Alan Anticevic1, Philip R Corlett2, Michael W Cole3, Aleksandar Savic4, Mark Gancsos2, Yanqing Tang5, Grega Repovs6, John D Murray7, Naomi R Driesen8, Peter T Morgan2, Ke Xu9, Fei Wang10, John H Krystal11. 1. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut. 2. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut. 3. Center for Molecular & Behavioral Neuroscience, Rutgers University, Newark, New Jersey. 4. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut; University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb, Croatia. 5. Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China. 6. Department of Psychology, University of Ljubljana, Ljubljana, Slovenia. 7. Department of Neurobiology, Yale University, New Haven, Connecticut; Department of Physics, Yale University, New Haven, Connecticut. 8. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut. 9. Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China. 10. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China. Electronic address: fei.wang@yale.edu. 11. Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut; Department of Psychiatry, Yale-New Haven Hospital, New Haven, Connecticut.
Abstract
BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.
BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.
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