TY - JOUR
T1 - Hypofrontality and Posterior Hyperactivity in Early Schizophrenia
T2 - Imaging and Behavior in a Preclinical Model
AU - Kaneko, Gen
AU - Sanganahalli, Basavaraju G.
AU - Groman, Stephanie M.
AU - Wang, Helen
AU - Coman, Daniel
AU - Rao, Jyotsna
AU - Herman, Peter
AU - Jiang, Lihong
AU - Rich, Katherine
AU - de Graaf, Robin A.
AU - Taylor, Jane R.
AU - Hyder, Fahmeed
N1 - Publisher Copyright:
© 2016 Society of Biological Psychiatry
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - Background 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. Methods 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. Results 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. Conclusions 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.
AB - Background 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. Methods 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. Results 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. Conclusions 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.
KW - Decision making
KW - fMRI
KW - GABA
KW - Glucose oxidation
KW - Glutamate
KW - Reinforcement learning
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U2 - 10.1016/j.biopsych.2016.05.019
DO - 10.1016/j.biopsych.2016.05.019
M3 - Article
C2 - 27450031
AN - SCOPUS:84979505713
VL - 81
SP - 503
EP - 513
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 6
ER -