title: EEG biomarkers of target engagement, therapeutic effect, and disease process.
abstract: Studies suggest that abnormalities in glutamate and GABA signaling contribute to deficits in schizophrenia and related conditions and that these neurochemical abnormalities produce changes in electroencephalographic (EEG) indices, including event-related potentials and event-related power within specific frequency ranges. Furthermore, clinical studies suggest that a subset of EEG biomarkers is associated with symptoms. This review addresses the relationship between EEG and behavior in preclinical models of N-methyl-d-aspartate (NMDA)-receptor hypofunction, as well as how these models can be used to screen therapies. Data from schizophrenia patients are juxtaposed with data from animal models, and EEG and behavioral data from mice with disruption of NMDA receptors in excitatory and/or inhibitory neurons are then compared to the pattern observed in schizophrenia. Also discussed are results following exposure to potential therapeutic agents, including GABAB agonists. Furthermore, evidence demonstrates that elevated resting gamma power is associated with deficits in social interactions. Consistent with elevated baseline noise, excitatory neurons from transgenic mice show increased intrinsic excitability in in vitro-slice patch-clamp studies across model systems. GABAB receptor agonists reduce this excitability, improve gamma-band responses, and reverse behavioral deficits in mice. Data suggest that baseline gamma power is associated with social function and GABAB agonists may be useful for schizophrenia. Translational EEG biomarkers reflect target engagement and can contribute to the design of more efficient drug trials, likely accelerating the development of new therapeutics for central nervous system disorders.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Featherstone
authors.forename: Mary F
authors.initials: MF
authors.lastname: McMullen
authors.forename: Katelyn R
authors.initials: KR
authors.lastname: Ward
authors.forename: Jakyung
authors.initials: J
authors.lastname: Bang
authors.forename: Jane
authors.initials: J
authors.lastname: Xiao
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers; D004195:Disease Models, Animal; D004569:Electroencephalography; D005071:Evoked Potentials; D058786:GABA-B Receptor Agonists / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D018080:Receptors, GABA-B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D057170:Translational Research, Biomedical
chemical_list: D015415:Biomarkers; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate
keywords: EEG; NMDA; schizophrenia