Auditory gating deficit to human voices in schizophrenia: A MEG study

Schizophrenia Research 117 (2010) 61–67

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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Auditory gating deficit to human voices in schizophrenia: A MEG study Yoji Hirano a, Shogo Hirano a, Toshihiko Maekawa a, Choji Obayashi a, Naoya Oribe a, Akira Monji a, Kiyoto Kasai b, Shigenobu Kanba a, Toshiaki Onitsuka a,⁎ a b

Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 26 January 2009 Received in revised form 21 July 2009 Accepted 1 September 2009 Available online 23 September 2009 Keywords: Schizophrenia Auditory sensory gating Human voices Magnetoencephalography Auditory hallucination Negative symptom

a b s t r a c t Background: Patients with schizophrenia have auditory gating deficits; however, little is known about P50 auditory gating to human voices and its association with clinical symptoms. We examined the functioning of auditory gating and its relationship with the clinical symptoms in schizophrenia. Methods: Auditory evoked magnetoencephalography responses to the first and the second voices stimuli were recorded in 22 schizophrenia patients and 28 normal control subjects. The auditory gating ratios of P50m and N100m were investigated and P50m-symptom correlations were also investigated. Results: Patients showed significantly higher P50m gating ratios to human voices specifically in the left hemisphere. Moreover, patients with higher left P50m gating ratios showed more severe auditory hallucinations, while patients with higher right P50m gating ratios showed more severe negative symptoms. Conclusions: The present study suggests that schizophrenia patients have auditory gating deficits to human voices, specifically in the left hemisphere and auditory hallucinations of schizophrenia may be associated with sensory overload to human voices in the auditory cortex. © 2009 Elsevier B.V. All rights reserved.

1. Introduction The ability of the brain to suppress incoming irrelevant sensory input is termed sensory gating. The brain must prepare to select necessary information, such as conversational voices while filtering out redundant information from the flood of extraneous information. Schizophrenia is a severe mental disorder characterized by positive and negative symptoms, with cognitive dysfunction. Patients with schizophrenia have been hypothesized to have a functional impairment in filtering irrelevant sensory information, which may result in positive symptoms such as hallucinations or delusions (Venables, 1964; Freedman et al., 1991, 2002). Furthermore, this impairment in

⁎ Corresponding author. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka, 812-8582, Japan. Tel.: +81 92 642 5627; fax: +81 92 642 5644. E-mail address: [email protected] (T. Onitsuka). 0920-9964/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2009.09.003

auditory processing has been indexed by a particular neurophysiological abnormality, P50 auditory gating deficit. P50 is a positive potential at around 50 ms elicited by auditory stimuli. P50 auditory gating is indexed by P50 suppression to the second auditory stimulus, and the gating ratio is defined as the response to the second stimulus (S2) divided by the response to the first stimulus (S1) with a paired-click paradigm (i.e., the conditioning-testing paradigm) (Adler et al., 1982; Potter et al., 2005). P50 suppression is often absent or reduced in patients with schizophrenia (e.g., Adler et al., 1982; Freedman et al., 1996; Bramon et al., 2004) and this deficit is considered to be a well validated and heritable neurophysiological biomarker of schizophrenia (Adler et al., 1999; Siegel et al., 1984; Waldo et al., 1991; Clementz et al., 1998; Bramon et al., 2004; Heinrichs, 2004). Electroencephalography (EEG) is a widely used method for determining the brain activity, with high temporal resolution, on which most of the reports of auditory gating deficit has relied (Adler et al., 1982, 1990, 1999, 2004; Freedman et al., 1991, 1996;

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Clementz et al., 1997, 1998; Cullum et al., 1993; Judd et al., 1992; Myles-Worsley, 2002; Bramon et al., 2004; Louchart-de la Chapelle et al., 2005). However, the test–retest reliability of the P50 auditory gating ratio is not as high as auditory N100 and P200 (Fuerst et al., 2007), thus prompting researchers to improve the reliability of P50-derived auditory gating measures. Magnetoencephalography (MEG) also has a high spatiotemporal resolution to record cortical brain activity. MEG is complementary to EEG and it is superior for the localization and analysis of lateralized cortical auditory responses. MEG can detect neural activities tangential to the surface of the cortex for both hemispheres accurately, because magnetic fields are minimally influenced by conductivities such as brain tissue, skull and scalp, whereas EEG is more influenced by volume conductors (Hämäläinen et al., 1993). When comparing MEG to EEG, Lu et al. (2007) reported that the gating ratio of the magnetic analog of P50 (P50m) from the primary auditory cortices (mainly Heschl's gyrus [HG]) offers higher reliability than electroencephalographic P50 derived auditory gating. While the P50 component contains activities of multiple neural sources (e.g.,Huang et al., 2003; Onitsuka et al., 2000), MEG can discriminate and evaluate the activity of an individual auditory hemispheric source as P50m (Edgar et al., 2003; Leahy et al., 1998). Moreover, using the dipole source analysis, MEG studies have reported that the neural source of the P50m is located in or near the HG (e.g., Huang et al., 2003; Thoma et al., 2003). Because of the perspective of higher reliability and higher spatial resolution, MEG is suited to the study for evaluating the auditory gating in each hemisphere. Most studies of auditory gating have used clicks as stimuli, and consequently, little is known about P50 auditory gating to human voices and its association with the clinical symptoms in schizophrenia. However, no significant association has yet been reported between the P50 auditory gating deficits and positive symptoms like auditory verbal hallucinations, exhibited in approximately 60–80% of patients with schizophrenia (Sartorius et al., 1986; Andreasen and Flaum, 1991). With respect to the neural substrate of auditory verbal hallucinations, Dierks et al. (1999) demonstrated an increase of blood oxygenation level-dependent activity in the left HG during auditory hallucinations in patients with schizophrenia. Taken together, it may therefore be important to investigate auditory gating to human voices which activates the auditory cortex. The present study was designed to test the hypotheses that patients with schizophrenia show auditory gating deficits to human voices, and that this abnormality is associated with auditory hallucinations. 2. Methods 2.1. Subjects MEG data were acquired from 22 patients with schizophrenia (16 males) and 28 normal control subjects (18 males). The subjects were all nonsmokers, normal-hearing [no problems hearing a hand-watch clicking on both ears equally; by following Fuerst et al. (2007)] and right-handed [via Edinburgh Inventory (Oldfield, 1971)]. Demographic data for all subjects are presented in Table 1. Written informed consent was obtained from all patients after a detailed description of the study, which was approved by the Ethics commission of Kyushu University. Subject

Table 1 Demographic details of study groups. Variable

Age Sex (male/female) Handedness SES a Parental SES Education years Sleepiness scale b Medication dose c Age of onset Duration of illness (years) SAPS total score SANS total score

Schizophrenia patients (n = 22)

Nomal controls (n = 28)

Mean ± SD

Mean ± SD

df

t or x2

P

34.4 ± 10.9 16/6 98.4 ± 3.8 3.3 ± 0.9 2.2 ± 0.7 14.6 ± 2.1 2.1 ± 0.6 494.5 ± 328.5 23.2 ± 5.9 11.1 ± 9.7

34.7 ± 6.9 18/10 98.1 ± 4.3 1.7 ± 0.9 2.3 ± 0.7 15.8 ± 2.3 2.0 ± 0.6

48 1 48 48 48 48 48

− 0.13 0.4 0.31 5.84 − 0.81 − 1.83 0.25

0.89 0.53 0.75 <0.001 0.42 0.07 0.80

83.45 ± 34.0 59.1 ± 20.0

a Patients with schizophrenia showed significantly lower SES (SocioEconomic Status) than normal controls. b Stanford sleepiness scale. c Antipsychotic dose in chlorpromazine equivalents (mg/day).

recruitment, inclusion criteria, and diagnostic evaluations followed our previous publication (Hirano et al., 2008). All patients were taking stable doses of antipsychotic medication, with a mean daily dose equivalent to 494.5±328.5 mg of chlorpromazine [typical antipsychotic (2 of the 22patients), atypical (13), or both (7)]. No patients had received antidepressants. The clinical symptoms of all patients were assessed by 2 consultants, just before the experiment. The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1990) were administered to the patients.

2.2. Stimulation and procedures During the experiment (for the recording and the MEG equipment, see Section 2.3), all subjects were in the lateral recumbent position on a bed in a magnetically shielded room at Kyushu University Hospital. Auditory evoked responses in both hemispheres were recorded alternately (left and right hemispheres counterbalanced between subjects). The subjects were instructed to keep their eyes open and not to sleep. In the present study, the Stanford Sleepiness Scale (Hoddes et al., 1973) was used to assess the sleepiness of the subjects (1=wide-awake, 7=sleep onset soon). The Japanese vowel sound /a/ was used as an auditory speech stimulus. The speech stimulus was spoken by a professional actor who was a native Japanese speaker. The frequencies for the formants (F) of the vowel /a/ were as follows: F0=140 Hz, F1=760, F2=1250, F3=2750, F4=3600. Stimuli were digitized and edited with 200-ms duration (rise/fall 10 ms). In the earphones, the intensity of each stimulus was the 60dB SPL. The software program for stimulus generation was run on a mini-computer. A conditioning-testing paradigm presented vocal stimuli with an intrapair interval of 500 ms and interstimulus interval of 6 s. Stimuli were delivered to the ear contralateral to the hemisphere being recorded through a 2.3-m plastic tube with a plastic insert earpiece at the tip. The

Y. Hirano et al. / Schizophrenia Research 117 (2010) 61–67

stimuli were presented consecutively as a series of 120 paired vocal stimuli.

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3. Results 3.1. Demographics

2.3. Data acquisition and analysis The subjects lay down in a room and vocal stimuli were presented to each ear. As noted in the introduction section, the present study used the conditioning-testing paradigm, and the gating ratio was investigated. A 37-channel biomagnetometer (Magnes, Biomagnetic Technologies) was used for the magnetic measurements. All signals were digitized at 4167 Hz and stored in a magneto-optical disk. The data were collected and analyzed using a software package (MSI-software) on a workstation (SPARC-Station™). In the off line analysis, the MEG was triggered by stimulus onset with a sampling rate of 4167 Hz and it was averaged for each condition. The epochs with signal variations exceeding 4.0 pT were excluded from averaging. The epochs were 400 ms duration including 100 ms prestimulus interval. The final responses were filtered with between 1 and 100 Hz using a sharp digital bandpass filter with a slope of 12 dB/oct and the digital 60 Hz notch filter which selectively cut 60 Hz-band. A prestimulus baseline correction was performed using the averaged activity during 100 ms prestimulus interval for each channel. For each component, an assessment of the global magnetic field at the peak latency was carried out using the root mean square (RMS) values across the 37channels of MEG data with the following formula; RMS(t) = [Σx(i,t)2/37]0.5, where x(i,t) is the value of magnetic field for each channel (i = 1to37) at time t and Σx(i,t)2/37 is the square mean of the magnetic field of 37channels. The N100m peak latency was defined as the latency with the largest amplitude between 80 and 120 ms following stimulus onset. Isomagnetic contour maps of P50m and N100m were referenced to observe the polarity information. The P50m peak latency was also defined between 20 and 70 ms, where the P50m showed the reversed polarity to the N100m. When multiple peaks were observed, the largest amplitude was referred to as the peak of the response. P50m and N100m suppression for each hemisphere was expressed as (auditory gating) ratios: S2 (peak amplitude to the second stimulus) divided by S1 (peak amplitude to the first stimulus). As a result, the subjects with gating deficits thus show higher S2/S1 ratios. 2.4. Statistical analysis Gating ratios (S2/S1) and the peak latencies were submitted to a repeated-measures ANOVA analysis with group (schizophrenia, normal controls) as a between-subjects factor and component (P50m or N100m), hemisphere (left or right) as within-subjects factors. The degrees of freedom were adjusted with the Greenhouse–Geisser epsilon for factors with more than two levels. Two-tailed tests were used, with an alpha of <0.05 required for statistical significance. Exploratory analyses of the correlations between P50m gating ratios and demographic data were performed using Spearman's rho. Higher gating ratios were predicted to be correlated with increased severity of auditory hallucinations, the SAPS and SANS total scores. Therefore, positive correlations of gating ratios with scores on clinical measurements (using a significance level of p≤0.05) were assessed in the schizophrenia group.

The groups did not substantially differ regarding age, education years, or parental socioeconomic status (Hollingshead, 1965) as shown in Table 1. The patients had significantly lower socioeconomic status than normal controls (t[48]= 5.84, p < 0.001), consistent with reduced functioning secondary to their disorder. 3.2. Gating ratios Fig. 1 shows the scattergram of the gating ratios (S2/S1) for P50m and N100m in each group. For the gating ratios, a repeated measures ANOVA demonstrated significant main effects of group (F[1,48] = 6.6, p = 0.013) and component (F[1,48] = 52.8, p<0.001), but no main effect of hemisphere (F[1,48]=2.6, p= 0.11). There were significant component-by-group (F[1,48]= 10.9, p = 0.002) and hemisphere-by-group (F[1,48] = 7.2, p=0.01) interactions, with no significant component-by-hemisphere (F[1,48]=0.7, p=0.41) interaction. Of note, there was a significant component-by-hemisphere-by-group (F[1,48]=5.9, p=0.019) interactions, thus indicating that gating effects in one component and one hemisphere differed among groups. To disentangle the significant interactions, follow-up repeated measures ANOVAs were performed with group as a betweensubjects factor and hemisphere as a within-subjects factor for each component. For the P50m, ANOVAs revealed a significant main effect of group (F[1,48] = 12.4, p = 0.001), but no main effect of the hemisphere (F[1,48] = 0.01, p = 0.9). However, there was a significant hemisphere-by-group (F[1,48] = 9.0, p = 0.004) interaction. To further delineate the interaction, group differences in the P50m gating ratios were investigated using t-tests for each hemisphere. Patients with schizophrenia showed significantly higher P50m gating ratios in the left hemisphere (t[48] = 3.9, p = 0.001), but not in the right hemisphere (t[48] = 0.9, p = 0.36), thus indicating that schizophrenia patients showed P50m gating deficits to human voices in the left hemisphere. For the N100m, there were no main effects of group (F[1,48] = 0.01, p = 0.94) or hemisphere (F[1,48] = 3.7, p = 0.06), with no significant hemisphere-by-group (F[1,48] = 0.66, p = 0.42) interaction, thus indicating no group differences in N100m gating ratios to human voices in both hemispheres. 3.3. Peak latency For the P50m peak latencies, ANOVA showed main effects of hemisphere (F[1,48]=5.51, p=0.02) and stimulus (F[1,48]= 10.94, p=0.002) with no other significant main effects or interactions (0.39≤F[1,48]≤1.56, 0.22≤p≤0.53), thus indicating that the P50m latency of the right hemisphere was shorter than the left hemisphere and the P50m latency to the second stimulus was shorter than the first one in both groups. For N100m peak latencies, there was a trend towards a main effect of stimulus, which was not significant (F[1,48]=3.01, p=0.09) and no significant hemisphere-by- stimulus-by-group (F[1,48]= 0.13, p=0.72), hemisphere-by-group (F[1,48]=0.17, p=0.68) and stimulus-by-group (F[1,48]=0.57, p=0.45) interactions. In

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Fig. 1. Scattergrams of the P50m and N100m gating ratios in the left and the right hemispheres in schizophrenia patients and normal controls. ⁎The P50m gating ratios were significantly higher in schizophrenia patients specifically in the left hemisphere in comparison to normal controls (F[1,48] = 5.9, p = 0.019). The means are indicated by horizontal lines.

addition, the main effects of the group (F[1,48]=4.95, p=0.03) and hemisphere were observed (F[1,48] = 6.13, p = 0.02), indicating that both groups showed delayed N100m latency in the left hemisphere and that patients showed a delayed N100m

latency for both hemispheres in comparison to the normal controls (Fig. 2, Table 2).

3.4. Correlations between P50m gating ratios and demographic/ clinical measurements Since there were significant group differences in the P50m gating ratios in the present study, the associations between the P50m gating ratios and the demographic/clinical measurements were investigated. In normal controls, no significant correlations were observed between the gating ratios and the demographic variables. In patients with schizophrenia, no significant correlations were observed between the ratios and the demographic/clinical variables, with the exception of significant positive correlations between the left P50m gating ratio and the auditory hallucination scores (rho= 0.44, p= 0.04) and between the right P50m gating ratio and the SANS total scores (rho = 0.52, p =0.01). This significant P50m-hallucination association indicates that Table 2 Peak latency (ms) of normal controls and schizophrenia patients. Schizophrenia patients (n = 22)

Normal controls (n = 28)

Mean ± SD

Mean ± SD

df

t

p

Left

S1 S2

48.9 ± 7.1 46.6 ± 10.4

49.8 ± 10.2 43.7 ± 7.4

48 48

− 0.32 1.15

0.75 0.26

Right

S1 S2

47.8 ± 8.7 44.8 ± 9.9

45.4 ± 6.7 41.6 ± 8.1

48 48

1.09 1.27

0.28 0.21

Left

S1 S2

99.3 ± 12.5 98.1 ± 14.5

95.6 ± 8.0 92.9 ± 9.6

48 48

1.24 1.48

0.22 0.15

Right

S1 S2

96.8 ± 12.0 95.4 ± 9.8

92.8 ± 8.5 88.6 ± 8.7

48 48

1.39 2.56

0.17 0.01

P50m

Fig. 2. Scattergrams between the P50m gating ratios and clinical symptoms in schizophrenia patients. (a) The P50m gating ratios were significantly positively correlated with scores of auditory hallucinations in the left hemisphere (rho=0.44, p=0.04). (b) The P50m gating ratios were significantly positively correlated with SANS total scores in the right hemisphere (rho=0.52, p=0.01).

N100m

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patients with left auditory gating deficits showed more severe auditory hallucinations. 4. Discussion The major findings of this study were: (1) patients with schizophrenia showed significantly higher P50m gating ratios to human voices specifically in the left hemisphere, while no group differences were observed bilaterally in the N100m gating ratios; (2) patients with higher left P50m gating ratios showed more severe auditory hallucinations, while patients with higher right P50m gating ratios showed more severe negative symptoms; (3) patients showed a delayed N100m latency for both hemispheres in comparison to the normal controls. In the standard conditioning-testing paradigm, higher P50 gating ratios (auditory gating deficits) to click sounds have been repeatedly reported (e.g.,Adler et al., 1982; Freedman et al., 1996; Potter et al., 2005). The present study revealed higher P50 gating ratios to human voices, indicating that schizophrenia patients have auditory gating deficits to human voices specifically in the left hemisphere. Since the EEG response to auditory stimuli is the largest at the middle frontal electrode sites and it is unsuited to detect hemispheric differences, the novel finding of the current study is thus the fact that patients showed lefthemisphere-biased auditory gating deficits to human voices. By using MEG with paired click sounds, Thoma et al. (2003) found P50m gating deficits in the left hemisphere, thus suggesting that the asymmetry of gating deficits may be importantly related to schizophrenia pathophysiology. Schizophrenia may be characterized by left-lateralized auditory gating deficits including human voice perception which thus represents an evolutionary significant element of social communication. More importantly, in the present study, patients with higher left P50m gating ratios showed more severe auditory hallucinations, thus indicating a link between P50 gating deficits to human voices and auditory hallucinations in schizophrenia. It is hypothesized that deficits in auditory gating cause sensory overload in patients with schizophrenia (Venables, 1964; Braff, 1993). The present study suggests that auditory hallucinations of schizophrenia may be associated with overload to human voices. A structural MRI study reported that the anterior portion of left superior temporal gyrus (STG) gray matter volume reduction thus correlates with the severity of auditory hallucinations (Levitan et al., 1999). More severe hallucinations are therefore significantly correlated with a smaller left STG volume in chronic schizophrenia (Onitsuka et al., 2004). Functionally, Dierks et al. (1999) demonstrated an increase of the BOLD activity in the left HG during auditory hallucinations in schizophrenia. Hubl et al. (2007) suggested that the abnormal activation of the primary auditory cortex may be a constituent of auditory hallucinations. The association of auditory hallucinations with structural and functional abnormalities of the left STG including HG points to a possible anatomical substrate. Woodruff (2004) proposed the cognitive model of auditory verbal hallucination. In this model, they suggested the presence of hypersensitivity to external voices in the auditory cortex of schizophrenia. Several MEG studies have reported the P50m source to be localized in the lateral part of HG. The present study may partially support this model since patients

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with left auditory gating deficits showed more severe auditory hallucinations. One possibility is that the higher P50m gating ratios could be related to the phenomenon of cortical hyperexcitability that has been reported in studies of schizophrenia by using transcranial magnetic stimulation (Eichhammer et al., 2004; Hoffman et al., 2003). It is notable that auditory hallucinations are reduced by the application of slow repetitive transcranial magnetic stimulation, which thus reduces the excitability of the underlying cortex (Hoffman and Cavus, 2002). Boatman (2004) reported that electrocortical mapping localized the neural substrate for vocal discrimination in the circumscribed region within the middle posterior region of the left STG, and the region was located lateral to the primary auditory cortex in the parabelt region of the auditory association cortex. In patients with schizophrenia, the density of gamma-aminobutyric acidA (GABAA) receptor has been reported to increase in the left STG gray matter (Deng and Huang, 2006). They stated that the increase in GABAA receptor density reflects a compensatory up-regulation of receptors, which may be related to a reduction of GABA interneurons in the left STG in patients with schizophrenia. It was reported that GABAergic inhibitory neurons have been reported to play a crucial role in P50 gating (Daskalakis et al., 2007; Freedman et al., 2000). The current data suggest that schizophrenia may therefore be characterized by left hemisphere cortical hyperexcitability to voices, and this functional deficit, at the cellular level, may consist of a reduction of GABA interneurons. In the present study, patients with higher right P50m gating ratios showed more severe negative symptoms, although there was no significant group difference in P50m gating ratios in the right hemisphere. Ringel et al. (2004) reported that patients with higher scores of PANSS negative symptom show higher EEG-P50 gating ratios. Thoma et al. (2005) found that negative symptoms are positively correlated with right MEG-P50 gating ratios. Potkin et al. (2002) used positron emission tomography to compare cerebral metabolic patterns during a degradedstimulus continuous performance task in schizophrenia patients with predominantly negative symptoms and in those with predominantly positive symptoms. They found that subjects predominantly with negative symptoms have a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, than those patients who evinced predominantly positive symptoms. In patients with schizophrenia, many studies have so far suggested an association between negative symptoms and the frontal lobe (e.g., Blanchard et al., 1994). However, it is known that the right hemisphere plays a crucial role in the perception and production of prosodic elements (Heilman et al., 1984; Blonder et al., 1991; Pell 1998), and thus the association between right P50m and negative symptoms might reflect the contributions of the right hemisphere temporal cortex to emotional communications. In terms of the N100m, patients showed delayed N100m latency in both hemispheres in comparison to normal controls. It has been suggested that the N100m reflects the function of the auditory association area in the planum temporale. Prolonged N100m latencies may be associated with dysfunctions of the auditory association area in schizophrenia. In summary, patients with schizophrenia showed significantly higher P50m gating ratios to human voices, specifically in the left hemisphere, and patients with higher left

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P50m gating ratios showed more severe auditory hallucinations. The present study suggests that schizophrenia patients have auditory gating deficits to human voices specifically in the left hemisphere and auditory hallucinations of schizophrenia may be associated with a sensory overload to human voices in the auditory cortex. Role of funding source This work was partially supported by grants-in-aid for Scientific Research (C20591411 to Dr. Onitsuka and B19390306 to Dr. Kanba) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a grant from Ministry of Health, Labor and Welfare, Japan (H18 kokoroippan-012 to Dr. Kanba). The Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare had no further role in study design; in the collection, analysis and interpretation of data; in the writing report; and in the decision to submit the paper for publication. Contributors Drs. Onitsuka, Kasai, Y.Hirano and Kanba designed the study and wrote the protocol. Drs. Maekawa and Monji managed the literature searches. Drs. S.Hirano and Obayashi undertook the statistical analysis. Drs. Y.Hirano, S. Hirano and Oribe, collected the data. Dr. Y.Hirano wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest There is no conflict of interest. Acknowledgements The authors gratefully acknowledge the technical support of Miss Yuko Somehara.

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