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Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 213–219
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Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia Seung-Hwan Lee a,b,⁎, Kyongae Sung b, Kyong-Sang Lee b, Eunok Moon c, Chang-Gyu Kim d a
Department of Psychiatry, Inje University, Ilsan-Paik Hospital, 2240 Daehwa-dong, Ilsanseo-gu, Goyang, Republic of Korea Clinical Emotion and Cognition Research Laboratory, 2240 Daehwa-dong, Ilsanseo-gu, Goyang, Republic of Korea Department of Psychology, Chungbuk National University, Gaesin-dong, Heungdeok-gu, Cheongju-si, Chungbuk, Republic of Korea d Department of Psychology, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 22 June 2013 Received in revised form 28 September 2013 Accepted 13 October 2013 Available online 22 October 2013 Keywords: Functional outcome Mismatch negativity Neurocognition Schizophrenia Theory of mind
a b s t r a c t Objectives: Mismatch negativity (MMN) is known to be associated with neurocognition, social cognition, and functional outcomes. The present study explored the relationships of MMN with neurocognition, theory of mind, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. Methods: Twenty-five patients with schizophrenia, 21 first-degree relatives of patients with schizophrenia, and 29 healthy controls were recruited. We examined symptom severity, neurocognition, theory of mind, functional outcomes, and MMN. Results: MMN amplitudes decreased in order of patients with schizophrenia, then first-degree relatives, then healthy controls. MMN amplitude was significantly correlated with measures of neurocognition, theory of mind, and functional outcome measurements in patients with schizophrenia. However, the most powerful correlations were those between MMN in the frontal region and measures of functional outcomes. The power and frequency of the correlations were weaker in first-degree relatives and healthy controls than in patients with schizophrenia. Hierarchical regression analysis revealed that functional outcomes (relative to measures of neurocognition and theory of mind) constituted the most powerful predictor of MMN. Conclusions: Our results suggest that MMN reflects functional outcomes more efficiently than do measures of neurocognition and theory of mind in patients with schizophrenia. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Mismatch negativity (MMN) is an automatically generated ERP component when a sequence of relatively uniform stimuli is interrupted by the infrequent presentation of deviant stimuli. MMN is thought to reflect an automatic measure of detection of perceptual change or a sensory prerequisite of cognition (Naatanen et al., 1978). MMN deficiency appears to be an index of cognitive decline, irrespective of the specific symptomatologies and etiologies of the involved disorders (Naatanen et al., 2012). MMN deficits have been observed in patients with schizophrenia (Light and Braff, 2005a; Salisbury et al., 2002; Wynn et al., 2010). MMN has been known to be relatively uninfluenced by the effects of Abbreviations: MMN, mismatch negativity; GAF, Global Assessment of Functioning; PANSS, Positive and Negative Syndrome Scale; BACS, Brief Assessment of Cognition in Schizophrenia; TMT-A & B, Trail Making Test-A & -B; ToM, theory of mind; K-SAS, Korean version of the Social Adjustment Scale; SFQ, Social Functioning Questionnaire; EEG, electroencephalogram; EOG, electrooculograms; ANOVA, analysis of variance. ⁎ Corresponding author at: Department of Psychiatry, Inje University, Ilsan-Paik Hospital, 2240 Daehwa-dong, Ilsanseo-gu, Goyang 411-706, Republic of Korea. Tel.: +82 31 910 7260; fax: +82 31 910 7268. E-mail address: [email protected] (S.-H. Lee). 0278-5846/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.10.010
antipsychotic medication (Catts et al., 1995; Umbricht et al., 1998, 1999), and MMN deficit may reflect the progression of disease or premorbid neurocognitive impairment (Umbricht et al., 2006). Şevik et al. (2011) reported that patients with schizophrenia had similar MMN amplitudes to an age- and education-matched sibling group; however, they have lower MMN amplitudes than healthy controls. The major pathology of MMN deficit appears to originate from dysfunction of the N-methyl-D-aspartate (NMDA) receptor system (Javitt et al., 1996; Umbricht et al., 2002). NMDA-receptor-mediated glutamatergic dysfunction may well explain the pathology of both schizophrenia and other neuropsychiatric diseases (Umbricht et al., 2002), which explicitly reflect MMN deficits. Several groups have reported correlations between MMN and global social functioning in patients with chronic schizophrenia (Kawakubo and Kasai, 2006; Kiang et al., 2007; Light and Braff, 2005a; Rasser et al., 2011), and one study found a stable association over a 1-year period (Light and Braff, 2005b). Significant associations between MMN and Global Assessment of Functioning (GAF) scores have also been noted in healthy subjects (Light et al., 2007). The results of these studies imply that deficits in MMN can impact social functioning in the community. Functional outcomes are important in schizophrenia research. Recent work has demonstrated that social cognition is a more important
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mediator of functional outcomes than is neurocognition in patients with schizophrenia (Bae et al., 2010; Brekke et al., 2005). Wynn et al. (2010) studied the relationship among MMN, social cognition, and functioning in patients with schizophrenia; they reported that MMN deficits had a downstream impact on higher-order social cognition and community functioning. However, no previous studies have completely explored the relationships among early auditory processing (MMN), neurocognition, social cognition, and functional outcomes in patients with schizophrenia and their first-degree relatives. In the present study, we aimed to explore the relationships of MMN with neurocognition, social cognition, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. The first-degree relatives were recruited because they represent a continuum between patients with schizophrenia and healthy controls. This will also aid our understanding of MMN differences in schizophrenia and first-degree relatives. We hypothesized that MMN amplitude, neurocognition, social cognition, and functional outcomes would be lowest in patients with schizophrenia, followed by first-degree relatives and healthy controls. In addition, we hypothesized that MMN would show a stronger relation with functional outcomes than with social cognition and neurocognition in patients with schizophrenia as well as first-degree relatives of patients with schizophrenia and healthy controls.
2. Methods 2.1. Participants Patients with schizophrenia (n = 25, 13 female), first-degree relatives of patients with schizophrenia (n=21, 16 female), and healthy controls (n = 29, 13 female) were recruited from the Psychiatry Department of Inje University Ilsan Paik Hospital, Korea. Patients with schizophrenia were diagnosed according to the criteria set forth in the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I Psychiatric Disorders (First and Gibbon, 1997a). Their psychiatric symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). None of the patients had mental retardation or a history of central nervous system disease, alcohol or drug abuse, electroconvulsive therapy, or head injury with loss of consciousness. All patients were in stable condition and taking atypical antipsychotics (olanzapine, n = 11; risperidone, n = 14). First-degree relatives and healthy controls were recruited through posters displayed in the hospital and advertisements in local newspapers. An initial screening interview was conducted by a boardcertified psychiatrist in order to exclude subjects with identifiable psychiatric disorders or histories of head injury or neurological disorders. The first-degree relatives were siblings, parents, or children of people with schizophrenia; they were excluded if they had any personal history of psychiatric disease. Ten of the first-degree relatives were relatives of the patients in this sample, and 11 were not. Healthy controls were excluded if they had any personal history of psychiatric disease or family history of psychiatric illness. Potential healthy control subjects were interviewed using the Structured Clinical Interview for DSM-IV Axis II Disorders (First and Gibbon, 1997b) and excluded if they had any of paranoid, schizoid, or schizotypal personality disorders. All Structured Clinical Interviews and PANSS administrations were conducted by two psychiatry residents (KS and KSL); the interrater reliability value was 0.76. All subjects' normal hearing ability was confirmed by the 512-Hz tuning fork test (Burkey et al., 1998), and all were identified as righthanded, as they responded that they used that hand for writing and other precise motor skills. All subjects signed a written informed consent form approved by the Institutional Review Board of Inje University Ilsan Paik Hospital prior to participation in the study.
There were no significant between-group differences in terms of gender distribution or education (Table 1). However, the first-degree relatives were older than the patients with schizophrenia or healthy controls. 2.2. Neurocognition 2.2.1. Verbal fluency test — animal In this test, subjects state the names of as many animals as possible within 60 s. This evaluates verbal production and semantic memory abilities. This test was adapted from the Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004). 2.2.2. Symbol coding Patients were given 90s to write the numerals 1–9 to match symbols on a response sheet as quickly as possible to evaluate their capacity for psychomotor speed. Possible scores on this measure range 0–110. This task was adapted from the BACS (Keefe et al., 2004). 2.2.3. Trail Making Test-A & -B (TMT-A & TMT-B) In the TMT-A, subjects are asked to draw lines sequentially, connecting 25 consecutive, encircled numbers distributed across a sheet of paper within 360 s. In the TMT-B, subjects are instructed to draw lines alternating between numbers and Korean letters within 300 s (Seo et al., 2006). The TMT-A and TMT-B are scored according to the time taken to complete the task. The TMT-A mainly evaluates visual attention, while the TMT-B evaluates executive functioning. Longer time scores indicate worse performance. 2.3. Theory of mind (ToM) 2.3.1. Cartoon test We used the modified version of the cartoon test (Oh et al., 2005), the original version of which was developed by Sarfati et al. (1997). Subjects see four consecutive panels of a cartoon and are asked to determine the most appropriate still cut to place next. This test evaluates the ability to understand social context. This measure comprises 30 items; the total possible score is 30. 2.3.2. False belief task This test was developed to assess the ability to imagine other people's false beliefs in a specific situation described in a story. We used four short stories including first-order (Wimmer and Perner, 1983) and second-order false belief tasks (Perner and Wimmer, 1985), each of which asks about two stories.
Table 1 Demographic data and symptom ratings of patients with schizophrenia. Patients with First-degree schizophrenia relatives (n = 21) (n = 25) Sex (male/female) Age (years) Education (years) Number of hospitalizations Dosage of medication (CPZ equivalent, mg) PANSS score Positive Negative General Total
Healthy control F-test subjects (n = 29)
12/13 5/16 16/13 35.72 (11.33) 52.86 (13.16) 30.21 (11.17) 12.20 (3.35) 13.05 (3.99) 14.48 (4.31) 3.5 (2.5) 482 (170)
19.60 (6.54) 22.20 (5.37) 38.08 (10.19) 79.68 (12.73)
PANSS: Positive and Negative Syndrome Scale. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
2.62 23.34⁎⁎⁎ 2.33
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2.3.3. Physical story This test was originally developed to test the ability to read and understand situations (Happe, 1994). This test evaluates the ability to understand social situations rather than to mentalize other people's thoughts. As this is more of a control task and is not related to ToM, this test was not analyzed as a factor of ToM. 2.3.4. ToM-story This test was originally developed to test the ability to read and understand situations that require participants to mentalize other people's thoughts (Happe, 1994). This test asks subjects to read eight stories and includes the four subtypes of ToM tests (double bluff, white lie, persuasion, and misunderstanding) represented by two stories each. 2.4. Functional outcome measures 2.4.1. GAF scale This scale evaluates subjects' functioning in everyday life (American Psychiatric Association, 2000). Scores on this scale range 0–100. It subjectively measures adults' social, occupational, and psychological functioning. 2.4.2. Korean version of the Social Adjustment Scale (K-SAS) This test was originally developed by Weissman et al. (1971). The validity and reliability of the K-SAS were confirmed by Kim et al. (1999). This test contains 70 total questions distributed across 9 subtypes (instrumental role, chores, finances, family relationships, social leisure, friend relationships, romantic involvement, sexual adjustment, and personal well-being) and provides a global judgment of patients' social adjustment over the past 2 months. A higher score indicates worse performance. 2.4.3. Social Functioning Questionnaire (SFQ) This test is an eight-item self-report scale (Tyrer et al., 2005) developed for quick assessment of perceived social functioning. Scores range 0–24; higher scores indicate worse performance. 2.5. EEG recording The subjects were seated in a comfortable chair in a soundattenuated room. Stimulus presentation and data synchronization with the electroencephalogram (EEG) were accomplished with E-Prime (Psychology Software Tools, Pittsburgh, PA, USA). The auditory stimuli consisted of sounds at 85 dB SPL and 1000 Hz. Deviant tones lasting 100 ms were presented randomly, interspersed with standard tones lasting 50 ms (probabilities: 20% and 80%, respectively). In total, 400 auditory stimuli were presented; the rise and fall times were 10 ms, and the interstimulus interval was 1500 ms. These auditory stimuli were delivered via MDR-D777 headphones (Sony, Tokyo, Japan). The subjects were asked to watch a Charlie Chaplin movie without paying attention to sound. The experiment took about 15 min to complete. Breaks were permitted only when the subjects asked to rest. EEG activity was recorded using a NeuroScan SynAmps amplifier (Compumedics USA, El Paso, TX, USA) and Ag–AgCl electrodes mounted in a Quick Cap using a modified 10–20 placement scheme. A total of 62 scalp electrodes (FP1, FPZ, FP2, AF3, AF4, F7, F5, F3, F1, FZ, F2, F4, F6, F8, FT7, FC5, FC3, FC1, FCZ, FC2, FC4, FC6, FT8, T7, C5, C3, C1, CZ, C2, C4, C6, T8, TP7, CP5, CP3, CP1, CPZ, CP2, CP4, CP6, TP8, P7, P5, P3, P1, PZ, P2, P4, P6, P8, PO7, PO5, PO3, POZ, PO4, PO6, PO8, CB1, O1, OZ, O2, and CB2) were used in this study. Vertical electrooculograms (EOG) were recorded using two electrodes located above and below the left eye. Horizontal EOG was recorded at the outer canthus of each eye. EEG data were recorded with a 0.1–100-Hz band-pass filter at a sampling rate of 1000 Hz. The ground electrode was placed on the forehead, and the reference electrodes were located at both mastoids. Inter-
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electrode impedance was maintained at less than 5 kΩ. Averaging of the ERP waves and related procedures was performed using the NeuroScan version 4.3 software package (Compumedics USA). Gross movement artifacts were removed from the recorded data by visual inspection, and eye blinks were removed using established mathematical procedures (Semlitsch et al., 1986). Trials were rejected if they included significant physiological artifacts (amplitude exceeding ±75 μV) at any cortical electrode site. After artifact removal, baseline correction was conducted by subtracting the mean voltage at 100 ms before stimulus onset from the poststimulus data for each trial. The data were band-pass filtered at 0.1–30 Hz (24 dB/octave roll-off) and then divided into 1000-ms epochs from 100 ms prestimulus to 900 ms poststimulus. The MMN wave was generated by subtracting the standard ERP wave from the deviant ones. MMN amplitude was measured as the mean voltage between 100 and 250 ms at 27 electrode sites (Fp1, Fp2, F7, F3, Fz, F4, F8, FC5, FC1, FC2, FC6, T7, C3, Cz, C4, T8, CP5, CP1, CP2, CP6, P7, P3, Pz, P4, P8, O1, and O2) because the frontocentral electrodes have shown larger MMN peaks (Şevik et al., 2011; Umbricht et al., 2006; Wynn et al., 2010). Patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls had means (SDs) of 67.12 (12.08), 68.66 (11.10), and 71.57 (11.11) trials, respectively, for deviant tones following blink correction and artifact rejection. Increased negative amplitude of MMN indicates good performance. 2.6. Statistical analysis A chi-squared test and one-way analyses of variance (ANOVAs) were used to examine differences in demographic variables. A repeated-measures ANOVA with 27 electrodes as within-subjects variables, the three groups as the between-subjects variable, and age and sex as covariates were used to assess patterns of MMN activity. If any significant effects were found, each measurement was analyzed using a multivariate ANOVA with 3 groups as between-subjects variables, and age and sex as covariates. Post-hoc Bonferroni corrected t-tests were conducted for between-group comparisons. Effect sizes are expressed as partial eta squared (ηp2). The assumption of homogeneity of variance was not satisfied for the neurocognition, social cognition, and functional outcome scores; thus, Spearman's partial correlation analysis with age and sex as covariates was performed to analyze the relationships between MMN amplitudes and other test scores. Hierarchical regression analysis was conducted to answer the question about MMN's comparative relationship with other measurements. Demographic variables (age, sex, and educational level) were entered in the first step as predictors to control these demographic effects in the next step of the analysis; neurocognition, ToM, and functional outcomes were entered separately in the second step. Finally, the changes in explanatory power (R2 change) were calculated by subtracting the R2 of the demographic data from the R2 of each group variable. However, the statistical values of each item were calculated by entering each item separately in the second step. This regression analysis was performed with all of the subjects combined. An alpha level of p = 0.05 was used for all analyses except for the correlation analysis of MMN, for which alpha was set at a more conservative level (p = 0.01) to control for multiple comparisons. 3. Results 3.1. MMN Grand-averaged MMN waveforms and topographical maps for each group are shown in Fig. 1. All three groups exhibited peak MMN activity in the frontocentral regions, though the patients exhibited clearly reduced MMN amplitudes compared with those of first-degree relatives and normal controls.
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Fig. 1. (A) Topographic maps of MMN, and (B) MMN waves at FCz in patients with schizophrenia, first-degree relatives, and healthy control subjects.
A repeated-measures ANOVA on MMN amplitude revealed a significant main effect of group [F(2, 68) = 8.13, p = 0.001]. A multivariate ANOVA revealed significant main effects of group mainly for frontocentral electrodes [F3, F(2, 74) = 3.562, p = 0.034, η2p = 0.101; Fz, F(2, 74) = 5.428, p = 0.006, η2p = 0.158; F4, F(2, 74) = 8.692, p = 0.001, η2p = 0.217; FC1, F(2, 74) = 7.831, p = 0.001, η2p = 0.188; FC2, F(2, 74) = 9.271, p b 0.001, η2p = 0.222; FC6, F(2, 74) = 5.019, p = 0.009, η2p = 0.122; C3, F(2, 74) = 4.477, p = 0.015, η2p = 0.116; Cz, F(2, 74) = 6.172, p = 0.003, η2p = 0.167; C4, F(2, 74) = 8.346, p = 0.001, η2p = 0.200; CP2, F(2, 74) = 3.319, p = 0.042, η2p = 0.094]. Post hoc tests revealed several electrodes in the frontocentral region with significantly smaller MMN amplitudes in patients with schizophrenia than in healthy controls (Table 2). There was no significant electrode main effect or group by electrode interaction. The grand means of MMN were −0.45 (0.85) μV, −0.95 (0.97) μV, and −1.37 (0.88) μV for patients with schizophrenia, first-degree relatives, and healthy controls, respectively. 3.2. Neurocognition A multivariate ANOVA revealed significant main effects of group for all neurocognitive tests [verbal fluency test, F(2, 74) = 8.16, p = 0.011, η2p = 0.189; symbol coding, F(2, 74) = 14.92, p b 0.001, η2p = 0.299; TMT-A, F(2, 74) = 10.45, p b 0.001, η2p = 0.229; TMT-B, F(2, 74) = 11.87, p b 0.001, η2p = 0.253]. Post hoc tests revealed that patients with schizophrenia showed worse performance scores than shown by firstdegree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.3. ToM A multivariate ANOVA revealed significant main effects of group for all ToM tests [cartoon test, F(2, 74) = 3.58, p = 0.033, η2p = 0.093; ToMstory, F(2, 74) = 17.21, p b 0.001, η2p = 0.330] except for the false belief
Table 2 Mean (SD) amplitude of mismatch negativity, effect size, and F-test values of among-group difference. Age and sex were used as covariates. Site Patients with First-degree (μV) schizophreniaa relativesb (n = 25) (n = 21) Fp1 Fp2 F7 F3 Fz F4 F8 FC5 FC1 FC2 FC6 T7 C3 Cz C4 T8 CP5 CP1 CP2 CP6 P7 P3 Pz P4 P8 O1 O2
−0.44 (1.99) −0.36 (2.04) −0.20 (1.56) −0.76 (1.66) −0.80 (1.79) −0.62 (1.54) −0.53 (1.60) −0.70 (1.41) −0.68 (1.28) −0.74 (1.42) −0.72 (1.39) −0.17 (1.10) −0.71 (1.20) −0.65 (1.47) −0.75 (1.08) −0.11 (0.92) −0.34 (1.00) −0.64 (1.24) −0.55 (1.34) −0.30 (1.05) −0.08 (0.78) −0.46 (1.13) −0.40 (1.31) −0.37 (1.07) −0.03 (0.76) −0.21 (1.12) −0.07 (0.81)
⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
1.30 (9.75) −0.79 (1.45) −0.63 (1.58) −1.23 (1.43) −1.31 (1.48) −1.30 (1.45) −2.18 (4.37) −1.31 (1.49) −1.31 (1.56) −1.24 (1.46) −1.49 (1.71) −0.44 (1.06) −1.22 (1.54) −1.26 (1.55) −1.22 (1.49) −1.22 (1.81) −0.80 (1.10) −1.12 (1.65) −1.00 (1.55) −0.69 (1.31) −0.41 (0.98) −0.73 (1.34) −0.94 (1.57) −1.01 (1.64) −0.49 (0.88) −0.58 (1.04) −0.20 (0.84)
Healthy control subjectsc (n = 29)
Effect F value size (η2p)
−1.43 (1.16) −1.36 (1.74) −1.36 (1.74) −1.98 (1.60) −2.42 (1.63) −2.54 (1.74) −1.52 (2.17) −1.62 (1.23) −2.23 (1.35) −2.52 (1.53) −2.14 (1.78) −0.88 (1.03) −1.81 (1.21) −2.19 (1.45) −2.30 (1.48) −0.96 (1.49) −0.85 (0.98) −1.43 (1.23) −1.58 (1.26) −0.95 (1.16) −0.13 (0.86) −0.94 (1.26) −1.17 (1.35) −0.97 (1.02) −0.05 (0.93) −0.10 (0.94) −0.06 (0.73)
0.042 0.056 0.085 0.101 0.158 0.217 0.054 0.078 0.188 0.222 0.122 0.078 0.116 0.167 0.200 0.100 0.050 0.061 0.094 0.054 0.025 0.026 0.055 0.054 0.055 0.037 0.006
Post hoc (Bonferroni)
0.749 1.898 2.805 3.562⁎ 5.428⁎⁎ 8.692⁎⁎⁎ 1.320 3.016 7.831⁎⁎ 9.271⁎⁎⁎ 5.019⁎⁎
a b c, b b c abc abc
2.554 4.477⁎ 6.172⁎⁎ 8.346⁎⁎
abc abc abc
3.260 1.780 2.267 3.319⁎ 1.947 0.864 0.978 2.518 1.881 1.546 1.204 0.719
abc abc abc
abc
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story [F(2, 74) = 2.13, p = 0.12, η2p = 0.058]. Post hoc tests revealed that patients with schizophrenia showed worse performance scores than shown by first-degree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.4. Functional outcome A multivariate ANOVA revealed significant main effects of group for all tests of functional outcomes [GAF, F(2, 74) = 80.35, p b 0.001, η2p = 0.697; SAS, F(2, 74) = 35.37, p b 0.001, η2p = 0.503; SFQ, F(2, 74) = 12.26, p ≤ 0.001, η2p = 0.259]. Post hoc tests revealed that patients with schizophrenia showed worse scores than first-degree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.5. Correlation In patients with schizophrenia, there were significant correlations between MMN amplitudes and symptom severity, neurocognition, and functional outcome scores (Table 3). However, the strongest correlations were those of MMN at the Fz electrode with SAS (rho = −0.76, p b 0.001). Fig. 2 shows the scatter plots between MMN and GAF scores, and between MMN and SAS scores in patients with schizophrenia. In first-degree relatives and healthy controls, MMN amplitude was significantly correlated with ToM; however, the correlation power and frequency were weaker than those in patients with schizophrenia. In healthy controls, MMN amplitudes were significantly correlated with neurocognition, but the power and frequency were weaker than those in patients with schizophrenia. 3.6. Hierarchical regression A two-step hierarchical regression analysis was conducted to predict MMN (Table 4). The model was significant, with neurocognition accounting for 17.5% of the variance in MMN (F = 3.409, p = 0.003). The hierarchical regression model for ToM was significant, accounting Table 3 Spearman's partial correlations between MMN amplitudes and symptom severity, neurocognition, theory of mind, and functional outcomes. Age and sex were used as covariates. The rows shaded in gray show the distinction among symptom severity, neurocognition, ToM, and functional outcomes. The bold types mean the significant p value after applying conservative alpha (p = 0.01). Patients with schizophrenia (n=25) FZ – PANSS Total T7 – PANSS Total Cz – PANSS Total Cz – PANSS General FZ – Symbol Coding FZ – TMT B F4 – TMT A FC6 – TMT A T7 – TMT A F8 – TMT A CP5 – TMT A CP6 – TMT A P4 – VL P8 – VL P8 – TMT A O2 – VL FZ – ToM story CP2 – False belief task P8 – Cartoon FZ – GAF FZ – SAS FC6 – SFQ CZ – GAF CZ – SAS T8 – SAS CP6 – SAS P7 – GAF P3 – GAF P8 – GAF P8 – SAS O2 – GAF
First–degree relatives (n=21)
r
p
0.53 0.45 0.48 0.58 –0.42 0.43 0.50 0.58 0.46 0.60 0.46 0.61 –0.45 –0.42 0.46 –0.48 –0.44 –0.49 –0.46 –0.58 0.76 0.42 –0.44 0.51 0.42 0.45 –0.46 –0.44 –0.48 –0.45 –0.61
p = 0.009 p = 0.028 p = 0.019 p = 0.003 p = 0.042 p = 0.037 p = 0.015 p = 0.003 p = 0.024 p = 0.002 p = 0.026 p = 0.002 p = 0.030 p = 0.042 p = 0.026 p = 0.018 p = 0.036 p = 0.016 p = 0.025 p = 0.003 p = 0.000 p = 0.043 p = 0.035 p = 0.011 p = 0.046 p = 0.030 p = 0.025 p = 0.035 p = 0.020 p = 0.028 p = 0.002
F4 – TMT A C4 – TMT A CP5 – TMT A CP6 – TMT A F8 – False belief task F8 – ToMstory F8 – SFQ FC2 – GAF T8 – SFQ
r
p
0.48 0.46 0.53 0.50 –0.56 –0.64 0.52 –0.51 0.55
p = 0.037 p = 0.044 p = 0.019 p = 0.029 p = 0.011 p = 0.003 p = 0.022 p = 0.023 p = 0.013
Healthy control subjects (n=29) r p C3 – TMT B Cz – TMT A CP5 – TMT B Pz – Symbol coding P8 – TMT B O2 – TMT B C3 – False belief task CZ – False belief task CP5 – False belief task P7 – False belief task P4 – False belief task FP2 – GAF CP5 – GAF O1 – SAS O2 – SAS
0.44 –0.51 0.51 –0.39 0.43 0.40 –0.40 0.43 –0.40 –0.44 –0.44 0.42 0.49 –0.42 –0.44
p = 0.027 p = 0.009 p = 0.009 p = 0.050 p = 0.032 p = 0.044 p = 0.047 p = 0.032 p = 0.047 p = 0.026 p = 0.026 p = 0.033 p = 0.012 p = 0.037 p = 0.025
Fig. 2. (A) Scatter plots between MMN at the Fz electrode and GAF scores and (B) between MMN at the Fz electrode and SAS scores in patients with schizophrenia.
for 13% of the variance in MMN (F = 3.253, p = 0.007). The hierarchical regression model for functional outcomes was also significant, accounting for 24.1% of the variance in MMN (F = 5.636, p b 0.001).
4. Discussion In this study, we compared the correlation patterns of MMN with neurocognition, ToM, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. We found that MMN amplitudes were significantly lower in patients with schizophrenia than in healthy controls. MMN was generally well correlated with symptom severity, neurocognition, ToM, and functional outcomes across the three groups. However, the most potent correlation was found in functional outcomes in patients with schizophrenia. Furthermore, hierarchical regression analysis showed that in any person, not just schizophrenia patients, MMN amplitude was strongly predicted by functional outcomes (rather than neurocognition or ToM). The main finding of our study is that MMN is significantly correlated with functional outcomes and significantly predicted by them (compared with neurocognition and ToM) in patients with schizophrenia. Previous studies demonstrated that MMN was significantly correlated with GAF score in patients with schizophrenia (Kawakubo
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Table 4 Hierarchical regression analysis predicting mismatch negativity using neurocognition, theory of mind, and functional outcomes at Fz in all participants (N = 75).
Neurocognition
Theory of mind
Functional outcome
Variables
B value
Verbal fluency test Symbol coding TMT-A (time) TMT-B (time) Cartoon False belief task ToM-story GAF SAS SFQ
−0.058
Standard t error 0.030
−0.033 0.012 0.017 0.006 0.015 0.005 −0.017 0.033 0.038 0.067 −0.080 0.029 −0.045 −0.010 1.288 0.294 0.059 0.024
p
ΔR2
−1.932 0.058 0.175⁎⁎ −2.871 3.081 3.155 −0.496 0.559 −2.780 −4.394 4.387 2.490
0.005 0.003 0.002 0.622 0.130⁎⁎ 0.578 0.007 0.000 0.241⁎⁎⁎ 0.000 0.015
TMT: Trail Making Test, GAF: Global Assessment of Functioning, SAS: Social Adjustment Scale, SFQ: Social Functioning Questionnaire. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
and Kasai, 2006; Kiang et al., 2007; Light and Braff, 2005a). Light and Braff (2005a) suggested that MMN deficit represents a core neurophysiological dysfunction in patients with schizophrenia that is linked to global impairment in everyday functioning, and basic, preattentive cognitive deficits may be excellent predictors of functional outcomes. Wynn et al. (2010) demonstrated that MMN activity is closely tied to both functional outcomes and social cognition in patients with schizophrenia. They supposed that MMN may be closely related to aspects of work and independent living and suggested a cascade model of information processing in which deficits in early perceptual processing have a downstream impact on community functioning. In sum, previous studies revealed that MMN could be linked with functional outcomes in patients with schizophrenia, and that trend was replicated in our study. In addition, Light et al. (2007) found a correlation between MMN and GAF score in healthy controls. We also found potential trends of correlation between MMN and GAF in our healthy controls (p = 0.033 at FP2; p = 0.012 at CP5 under alpha level 0.01). In regression analysis, MMN was predicted more powerfully by functional outcomes rather than neurocognition or ToM in all participants, including patients and non-patients. Our comparative study results indicate that MMN could be linked strongly with subjects' social functioning relative to neurocognition and ToM. We also found that the MMN of patients with schizophrenia was significantly correlated with their PANSS total and general scores. Several previous studies (Catts et al., 1995; Javitt, 2000; Salisbury et al., 2002; Umbricht et al., 2006) have associated decreased MMN amplitude with severity of negative symptoms among patients with schizophrenia, suggesting that impaired MMN generation might index a core feature of the disorder. Even though we did not find a significant correlation between negative symptom scores and MMN, our results suggest that MMN decreases with worsened symptoms in patients with schizophrenia. In terms of neurocognitive functioning, the TMT-A results were significantly correlated with MMN in patients with schizophrenia, as were TMT-A and TMT-B results for healthy controls. However, there is controversy about the correlation patterns between MMN and neurocognitive functioning. Kiang et al. (2007) demonstrated that MMN was significantly correlated with verbal learning in patients with schizophrenia, but not in healthy controls. Mowszowski et al. (2012) demonstrated in patients with mild cognitive impairment that reduced MMN was significantly associated with poorer verbal learning and increased self-reported disability. However, other studies have shown no significant correlations between MMN and neuropsychological test scores in healthy controls (Baldeweg et al., 2004; Kasai et al., 2002; Light et al., 2007). Lin et al. (2012) did not show any
significant correlation between duration of MMN and scores on neuropsychological tests in patients with schizophrenia and healthy controls. Brockhaus-Dumke et al. (2005) did not show any significant correlations between MMN and the results of neuropsychological tests in prodromal subjects, patients with schizophrenia, and healthy controls. The test types and characteristics used to evaluate neurocognitive functioning might have influenced the previous results. We found a significant correlation between MMN and ToM only in the first-degree relatives; however, significant trends were found in patients with schizophrenia and healthy controls. Previously, Wynn et al. (2010) showed that greater MMN activity at frontocentral sites was associated with better social perception in patients with schizophrenia, while the MMN activity of healthy controls showed very few significant associations with social cognition measurements. However, their study did not compare the strength of the MMN associated relationships with social cognition or functional outcome. To our knowledge, this study is the first to explore the relationships of MMN with neurocognition, social cognition, and functional outcomes in a single study design. There are a few limitations to this study. First, the studied patients with schizophrenia were taking medication at the time of testing. However, neither typical nor atypical antipsychotics appear to affect MMN amplitude in patients with schizophrenia (Catts et al., 1995; Umbricht et al., 1998, 1999). Second, the relatively small sample size prevented regression analysis within patients with schizophrenia. Third, a large percentage of relatives were not genetically related to the patients in the current sample and was 20years older than the control and patient groups. Older age could decrease MMN amplitude (Kiang et al., 2009); however, we employed age as a covariate to minimize the age effect on MMN amplitude. Data from genetically related and unrelated first-degree relatives could also influence MMN amplitude in different ways. Thus, future research should be conducted with only individuals genetically related to the patients, to minimize the heterogeneous genetic effect on MMN. In conclusion, MMN was significantly correlated with symptom severity, neurocognition, and functional outcomes in patients with schizophrenia. However, our results suggest that in any person, not just schizophrenia patients, MMN is best predicted by functional outcome. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.pnpbp.2013.10.010. Acknowledgments This work was supported by the 2012 Inje University research grant. References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th, Text Revision ed. Washington, DC: American Psychiatric Association; 2000. Bae SM, Lee SH, Park YM, Hyun MH, Yoon H. Predictive factors of social functioning in patients with schizophrenia: exploration for the best combination of variables using data mining. Psychiatry Invest 2010;7:93–101. Baldeweg T, Klugman A, Gruzelier J, Hirsch SR. Mismatch negativity potentials and cognitive impairment in schizophrenia. Schizophr Res 2004;69:203–17. Brekke J, Kay DD, Lee KS, Green MF. Biosocial pathways to functional outcome in schizophrenia. Schizophr Res 2005;80:213–25. Brockhaus-Dumke A, Tendolkar I, Pukrop R, Schultze-Lutter F, Klosterkotter J, Ruhrmann S. Impaired mismatch negativity generation in prodromal subjects and patients with schizophrenia. Schizophr Res 2005;73:297–310. Burkey JM, Lippy WH, Schuring AG, Rizer FM. Clinical utility of the 512-Hz Rinne tuning fork test. Am J Otol 1998;19:59–62. Catts SV, Shelley AM, Ward PB, Liebert B, McConaghy N, Andrews S, et al. Brain potential evidence for an auditory sensory memory deficit in schizophrenia. Am J Psychiatry 1995;152:213–9. First MB, Gibbon M. User's guide for the Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I: clinician version. Amer Psychiatric Pub Incorporated; 1997a. First MB, Gibbon M. User's guide for the Structured Clinical Interview for DSM-IV Axis II Personality Disorders: SCID-II. Amer Psychiatric Pub Incorporated; 1997b. Happe FG. An advanced test of theory of mind: understanding of story characters' thoughts and feelings by able autistic, mentally handicapped, and normal children and adults. J Autism Dev Disord 1994;24:129–54.
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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp
Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia Seung-Hwan Lee a,b,⁎, Kyongae Sung b, Kyong-Sang Lee b, Eunok Moon c, Chang-Gyu Kim d a
Department of Psychiatry, Inje University, Ilsan-Paik Hospital, 2240 Daehwa-dong, Ilsanseo-gu, Goyang, Republic of Korea Clinical Emotion and Cognition Research Laboratory, 2240 Daehwa-dong, Ilsanseo-gu, Goyang, Republic of Korea Department of Psychology, Chungbuk National University, Gaesin-dong, Heungdeok-gu, Cheongju-si, Chungbuk, Republic of Korea d Department of Psychology, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 22 June 2013 Received in revised form 28 September 2013 Accepted 13 October 2013 Available online 22 October 2013 Keywords: Functional outcome Mismatch negativity Neurocognition Schizophrenia Theory of mind
a b s t r a c t Objectives: Mismatch negativity (MMN) is known to be associated with neurocognition, social cognition, and functional outcomes. The present study explored the relationships of MMN with neurocognition, theory of mind, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. Methods: Twenty-five patients with schizophrenia, 21 first-degree relatives of patients with schizophrenia, and 29 healthy controls were recruited. We examined symptom severity, neurocognition, theory of mind, functional outcomes, and MMN. Results: MMN amplitudes decreased in order of patients with schizophrenia, then first-degree relatives, then healthy controls. MMN amplitude was significantly correlated with measures of neurocognition, theory of mind, and functional outcome measurements in patients with schizophrenia. However, the most powerful correlations were those between MMN in the frontal region and measures of functional outcomes. The power and frequency of the correlations were weaker in first-degree relatives and healthy controls than in patients with schizophrenia. Hierarchical regression analysis revealed that functional outcomes (relative to measures of neurocognition and theory of mind) constituted the most powerful predictor of MMN. Conclusions: Our results suggest that MMN reflects functional outcomes more efficiently than do measures of neurocognition and theory of mind in patients with schizophrenia. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Mismatch negativity (MMN) is an automatically generated ERP component when a sequence of relatively uniform stimuli is interrupted by the infrequent presentation of deviant stimuli. MMN is thought to reflect an automatic measure of detection of perceptual change or a sensory prerequisite of cognition (Naatanen et al., 1978). MMN deficiency appears to be an index of cognitive decline, irrespective of the specific symptomatologies and etiologies of the involved disorders (Naatanen et al., 2012). MMN deficits have been observed in patients with schizophrenia (Light and Braff, 2005a; Salisbury et al., 2002; Wynn et al., 2010). MMN has been known to be relatively uninfluenced by the effects of Abbreviations: MMN, mismatch negativity; GAF, Global Assessment of Functioning; PANSS, Positive and Negative Syndrome Scale; BACS, Brief Assessment of Cognition in Schizophrenia; TMT-A & B, Trail Making Test-A & -B; ToM, theory of mind; K-SAS, Korean version of the Social Adjustment Scale; SFQ, Social Functioning Questionnaire; EEG, electroencephalogram; EOG, electrooculograms; ANOVA, analysis of variance. ⁎ Corresponding author at: Department of Psychiatry, Inje University, Ilsan-Paik Hospital, 2240 Daehwa-dong, Ilsanseo-gu, Goyang 411-706, Republic of Korea. Tel.: +82 31 910 7260; fax: +82 31 910 7268. E-mail address: [email protected] (S.-H. Lee). 0278-5846/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.10.010
antipsychotic medication (Catts et al., 1995; Umbricht et al., 1998, 1999), and MMN deficit may reflect the progression of disease or premorbid neurocognitive impairment (Umbricht et al., 2006). Şevik et al. (2011) reported that patients with schizophrenia had similar MMN amplitudes to an age- and education-matched sibling group; however, they have lower MMN amplitudes than healthy controls. The major pathology of MMN deficit appears to originate from dysfunction of the N-methyl-D-aspartate (NMDA) receptor system (Javitt et al., 1996; Umbricht et al., 2002). NMDA-receptor-mediated glutamatergic dysfunction may well explain the pathology of both schizophrenia and other neuropsychiatric diseases (Umbricht et al., 2002), which explicitly reflect MMN deficits. Several groups have reported correlations between MMN and global social functioning in patients with chronic schizophrenia (Kawakubo and Kasai, 2006; Kiang et al., 2007; Light and Braff, 2005a; Rasser et al., 2011), and one study found a stable association over a 1-year period (Light and Braff, 2005b). Significant associations between MMN and Global Assessment of Functioning (GAF) scores have also been noted in healthy subjects (Light et al., 2007). The results of these studies imply that deficits in MMN can impact social functioning in the community. Functional outcomes are important in schizophrenia research. Recent work has demonstrated that social cognition is a more important
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mediator of functional outcomes than is neurocognition in patients with schizophrenia (Bae et al., 2010; Brekke et al., 2005). Wynn et al. (2010) studied the relationship among MMN, social cognition, and functioning in patients with schizophrenia; they reported that MMN deficits had a downstream impact on higher-order social cognition and community functioning. However, no previous studies have completely explored the relationships among early auditory processing (MMN), neurocognition, social cognition, and functional outcomes in patients with schizophrenia and their first-degree relatives. In the present study, we aimed to explore the relationships of MMN with neurocognition, social cognition, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. The first-degree relatives were recruited because they represent a continuum between patients with schizophrenia and healthy controls. This will also aid our understanding of MMN differences in schizophrenia and first-degree relatives. We hypothesized that MMN amplitude, neurocognition, social cognition, and functional outcomes would be lowest in patients with schizophrenia, followed by first-degree relatives and healthy controls. In addition, we hypothesized that MMN would show a stronger relation with functional outcomes than with social cognition and neurocognition in patients with schizophrenia as well as first-degree relatives of patients with schizophrenia and healthy controls.
2. Methods 2.1. Participants Patients with schizophrenia (n = 25, 13 female), first-degree relatives of patients with schizophrenia (n=21, 16 female), and healthy controls (n = 29, 13 female) were recruited from the Psychiatry Department of Inje University Ilsan Paik Hospital, Korea. Patients with schizophrenia were diagnosed according to the criteria set forth in the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I Psychiatric Disorders (First and Gibbon, 1997a). Their psychiatric symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). None of the patients had mental retardation or a history of central nervous system disease, alcohol or drug abuse, electroconvulsive therapy, or head injury with loss of consciousness. All patients were in stable condition and taking atypical antipsychotics (olanzapine, n = 11; risperidone, n = 14). First-degree relatives and healthy controls were recruited through posters displayed in the hospital and advertisements in local newspapers. An initial screening interview was conducted by a boardcertified psychiatrist in order to exclude subjects with identifiable psychiatric disorders or histories of head injury or neurological disorders. The first-degree relatives were siblings, parents, or children of people with schizophrenia; they were excluded if they had any personal history of psychiatric disease. Ten of the first-degree relatives were relatives of the patients in this sample, and 11 were not. Healthy controls were excluded if they had any personal history of psychiatric disease or family history of psychiatric illness. Potential healthy control subjects were interviewed using the Structured Clinical Interview for DSM-IV Axis II Disorders (First and Gibbon, 1997b) and excluded if they had any of paranoid, schizoid, or schizotypal personality disorders. All Structured Clinical Interviews and PANSS administrations were conducted by two psychiatry residents (KS and KSL); the interrater reliability value was 0.76. All subjects' normal hearing ability was confirmed by the 512-Hz tuning fork test (Burkey et al., 1998), and all were identified as righthanded, as they responded that they used that hand for writing and other precise motor skills. All subjects signed a written informed consent form approved by the Institutional Review Board of Inje University Ilsan Paik Hospital prior to participation in the study.
There were no significant between-group differences in terms of gender distribution or education (Table 1). However, the first-degree relatives were older than the patients with schizophrenia or healthy controls. 2.2. Neurocognition 2.2.1. Verbal fluency test — animal In this test, subjects state the names of as many animals as possible within 60 s. This evaluates verbal production and semantic memory abilities. This test was adapted from the Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004). 2.2.2. Symbol coding Patients were given 90s to write the numerals 1–9 to match symbols on a response sheet as quickly as possible to evaluate their capacity for psychomotor speed. Possible scores on this measure range 0–110. This task was adapted from the BACS (Keefe et al., 2004). 2.2.3. Trail Making Test-A & -B (TMT-A & TMT-B) In the TMT-A, subjects are asked to draw lines sequentially, connecting 25 consecutive, encircled numbers distributed across a sheet of paper within 360 s. In the TMT-B, subjects are instructed to draw lines alternating between numbers and Korean letters within 300 s (Seo et al., 2006). The TMT-A and TMT-B are scored according to the time taken to complete the task. The TMT-A mainly evaluates visual attention, while the TMT-B evaluates executive functioning. Longer time scores indicate worse performance. 2.3. Theory of mind (ToM) 2.3.1. Cartoon test We used the modified version of the cartoon test (Oh et al., 2005), the original version of which was developed by Sarfati et al. (1997). Subjects see four consecutive panels of a cartoon and are asked to determine the most appropriate still cut to place next. This test evaluates the ability to understand social context. This measure comprises 30 items; the total possible score is 30. 2.3.2. False belief task This test was developed to assess the ability to imagine other people's false beliefs in a specific situation described in a story. We used four short stories including first-order (Wimmer and Perner, 1983) and second-order false belief tasks (Perner and Wimmer, 1985), each of which asks about two stories.
Table 1 Demographic data and symptom ratings of patients with schizophrenia. Patients with First-degree schizophrenia relatives (n = 21) (n = 25) Sex (male/female) Age (years) Education (years) Number of hospitalizations Dosage of medication (CPZ equivalent, mg) PANSS score Positive Negative General Total
Healthy control F-test subjects (n = 29)
12/13 5/16 16/13 35.72 (11.33) 52.86 (13.16) 30.21 (11.17) 12.20 (3.35) 13.05 (3.99) 14.48 (4.31) 3.5 (2.5) 482 (170)
19.60 (6.54) 22.20 (5.37) 38.08 (10.19) 79.68 (12.73)
PANSS: Positive and Negative Syndrome Scale. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
2.62 23.34⁎⁎⁎ 2.33
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2.3.3. Physical story This test was originally developed to test the ability to read and understand situations (Happe, 1994). This test evaluates the ability to understand social situations rather than to mentalize other people's thoughts. As this is more of a control task and is not related to ToM, this test was not analyzed as a factor of ToM. 2.3.4. ToM-story This test was originally developed to test the ability to read and understand situations that require participants to mentalize other people's thoughts (Happe, 1994). This test asks subjects to read eight stories and includes the four subtypes of ToM tests (double bluff, white lie, persuasion, and misunderstanding) represented by two stories each. 2.4. Functional outcome measures 2.4.1. GAF scale This scale evaluates subjects' functioning in everyday life (American Psychiatric Association, 2000). Scores on this scale range 0–100. It subjectively measures adults' social, occupational, and psychological functioning. 2.4.2. Korean version of the Social Adjustment Scale (K-SAS) This test was originally developed by Weissman et al. (1971). The validity and reliability of the K-SAS were confirmed by Kim et al. (1999). This test contains 70 total questions distributed across 9 subtypes (instrumental role, chores, finances, family relationships, social leisure, friend relationships, romantic involvement, sexual adjustment, and personal well-being) and provides a global judgment of patients' social adjustment over the past 2 months. A higher score indicates worse performance. 2.4.3. Social Functioning Questionnaire (SFQ) This test is an eight-item self-report scale (Tyrer et al., 2005) developed for quick assessment of perceived social functioning. Scores range 0–24; higher scores indicate worse performance. 2.5. EEG recording The subjects were seated in a comfortable chair in a soundattenuated room. Stimulus presentation and data synchronization with the electroencephalogram (EEG) were accomplished with E-Prime (Psychology Software Tools, Pittsburgh, PA, USA). The auditory stimuli consisted of sounds at 85 dB SPL and 1000 Hz. Deviant tones lasting 100 ms were presented randomly, interspersed with standard tones lasting 50 ms (probabilities: 20% and 80%, respectively). In total, 400 auditory stimuli were presented; the rise and fall times were 10 ms, and the interstimulus interval was 1500 ms. These auditory stimuli were delivered via MDR-D777 headphones (Sony, Tokyo, Japan). The subjects were asked to watch a Charlie Chaplin movie without paying attention to sound. The experiment took about 15 min to complete. Breaks were permitted only when the subjects asked to rest. EEG activity was recorded using a NeuroScan SynAmps amplifier (Compumedics USA, El Paso, TX, USA) and Ag–AgCl electrodes mounted in a Quick Cap using a modified 10–20 placement scheme. A total of 62 scalp electrodes (FP1, FPZ, FP2, AF3, AF4, F7, F5, F3, F1, FZ, F2, F4, F6, F8, FT7, FC5, FC3, FC1, FCZ, FC2, FC4, FC6, FT8, T7, C5, C3, C1, CZ, C2, C4, C6, T8, TP7, CP5, CP3, CP1, CPZ, CP2, CP4, CP6, TP8, P7, P5, P3, P1, PZ, P2, P4, P6, P8, PO7, PO5, PO3, POZ, PO4, PO6, PO8, CB1, O1, OZ, O2, and CB2) were used in this study. Vertical electrooculograms (EOG) were recorded using two electrodes located above and below the left eye. Horizontal EOG was recorded at the outer canthus of each eye. EEG data were recorded with a 0.1–100-Hz band-pass filter at a sampling rate of 1000 Hz. The ground electrode was placed on the forehead, and the reference electrodes were located at both mastoids. Inter-
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electrode impedance was maintained at less than 5 kΩ. Averaging of the ERP waves and related procedures was performed using the NeuroScan version 4.3 software package (Compumedics USA). Gross movement artifacts were removed from the recorded data by visual inspection, and eye blinks were removed using established mathematical procedures (Semlitsch et al., 1986). Trials were rejected if they included significant physiological artifacts (amplitude exceeding ±75 μV) at any cortical electrode site. After artifact removal, baseline correction was conducted by subtracting the mean voltage at 100 ms before stimulus onset from the poststimulus data for each trial. The data were band-pass filtered at 0.1–30 Hz (24 dB/octave roll-off) and then divided into 1000-ms epochs from 100 ms prestimulus to 900 ms poststimulus. The MMN wave was generated by subtracting the standard ERP wave from the deviant ones. MMN amplitude was measured as the mean voltage between 100 and 250 ms at 27 electrode sites (Fp1, Fp2, F7, F3, Fz, F4, F8, FC5, FC1, FC2, FC6, T7, C3, Cz, C4, T8, CP5, CP1, CP2, CP6, P7, P3, Pz, P4, P8, O1, and O2) because the frontocentral electrodes have shown larger MMN peaks (Şevik et al., 2011; Umbricht et al., 2006; Wynn et al., 2010). Patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls had means (SDs) of 67.12 (12.08), 68.66 (11.10), and 71.57 (11.11) trials, respectively, for deviant tones following blink correction and artifact rejection. Increased negative amplitude of MMN indicates good performance. 2.6. Statistical analysis A chi-squared test and one-way analyses of variance (ANOVAs) were used to examine differences in demographic variables. A repeated-measures ANOVA with 27 electrodes as within-subjects variables, the three groups as the between-subjects variable, and age and sex as covariates were used to assess patterns of MMN activity. If any significant effects were found, each measurement was analyzed using a multivariate ANOVA with 3 groups as between-subjects variables, and age and sex as covariates. Post-hoc Bonferroni corrected t-tests were conducted for between-group comparisons. Effect sizes are expressed as partial eta squared (ηp2). The assumption of homogeneity of variance was not satisfied for the neurocognition, social cognition, and functional outcome scores; thus, Spearman's partial correlation analysis with age and sex as covariates was performed to analyze the relationships between MMN amplitudes and other test scores. Hierarchical regression analysis was conducted to answer the question about MMN's comparative relationship with other measurements. Demographic variables (age, sex, and educational level) were entered in the first step as predictors to control these demographic effects in the next step of the analysis; neurocognition, ToM, and functional outcomes were entered separately in the second step. Finally, the changes in explanatory power (R2 change) were calculated by subtracting the R2 of the demographic data from the R2 of each group variable. However, the statistical values of each item were calculated by entering each item separately in the second step. This regression analysis was performed with all of the subjects combined. An alpha level of p = 0.05 was used for all analyses except for the correlation analysis of MMN, for which alpha was set at a more conservative level (p = 0.01) to control for multiple comparisons. 3. Results 3.1. MMN Grand-averaged MMN waveforms and topographical maps for each group are shown in Fig. 1. All three groups exhibited peak MMN activity in the frontocentral regions, though the patients exhibited clearly reduced MMN amplitudes compared with those of first-degree relatives and normal controls.
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Fig. 1. (A) Topographic maps of MMN, and (B) MMN waves at FCz in patients with schizophrenia, first-degree relatives, and healthy control subjects.
A repeated-measures ANOVA on MMN amplitude revealed a significant main effect of group [F(2, 68) = 8.13, p = 0.001]. A multivariate ANOVA revealed significant main effects of group mainly for frontocentral electrodes [F3, F(2, 74) = 3.562, p = 0.034, η2p = 0.101; Fz, F(2, 74) = 5.428, p = 0.006, η2p = 0.158; F4, F(2, 74) = 8.692, p = 0.001, η2p = 0.217; FC1, F(2, 74) = 7.831, p = 0.001, η2p = 0.188; FC2, F(2, 74) = 9.271, p b 0.001, η2p = 0.222; FC6, F(2, 74) = 5.019, p = 0.009, η2p = 0.122; C3, F(2, 74) = 4.477, p = 0.015, η2p = 0.116; Cz, F(2, 74) = 6.172, p = 0.003, η2p = 0.167; C4, F(2, 74) = 8.346, p = 0.001, η2p = 0.200; CP2, F(2, 74) = 3.319, p = 0.042, η2p = 0.094]. Post hoc tests revealed several electrodes in the frontocentral region with significantly smaller MMN amplitudes in patients with schizophrenia than in healthy controls (Table 2). There was no significant electrode main effect or group by electrode interaction. The grand means of MMN were −0.45 (0.85) μV, −0.95 (0.97) μV, and −1.37 (0.88) μV for patients with schizophrenia, first-degree relatives, and healthy controls, respectively. 3.2. Neurocognition A multivariate ANOVA revealed significant main effects of group for all neurocognitive tests [verbal fluency test, F(2, 74) = 8.16, p = 0.011, η2p = 0.189; symbol coding, F(2, 74) = 14.92, p b 0.001, η2p = 0.299; TMT-A, F(2, 74) = 10.45, p b 0.001, η2p = 0.229; TMT-B, F(2, 74) = 11.87, p b 0.001, η2p = 0.253]. Post hoc tests revealed that patients with schizophrenia showed worse performance scores than shown by firstdegree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.3. ToM A multivariate ANOVA revealed significant main effects of group for all ToM tests [cartoon test, F(2, 74) = 3.58, p = 0.033, η2p = 0.093; ToMstory, F(2, 74) = 17.21, p b 0.001, η2p = 0.330] except for the false belief
Table 2 Mean (SD) amplitude of mismatch negativity, effect size, and F-test values of among-group difference. Age and sex were used as covariates. Site Patients with First-degree (μV) schizophreniaa relativesb (n = 25) (n = 21) Fp1 Fp2 F7 F3 Fz F4 F8 FC5 FC1 FC2 FC6 T7 C3 Cz C4 T8 CP5 CP1 CP2 CP6 P7 P3 Pz P4 P8 O1 O2
−0.44 (1.99) −0.36 (2.04) −0.20 (1.56) −0.76 (1.66) −0.80 (1.79) −0.62 (1.54) −0.53 (1.60) −0.70 (1.41) −0.68 (1.28) −0.74 (1.42) −0.72 (1.39) −0.17 (1.10) −0.71 (1.20) −0.65 (1.47) −0.75 (1.08) −0.11 (0.92) −0.34 (1.00) −0.64 (1.24) −0.55 (1.34) −0.30 (1.05) −0.08 (0.78) −0.46 (1.13) −0.40 (1.31) −0.37 (1.07) −0.03 (0.76) −0.21 (1.12) −0.07 (0.81)
⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
1.30 (9.75) −0.79 (1.45) −0.63 (1.58) −1.23 (1.43) −1.31 (1.48) −1.30 (1.45) −2.18 (4.37) −1.31 (1.49) −1.31 (1.56) −1.24 (1.46) −1.49 (1.71) −0.44 (1.06) −1.22 (1.54) −1.26 (1.55) −1.22 (1.49) −1.22 (1.81) −0.80 (1.10) −1.12 (1.65) −1.00 (1.55) −0.69 (1.31) −0.41 (0.98) −0.73 (1.34) −0.94 (1.57) −1.01 (1.64) −0.49 (0.88) −0.58 (1.04) −0.20 (0.84)
Healthy control subjectsc (n = 29)
Effect F value size (η2p)
−1.43 (1.16) −1.36 (1.74) −1.36 (1.74) −1.98 (1.60) −2.42 (1.63) −2.54 (1.74) −1.52 (2.17) −1.62 (1.23) −2.23 (1.35) −2.52 (1.53) −2.14 (1.78) −0.88 (1.03) −1.81 (1.21) −2.19 (1.45) −2.30 (1.48) −0.96 (1.49) −0.85 (0.98) −1.43 (1.23) −1.58 (1.26) −0.95 (1.16) −0.13 (0.86) −0.94 (1.26) −1.17 (1.35) −0.97 (1.02) −0.05 (0.93) −0.10 (0.94) −0.06 (0.73)
0.042 0.056 0.085 0.101 0.158 0.217 0.054 0.078 0.188 0.222 0.122 0.078 0.116 0.167 0.200 0.100 0.050 0.061 0.094 0.054 0.025 0.026 0.055 0.054 0.055 0.037 0.006
Post hoc (Bonferroni)
0.749 1.898 2.805 3.562⁎ 5.428⁎⁎ 8.692⁎⁎⁎ 1.320 3.016 7.831⁎⁎ 9.271⁎⁎⁎ 5.019⁎⁎
a b c, b b c abc abc
2.554 4.477⁎ 6.172⁎⁎ 8.346⁎⁎
abc abc abc
3.260 1.780 2.267 3.319⁎ 1.947 0.864 0.978 2.518 1.881 1.546 1.204 0.719
abc abc abc
abc
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story [F(2, 74) = 2.13, p = 0.12, η2p = 0.058]. Post hoc tests revealed that patients with schizophrenia showed worse performance scores than shown by first-degree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.4. Functional outcome A multivariate ANOVA revealed significant main effects of group for all tests of functional outcomes [GAF, F(2, 74) = 80.35, p b 0.001, η2p = 0.697; SAS, F(2, 74) = 35.37, p b 0.001, η2p = 0.503; SFQ, F(2, 74) = 12.26, p ≤ 0.001, η2p = 0.259]. Post hoc tests revealed that patients with schizophrenia showed worse scores than first-degree relatives of patients with schizophrenia or healthy controls (Supplementary Table 1). 3.5. Correlation In patients with schizophrenia, there were significant correlations between MMN amplitudes and symptom severity, neurocognition, and functional outcome scores (Table 3). However, the strongest correlations were those of MMN at the Fz electrode with SAS (rho = −0.76, p b 0.001). Fig. 2 shows the scatter plots between MMN and GAF scores, and between MMN and SAS scores in patients with schizophrenia. In first-degree relatives and healthy controls, MMN amplitude was significantly correlated with ToM; however, the correlation power and frequency were weaker than those in patients with schizophrenia. In healthy controls, MMN amplitudes were significantly correlated with neurocognition, but the power and frequency were weaker than those in patients with schizophrenia. 3.6. Hierarchical regression A two-step hierarchical regression analysis was conducted to predict MMN (Table 4). The model was significant, with neurocognition accounting for 17.5% of the variance in MMN (F = 3.409, p = 0.003). The hierarchical regression model for ToM was significant, accounting Table 3 Spearman's partial correlations between MMN amplitudes and symptom severity, neurocognition, theory of mind, and functional outcomes. Age and sex were used as covariates. The rows shaded in gray show the distinction among symptom severity, neurocognition, ToM, and functional outcomes. The bold types mean the significant p value after applying conservative alpha (p = 0.01). Patients with schizophrenia (n=25) FZ – PANSS Total T7 – PANSS Total Cz – PANSS Total Cz – PANSS General FZ – Symbol Coding FZ – TMT B F4 – TMT A FC6 – TMT A T7 – TMT A F8 – TMT A CP5 – TMT A CP6 – TMT A P4 – VL P8 – VL P8 – TMT A O2 – VL FZ – ToM story CP2 – False belief task P8 – Cartoon FZ – GAF FZ – SAS FC6 – SFQ CZ – GAF CZ – SAS T8 – SAS CP6 – SAS P7 – GAF P3 – GAF P8 – GAF P8 – SAS O2 – GAF
First–degree relatives (n=21)
r
p
0.53 0.45 0.48 0.58 –0.42 0.43 0.50 0.58 0.46 0.60 0.46 0.61 –0.45 –0.42 0.46 –0.48 –0.44 –0.49 –0.46 –0.58 0.76 0.42 –0.44 0.51 0.42 0.45 –0.46 –0.44 –0.48 –0.45 –0.61
p = 0.009 p = 0.028 p = 0.019 p = 0.003 p = 0.042 p = 0.037 p = 0.015 p = 0.003 p = 0.024 p = 0.002 p = 0.026 p = 0.002 p = 0.030 p = 0.042 p = 0.026 p = 0.018 p = 0.036 p = 0.016 p = 0.025 p = 0.003 p = 0.000 p = 0.043 p = 0.035 p = 0.011 p = 0.046 p = 0.030 p = 0.025 p = 0.035 p = 0.020 p = 0.028 p = 0.002
F4 – TMT A C4 – TMT A CP5 – TMT A CP6 – TMT A F8 – False belief task F8 – ToMstory F8 – SFQ FC2 – GAF T8 – SFQ
r
p
0.48 0.46 0.53 0.50 –0.56 –0.64 0.52 –0.51 0.55
p = 0.037 p = 0.044 p = 0.019 p = 0.029 p = 0.011 p = 0.003 p = 0.022 p = 0.023 p = 0.013
Healthy control subjects (n=29) r p C3 – TMT B Cz – TMT A CP5 – TMT B Pz – Symbol coding P8 – TMT B O2 – TMT B C3 – False belief task CZ – False belief task CP5 – False belief task P7 – False belief task P4 – False belief task FP2 – GAF CP5 – GAF O1 – SAS O2 – SAS
0.44 –0.51 0.51 –0.39 0.43 0.40 –0.40 0.43 –0.40 –0.44 –0.44 0.42 0.49 –0.42 –0.44
p = 0.027 p = 0.009 p = 0.009 p = 0.050 p = 0.032 p = 0.044 p = 0.047 p = 0.032 p = 0.047 p = 0.026 p = 0.026 p = 0.033 p = 0.012 p = 0.037 p = 0.025
Fig. 2. (A) Scatter plots between MMN at the Fz electrode and GAF scores and (B) between MMN at the Fz electrode and SAS scores in patients with schizophrenia.
for 13% of the variance in MMN (F = 3.253, p = 0.007). The hierarchical regression model for functional outcomes was also significant, accounting for 24.1% of the variance in MMN (F = 5.636, p b 0.001).
4. Discussion In this study, we compared the correlation patterns of MMN with neurocognition, ToM, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. We found that MMN amplitudes were significantly lower in patients with schizophrenia than in healthy controls. MMN was generally well correlated with symptom severity, neurocognition, ToM, and functional outcomes across the three groups. However, the most potent correlation was found in functional outcomes in patients with schizophrenia. Furthermore, hierarchical regression analysis showed that in any person, not just schizophrenia patients, MMN amplitude was strongly predicted by functional outcomes (rather than neurocognition or ToM). The main finding of our study is that MMN is significantly correlated with functional outcomes and significantly predicted by them (compared with neurocognition and ToM) in patients with schizophrenia. Previous studies demonstrated that MMN was significantly correlated with GAF score in patients with schizophrenia (Kawakubo
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Table 4 Hierarchical regression analysis predicting mismatch negativity using neurocognition, theory of mind, and functional outcomes at Fz in all participants (N = 75).
Neurocognition
Theory of mind
Functional outcome
Variables
B value
Verbal fluency test Symbol coding TMT-A (time) TMT-B (time) Cartoon False belief task ToM-story GAF SAS SFQ
−0.058
Standard t error 0.030
−0.033 0.012 0.017 0.006 0.015 0.005 −0.017 0.033 0.038 0.067 −0.080 0.029 −0.045 −0.010 1.288 0.294 0.059 0.024
p
ΔR2
−1.932 0.058 0.175⁎⁎ −2.871 3.081 3.155 −0.496 0.559 −2.780 −4.394 4.387 2.490
0.005 0.003 0.002 0.622 0.130⁎⁎ 0.578 0.007 0.000 0.241⁎⁎⁎ 0.000 0.015
TMT: Trail Making Test, GAF: Global Assessment of Functioning, SAS: Social Adjustment Scale, SFQ: Social Functioning Questionnaire. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.
and Kasai, 2006; Kiang et al., 2007; Light and Braff, 2005a). Light and Braff (2005a) suggested that MMN deficit represents a core neurophysiological dysfunction in patients with schizophrenia that is linked to global impairment in everyday functioning, and basic, preattentive cognitive deficits may be excellent predictors of functional outcomes. Wynn et al. (2010) demonstrated that MMN activity is closely tied to both functional outcomes and social cognition in patients with schizophrenia. They supposed that MMN may be closely related to aspects of work and independent living and suggested a cascade model of information processing in which deficits in early perceptual processing have a downstream impact on community functioning. In sum, previous studies revealed that MMN could be linked with functional outcomes in patients with schizophrenia, and that trend was replicated in our study. In addition, Light et al. (2007) found a correlation between MMN and GAF score in healthy controls. We also found potential trends of correlation between MMN and GAF in our healthy controls (p = 0.033 at FP2; p = 0.012 at CP5 under alpha level 0.01). In regression analysis, MMN was predicted more powerfully by functional outcomes rather than neurocognition or ToM in all participants, including patients and non-patients. Our comparative study results indicate that MMN could be linked strongly with subjects' social functioning relative to neurocognition and ToM. We also found that the MMN of patients with schizophrenia was significantly correlated with their PANSS total and general scores. Several previous studies (Catts et al., 1995; Javitt, 2000; Salisbury et al., 2002; Umbricht et al., 2006) have associated decreased MMN amplitude with severity of negative symptoms among patients with schizophrenia, suggesting that impaired MMN generation might index a core feature of the disorder. Even though we did not find a significant correlation between negative symptom scores and MMN, our results suggest that MMN decreases with worsened symptoms in patients with schizophrenia. In terms of neurocognitive functioning, the TMT-A results were significantly correlated with MMN in patients with schizophrenia, as were TMT-A and TMT-B results for healthy controls. However, there is controversy about the correlation patterns between MMN and neurocognitive functioning. Kiang et al. (2007) demonstrated that MMN was significantly correlated with verbal learning in patients with schizophrenia, but not in healthy controls. Mowszowski et al. (2012) demonstrated in patients with mild cognitive impairment that reduced MMN was significantly associated with poorer verbal learning and increased self-reported disability. However, other studies have shown no significant correlations between MMN and neuropsychological test scores in healthy controls (Baldeweg et al., 2004; Kasai et al., 2002; Light et al., 2007). Lin et al. (2012) did not show any
significant correlation between duration of MMN and scores on neuropsychological tests in patients with schizophrenia and healthy controls. Brockhaus-Dumke et al. (2005) did not show any significant correlations between MMN and the results of neuropsychological tests in prodromal subjects, patients with schizophrenia, and healthy controls. The test types and characteristics used to evaluate neurocognitive functioning might have influenced the previous results. We found a significant correlation between MMN and ToM only in the first-degree relatives; however, significant trends were found in patients with schizophrenia and healthy controls. Previously, Wynn et al. (2010) showed that greater MMN activity at frontocentral sites was associated with better social perception in patients with schizophrenia, while the MMN activity of healthy controls showed very few significant associations with social cognition measurements. However, their study did not compare the strength of the MMN associated relationships with social cognition or functional outcome. To our knowledge, this study is the first to explore the relationships of MMN with neurocognition, social cognition, and functional outcomes in a single study design. There are a few limitations to this study. First, the studied patients with schizophrenia were taking medication at the time of testing. However, neither typical nor atypical antipsychotics appear to affect MMN amplitude in patients with schizophrenia (Catts et al., 1995; Umbricht et al., 1998, 1999). Second, the relatively small sample size prevented regression analysis within patients with schizophrenia. Third, a large percentage of relatives were not genetically related to the patients in the current sample and was 20years older than the control and patient groups. Older age could decrease MMN amplitude (Kiang et al., 2009); however, we employed age as a covariate to minimize the age effect on MMN amplitude. Data from genetically related and unrelated first-degree relatives could also influence MMN amplitude in different ways. Thus, future research should be conducted with only individuals genetically related to the patients, to minimize the heterogeneous genetic effect on MMN. In conclusion, MMN was significantly correlated with symptom severity, neurocognition, and functional outcomes in patients with schizophrenia. However, our results suggest that in any person, not just schizophrenia patients, MMN is best predicted by functional outcome. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.pnpbp.2013.10.010. Acknowledgments This work was supported by the 2012 Inje University research grant. References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th, Text Revision ed. Washington, DC: American Psychiatric Association; 2000. Bae SM, Lee SH, Park YM, Hyun MH, Yoon H. Predictive factors of social functioning in patients with schizophrenia: exploration for the best combination of variables using data mining. Psychiatry Invest 2010;7:93–101. Baldeweg T, Klugman A, Gruzelier J, Hirsch SR. Mismatch negativity potentials and cognitive impairment in schizophrenia. Schizophr Res 2004;69:203–17. Brekke J, Kay DD, Lee KS, Green MF. Biosocial pathways to functional outcome in schizophrenia. Schizophr Res 2005;80:213–25. Brockhaus-Dumke A, Tendolkar I, Pukrop R, Schultze-Lutter F, Klosterkotter J, Ruhrmann S. Impaired mismatch negativity generation in prodromal subjects and patients with schizophrenia. Schizophr Res 2005;73:297–310. Burkey JM, Lippy WH, Schuring AG, Rizer FM. Clinical utility of the 512-Hz Rinne tuning fork test. Am J Otol 1998;19:59–62. Catts SV, Shelley AM, Ward PB, Liebert B, McConaghy N, Andrews S, et al. Brain potential evidence for an auditory sensory memory deficit in schizophrenia. Am J Psychiatry 1995;152:213–9. First MB, Gibbon M. User's guide for the Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I: clinician version. Amer Psychiatric Pub Incorporated; 1997a. First MB, Gibbon M. User's guide for the Structured Clinical Interview for DSM-IV Axis II Personality Disorders: SCID-II. Amer Psychiatric Pub Incorporated; 1997b. Happe FG. An advanced test of theory of mind: understanding of story characters' thoughts and feelings by able autistic, mentally handicapped, and normal children and adults. J Autism Dev Disord 1994;24:129–54.
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