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      Neural mechanisms of mismatch negativity (MMN) dysfunction in schizophrenia

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      , M.D., Ph.D. 1 , 2 , , M.D., Ph.D. 1 , 2 , , Ph.D. 2 , , M.D. Ph.D. 2 , , Ph.D. 1 , 2 , , M.D. 1 , 2 , , Ph.D. 1 , 2 , , M.D., Ph.D. 1 , 2

      Molecular psychiatry

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          Abstract

          Schizophrenia is associated with cognitive deficits that reflect impaired cortical information processing. Mismatch negativity (MMN) indexes pre-attentive information processing dysfunction at the level of primary auditory cortex. This study investigates mechanisms underlying MMN impairments in schizophrenia using event-related potential (ERP), event-related spectral decomposition (ERSP) and resting state functional connectivity (rsfcMRI) approaches. For this study, MMN data to frequency, intensity and duration deviants were analyzed from 69 schizophrenia patients and 38 healthy controls. rsfcMRI was obtained from a subsample of 38 patients and 23 controls. As expected, schizophrenia patients showed highly significant, large effect-size (p=.0004, d=1.0) deficits in MMN generation across deviant types. In ERSP analyses, responses to deviants occurred primarily the theta (4–7 Hz) frequency range consistent with distributed corticocortical processing, while responses to standards occurred primarily in alpha (8–12 Hz) range consistent with known frequencies of thalamocortical activation. Independent deficits in schizophrenia were observed in both the theta response to deviants (p=.021) and the alpha-response to standards (p=.003). At the single trial level, differential patterns of response were observed for frequency vs. duration/intensity deviants, along with At the network level, MMN deficits engaged canonical somatomotor, ventral attention and default networks, with a differential pattern of engagement across deviant types (p<.0001). Findings indicate that deficits in thalamocortical, as well as cortico-cortical, connectivity contribute to auditory dysfunction in schizophrenia. In addition, differences in ERSP and rsfcMRI profiles across deviant types suggest potential differential engagement of underlying generator mechanisms.

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          Most cited references 58

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          Mining event-related brain dynamics.

          This article provides a new, more comprehensive view of event-related brain dynamics founded on an information-based approach to modeling electroencephalographic (EEG) dynamics. Most EEG research focuses either on peaks 'evoked' in average event-related potentials (ERPs) or on changes 'induced' in the EEG power spectrum by experimental events. Although these measures are nearly complementary, they do not fully model the event-related dynamics in the data, and cannot isolate the signals of the contributing cortical areas. We propose that many ERPs and other EEG features are better viewed as time/frequency perturbations of underlying field potential processes. The new approach combines independent component analysis (ICA), time/frequency analysis, and trial-by-trial visualization that measures EEG source dynamics without requiring an explicit head model.
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            Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.

            Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.
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              From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment.

              Glutamate is the primary excitatory neurotransmitter in mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimer's disease, and autism-spectrum disorders. Glutamatergic theories of schizophrenia are based on the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex. Based on this mechanism, normalizing excess glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to potential identification of the first non-monoaminergic target with comparable efficacy as conventional antipsychotic drugs for treating positive and negative symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that are active targets for drug development, several of which show promise in preclinical/early clinical trials targeting both symptoms and cognition. To date, most studies have been done with orthosteric agonists and/or antagonists at specific sites. However, allosteric modulators, both positive and negative, may offer superior efficacy with less danger of downregulation.
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                Author and article information

                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                3 January 2017
                07 February 2017
                08 August 2017
                Affiliations
                [1 ]Division of Experimental Therapeutics, Department of Psychiatry, Columbia University, New York, NY 10032
                [2 ]Schizophrenia Research Division, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962
                Author notes
                Correspondence: Daniel C. Javitt, M.D., Ph.D., Director, Division of Experimental Therapeutics, Professor of Psychiatry and Neuroscience, Columbia University College of Physicians and Surgeons, 1051 Riverside Dr., Unit 21, New York, NY 10032, dcj2113@ 123456columbia.edu / javitt@ 123456nki.rfmh.org
                Article
                NIHMS834847
                10.1038/mp.2017.3
                5547016
                28167837
                1a763714-c09d-4435-acec-a42fe9d03f80

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                Molecular medicine

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