title: Mismatch negativity indexes illness-specific impairments of cortical plasticity in schizophrenia: a comparison with bipolar disorder and Alzheimer's disease.
abstract: Cognitive impairment is an important predictor of functional outcome in patients with schizophrenia, yet its neurobiology is still incompletely understood. Neuropathological evidence of impaired synaptic connectivity and NMDA receptor-dependent transmission in superior temporal cortex motivated us to explore the correlation of in vivo mismatch negativity (MMN) with cognitive status in patients with schizophrenia. MMN elicited in a roving stimulus paradigm displayed a response proportional to the number of stimulus repetitions (memory trace effect). Preliminary evidence in patients with chronic schizophrenia suggests that attenuation of this MMN memory trace effect was correlated with the degree of neuropsychological memory dysfunction. Here we present data from a larger confirmatory study in patients with schizophrenia, bipolar disorder, probable Alzheimer's disease and healthy controls. We observed that the diminution of the MMN memory trace effect and its correlation with memory impairment was only found in the schizophrenia group. Recent pharmacological studies using the roving paradigm suggest that attenuation of the MMN trace effect can be understood as abnormal modulation of NMDA receptor-dependent plasticity. We suggest that the convergence of the previously identified synaptic pathology in supragranular cortical layers with the intracortical locus of MMN generation accounts for the remarkable robustness of MMN impairments in schizophrenia. We further speculate that this layer-specific synaptic pathology identified in supragranular neurons plays a pivotal computational role, by weakening the encoding and propagation of prediction errors to higher cortical modules. According to predictive coding theory such breakdown will have grave implications not only for perception, but also for higher-order cognition and may thus account for the MMN-cognition correlations observed here. Finally, MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well suited for the exploration of novel cognition-enhancing agents in humans.
authors.affiliation: University College London, Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, United Kingdom. Electronic address: T.Baldeweg@ucl.ac.uk.
authors.forename: Torsten
authors.initials: T
authors.lastname: Baldeweg
authors.affiliation: Division of Neuroscience & Psychological Medicine, Imperial College School of Science, Technology and Medicine, Charing Cross Hospital, London W6 8RP, United Kingdom.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Hirsch
mesh_terms: D000161:Acoustic Stimulation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology*; D000704:Analysis of Variance; D001714:Bipolar Disorder / Q000150:complications / Q000473:pathology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D003072:Cognition Disorders / Q000209:etiology; D003265:Contingent Negative Variation / Q000502:physiology*; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000502:physiology; D006801:Humans; D008570:Memory, Short-Term / Q000502:physiology; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology*; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales
keywords: Bipolar illness; Cognition; Mismatch negativity; Plasticity; Schizophrenia