The authors have declared that no competing interests exist.
Conceived and designed the experiments: YH T. Sumiyoshi. Performed the experiments: YH T. Seo TM. Analyzed the data: YH YK. Contributed reagents/materials/analysis tools: T. Sumiyoshi MS. Wrote the paper: YH T. Sumiyoshi.
A shorter duration of untreated psychosis has been associated with better prognosis in schizophrenia. In this study, we measured the duration mismatch negativity (dMMN), an event-related potential, and cognitive performance in subjects with at-risk mental state (ARMS), patients with first-episode or chronic schizophrenia, and healthy volunteers. The main interest was to determine if these neurocognitive measures predict progression to overt schizophrenia in ARMS subjects.
Seventeen ARMS subjects, meeting the criteria of the Comprehensive Assessment of At-Risk Mental State, 31 schizophrenia patients (20 first-episode and 11 chronic) and healthy controls (N = 20) participated in the study. dMMN was measured by an auditory odd-ball paradigm at baseline. Neuropsychological performance was evaluated by the Japanese version of the Brief assessment of cognitive function of schizophrenia (BACS-J). The first-episode schizophrenia group showed significantly smaller amplitudes at frontal electrodes than did control subjects whereas chronic patients elicited smaller amplitudes at frontal and central electrodes, consistent with previous reports. During the follow-up period, 4 out of the 17 ARMS subjects transitioned to schizophrenia (converters) while 13 did not (non-converters). Specifically, dMMN amplitudes of non-converters did not differ from those of healthy controls, while converters showed significantly smaller dMMN amplitudes at some electrodes compared to control subjects. Converters performed significantly worse on tests of working memory, verbal fluency, and attention/information processing than did non-converters. There was a significant positive correlation between dMMN amplitudes at the frontal electrodes and verbal fluency, as measured by the BACS, in the AMRS subjects as a whole.
ARMS subjects who later developed schizophrenia elicited smaller dMMN amplitudes to begin with, compared to non-converters. Notably, we have provided the first evidence for the ability of verbal fluency to predict dMMN amplitudes in ARMS subjects. These findings are expected to add to the efforts for early diagnosis and intervention of schizophrenia.
Schizophrenia usually develops around the adolescence period, with the whole life risk of about 0.85% [1]. Patients with schizophrenia suffer from positive symptoms (hallucination, delusion, thought disturbance, and etc.), negative symptoms (blunted affect, lack of volition, social withdrawal and etc.), and impairment in a range of cognitive domains, e.g. several types of memory, executive function, attention, verbal fluency [2,3,4,5]. Especially, cognitive function is considered to be a major determinant of outcome, including quality of life and social function [6]. It is interesting that the classification of cognitive domains differs across neuropsychological test batteries. For example, verbal fluency is categorized as an independent domain in the Brief Assessment of Cognition in Schizophrenia (BACS) [7,8], while it is regarded as one of the components of processing speed (of information) in the Measurement and Treatment Research to Improve Cognition in Schizophrenia – Consensus Cognitive Battery [9].
In order to achieve satisfactory long-term outcome, early detection, intervention and treatment of schizophrenia are needed. Specifically, a shorter duration of untreated psychosis (DUP) has been associated with a greater response to antipsychotic drugs in terms of symptoms and quality of life
For the purpose of early diagnosis, objective biomarkers, particularly, those based on brain morphology, neurophysiology, and neuropsychology have been reported to provide useful information
MMN is another component of ERPs generated in response to occasional variations (e.g., duration, frequency, intensity) of acoustic stimuli, and is suggested to reflect pre-attentive cognitive operations
There are several types of MMNs, such as duration MMN (dMMN) and frequency MMN (fMMN), based on the mode of presentation of stimuli. Attenuation of the fMMN amplitude, resulting from changes in the frequency of stimuli, reflects the progress of the disease, i.e. a function of duration of the illness. On the other hand, deficits of dMMN deficiency, resulting from changes in the duration of stimuli, may be more closely linked to the genetic aspect of schizophrenia
Recently, dMMN amplitudes have been shown to be reduced already in the prodromal stage of schizophrenia. Thus, Jahshan et al (2011) found dMMN amplitudes in subjects with at-risk for psychosis patients were reduced compared to normal controls, but the deficits were milder than those in patients with first episode schizophrenia
Cognitive impairment, a core symptom of schizophrenia, is present at onset of illness
To date, little information is available about the relationship between neurophysiological indices, e.g. dMMN, and neuropsychological performance. So far, Lin et al (2012) investigated the correlation between neuropsychological performance and MMN amplitudes only in patients with schizophrenia
In this study, we measured dMMN amplitudes and cognitive performance in subjects with ARMS, first episode schizophrenia, or chronic phase of the illness, and compared them with those of normal control subjects. Specifically, we compared the results from ARMS subjects who later developed schizophrenia (converters) and those who did not (non-converters). The hypotheses tested were; 1) if correlations exist between the decrease in dMMN amplitudes and the impairment of neuropsychological performance in subjects with ARMS, and 2) if the impairments of neurophysiological and neuropsychological functions would similarly predict progression to overt psychosis in these subjects.
This protocol was approved by the Committee on Medical Ethics of the University of Toyama. After complete and detail description of the study to the subjects, written informed consent was obtained.
Clinical staff explained the nature of the study to the subjects, the risks and benefits, and the option not to participate in research. If the mental status of a subject was impaired to the point where s/he could not understand these issues, the subject was not approached to be in the research. In case there was a possibility that the capacity of a participant to consent was compromised, an additional consent was obtained from next of kin, care takers, or guardians of such subject.
Diagnosis was made based on the Structured Clinical Interview for DSM-IV (SCID) for schizophrenia and the Comprehensive Assessment of At-Risk Mental State (CAARMS) for ARMS
All participants were right-handed. A psychiatric and treatment history was obtained from the subjects, families, and medical records. Subjects with a current history of substance abuse or dependence, seizure or head injury were excluded from the study. Eligible patients had a complete physical examination and standard laboratory testing was normal. Demographic data at baseline evaluation are shown in
Healthy controls(n = 20) | ARMS(n = 17) | First episode schizophrenia(n = 20) | Chronic schizophrenia (n = 11) | |
Male/female | 14/6 | 4/13 | 9/11 | 6/5 |
Age (years) | 25.4 (6.9), range 16–45 | 19.4 (4.4) |
27.2 (7.3), range 16–38 | 28.1 (8.0), range 18–44 |
Age of onset (years) | – | – | 26.5 (7.1) | 20.2 (4.7) |
Duration of illness (years) | – | – | 0.65 (0.51) | 7.9 (6.9) |
Drug dose a) | – | 0.1(0.4) | 2.1(2.3) | 3.2 (2.4) |
SAPS | – | 13.2 (9.3) | 15.7 (13.1) | 17.6 (19.1) |
SANS | – | 50.3 (20.1) | 53.8 (25.9) | 51.5 (26.1) |
dMMN amplitude[µV] | ||||
F3 | 7.5 (1.3) | 7.6 (2.2) | 5.3 (1.5) ** | 4.5 (1.0) ** |
F4 | 7.3 (1.2) | 7.5 (2.1) | 5.6 (1.8) |
5.0 (1.3) ** |
Fz | 7.9 (1.1) | 7.9 (2.1) | 5.6 (1.7) ** | 5.1 (1.7) ** |
Cz | 6.6 (1.5) | 6.6 (2.2) | 5.1 (1.5) | 4.2 (1.7) ** |
Pz | 4.5 (1.7) | 4.2 (2.0) | 3.5 (1.2) | 2.5 (1.0) ** |
Values represent mean (SD).
a) Risperidone equivalent [mg/day].
ARMS, at-risk mental state.
SAPS, Scale for the Assessment of Positive Symptoms;
SANS, Scale for the Assessment of Negative Symptoms.
p<0.05 and ** p<0.01, compared to healthy control.
ARMS subjects were followed-up continuously at the hospital. Four out of the 17 ARMS subjects transitioned to schizophrenia during the observation period. When DSM-IV criteria were met, e.g. auditory hallucinations persisted or any delusion (for example, disturbance of the self) clearly observed, the subject was regarded to have converted to schizophrenia (converters; Conv.). Subjects who did not develop psychosis were defined as non-converters (Non-C.). The average observation period for ARMS subjects was 2.1±1.1 (Non-C.; 1.6±0.8) years.
The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS)
Neuropsychological performance, measured by the Japanese version of the BACS (BACS-J)
Electroencephalograms (EEGs) were recorded based on the previous report of our laboratory
Measurements of dMMN were based on our previous report
Averaging of ERP waves and related procedures were performed using Vital Tracer and EPLYZER II software (Kissei Comtec, Co. Ltd. Nagano, Japan). Epochs were 600 msec, including a 100-msec pre-stimulus baseline. Eye movement artifacts (blinks and eye movements) were manually rejected. MMN waveforms were obtained by subtract standard waveforms from target ones. ERP component peaks were identified within the 150–250 msec search windows. We selected F3, F4, Fz, Cz and Pz electrodes for analysis, based on our previous report
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 19.0 (SPSS Japan Inc., Tokyo, Japan). In order to investigate group differences in MMN, repeated measures analysis of variance (ANOVA) with electrode site as within-subject variable and diagnostic group as between-subject variable was performed. BACS-J domain scores were analyzed with a two-way ANOVA with BACS-J domains as the within factor and group as the between factor. Group×electrode interactions and group×BACS-J domain score interactions were decomposed using one-way ANOVA, with Bonferroni correction. Relationships between MMN amplitudes at the Fz electrode and BACS -J domain scores were analyzed using Spearman rank correlations.
Raters (psychiatrist, psychologist) were not informed of subjects’ profiles and diagnosis.
Demographic data of participants are shown in
ARMS (n = 17) | Analyze of variance (df = 1,16), Group Effect | |||
Non-C. (n = 13) | Conv. (n = 4) | F | p | |
Male/female | 2/11 | 2/2 | ||
Age [years] | 18.5 (3.8), range 15–29 | 22.3 (5.6), range 17–30 | ||
Drug dose a) | – | 0.5 (0.7) | ||
SAPS | 11.4 (9.3) | 18.0 (8.6) | ||
SANS | 42.9 (15.9) | 69.0 (18.4) |
||
dMMN amplitude[µV] | ||||
F3 | 8.2 (2.0) | 5.6 (1.7) | 3.78 | n.s. |
F4 | 8.2 (1.6) | 5.2 (1.8) | 10.61 | 0.05 |
Fz | 8.6 (1.6) | 5.7 (2.0) | 8.25 | 0.01 |
Cz | 7.3 (1.8) | 4.3 (1.7) | 8.31 | 0.01 |
Pz | 4.8 (1.8) | 2.4 (1.2) | 4.74 | 0.04 |
BACS-J | ||||
Verbal memory | 51.0 (7.8) | 47.2 (11.3) | 0.57 | n.s. |
Working memory | 19.1 (3.2) | 14.7 (2.2) | 6.33 | 0.02 |
Motor function | 69.3 (12.5) | 60.5 (9.0) | 1.66 | n.s. |
Verbal fluency | 46.7 (12.1) | 29.0 (9.5) | 7.03 | 0.01 |
Attention | 74.0 (12.7) | 56.2 (5.8) | 7.05 | 0.01 |
Executive function | 17.8 (2.1) | 18.5 (2.6) | 0.24 | n.s. |
Values represent mean (SD).
a) Risperidone equivalent [mg/day].
ARMS, at-risk mental state.
Non-C., ARMS non-converters; Conv., ARMS converters.
SAPS, Scale for the Assessment of Positive Symptoms;
SANS, Scale for the Assessment of Negative Symptoms;
BACS-J, Brief Assessment of Cognition in Schizophrenia, Japanese version.
p<0.05 compared to Non-C. (student’s t-test).
dMMN data are shown in
A. Waveforms are presented for healthy controls (HC, blue line), at-risk mental state (ARMS, red line), first episode schizophrenia (FES, light green line) and chronic schizophrenia (CS, dark green line). B. Distribution of amplitudes are presented for healthy controls (HC, blue dots), ARMS (red dots), first episode schizophrenia (light green dots) and chronic schizophrenia (dark green dots). * p<0.05 and ** p<0.01, compared to each groups.
Conv. subjects showed significant reduction in dMMN amplitudes at F4, Fz, Cz, and Pz electrode sites compared with Non-C. subjects (
A. Waveforms are presented for healthy controls (blue line), ARMS, converters (Conv.) and non-converter (Non-C.) (black lines), FES (light green line). B. Distribution of amplitudes are presented for healthy controls (blue dots), ARMS, converters (Conv.) and non-converter (Non-C.) (black dots), FES (light green dots). * p<0.05 and ** p<0.01, compared to each groups.
Conv. subjects demonstrated significantly smaller BACS-J scores compared to Non-Conv. subjects for working memory, verbal fluency, and attention (
Black symbols(•) and white ones(○) represent scores of non-converters and converters, respectively.
Black and white symbols represent scores of non-converters and converters, respectively. Relationships were analyzed using Pearson’s product-moment correlation coefficient.
To our knowledge, this study is the first to report a relationship between dMMN amplitudes and neuropsychological performance in individuals with ARMS. ARMS subjects who later converted to overt schizophrenia elicited reduced dMMN amplitudes at frontal and central leads compared with non-converters and normal subjects, consistent with previous reports
The score of SANS/SAPS of ARMS were similar to schizophrenia (
Compared to non-converters, dMMN amplitudes in converters were significantly reduced at F4, Fz, Cz and Pz leads (
MMN is a pre-attentional response to a change of stimuli, and plays a critical role in establishing learning and memory. This electrophysiological event has been suggested to be generated by the glutamate (Glu)/N-methyl-D-aspartate (NMDA) system
Neuropsychological deficits have been shown to exist in the early stage of schizophrenia
The major finding of the present study was the ability of performance on the verbal fluency tasks to predict dMMN amplitudes in subjects with ARMS (
In conclusion, this study confirmed that ARMS subjects who later develop schizophrenia elicit smaller dMMN amplitudes to begin with, compared to non-converters. Notably, we have provided the first evidence for the ability of verbal fluency or attention/information processing to predict dMMN amplitudes in ARMS subjects. These findings are expected to add to the efforts for early diagnosis and intervention of schizophrenia.
The main limitations of this study include that ARMS subjects were younger and had a larger female/male ratio compared to other groups. Clearly, further study with a larger number of matched subjects is warranted. Part of ARMS subjects was taking antipsychotic drugs which is another limitation of the study.
The observation periods of Non-C. were relatively short (1.6±0.8 year), compared to similar studies