarkers; D008746:Methylazoxymethanol Acetate
keywords: Decision making; GABA; Glucose oxidation; Glutamate; Reinforcement learning; fMRI