Auditory M50 and M100 sensory gating deficits in bipolar disorder: A MEG study

Journal of Affective Disorders 152-154 (2014) 131–138

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Auditory M50 and M100 sensory gating deficits in bipolar disorder: A MEG study$ Ying Wang a,b,1, Yigang Feng c,1, Yanbin Jia d, Wensheng Wang c, Yanping Xie c, Yufang Guan c, Shuming Zhong d, Dan Zhu c, Li Huang a,n a

Medical Imaging Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China Clinical Experimental Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China c Medical Imaging Center, Guangdong 999 Brain Hospital, Guangzhou 510510, China d Department of Psychiatry, First Affiliated Hospital of Jinan University, Guangzhou 510630, China b

art ic l e i nf o

a b s t r a c t

Article history: Received 10 May 2013 Received in revised form 12 August 2013 Accepted 12 August 2013 Available online 26 August 2013

Objectives: Auditory sensory gating deficits have been reported in subjects with bipolar disorder, but the hemispheric and neuronal origins of this deficit are not well understood. Moreover, gating of the auditory evoked components reflecting early attentive stage of information processing has not been investigated in bipolar disorder. The objectives of this study were to investigate the right and left hemispheric auditory sensory gating of the M50 (preattentive processing) and M100 (early attentive processing) in patients diagnosed with bipolar I disorder by utilizing magnetoencephalography (MEG). Methods: Whole-head MEG data were acquired during the standard paired-click paradigm in 20 bipolar I disorder patients and 20 healthy controls. The M50 and the M100 responses were investigated, and dipole source localizations were also investigated. Sensory gating were determined by measuring the strength of the M50 and the M100 response to the second click divided by that of the first click (S2/S1). Results: In every subject, M50 and M100 dipolar sources localized to the left and right posterior portion of superior temporal gyrus (STG). Bipolar I disorder patients showed bilateral gating deficits in M50 and M100. The bilateral M50 S2 source strengths were significantly higher in the bipolar I disorder group compared to the control group. Limitations: The sample size was relatively small. More studies with larger sample sizes are warranted. Bipolar subjects were taking a wide range of medications that could not be readily controlled for. Conclusions: These findings suggest that bipolar I disorder patients have auditory gating deficits at both pre-attentive and early attentive levels, which might be related to STG structural abnormality. & 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder Magnetoencephalography Auditory sensory gating M50 M100 Superior temporal gyrus

1. Introduction Bipolar disorder is one of the most severe illnesses of the major mental disorders, which is a leading cause of premature mortality due to suicide and associated medical conditions, such as diabetes mellitus and cardiovascular disease (Merikangas et al., 2007). It is characterized by the core feature of recurrence of hypomanic or manic and depressive episodes that seriously affect the quality of life and social functions of patients. According to World Health Organization estimates, bipolar disorder has been ranked seventh

☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. n Corresponding author. Tel.: þ 86 20 38688005; fax: þ86 20 38688000. E-mail address: [email protected] (L. Huang). 1 Authors Ying Wang and Yigang Feng are joint first authors.

among the worldwide causes of non-fatal disease burden (WHO, 2001). Despite being a common and important psychiatric illness, the specific neurophysiologic basis of bipolar disorder is unknown. The ability of the brain to inhibit or suppress irrelevant and redundant incoming sensory input is termed sensory gating. When it is inadequate, higher brain functions are flooded with a sensory overload and subjects evidence cognitive fragmentation and behavioral disturbances (Ancín et al., 2011; Venables, 1967). There is a large body of literature to suggest that a significant proportion of patients with schizophrenia have sensory gating impairments (Bramon et al., 2004; De Wilde et al., 2007; Potter et al., 2006). Some studies (Adler et al., 1990; Ancín et al., 2011; Cabranes et al., 2012; Carroll et al., 2008; Lijffijt et al., 2009; Sánchez‐Morla et al., 2008), but not all (Olincy and Martin, 2005; Patterson et al., 2009) have also revealed similar gating deficits in bipolar disorder patients. Recent studies suggest that schizophrenia and bipolar disorder may share a similar etiopathology. The paired-stimulus paradigm (i.e., the conditioning-testing paradigm)

0165-0327/$ - see front matter & 2013 The Authors. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.08.010

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has been adapted in psychophysiological research as a test of “sensory gating”. In healthy individuals, a first (or “conditioning”) stimulus activates inhibitory gating mechanisms to minimize the disruptive effects of an identical second (or “testing”) stimulus that occurs 500 ms later (Adler et al.,1982; Franks et al.,1983; Freedman et al., 1987). Typically, gating capacity is expressed in terms of the suppression ratio S2/S1 (S2 amplitude /S1 amplitude), which is higher in psychopathological populations and is thought to reflect weak inhibition or the gating of the repeated stimulus (Freedman et al., 1987). P50 is a positive auditory evoked potential (AEP) that occurs at about 50 ms following stimulus presentation, which is widely used to study sensory gating in a number of psychiatric and neurological conditions. Thus far only gating at the P50 stage of information processing has been extensively examined (Boutros et al., 2004; Potter et al., 2006), While sensory gating occurring at the N100 (a negative component peaking between 75 and 150 ms) stage of information processing has not yet been fully explored. Moreover, some studies showed that the test–retest reliability of the N100 auditory gating ratio was better than P50 as a gating index (Fuerst et al., 2007; Rentzsch et al., 2008; Smith et al.,1994). Several studies have found impairments in N100 sensory gating in schizophrenia (Boutros et al.,1999, 2004; Brockhaus-Dumke et al., 2008; Hanlon et al., 2005), however negative findings have also been reported (Clementz et al., 1997; Hsieh et al., 2004; Waldo et al.,1988). To our knowledge, only one N100 sensory gating study was conducted in patients with bipolar disorder. Lijffijt et al. (2009) found that decreased gating of N100 and P50 in euthymic patients with bipolar I disorder, suggesting impaired filtering at both pre-attentive and early attentive levels. However, when examining electroencephalography (EEG) P50 and N100 at Cz it is not possible to determine whether the sensory gating deficit observed in patients with bipolar disorder is a bilateral or unilateral deficit within a particular hemisphere. Today, EEG is a standard clinical procedure in brain research, with high temporal resolution, on which most of the reports of auditory gating deficit have relied (Adler et al.,1982; Bramon et al., 2004; Clementz et al., 1997; Freedman et al., 1991). However, the appeal of P50 gating ratio has been limited by its low signal to noise ratio (SNR) and poor test–retest reliability (Fuerst et al., 2007; Lu et al., 2007; Smith et al., 1994). In addition, examining P50 at the midline Cz site does not lend itself to identification of the presumably lateralized cortical generators. As an alternative, magnetoencephalography (MEG) is a noninvasive neuroimaging technique for investigating neuronal activity in the living human brain, which can overcome the conductivity and resistivity variations with both high spatial and temporal resolution (Hämäläinen et al.,1993; Hirano et al., 2010; Pekkonen et al., 2007). In contrast to the electric potentials, the magnetic fields are less distorted by the resistive properties of skull and scalp which may result in an improved spatial resolution (Hämäläinen et al., 1993). In particular, MEG source localization allows for the separation of left and right-hemisphere auditory sensory gating. Thus, M50 and M100, which are magnetic counterparts to P50 and N100, can be reliably measured with MEG making it an ideal tool to investigate cortical auditory processing within each hemisphere. Furthermore, studies suggested that electric and magnetic sources of the P50 and N100 can be considerably explained by one another (Korzyukov et al., 2007; Pekkonen et al., 2002; Thoma et al., 2003) and reflect the same brain-source activities (Lopes da Silva et al., 1991). A handful of studies have used MEG to examine auditory gating deficit in schizophrenia (Clementz et al., 1997; Huang et al., 2003; Thoma et al., 2003; Hanlon et al., 2005) but not in bipolar disorder. M50 responses have been localized to posterior areas of the bilateral superior temporal gyrus (STG) (Edgar et al., 2003; Hanlon et al., 2005; Huang et al., 2003; Lu et al., 2007; Thoma et al., 2003),

Whereas M100 have been localized to near Heschl′s gyrus and the planum temporale (Hanlon et al., 2005; Teale et al.,1998). Moreover, it has been shown in healthy controls that the bilateral M50 STG sources accounted for 97% of the variance in P50 responses at the electrode Cz, which demonstrated that the P50 auditory evoked potential can be attributed to the bilateral M50 STG source localizations (Huang et al., 2003). Thoma et al. (2003) found a M50 sensory gating deficit for schizophrenia patients in the left but not the right hemisphere, suggesting left-hemisphere dysfunction as the substrate for the well-established P50 gating deficit in schizophrenia. Further, Hanlon et al. (2005) reported that schizophrenia patients had a left-hemisphere gating deficit in M50 and a bilateral gating deficit in M100, and a left-hemisphere M100 gating deficit was coupled with the left M50 gating deficit. These findings confirm the importance of evaluating hemispheres separately for sensory gating deficits. However, there are no studies using MEG to investigate possible lateralization of the M50 or M100 gating deficits in bipolar patients. In the current study, a whole-head MEG-device was employed to investigate the specific gating effects in bipolar I disorder patients as reflected by the bilateral M50 and M100. The objectives of this study were (1) to obtain the location, strength and latency of the M50 and M100 sensory gating for each hemisphere in bipolar I disorder patients and normal subjects; (2) to assess the associations between bipolar I disorder symptom severity and hemispheric M50, M100 sensory gating. We hypothesized that patients with bipolar I disorder show left lateralized auditory sensory gating deficits occurring at both pre-attentive and early attentive phase of information processing, and that this abnormality is associated with symptom severity.

2. Methods 2.1. Participants In total, 20 out- or in-patients with bipolar I disorder were recruited from the psychiatry department of First Affiliated Hospital of Jinan University, Guangzhou, China. All patients met DSM-IV criteria for bipolar I disorder according to the diagnostic assessment by the Structured Clinical Interview for DSM-IV Patient Edition (SCID-P). Exclusion criteria included the presence of (1) other Axis I psychiatric disorders and symptoms, (2) a history of organic brain disorder, neurological disorders, or cardiovascular diseases, (3) alcohol/substance abuse within 6 months before study entry, and (4) pregnancy or any physical illness demonstrated by personal history, or clinical or laboratory examinations. All bipolar patients were suffering from depression, and receiving pharmacotherapy, including antidepressants (duloxetine or paroxetine) and/or mood stabilizers (lithium or sodium valproate). There were no patients with a history of psychotic episodes. None of the patients had ever received electroconvulsive therapy prior to study participation. Both the Hamilton Depression Rating Scale (HDRS) (17-item version) and Young Mania Rating Scale (YMRS) were used to evaluate the severity of mood symptoms. A total of 20 healthy control subjects were also recruited via local advertisements. They were carefully screened through a diagnostic interview, the Structured Clinical Interview for DSMIV Nonpatient Edition (SCID-NP), to rule out the presence of current or past psychiatric illness. Further exclusion criteria for healthy controls were any history of psychiatric illness in firstdegree relatives, current or past significant medical or neurological illness, and hearing impairment. All participants were nonsmokers, good hearing (at least 60 dB in each ear), and right-handed. The study was approved by the Ethics Committee of First Affiliated Hospital of Jinan University,

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China. All subjects signed a written informed consent form after a full written and verbal explanation of the study. Two senior clinical psychiatrists confirmed that all subjects had the ability to consent to participate in the examination. 2.2. Neuroimaging data collection 2.2.1. Paired-click paradigm The procedure followed the protocol of (Adler et al.,1982), in which 3-ms binaural clicks were presented in pairs (S1 and S2) with a 500-ms inter-stimulus interval (ISI) at 60 dB. The intertrial intervals (ITI) varied between 7 and 11 s, averaging 9 s. The clicks were generated with BrainX software (Xiang et al., 2001) and delivered through the plastic tubes with plastic insert earpieces at the tip. Participants were instructed to keep their eyes open and not to sleep. 2.2.2. MEG and MRI data collection Studies were performed using a 148-channel whole-head biomagnetometer (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, USA), a helmet shaped device covering the entire adult head, except the face. The subjects lay on the positioning bed inside the magnetically shielded room and auditory stimuli were presented to each ear. Three small electrode coils, used to transmit subject location information to the neuromagnetometer probe, were taped to the forehead with two-sided tape. Two electrode coils were taped in front of the right and left preauricular point. These coils provide for specification of the position and orientation of the MEG sensors relative to the head. A 3D digitization system was used to determine the subject′s head shape in a head centered coordinate system defined by the nasion and right and left preauricular points. The x-axis defined anterior–posterior directions, y defined the right and left directions, and z defined superior–inferior directions. Activation of these electrode coils before and after each study allowed the localization of the MEG measurement array with respect to the subject′s head. The shape of the head was also digitized for help with later coregistration to a standard MRI scan. The MEG was recorded with a 678.17 Hz sampling rate, using a bandpass filter of 0.1–200 Hz. Epochs 100 ms pre-stimulus to 300 ms post-stimulus were defined from the continuous recordings. Epochs with amplitude 44000 fT and/or temporal gradients 42500 fT/sample were rejected. After the MEG session, structural magnetic resonance imaging (MRI) provided T1-weighted, three-dimensional (3D) anatomic images using the Gyroscan Intera 1.5T (Philips Medical Systems, The Netherlands). The pulse sequence was a T1-weighted 3 D fast field echo (FFE) with the following parameters: TR¼ 25 ms, TE ¼4.6 ms, field of view¼240 mm, flip angle ¼ 301, matrix 256  256, slice thickness¼1.2 mm, no gap, 140 slices obtained in 3 min 16 s. Three points were marked on the nasion and bilateral preauricular points to be visualized on MRI images with small oil-containing capsules (3 mm diameter). T1-weighted images (axial, coronal and sagittal slices) were used for overlays, with the equivalent current dipole sources detected by MEG. 2.2.3. MEG data processing and source localization The data were collected and analyzed using a software package (MSI software, WHS version 1.2.4, Biomagnetometer system) on a workstation (SUN, SPARC Station™). In the off line analysis, the MEG was triggered by stimulus onset and it was averaged for each condition. A 1–40 Hz bandpass filter was applied to each subject′s cross-trial-averaged MEG data. The M100 peak latency was defined as the latency with the largest amplitude between 80 and 150 ms post-stimulus. The M50 peak latency was also defined between 30 and 70 ms. A single equivalent current dipole model

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was adopted for MEG source analysis, which assumes that the neuronal sources were focal. Peak source strength, latency, and location of M50 and M100 sources in left and right hemispheres were determined by fitting a single dipole separately over the left and right hemispheres using subsets of 34 planar gradiometers over each temporal lobe. Dipolar sources were identified in the bilateral hemispheres for M50 and M100 responses to the first stimulus (S1) of the pair. MEG data were superimposed over T1-weighted structural MRI images for data coregistration. Only equivalent current dipoles with goodness-of-fit values (a measure of the correlation between calculated and measured signal) exceeding 80% were accepted for further analysis. Peak strength of the source over the 10-ms period was then determined. M50 and M100 suppression for each hemisphere was expressed as (auditory gating) ratios: S2 (dipole peak strength to the second stimulus) divided by S1 (dipole peak strength to the first stimulus). As a result, the subjects with gating deficits thus show higher S2/S1 ratios.

2.3. Statistical analysis All data analyses were performed using SPSS for Windows software, version 15.0 (SPSS Inc., Chicago, III, USA) and two tailed significance level was set at p o0.05. Data were presented as means and standard deviations. Gating ratios (S2/S1), source strengths, latencies were submitted to a repeated-measures ANOVA analysis with group (bipolar disorder, normal controls) as a between-subjects factor, and hemisphere (left or right) as within-subjects factors. Spearman′s correlation coefficients were used to correlate clinical variables to the measured M50 and M100 gating ratios, source strengths.

3. Results 3.1. Demographics Table 1 shows the demographic and clinical data of all study participants. We included 20 bipolar I patients (9 men, 11 women) with a mean age of 31.38710.00 (range 18–52) years and 20 healthy controls (8 men, 12 women) with a mean age of 35.1879.90 (18–54) years. The mean number of education years was 15.5372.09 (12–18) years for patients and 14.4772.44 (8–19) years for controls. Among patients, the mean duration of illness was 2.5772.01 years, the mean HDRS score was 22.6074.98 (17–27) and YMRS score was 3.9572.86 (2–7). There were no significant differences in sex, age, and education status between the bipolar disorder group and the healthy control group.

Table 1 Demographic and clinical data and (standard deviations) by group.

Number of subjects Age (years) Age range (years) Gender (male/female) Education (years) 17-item HDRS score (points) YMRS score (points) Duration of illness (years)

Bipolar I disorder

Control

20 31.38 (10.00) 18–52 11-Sep 15.53 (2.09) 22.60 (4.98) 3.95 (2.86) 2.57 (2.01)

20 35.18 (9.90) 18–54 12-Aug 14.47 (2.44) n/a n/a n/a

Means (with standard deviations in parentheses) are reported unless otherwise noted. HDRS¼ Hamilton Depression Rating Scale. YMRS¼ Young Mania Rating Scale.

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3.2. M50 and M100 dipole locations

3.3. M50 and M100 sensory gating ratios

Fig. 1 provides an example of the 148 MEG sensor waveforms at the first click for one subject. Magnetic source imaging (MSI) showed that sources of M50 and M100 to S1 were located in the left and right posterior portion of STG or near primary auditory cortex in both bipolar disorder and control groups (Fig. 2). The M50 and M100 source dipole position for all subjects were expressed in distance (mm) on the x-(anterior/posterior), y(medial/lateral, left lateral o 0, right lateral 4 0), and z-(inferior/superior) axes from the center of a spherical head model. There was no significant difference in the M50 and M100 source position (x, y, and z codes) in the left or right hemispheres between the two groups.

Means and standard deviations for source strength, latencies, and S2/S1 ratio scores in each hemisphere are listed in Table 2. There was a significant main effect for group (F(1,37)¼6.590, p¼0.014), with the bipolar I group showing higher M50 gating ratios. There was no significant difference for hemisphere (F(1,37)¼ 0.064, p¼0.801). Although the group  hemisphere interaction was not significant (F(1,37)¼0.029, p¼0.866), one of the objectives in the current study was to explore the potential lateralization of auditory gating. Therefore, a one-way ANOVA was conducted between groups for each hemisphere. However, patients had higher M50 gating ratios in both left (F(1,37)¼5.275, p¼ 0.027) and right (F(1,37)¼4.208, p¼ 0.047) hemispheres compared to control subjects,

Fig. 1. The 148 channels of MEG waveforms to S1 and S2 from a 28-year-old male patient with bipolar I disorder. The MEG waveforms to S1 (A) and S2 (B).

Fig. 2. An example of cortical localization for bilateral M50 and M100 dipole sources. For all subjects, the M50 and M100 response localized to the left and right posterior portion of superior temporal gyrus. The M50 source is shown in yellow and the M100 source in blue. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Table 2 cMean (SD) S1 and S2 source strength, latency, and S2/S1 Gating ratio for controls (Con) and bipolar disorder type I (BDI) subjects for both hemispheres. Source strength (nA-m)

Latency (ms)

Gating ratio

S1

S2

S1

S2

S2/S1

Con, n¼20 M50L M50R M100L M100R

21.69 (10.86) 21.82 (15.56) 31.04 (17.27) 32.57 (14.57)

10.38 (5.55) 9.76 (5.77) 15.93(8.25) 16.07(5.98)

62.46 (9.89) 59.17 (12.06) 114.33 (17.17) 121.33 (17.57)

58.89 (10.55) 57.32 (9.89) 114.61 (15.15) 116.56 (13.18)

0.53 0.53 0.55 0.52

(0.28) (0.34) (0.22) (0.16)

BDI, n¼ 20 M50L M50R M100L M100R

28.97 (17.32) 26.64 (14.57) 34.92(28.82) 31.59 (22.06)

18.75 (7.69) b 18.21 (10.48) b 20.96(14.61) 22.33 (14.92)

59.27 (11.53) 62.36 (10.96) 114.60 (13.15) 121.58 (13.24)

58.87 (10.67) 59.36 (10.61) 116.29 (15.01) 119.20 (16.97)

0.79 0.76 0.71 0.77

(0.41) (0.36) (0.41) (0.37)

a b

a a

b

ANOVA between-subject comparisons significant at the 0.05 level. 0.01 Level.

confirming weaker bilateral M50 gating in subjects with bipolar I disorder. Similarly, there was a significant main effect for group (F(1,36)¼6.687, p¼0.014), with the bipolar I group showing higher M100 gating ratios, but no effect for hemisphere (F(1,36)¼ 0.200, p¼ 0.657) or the interaction (F(1,36)¼0.796, p¼0.378). A one-way ANOVA for M100 gating ratios showed patients having higher scores in right (F(1,37)¼ 8.018, p¼0.007) but not left (F(1,36)¼2.543, p¼ 0.119) hemispheres compared to control subjects. However, a significant group effect with no significant hemisphere-by-group interactions indicated bilateral M100 gating deficits in subjects with bipolar I disorder. Fig. 3 shows the bar graph of the gating ratios (S2/ S1) for M50 and M100 in each group.

3.4. M50 and M100 source strengths and latencies for S1 and S2 For source strengths, a group  hemisphere ANOVA for M50 S2 source strength showed patients having higher scores than controls (F(1,37) ¼18.106, p ¼0.000), but no effect for hemisphere (F(1,37) ¼0.195, p¼ 0.662) or the interaction (F(1,37) ¼0.001, p ¼ 0.975). A one-way ANOVA for M50 S2 source strengths showed patients having higher scores in both left (F(1,37) ¼ 15.559, p ¼0.000) and right (F(1,37) ¼10.586, p ¼ 0.002) hemispheres compared to controls, suggesting a primary role for bilateral S2 in group differences in conventional sensory gating ratios. Analyses of M50 S1 source strength, M100 S1 and S2 source strengths found no significant effects. For M50 and M100 latency, there were no significant between-subjects effects, within-hemisphere effects, or significant interactions. Furthermore, this study has failed to find a significant correlation between HDRS or YMRS scores and gating measures, suggesting no effect of affect on sensory gating within the relatively limited range of symptoms in this group of subjects.

4. Discussion Until now, findings concerning brain inhibitory function in bipolar disorder population are limited. To the best of our knowledge, this is the first study using a whole-head MEG-device to examine the hemispheric M50 and M100 auditory sensory gating in subjects with bipolar I disorder and normal control. In the present study, the use of MSI allowed localization of the auditory M50 and M100 to posterior STG in both groups. Bipolar I patients had bilateral M50 gating impairment and that this impaired sensory gating was related to the high S2 source strengths. Alternatively, bipolar I disorder patients showed bilateral M100 gating deficits compared with the control subjects.

Fig. 3. Left- and right-hemisphere M50 and M100 gating ratios in bipolar I disorder patients and normal controls. Bars indicate standard error (SE).

In addition, M50, M100 gating did not show a significant relationship with mood symptoms. In the current study, bipolar I patients showed significantly larger bilateral M50 ratio scores (S2/S1) compared with the control subjects, demonstrating pre-attentive auditory gating deficit in both hemispheres. It has been argued that the sensory gating problem may result from neuronal hyperexcitability stemming from a defect in neuronal inhibitory pathways of cortical and subcortical areas (Adler et al., 1982; Freedman et al., 1991). Our results are in agreement with a number of previous EEG-studies on P50 (Ancín et al., 2011; Cabranes et al., 2012; Carroll et al., 2008; Lijffijt et al., 2009), which is an electric counterpart to M50 response. Since P50 is best observed in the midline electrode Cz site using EEG and it is unsuited to detect hemispheric differences, investigation of possible lateralized differences in the latency and response magnitude of the hemispheric generators may help to specify the nature of sensory filtering deficits in bipolar disorder. By using MEG with paired click sounds, previous studies found M50 gating deficits in the left hemisphere in schizophrenia patients (Hanlon et al., 2005; Hirano et al., 2010; Smith et al., 2010; Thoma et al., 2003), thus suggesting that the asymmetry of gating deficits may be importantly related to schizophrenia pathophysiology. However, our study of patients with bipolar I disorder did not exhibit a lateralized M50 gating deficit measurable with MEG. Furthermore, we observed increased bilateral hemispheres S2 source strengths (instead of reduced S1 source strengths) in M50 sensory gating deficits. This finding suggests that M50 gating impairments would result from decreased inhibition of the M50

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evoked by S2 in bipolar I patients. Conceptually, the S2/S1 ratio is used to assess a failure of sensory gating, which is typically interpreted as a failure to gate S2 in order to protect processing of S1. The decreased attenuation of S2 response has been reported in some studies finding a P50 S2/S1 gating failure in schizophrenia (Hong et al., 2009; Shan et al., 2010) and bipolar disorder (Cabranes et al., 2012; Olincy and Martin, 2005; Schulze et al., 2007), and these findings were further supported by a recent meta-analytic study (Chang et al.,2011). These results might reflect that defective inhibition of repeating redundant input rather than an abnormal response to novel stimuli, suggesting a “gating out” habituation problem in bipolar patients. In addition, Adler et al. (1998) found that nicotine improved P50 sensory gating through diminished S2 amplitude, which was thought to reflect enhanced sensory gating through the activation of the alpha-7 nicotinic receptors. Kreinin et al. (2012) also reported that bipolar patients smoked more than the general population, suggesting nicotinic systems may play a role in bipolar disorder. Recent two studies reported that single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) were associated with both bipolar disorder and the P50 auditory evoked potential sensory gating deficit (Ancin et al., 2011; Martin et al., 2007), suggesting bipolar disorder may have a type of illness genetically and biologically more similar to schizophrenia. However, sensory gating deficits are not specific for schizophrenia and bipolar disorder, as these have also been reported in neuropsychiatric disorders including post-traumatic stress disorder (PTSD), epilepsy, Alzheimer′s disease, traumatic head injury and Huntington′s Chorea (Cromwell et al., 2008). We also found increased bilateral M100 sensory gating ratios of those diagnosed with bipolar I disorder in comparison to the healthy controls. To our knowledge, bilateral M100 gating deficit has not been previously reported in bipolar disorder literature. Lijffijt et al. (2009) reported higher N100 ratios in patients with euthymic bipolar I disorder compared with controls. Patterson et al. (2009) also found larger P85 gating ratios for both bipolar I subgroups with and without psychosis than for controls. These findings are in agreement with our results suggesting bipolar I disorder patients had defects in the ability of early information processing at the attention stage. Their study auditory signal measured at Cz is similar to averaging left and right-hemisphere M100 source strengths. In this study, the M100 auditory sensory gating deficit was found in both hemispheres in bipolar patients. Hanlon et al. (2005) also found bilateral M100 sensory gating deficit in schizophrenia, hypothesizing an early deficit may affect later processing. However, we failed to support our hypothesis of left lateralized gating deficits in bipolar disorder. In addition, our results further showed that there were no significant difference in the bilateral S1 and S2 M100 source strengths between bipolar I patients and healthy controls, indicating that group differences in M100 ratio scores were not explained solely by either a pure encoding deficit (driven by S1) or a pure gating deficit (driven by S2). Boutros et al. (1999) proposed that two physiological aberrations, abnormally low S1 responses and abnormally decreased ability to suppress S2 responses, were demonstrated in patients and that these two abnormalities may not be completely independent, which supported our finding of M100 sensory gating deficit. Some scholars thought that the sensory gating deficit were state markers correlated with the symptoms of mood disorders. Three early studies (Adler et al., 1990; Baker et al., 1990; Franks et al., 1983) observed abnormal P50 sensory gating that related to symptom severity only in patients with mania. However, few previous studies have examined sensory gating specific to bipolar patients in the depressive state. The current study failed to find any relationship between M50, M100 gating parameters and

HDRS scores. Contrary to findings of present studies, Baker et al. (1987) found the negative relationship between P50 ratios and Brief Psychiatric Rating Scale (BPRS) rating in depressive patients. On the other hand, several studies found larger P50 ratios in bipolar groups with a history of psychosis (Hall et al., 2008; Martin et al., 2007; Olincy and Martin, 2005; Schulze et al., 2007). While the current study found impaired bilateral M50 and M100 gating for bipolar patients without a history of psychosis. In agreement with the findings of Lijffijt et al. (2009), the P50 gating ratio did not differ between bipolar I subjects with and without a history of psychosis. Thus, it is uncertain whether P50 and M50 deficits are trait markers or state markers of bipolar disorder and whether they could be relieved with the improvement of clinical symptoms, a point which should be further investigated. Our results showed that M50 and M100 dipolar sources localized to the bilateral posterior portion of the STG in bipolar I disorder and control groups. Investigators recording the ERP using intraoperative electrocorticography (Grunwald et al., 2003; Korzyukov et al., 2007; Liegeois-Chauvel et al., 1994), chronic subdural electrodes (Lee et al., 1984) and also reported that P50 was a near-field potential in the primary auditory cortex. Hunter et al. (2011) demonstrated that the extent of thinning in the auditory cortex was correlated with the extent of impairment in auditory gating ratio in patients with PTSD, suggesting that cortical structural abnormality was related in a consistent manner with regional cortical function. Several structural MRI studies reported that reduced the STG gray matter volumes in bipolar disorder (Kempton et al., 2008; Nugent et al., 2006; Takahashi et al., 2010). Functional neuroimaging studies demonstrated changed glucose metabolism and cerebral blood flow in the STG (Mitchell et al., 2004; Pavuluri et al., 2007; Suwa et al., 2012). In addition, postmortem studies also revealed altered neuronal organization within the STG (Beasley et al., 2005). Taking all this together, these results suggest that the M50 and M100 gating impairment in bipolar disorder would be related to STG structural abnormality. We have shown that MEG provided good spatial and temporal resolutions for investigating bipolar disorder, which is considerable strength of this study. However, some potential limitations of the present study should be taken in consideration. First, the sample size was relatively small. It is possible that the association between bipolar disorder symptom severity and gating measures would have been detected in a larger sample size. Consequently, further studies on this subject are warranted. Second, the patients included had taken medicine prior to MEG and MRI scanning and it is difficult to ascertain the specific duration of drug treatment for each patient. Therefore, the effects of medication could be confounding factors in the analysis. Nevertheless, previous evidences found these deficits regardless of pharmacological treatment (Lijffijt et al., 2009; Olincy and Martin, 2005). Furthermore, diminished P50 suppression also occurred among the unaffected relatives of patients with bipolar disorder (Schulze et al., 2007), suggesting that this effect may be familial, relating to the genetic liability for bipolar disorder. Thus, it has been proposed that the sensory gating deficit was possibly a candidate intermediate phenotype (endophenotype) for studies seeking to identify susceptibility genes for this illness (Cabranes et al., 2012). Third, both animal and invasive human neuroimaging techniques suggested that sensory gating was mediated by a network, including the STG, hippocampus, dorsolateral prefrontal cortex (DLPFC), thalamus, parietal and cingulate cortexes (Grunwald et al., 2003; Williams et al., 2011). However, we were not able to assess simultaneously active neuronal generators involved in gating by MEG. Thus, the neuronal generators of the gating response should be further investigated by using non-invasive multi-modal neuroimaging techniques, such as functional MRI, standardized low

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resolution brain electromagnetic tomography (sLORETA). Four, the P50, N100, and P200 evoked responses were thought to reflect sensory “gating-out” (Gjini et al., 2010). The gating function includes both the ability to inhibit incoming redundant input (gating out) and the ability of the brain to respond when the stimulus changes (gating in). Therefore, the interrelationship between sensory gating out (M50, M100, M200 gating) and gating in (MMN and M300) should be further examined. In conclusion, the auditory gating deficit in bipolar I disorder is observable in both hemispheres for M50 and M100, suggesting impaired filtering at both pre-attentive and early attentive levels. Moreover, gating deficit may be related to STG structural abnormality. Future studies should also investigate the neuronal sources of M50 and M100 sensory gating in bipolar disorder and their relation to anatomy, symptom severity, neuropsychological function, response to treatment, and risk of relapse. This may ultimately provide new insights for the development of better treatment and prevention strategies for those diagnosed with bipolar disorder.

Role of funding source Our sponsor, recognized in the acknowledgments, served no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Conflict of interest All of the authors reported no financial interests or potential conflicts of interest.

Acknowledgements Funding for this study was provided by Medical Scientific Research Foundation of Guangdong Province, China (B2013218), the Fundamental Research Funds for the Central Universities of China (no. 21613309, 21612432) and the Cultivation Fund of First Affiliated Hospital of Jinan University (no. 2013201). The funding source had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

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