Gray Matter Deficits, Mismatch Negativity, and Outcomes in Schizophrenia

Priority Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, Australia.
Schizophrenia Bulletin (Impact Factor: 8.45). 07/2009; 37(1):131-40. DOI: 10.1093/schbul/sbp060
Source: PubMed


Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients' levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

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Available from: Patricia T Michie
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    • "The MMN amplitude reduction in schizophrenia varies with type of stimulus deviance [11]. While MMN reduction to frequency deviant tones may develop over the course of the illness [11]–[13], those to duration- and intensity-deviant tones have been shown from early on [13]. "
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    ABSTRACT: The Mismatch Negativity (MMN) is an event-related potential (ERP) sensitive to early auditory deviance detection and has been shown to be reduced in schizophrenia patients. Moreover, MMN amplitude reduction to duration deviant tones was found to be related to functional outcomes particularly, to neuropsychological (working memory and verbal domains) and psychosocial measures. While MMN amplitude is thought to be correlated with deficits of early sensory processing, the functional significance of MMN latency remains unclear so far. The present study focused on the investigation of MMN in relation to neuropsychological function in schizophrenia. Forty schizophrenia patients and 16 healthy controls underwent a passive oddball paradigm (2400 binaural tones; 88% standards [1 kHz, 80 db, 80 ms], 11% frequency deviants [1.2 kHz], 11% duration deviants [40 ms]) and a neuropsychological test-battery. Patients were assessed with regard to clinical symptoms. Compared to healthy controls schizophrenia patients showed diminished MMN amplitude and shorter MMN latency to both deviants as well as an impaired neuropsychological test performance. Severity of positive symptoms was related to decreased MMN amplitude to duration deviants. Furthermore, enhanced verbal memory performance was associated with prolonged MMN latency to frequency deviants in patients. The present study corroborates previous results of a diminished MMN amplitude and its association with positive symptoms in schizophrenia patients. Both, the findings of a shorter latency to duration and frequency deviants and the relationship of the latter with verbal memory in patients, emphasize the relevance of the temporal aspect of early auditory discrimination processing in schizophrenia.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "The P3 amplitude, which correlates to memory and attentive processes, has been demonstrated to be exclusively disturbed in future converters by one study (48). Of the published studies evaluating the MMN, a correlate of pre-attentive stimulus discrimination presumably sensitive to the stage of illness (49–54), the majority consistently demonstrated MMN deficits in future converters but not in non-converters (55–60). Bodatsch et al. and later on Perez et al. provided evidence that MMN amplitude deficits predict psychosis onset and allow for an estimation of the remaining time until transition (55, 61). "
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    ABSTRACT: In the recent decades, a paradigmatic change in psychosis research and treatment shifted attention towards the early and particularly the prodromal stages of illness. Despite substantial progress with regard to the neuronal underpinnings of psychosis development, the crucial biological mechanisms leading to manifest illness are yet insufficiently understood. Until today, one significant approach to elucidate the neurobiology of psychosis has been the modeling of psychotic symptoms by psychedelic substances in healthy individuals. These models bear the opportunity to evoke particular neuronal aberrations and the respective psychotic symptoms in a controlled experimental setting. In the present paper, we hypothesize that experimental psychiatry bears unique opportunities in elucidating the biological mechanisms of the prodromal stages of psychosis. Psychosis risk symptoms are attenuated, transient, and often only retrospectively reported. The respective neuronal aberrations are thought being dynamic. The correlation of unstable psychopathology with observed, e. g., neurophysiological disturbances is thus yet largely unclear. In modeling psychosis, the experimental setting allows not only for evoking particular symptoms, but for the concomitant assessment of psychopathology, neurophysiology, and neuropsychology. Herein, the glutamatergic model will be highlighted exemplarily, with special emphasis on its potential contribution to the elucidation of psychosis development. This model of psychosis appears as candidate for modeling the prodrome since it induces psychopathological, neurocognitive and neurofunctional changes that are comparable to clinical features of the prodrome.As exemplarily illustrated by the PCP/NMDA model of psychosis many aspects advocate that prodromal stages might be validly mimicked by psychedelic substances. In summary, experimental psychiatry bears the potential to further elucidate the biological mechanisms of the psychosis prodrome.
    Full-text · Article · Dec 2013 · Frontiers in Psychiatry
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    • "MMN can be assessed in fetuses, newborn babies (Alho et al., 1990; Nashida et al., 2000; Huotilainen et al., 2003; Draganova et al., 2005) and even individuals who are comatose or in a persistent vegetative state prior to regaining consciousness (Kane et al., 1996; Morlet et al., 2000; Wijnen et al., 2007). Both MMN and P3a are important measures in neuropsychiatric research since they show significant deficits in schizophrenia patients (Turetsky et al., 1998; Mathalon et al., 2000b; Michie, 2001; Umbricht and Krljes, 2005; Turetsky et al., 2007; Kiang et al., 2009a; Rissling et al., 2012) and are associated with important clinical features of the illness, including social cognition (Wynn et al., 2010), functional status and outcome (Light and Braff, 2005a, 2005b; Kawakubo and Kasai, 2006; Rasser et al., 2011; Friedman et al., 2012). These measures have been used as endophenotypes in genetic association studies (Hall et al., 2006; Hall et al., 2007), as biomarkers for tracking the emergence and progression of deficits across the course of illness (Salisbury et al., 2002; Umbricht et al., 2006; Atkinson et al., 2012; Jahshan et al., 2012; Kaur et al., 2012; Shaikh et al., 2012) and as responses to pharmacologic and psychosocial interventions (Umbricht et al., 2003; Kawakubo et al., 2007; Lavoie et al., 2007). "
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    ABSTRACT: Background: Mismatch negativity (MNN) and P3a are event related potential (ERP) measures of early sensory information processing. These components are usually conceptualized as being "pre-attentive" and therefore immune to changes with variations in attentional functioning. This study aimed to determine whether manipulations of attention influence the amplitudes and latencies of MMN and P3a and, if so, the extent to which these early sensory processes govern concurrent behavioral vigilance performance in schizophrenia patients and normal subjects. Methods: Schizophrenia patients (SZ; n = 20) and Nonpsychiatric Control Subjects (NCS; n = 20) underwent auditory ERP testing to assess MMN and P3a across 4 EEG recording sessions in which attentional demand (low vs. high) and sensory modality of directed attention (visual vs. auditory) were experimentally varied. Results: Across conditions, SZ patients exhibited deficits in MMN and P3a amplitudes. Significant amplitude and latency modulation were observed in both SZ and NCS but there were no group-by-condition interactions. The amount of MMN amplitude attenuation from low- to high-demand tasks was significantly associated with increased vigilance performance in both SZ and NCS groups (r = -0.67 and r = -0.60). Several other robust associations were also observed among neurophysiologic, clinical and cognitive variables. Conclusions: Attentional demand and modality of directed attention significantly influence the amplitude and latencies of "pre-attentive" ERP components in both SZ and NCS. Deficits in MMN and P3a were not "normalized" when attention was directed to the auditory stimuli in schizophrenia patients. The adaptive modulation of early sensory information processing appears to govern concurrent attentional task performance. The temporal window reflecting automatic sensory discrimination as indexed as MMN and P3a may serve as a gateway to some higher order cognitive operations necessary for psychosocial functioning.
    Full-text · Article · Mar 2013 · Schizophrenia Research
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