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Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade

Rosch, RE; Auksztulewicz, R; Leung, PD; Friston, KJ; Baldeweg, T; (2019) Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging , 4 (2) pp. 140-150. 10.1016/j.bpsc.2018.07.003. Green open access

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Abstract

BACKGROUND: Disturbances in N-methyl-D-aspartate receptors (NMDARs)-as implicated in patients with schizophrenia-can cause regionally specific electrophysiological effects. Both animal models of NMDAR blockade and clinical studies in patients with schizophrenia have suggested that behavioral phenotypes are associated with reduction in inhibition within the frontal cortex. METHODS: Here we investigate event-related potentials to a roving auditory oddball paradigm under ketamine in healthy human volunteers (N= 18; double-blind, placebo-controlled, crossover design). Using recent advances in Bayesian modeling of group effects in dynamic causal modeling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp event-related potential recordings. This allowed us to identify regionally specific effects of ketamine in a distributed network of interacting cortical sources. RESULTS: We show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources, compared with temporal sources. Simulations of these changes in an integrated microcircuit model shows that they are associated with a reduction in superficial pyramidal cell activity that can explain drug effects observed in the event-related potential. CONCLUSIONS: These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory interneuron-specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities induced by NMDAR blockade in human subjects.

Type: Article
Title: Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bpsc.2018.07.003
Publisher version: https://doi.org/10.1016/j.bpsc.2018.07.003
Language: English
Additional information: © 2018 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Dynamic causal modeling, EEG, ERP, Event-related potential, Ketamine, Mismatch negativity, NMDA receptor
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Imaging Neuroscience
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10055151
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