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: 8.61). 07/2009; 37(1):131-40. DOI: 10.1093/schbul/sbp060
Source: PubMed

ABSTRACT 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, Aug 08, 2015
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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.
    Schizophrenia Research 03/2013; 146(1-3). DOI:10.1016/j.schres.2013.01.035 · 4.43 Impact Factor
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    • "Moreover, Salisbury et al. (2007) found that associations between MMN and left temporal gray matter reductions upon hospital entrance, and between progressive gray matter and MMN reductions following the first episode. Recent studies suggest that decreased MMN amplitude has been correlated with bilateral Heschl's gyrus gray matter pathology in schizophrenia patients (Rasser et al., 2011). Furthermore, P300 amplitude reduction was associated with gray matter volume in subjects with early symptoms of psychosis (Fusar-Poli et al., 2011). "
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    ABSTRACT: Higher cognitive dysfunction, lower perceptual disturbance and its relation to the structures that implicate such processes have been considered as key features in patients with schizophrenia. However, little is known about the relationship between perceptual processing and structural deficits in ultra-high-risk for psychosis. We investigated the dipole moment of M100 auditory evoked response using a magnetoencephalography in 18 patients with schizophrenia, 16 ultra-high-risk for psychosis and 16 healthy controls, and their relation to cortical thinning on Heschl's gyrus and planum temporale. The auditory evoked M100 dipole moment was decreased in the ultra-high-risk subjects and in the patients with schizophrenia. Ultra-high-risk subjects showed impaired right M100 dipole magnitude, similar to patients with schizophrenia. Robust correlations between the cortical thickness of left Heschl's gyrus and the left M100 dipole moment were found in patients with schizophrenia. Moreover, correlations were also evident between right Heschl's gyrus and right M100 in subjects at ultra-high-risk for psychosis. The primary feature of auditory perception in ultra-high-risk subjects and schizophrenia patients is an encoding deficit that manifests as a reduced M100 dipole moment. The relationship between abnormal M100, thinning of cortical generators and their symptomatology were shown to exist prior to the onset of overt psychosis and progressively worsen over time. Therefore, they may be a potential indicator of the development of schizophrenia.
    Schizophrenia Research 07/2012; 140(1-3):93-8. DOI:10.1016/j.schres.2012.06.014 · 4.43 Impact Factor
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    • "Recent studies have also demonstrated that MMN is highly associated with psychosocial functioning in schizophrenia patients (Light & Braff, 2005b ; Kawakubo et al. 2007 ; Wynn et al. 2010 ; Rasser et al. 2011) as well as in healthy subjects (Light et al. 2007). "
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    ABSTRACT: Deficits in automatic sensory discrimination, as indexed by a reduction in the mismatch negativity (MMN) and P3a event-related potential amplitudes, are well documented in chronic schizophrenia. However, MMN and P3a have not been sufficiently studied early in the course of psychotic illness. The present study aimed to investigate MMN, P3a and reorienting negativity (RON) across the course of schizophrenia. MMN, P3a, and RON were assessed in 118 subjects across four groups: (1) individuals at risk for psychosis (n=26); (2) recent-onset patients (n=31); (3) chronic patients (n=33); and (4) normal controls (n=28) using a duration-deviant auditory oddball paradigm. Frontocentral deficits in MMN and P3a were present in all patient groups. The at-risk group's MMN and P3a amplitudes were intermediate to those of the control and recent-onset groups. The recent-onset and chronic patients, but not the at-risk subjects, showed significant RON amplitude reductions, relative to the control group. Associations between MMN, P3a, RON and psychosocial functioning were present in the chronic patients. In the at-risk subjects, P3a and RON deficits were significantly associated with higher levels of negative symptoms. Abnormalities in the automatic processes of sensory discrimination, orienting and reorienting of attention are evident in the early phases of schizophrenia and raise the possibility of progressive worsening across stages of the illness. The finding that MMN and P3a, but not RON, were reduced before psychosis onset supports the continued examination of these components as potential early biomarkers of schizophrenia.
    Psychological Medicine 07/2011; 42(1):85-97. DOI:10.1017/S0033291711001061 · 5.43 Impact Factor
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