Roberto Limongi1, Peter Jeon2, Michael Mackinley3, Tushar Das4, Kara Dempster5, Jean Théberge6, Robert Bartha2, Dickson Wong7, Lena Palaniyappan8. 1. Department of Psychiatry, Western University, London, Ontario, Canada; Robarts Research Institute, Western University, London, Ontario, Canada. Electronic address: rlimongi@uwo.ca. 2. Department of Medical Biophysics, Western University, London, Ontario, Canada. 3. Department of Psychiatry, Western University, London, Ontario, Canada; Robarts Research Institute, Western University, London, Ontario, Canada. 4. Department of Strategic Enterprise Solutions, Fanshawe College, London, Ontario, Canada. 5. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. 6. Department of Psychiatry, Western University, London, Ontario, Canada; Department of Medical Biophysics, Western University, London, Ontario, Canada; Department of Medical Imaging, Western University, London, Ontario, Canada; Neuropsychiatry Imaging Lab, Lawson Health Research Institute, London, Ontario, Canada; Department of Diagnostic Imaging, St. Joseph's Health Care London, London, Ontario, Canada. 7. Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 8. Department of Psychiatry, Western University, London, Ontario, Canada; Robarts Research Institute, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: lpalaniy@uwo.ca.
Abstract
BACKGROUND: Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computational terms, this produces a pathology of evidence accumulation and ensuing inference in the brain. Finally, the pathophysiology and aberrant inference would partially account for the psychopathology of schizophrenia as measured in terms of symptoms and signs. We refer to this formulation as the 3-level hypothesis. METHODS: We tested the hypothesis in core nodes of the salience network (the dorsal anterior cingulate cortex [dACC] and the anterior insula) of 20 patients with first-episode psychosis and 20 healthy control subjects. We established 3-way correlations between the magnetic resonance spectroscopy measures of glutamate, effective connectivity of resting-state functional magnetic resonance imaging, and correlations between measures of this connectivity and estimates of precision (inherent in evidence accumulation in the Stroop task) and psychopathology. RESULTS: Glutamate concentration in the dACC was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula, respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of subjects with first-episode psychosis. Furthermore, aberrant computational parameters of the Stroop task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the anterior insula correlated negatively with severity of social withdrawal. CONCLUSIONS: These findings support a link between glutamate-mediated cortical disinhibition, effective-connectivity deficits, and computational performance in psychosis.
BACKGROUND: Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computational terms, this produces a pathology of evidence accumulation and ensuing inference in the brain. Finally, the pathophysiology and aberrant inference would partially account for the psychopathology of schizophrenia as measured in terms of symptoms and signs. We refer to this formulation as the 3-level hypothesis. METHODS: We tested the hypothesis in core nodes of the salience network (the dorsal anterior cingulate cortex [dACC] and the anterior insula) of 20 patients with first-episode psychosis and 20 healthy control subjects. We established 3-way correlations between the magnetic resonance spectroscopy measures of glutamate, effective connectivity of resting-state functional magnetic resonance imaging, and correlations between measures of this connectivity and estimates of precision (inherent in evidence accumulation in the Stroop task) and psychopathology. RESULTS:Glutamate concentration in the dACC was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula, respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of subjects with first-episode psychosis. Furthermore, aberrant computational parameters of the Stroop task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the anterior insula correlated negatively with severity of social withdrawal. CONCLUSIONS: These findings support a link between glutamate-mediated cortical disinhibition, effective-connectivity deficits, and computational performance in psychosis.
Authors: Ji Chen; Veronika I Müller; Juergen Dukart; Felix Hoffstaedter; Justin T Baker; Avram J Holmes; Deniz Vatansever; Thomas Nickl-Jockschat; Xiaojin Liu; Birgit Derntl; Lydia Kogler; Renaud Jardri; Oliver Gruber; André Aleman; Iris E Sommer; Simon B Eickhoff; Kaustubh R Patil Journal: Biol Psychiatry Date: 2020-10-03 Impact factor: 13.382
Authors: Roberto Limongi; Michael Mackinley; Kara Dempster; Ali R Khan; Joseph S Gati; Lena Palaniyappan Journal: Eur Arch Psychiatry Clin Neurosci Date: 2020-07-19 Impact factor: 5.270
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