title: Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.
abstract: Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled. Lastly, we examined the efficacy of cognition enhancers to normalize those aberrant oscillations. Cognition enhancers elicited systematic ("fingerprint") enhancement of cortical slow theta (4.5-6 Hz) and gamma (30.5-50 Hz) oscillations correlated with lower activity levels. Principal component analysis (PCA) revealed a compact cluster that corresponds to shared underlying mechanisms as compared to different drug classes. Functional network connectivity revealed consistent elevated coherent slow theta activity in parieto-occipital and between interhemispheric cortical areas. In rats instrumented with depth hippocampal CA1-CA3 electrodes, donepezil elicited similar oscillatory and coherent activities in cortico-hippocampal networks. When combined with scopolamine, the cognition enhancers attenuated the leftward shift in coherent slow delta activity. Such a consistent shift in EEG coherence into slow oscillations associated with altered slow theta and gamma oscillations may underlie cognitive deficits in scopolamine-treated animals, whereas enhanced coherent slow theta and gamma activity may be a relevant mechanism by which cognition enhancers exert their beneficial effect on plasticity and cognitive processes. The findings underscore that PCA and network connectivity are valuable tools to assess efficacy of novel therapeutic drugs with cognition enhancing potential.
authors.affiliation: Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address: aahnaou@its.jnj.com.
authors.forename: A
authors.initials: A
authors.lastname: Ahnaou
authors.affiliation: Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Huysmans
authors.affiliation: Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Jacobs
authors.affiliation: Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: W H I M
authors.initials: WH
authors.lastname: Drinkenburg
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D000077265:Donepezil; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000379:methods*; D005702:Galantamine / Q000494:pharmacology; D065818:Gamma Rhythm / Q000187:drug effects; D007189:Indans / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D048448:Phenylcarbamates / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D025341:Principal Component Analysis; D017207:Rats, Sprague-Dawley; D000068836:Rivastigmine; D012601:Scopolamine / Q000494:pharmacology; D012815:Signal Processing, Computer-Assisted; D013619:Tacrine / Q000494:pharmacology; D013826:Theta Rhythm / Q000187:drug effects
chemical_list: D007189:Indans; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D048448:Phenylcarbamates; D010880:Piperidines; D005702:Galantamine; D013619:Tacrine; D000077265:Donepezil; D012601:Scopolamine; D000068836:Rivastigmine; D008559:Memantine
keywords: Animal model; Cognition enhancers; Coherent functional network; EEG oscillations; Neurodegenerative disorders; Translational biomarker