Impaired Potentiation of Theta Oscillations During a Visual Cortical Plasticity Paradigm in Individuals With Schizophrenia.

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP in vitro and in vivo in animal models, repeated high frequency presentation of a visual stimulus in humans in vivo has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.
Competing Interests: DM is a consultant for Boehringer Ingelheim and Cadent Therapeutics. IC has been an employee of Pfizer, BMS, Alexion, Worldwide Clinical Trials, and has consulted for Biohaven and Seelos Therapeutics. WC is co-founder of Neuroscouting, LLC. JK consults for Aptinyx, Inc., AstraZeneca Pharmaceuticals, Atai Life Sciences, Biogen Idec, Biomedisyn Corporation, Bionomics Ltd., Boehringer Ingelheim International, Cadent Therapeutics, Inc., Clexio Bioscience, Ltd., COMPASS Pathways Ltd., Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Greenwich Biosciences, Inc., Heptares Therapeutics Ltd., Janssen Research & Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, and Taisho Pharmaceutical Co., Ltd.; is a scientific advisor of Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC, EpiVario, Inc., Eisai, Inc., Lohocla Research Corporation, Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., and Terran Biosciences, Inc.; holds stock or stock options with Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Inc., BlackThorn Therapeutics, Inc., EpiVario, Inc., and Terran Biosciences, Inc.; and is editor of Biological Psychiatry. JK also was awarded the following patents: (1) Seibyl JP, Krystal JH, Charney DS. Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia. U.S. Patent No. 5,447,948. September 5, 1995; (2) Vladimir C, Krystal JH, Sanacora G. Glutamate Modulating Agents in the Treatment of Mental Disorders. U.S. Patent No. 8,778,979 B2. Patent Issue Date July 15, 2014. U.S. Patent Application No. 15/695,164. Filing Date September 5, 2017; (3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C. Intranasal Administration of Ketamine to Treat Depression. U.S. Patent Application No. 14/197,767 filed on March 5, 2014. U.S. Application or Patent Cooperation Treaty International Application No. 14/306,382 filed on Jun 17, 2014; (4) Zarate C, Charney DS, Manji HK, Mathew SJ, Krystal JH, Department of Veterans Affairs. Methods for Treating Suicidal Ideation. Patent Application No. 14/197.767 filed on Mar 5, 2014 by Yale University Office of Cooperative Research; (5) Arias A, Petrakis I, Krystal JH. Composition and Methods to Treat Addiction. Provisional Use Patent Application No. 61/973/961. Apr 2, 2014. Filed by Yale University Office of Cooperative Research; (6) Chekroud A, Gueorguieva R, Krystal JH. Treatment Selection for Major Depressive Disorder. U.S. Patent and Trademark Office Docket No. Y0087.70116US00. Filed Jun 3, 2016. Provisional patent submission by Yale University; (7) Gihyun Y, Petrakis I, Krystal JH. Compounds, Compositions, and Methods for Treating or Preventing Depression and Other Diseases. U.S. Provisional Patent Application No. 62/444,552. Filed on Jan 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; (8) Abdallah C, Krystal JH, Duman R, Sanacora G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62/719,935. Filed on Aug 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2020 Hamilton, Roach, Cavus, Teyler, Clapp, Ford, Tarakci, Krystal and Mathalon.)