title: Modeling ketamine effects on synaptic plasticity during the mismatch negativity.
abstract: This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary "adaptation" and "model adjustment" MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data.
authors.affiliation: University Hospital of Psychiatry, Neuropsychopharmacology and Brain Imaging.
authors.forename: André
authors.initials: A
authors.lastname: Schmidt
authors.forename: Andreea O
authors.initials: AO
authors.lastname: Diaconescu
authors.forename: Michael
authors.initials: M
authors.lastname: Kometer
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Friston
authors.forename: Klaas E
authors.initials: KE
authors.lastname: Stephan
authors.forename: Franz X
authors.initials: FX
authors.lastname: Vollenweider
mesh_terms: D000328:Adult; D005071:Evoked Potentials / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine