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

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Journal of Affective Disorders

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Research report 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 b Clinical Experimental Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China c Medical Imaging Center, Guangdong 999 Hospital, Guangzhou 510510, China d Department of Psychiatry, First Affiliated Hospital of Jinan University, Guangzhou 510630, China article info abstract

Article history: Objectives: Auditory sensory gating deficits have been reported in subjects with bipolar disorder, but the Received 10 May 2013 hemispheric and neuronal origins of this deficit are not well understood. Moreover, gating of the auditory Received in revised form evoked components reflecting early attentive stage of information processing has not been investigated 12 August 2013 in bipolar disorder. The objectives of this study were to investigate the right and left hemispheric Accepted 12 August 2013 auditory sensory gating of the M50 (preattentive processing) and M100 (early attentive processing) in Available online 26 August 2013 patients diagnosed with bipolar I disorder by utilizing (MEG). Keywords: Methods: Whole-head MEG data were acquired during the standard paired-click paradigm in 20 bipolar I Bipolar disorder disorder patients and 20 healthy controls. The M50 and the M100 responses were investigated, and Magnetoencephalography dipole source localizations were also investigated. Sensory gating were determined by measuring the Auditory sensory gating strength of the M50 and the M100 response to the second click divided by that of the first click (S2/S1). M50 M100 Results: In every subject, M50 and M100 dipolar sources localized to the left and right posterior portion Superior temporal gyrus 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.

1. Introduction among the worldwide causes of non-fatal disease burden (WHO, 2001). Despite being a common and important psychiatric illness, Bipolar disorder is one of the most severe illnesses of the major the specific neurophysiologic basis of bipolar disorder is unknown. mental disorders, which is a leading cause of premature mortality The ability of the brain to inhibit or suppress irrelevant and due to suicide and associated medical conditions, such as diabetes redundant incoming sensory input is termed sensory gating. mellitus and cardiovascular disease (Merikangas et al., 2007). It When it is inadequate, higher brain functions are flooded with is characterized by the core feature of recurrence of hypomanic or a and subjects evidence cognitive fragmentation manic and depressive episodes that seriously affect the quality and behavioral disturbances (Ancín et al., 2011; Venables, 1967). of life and social functions of patients. According to World Health There is a large body of literature to suggest that a significant Organization estimates, bipolar disorder has been ranked seventh proportion of patients with 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; ☆This is an open-access article distributed under the terms of the Creative Cabranes et al., 2012; Carroll et al., 2008; Lijffijt et al., 2009; Commons Attribution-NonCommercial-No Derivative Works License, which per- Sánchez‐Morla et al., 2008), but not all (Olincy and Martin, 2005; mits non-commercial use, distribution, and reproduction in any medium, provided Patterson et al., 2009) have also revealed similar gating deficits in the original author and source are credited. n bipolar disorder patients. Recent studies suggest that schizophre- Corresponding author. Tel.: þ86 20 38688005; fax: þ86 20 38688000. E-mail address: [email protected] (L. Huang). nia and bipolar disorder may share a similar etiopathology. The 1 Authors Ying Wang and Yigang Feng are joint first authors. 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.2013.08.010 132 Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138 has been adapted in psychophysiological research as a test of Whereas M100 have been localized to near Heschl′s gyrus and “sensory gating”. In healthy individuals, a first (or “conditioning”) the planum temporale (Hanlon et al., 2005; Teale et al.,1998). stimulus activates inhibitory gating mechanisms to minimize Moreover, it has been shown in healthy controls that the bilateral the disruptive effects of an identical second (or “testing”) stimulus M50 STG sources accounted for 97% of the variance in P50 that occurs 500 ms later (Adler et al.,1982; Franks et al.,1983; responses at the electrode Cz, which demonstrated that the P50 Freedman et al., 1987). Typically, gating capacity is expressed in auditory evoked potential can be attributed to the bilateral M50 STG terms of the suppression ratio S2/S1(S2 amplitude /S1 amplitude), source localizations (Huang et al., 2003). Thoma et al. (2003) found which is higher in psychopathological populations and is thought a M50 sensory gating deficit for schizophrenia patients in the left to reflect weak inhibition or the gating of the repeated stimulus but not the right hemisphere, suggesting left-hemisphere dysfunc- (Freedman et al., 1987). tion as the substrate for the well-established P50 gating deficit in P50 is a positive auditory evoked potential (AEP) that occurs schizophrenia. Further, Hanlon et al. (2005) reported that schizo- at about 50 ms following stimulus presentation, which is widely phrenia patients had a left-hemisphere gating deficit in M50 and used to study sensory gating in a number of psychiatric and a bilateral gating deficit in M100, and a left-hemisphere M100 neurological conditions. Thus far only gating at the P50 stage of gating deficit was coupled with the left M50 gating deficit. information processing has been extensively examined (Boutros These findings confirm the importance of evaluating hemispheres et al., 2004; Potter et al., 2006), While sensory gating occurring at separately for sensory gating deficits. However, there are no studies the (a negative component peaking between 75 and 150 ms) using MEG to investigate possible lateralization of the M50 or M100 stage of information processing has not yet been fully explored. gating deficits in bipolar patients. Moreover, some studies showed that the test–retest reliability of In the current study, a whole-head MEG-device was employed to the N100 auditory gating ratio was better than P50 as a gating investigate the specific gating effects in bipolar I disorder patients index (Fuerst et al., 2007; Rentzsch et al., 2008; Smith et al.,1994). as reflected by the bilateral M50 and M100. The objectives of this Several studies have found impairments in N100 sensory gating in study were (1) to obtain the location, strength and latency of schizophrenia (Boutros et al.,1999, 2004; Brockhaus-Dumke et al., the M50 and M100 sensory gating for each hemisphere in bipolar 2008; Hanlon et al., 2005), however negative findings have also I disorder patients and normal subjects; (2) to assess the associa- been reported (Clementz et al., 1997; Hsieh et al., 2004; Waldo tions between bipolar I disorder symptom severity and hemispheric et al.,1988). To our knowledge, only one N100 sensory gating study M50, M100 sensory gating. We hypothesized that patients with was conducted in patients with bipolar disorder. Lijffijt et al. bipolar I disorder show left lateralized auditory sensory gating (2009) found that decreased gating of N100 and P50 in euthymic deficits occurring at both pre-attentive and early attentive phase of patients with bipolar I disorder, suggesting impaired filtering at information processing, and that this abnormality is associated with both pre-attentive and early attentive levels. However, when symptom severity. examining (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 2. Methods within a particular hemisphere. Today, EEG is a standard clinical procedure in brain research, 2.1. Participants with high temporal resolution, on which most of the reports of auditory gating deficit have relied (Adler et al.,1982; Bramon et al., In total, 20 out- or in-patients with bipolar I disorder were 2004; Clementz et al., 1997; Freedman et al., 1991). However, the recruited from the psychiatry department of First Affiliated appeal of P50 gating ratio has been limited by its low signal to Hospital of Jinan University, Guangzhou, China. All patients met noise ratio (SNR) and poor test–retest reliability (Fuerst et al., DSM-IV criteria for bipolar I disorder according to the diagnostic 2007; Lu et al., 2007; Smith et al., 1994). In addition, examining assessment by the Structured Clinical Interview for DSM-IV Patient P50 at the midline Cz site does not lend itself to identification Edition (SCID-P). Exclusion criteria included the presence of of the presumably lateralized cortical generators. As an alternative, (1) other Axis I psychiatric disorders and symptoms, (2) a history magnetoencephalography (MEG) is a noninvasive neuroimaging of organic brain disorder, neurological disorders, or cardiovascular technique for investigating neuronal activity in the living human diseases, (3) alcohol/substance abuse within 6 months before brain, which can overcome the conductivity and resistivity varia- study entry, and (4) pregnancy or any physical illness demon- tions with both high spatial and temporal resolution (Hämäläinen strated by personal history, or clinical or laboratory examinations. et al.,1993; Hirano et al., 2010; Pekkonen et al., 2007). In contrast All bipolar patients were suffering from depression, and receiving to the electric potentials, the magnetic fields are less distorted by pharmacotherapy, including antidepressants (duloxetine or par- the resistive properties of skull and scalp which may result in an oxetine) and/or mood stabilizers (lithium or sodium valproate). improved spatial resolution (Hämäläinen et al., 1993). In particular, There were no patients with a history of psychotic episodes. None MEG source localization allows for the separation of left and of the patients had ever received electroconvulsive therapy prior right-hemisphere auditory sensory gating. Thus, M50 and M100, to study participation. Both the Hamilton Depression Rating Scale which are magnetic counterparts to P50 and N100, can be reliably (HDRS) (17-item version) and Young Mania Rating Scale (YMRS) measured with MEG making it an ideal tool to investigate cortical were used to evaluate the severity of mood symptoms. auditory processing within each hemisphere. Furthermore, studies A total of 20 healthy control subjects were also recruited suggested that electric and magnetic sources of the P50 and N100 via local advertisements. They were carefully screened through can be considerably explained by one another (Korzyukov et al., a diagnostic interview, the Structured Clinical Interview for DSM- 2007; Pekkonen et al., 2002; Thoma et al., 2003) and reflect the IV Nonpatient Edition (SCID-NP), to rule out the presence of same brain-source activities (Lopes da Silva et al., 1991). current or past psychiatric illness. Further exclusion criteria for A handful of studies have used MEG to examine auditory gating healthy controls were any history of psychiatric illness in first- deficit in schizophrenia (Clementz et al., 1997; Huang et al., 2003; degree relatives, current or past significant medical or neurological Thoma et al., 2003; Hanlon et al., 2005) but not in bipolar disorder. illness, and hearing impairment. M50 responses have been localized to posterior areas of the All participants were nonsmokers, good hearing (at least 60 bilateral superior temporal gyrus (STG) (Edgar et al., 2003; Hanlon dB in each ear), and right-handed. The study was approved by the et al., 2005; Huang et al., 2003; Lu et al., 2007; Thoma et al., 2003), Ethics Committee of First Affiliated Hospital of Jinan University, Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138 133

China. All subjects signed a written informed consent form after was adopted for MEG source analysis, which assumes that the a full written and verbal explanation of the study. Two senior neuronal sources were focal. Peak source strength, latency, and clinical psychiatrists confirmed that all subjects had the ability to location of M50 and M100 sources in left and right hemispheres consent to participate in the examination. were determined by fitting a single dipole separately over the left and right hemispheres using subsets of 34 planar gradiometers fi 2.2. Neuroimaging data collection over each temporal lobe. Dipolar sources were identi ed in the bilateral hemispheres for M50 and M100 responses to the first 2.2.1. Paired-click paradigm stimulus (S1) of the pair. MEG data were superimposed over The procedure followed the protocol of (Adler et al.,1982), T1-weighted structural MRI images for data coregistration. Only fi in which 3-ms binaural clicks were presented in pairs (S1andS2) equivalent current dipoles with goodness-of- t values (a measure with a 500-ms inter-stimulus interval (ISI) at 60 dB. The intertrial of the correlation between calculated and measured signal) intervals (ITI) varied between 7 and 11 s, averaging 9 s. The clicks exceeding 80% were accepted for further analysis. Peak strength were generated with BrainX software (Xiang et al., 2001)and of the source over the 10-ms period was then determined. M50 delivered through the plastic tubes with plastic insert earpieces at and M100 suppression for each hemisphere was expressed as the tip. Participants were instructed to keep their eyes open and not (auditory gating) ratios: S2 (dipole peak strength to the second fi to sleep. stimulus) divided by S1 (dipole peak strength to the rst stimulus). As a result, the subjects with gating deficits thus show higher S2/S1 ratios. 2.2.2. MEG and MRI data collection Studies were performed using a 148-channel whole-head bio- magnetometer (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, 2.3. Statistical analysis USA), a helmet shaped device covering the entire adult head, except the face. The subjects lay on the positioning bed inside the All data analyses were performed using SPSS for Windows magnetically shielded room and auditory stimuli were presented software, version 15.0 (SPSS Inc., Chicago, III, USA) and two tailed to each ear. Three small electrode coils, used to transmit subject significance level was set at po0.05. Data were presented location information to the neuromagnetometer probe, were taped as means and standard deviations. Gating ratios (S2/S1), source to the forehead with two-sided tape. Two electrode coils were strengths, latencies were submitted to a repeated-measures taped in front of the right and left preauricular point. These coils ANOVA analysis with group (bipolar disorder, normal controls) provide for specification of the position and orientation of the MEG as a between-subjects factor, and hemisphere (left or right) as sensors relative to the head. A 3D digitization system was used to within-subjects factors. Spearman′s correlation coefficients were determine the subject′s head shape in a head centered coordinate used to correlate clinical variables to the measured M50 and M100 system defined by the nasion and right and left preauricular points. gating ratios, source strengths. 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 3. Results respect to the subject′s head. The shape of the head was also digitized for help with later coregistration to a standard MRI scan. 3.1. Demographics The MEG was recorded with a 678.17 Hz sampling rate, using abandpassfilter of 0.1–200 Hz. Epochs 100 ms pre-stimulus to Table 1 shows the demographic and clinical data of all study 300 ms post-stimulus were defined from the continuous record- participants. We included 20 bipolar I patients (9 men, 11 women) ings. Epochs with amplitude 44000 fT and/or temporal gradients with a mean age of 31.38710.00 (range 18–52) years and 20 healthy 42500 fT/sample were rejected. controls (8 men, 12 women) with a mean age of 35.1879.90 (18–54) After the MEG session, structural magnetic resonance imaging years. The mean number of education years was 15.5372.09 (12–18) (MRI) provided T1-weighted, three-dimensional (3D) anatomic years for patients and 14.4772.44 (8–19) years for controls. Among images using the Gyroscan Intera 1.5T (Philips Medical Systems, patients, the mean duration of illness was 2.5772.01 years, the The Netherlands). The pulse sequence was a T1-weighted 3 D fast mean HDRS score was 22.6074.98 (17–27) and YMRS score was field echo (FFE) with the following parameters: TR¼25 ms, 3.9572.86 (2–7). There were no significant differences in sex, age, TE¼4.6 ms, field of view¼240 mm, flip angle¼301, matrix and education status between the bipolar disorder group and the 256 256, slice thickness¼1.2 mm, no gap, 140 slices obtained healthy control group. 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 Table 1 images (axial, coronal and sagittal slices) were used for overlays, Demographic and clinical data and (standard deviations) by group. with the equivalent current dipole sources detected by MEG. Bipolar I disorder Control

2.2.3. MEG data processing and source localization Number of subjects 20 20 The data were collected and analyzed using a software package Age (years) 31.38 (10.00) 35.18 (9.90) – – (MSI software, WHS version 1.2.4, Biomagnetometer system) on Age range (years) 18 52 18 54 ™ Gender (male/female) 11-Sep 12-Aug a workstation (SUN, SPARC Station ). In the off line analysis, the Education (years) 15.53 (2.09) 14.47 (2.44) MEG was triggered by stimulus onset and it was averaged for 17-item HDRS score (points) 22.60 (4.98) n/a each condition. A 1–40 Hz bandpass filter was applied to each YMRS score (points) 3.95 (2.86) n/a subject′s cross-trial-averaged MEG data. The M100 peak latency Duration of illness (years) 2.57 (2.01) n/a was defined as the latency with the largest amplitude between 80 Means (with standard deviations in parentheses) are reported unless otherwise fi and 150 ms post-stimulus. The M50 peak latency was also de ned noted. HDRS¼Hamilton Depression Rating Scale. YMRS¼Young Mania between 30 and 70 ms. A single equivalent current dipole model Rating Scale. 134 Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138

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 Means and standard deviations for source strength, latencies, at the first click for one subject. Magnetic source imaging (MSI) and S2/S1 ratio scores in each hemisphere are listed in Table 2. showed that sources of M50 and M100 to S1 were located in the There was a significant main effect for group (F(1,37)¼6.590, left and right posterior portion of STG or near primary auditory p¼0.014), with the bipolar I group showing higher M50 gating cortex in both bipolar disorder and control groups (Fig. 2). The ratios. There was no significant difference for hemisphere (F(1,37)¼ M50 and M100 source dipole position for all subjects were 0.064, p¼0.801). Although the group hemisphere interaction was expressed in distance (mm) on the x-(anterior/posterior), not significant (F(1,37)¼0.029, p¼0.866), one of the objectives in y(medial/lateral, left lateral o0, right lateral 40), and z-(infer- the current study was to explore the potential lateralization ior/superior) axes from the center of a spherical head model. of auditory gating. Therefore, a one-way ANOVA was conducted There was no significant difference in the M50 and M100 source between groups for each hemisphere. However, patients had higher position (x, y,andz codes) in the left or right hemispheres M50 gating ratios in both left (F(1,37)¼5.275, p¼0.027) and right between the two groups. (F(1,37)¼4.208, p¼0.047) 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.) Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138 135

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 21.69 (10.86) 10.38 (5.55) 62.46 (9.89) 58.89 (10.55) 0.53 (0.28) M50R 21.82 (15.56) 9.76 (5.77) 59.17 (12.06) 57.32 (9.89) 0.53 (0.34) M100L 31.04 (17.27) 15.93(8.25) 114.33 (17.17) 114.61 (15.15) 0.55 (0.22) M100R 32.57 (14.57) 16.07(5.98) 121.33 (17.57) 116.56 (13.18) 0.52 (0.16)

BDI, n¼20 M50L 28.97 (17.32) 18.75 (7.69) b 59.27 (11.53) 58.87 (10.67) 0.79 (0.41) a M50R 26.64 (14.57) 18.21 (10.48) b 62.36 (10.96) 59.36 (10.61) 0.76 (0.36) a M100L 34.92(28.82) 20.96(14.61) 114.60 (13.15) 116.29 (15.01) 0.71 (0.41) M100R 31.59 (22.06) 22.33 (14.92) 121.58 (13.24) 119.20 (16.97) 0.77 (0.37) b

a ANOVA between-subject comparisons significant at the 0.05 level. b 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)¼0.200, p¼0.657) 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)¼8.018, p¼0.007) but not left (F(1,36)¼2.543, p¼0.119) 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 Fig. 3. Left- and right-hemisphere M50 and M100 gating ratios in bipolar I disorder S2 source strength showed patients having higher scores than patients and normal controls. Bars indicate standard error (SE). controls (F(1,37)¼18.106, p¼0.000), but no effect for hemisphere ¼ ¼ ¼ ¼ (F(1,37) 0.195, p 0.662) or the interaction (F(1,37) 0.001, p In addition, M50, M100 gating did not show a significant relation- 0.975). A one-way ANOVA for M50 S2 source strengths showed ship with mood symptoms. ¼ patients having higher scores in both left (F(1,37) 15.559, In the current study, bipolar I patients showed significantly ¼ ¼ ¼ p 0.000) and right (F(1,37) 10.586, p 0.002) hemispheres com- larger bilateral M50 ratio scores (S2/S1) compared with the control pared to controls, suggesting a primary role for bilateral S2in subjects, demonstrating pre-attentive auditory gating deficit in group differences in conventional sensory gating ratios. Analyses both hemispheres. It has been argued that the sensory gating of M50 S1 source strength, M100 S1 and S2 source strengths found problem may result from neuronal hyperexcitability stemming fi no signi cant effects. For M50 and M100 latency, there were no from a defect in neuronal inhibitory pathways of cortical and sub- fi signi cant between-subjects effects, within-hemisphere effects, or cortical areas (Adler et al., 1982; Freedman et al., 1991). Our results fi signi cant interactions. are in agreement with a number of previous EEG-studies on P50 fi fi Furthermore, this study has failed to nd a signi cant correla- (Ancín et al., 2011; Cabranes et al., 2012; Carroll et al., 2008; Lijffijt tion between HDRS or YMRS scores and gating measures, suggest- et al., 2009), which is an electric counterpart to M50 response. ing no effect of affect on sensory gating within the relatively Since P50 is best observed in the midline electrode Cz site using limited range of symptoms in this group of subjects. EEG and it is unsuited to detect hemispheric differences, investi- gation of possible lateralized differences in the latency and response magnitude of the hemispheric generators may help to 4. Discussion specify the nature of sensory filtering deficits in bipolar disorder. By using MEG with paired click sounds, previous studies found Until now, findings concerning brain inhibitory function in M50 gating deficits in the left hemisphere in schizophrenia bipolar disorder population are limited. To the best of our knowl- patients (Hanlon et al., 2005; Hirano et al., 2010; Smith et al., edge, this is the first study using a whole-head MEG-device 2010; Thoma et al., 2003), thus suggesting that the asymmetry of to examine the hemispheric M50 and M100 auditory sensory gating deficits may be importantly related to schizophrenia gating in subjects with bipolar I disorder and normal control. In pathophysiology. However, our study of patients with bipolar the present study, the use of MSI allowed localization of the I disorder did not exhibit a lateralized M50 gating deficit measur- auditory M50 and M100 to posterior STG in both groups. Bipolar able with MEG. I patients had bilateral M50 gating impairment and that this Furthermore, we observed increased bilateral hemispheres impaired sensory gating was related to the high S2 source S2 source strengths (instead of reduced S1 source strengths) in strengths. Alternatively, bipolar I disorder patients showed bilat- M50 sensory gating deficits. This finding suggests that M50 gating eral M100 gating deficits compared with the control subjects. impairments would result from decreased inhibition of the M50 136 Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138 evoked by S2 in bipolar I patients. Conceptually, the S2/S1 ratio HDRS scores. Contrary to findings of present studies, Baker et al. is used to assess a failure of sensory gating, which is typically (1987) found the negative relationship between P50 ratios and interpreted as a failure to gate S2 in order to protect processing of Brief Psychiatric Rating Scale (BPRS) rating in depressive patients. S1. The decreased attenuation of S2 response has been reported in On the other hand, several studies found larger P50 ratios in some studies finding a P50 S2/S1 gating failure in schizophrenia bipolar groups with a history of psychosis (Hall et al., 2008; Martin (Hong et al., 2009; Shan et al., 2010) and bipolar disorder et al., 2007; Olincy and Martin, 2005; Schulze et al., 2007). While (Cabranes et al., 2012; Olincy and Martin, 2005; Schulze et al., the current study found impaired bilateral M50 and M100 gating 2007), and these findings were further supported by a recent for bipolar patients without a history of psychosis. In agreement meta-analytic study (Chang et al.,2011). These results might reflect with the findings of Lijffijt et al. (2009), the P50 gating ratio did that defective inhibition of repeating redundant input rather than not differ between bipolar I subjects with and without a history of an abnormal response to novel stimuli, suggesting a “gating out” psychosis. Thus, it is uncertain whether P50 and M50 deficits are habituation problem in bipolar patients. In addition, Adler et al. trait markers or state markers of bipolar disorder and whether (1998) found that nicotine improved P50 sensory gating through they could be relieved with the improvement of clinical symp- diminished S2 amplitude, which was thought to reflect enhanced toms, a point which should be further investigated. sensory gating through the activation of the alpha-7 nicotinic Our results showed that M50 and M100 dipolar sources receptors. Kreinin et al. (2012) also reported that bipolar patients localized to the bilateral posterior portion of the STG in bipolar I smoked more than the general population, suggesting nicotinic disorder and control groups. Investigators recording the ERP using systems may play a role in bipolar disorder. Recent two studies intraoperative electrocorticography (Grunwald et al., 2003; reported that single nucleotide allelic variants in the promoter Korzyukov et al., 2007; Liegeois-Chauvel et al., 1994), chronic region of the chromosome 15 alpha-7 acetylcholine nicotinic subdural electrodes (Lee et al., 1984) and also reported that P50 receptor gene (CHRNA7) were associated with both bipolar dis- was a near-field potential in the primary . Hunter order and the P50 auditory evoked potential sensory gating deficit et al. (2011) demonstrated that the extent of thinning in the (Ancin et al., 2011; Martin et al., 2007), suggesting bipolar disorder auditory cortex was correlated with the extent of impairment in may have a type of illness genetically and biologically more similar auditory gating ratio in patients with PTSD, suggesting that to schizophrenia. However, sensory gating deficits are not specific cortical structural abnormality was related in a consistent manner for schizophrenia and bipolar disorder, as these have also been with regional cortical function. Several structural MRI studies reported in neuropsychiatric disorders including post-traumatic reported that reduced the STG gray matter volumes in bipolar stress disorder (PTSD), epilepsy, Alzheimer′s disease, traumatic disorder (Kempton et al., 2008; Nugent et al., 2006; Takahashi head injury and Huntington′s Chorea (Cromwell et al., 2008). et al., 2010). Functional neuroimaging studies demonstrated We also found increased bilateral M100 sensory gating ratios of changed glucose metabolism and cerebral blood flow in the STG those diagnosed with bipolar I disorder in comparison to the (Mitchell et al., 2004; Pavuluri et al., 2007; Suwa et al., 2012). healthy controls. To our knowledge, bilateral M100 gating deficit In addition, postmortem studies also revealed altered neuronal has not been previously reported in bipolar disorder literature. organization within the STG (Beasley et al., 2005). Taking all this Lijffijt et al. (2009) reported higher N100 ratios in patients with together, these results suggest that the M50 and M100 gating euthymic bipolar I disorder compared with controls. Patterson impairment in bipolar disorder would be related to STG structural et al. (2009) also found larger P85 gating ratios for both bipolar abnormality. I subgroups with and without psychosis than for controls. These We have shown that MEG provided good spatial and temporal findings are in agreement with our results suggesting bipolar I resolutions for investigating bipolar disorder, which is consider- disorder patients had defects in the ability of early information able strength of this study. However, some potential limitations of processing at the attention stage. Their study auditory signal the present study should be taken in consideration. First, the measured at Cz is similar to averaging left and right-hemisphere sample size was relatively small. It is possible that the association M100 source strengths. In this study, the M100 auditory sensory between bipolar disorder symptom severity and gating measures gating deficit was found in both hemispheres in bipolar patients. would have been detected in a larger sample size. Consequently, Hanlon et al. (2005) also found bilateral M100 sensory gating further studies on this subject are warranted. Second, the patients deficit in schizophrenia, hypothesizing an early deficit may affect included had taken medicine prior to MEG and MRI scanning and later processing. However, we failed to support our hypothesis of it is difficult to ascertain the specific duration of drug treatment for left lateralized gating deficits in bipolar disorder. In addition, our each patient. Therefore, the effects of medication could be con- results further showed that there were no significant difference in founding factors in the analysis. Nevertheless, previous evidences the bilateral S1 and S2 M100 source strengths between bipolar I found these deficits regardless of pharmacological treatment patients and healthy controls, indicating that group differences (Lijffijt et al., 2009; Olincy and Martin, 2005). Furthermore, in M100 ratio scores were not explained solely by either a pure diminished P50 suppression also occurred among the unaffected encoding deficit (driven by S1) or a pure gating deficit (driven relatives of patients with bipolar disorder (Schulze et al., 2007), by S2). Boutros et al. (1999) proposed that two physiological suggesting that this effect may be familial, relating to the genetic aberrations, abnormally low S1 responses and abnormally liability for bipolar disorder. Thus, it has been proposed that decreased ability to suppress S2 responses, were demonstrated the sensory gating deficit was possibly a candidate intermediate in patients and that these two abnormalities may not be com- phenotype () for studies seeking to identify pletely independent, which supported our finding of M100 sen- susceptibility genes for this illness (Cabranes et al., 2012). Third, sory gating deficit. both animal and invasive human neuroimaging techniques sug- Some scholars thought that the sensory gating deficit were gested that sensory gating was mediated by a network, including state markers correlated with the symptoms of mood disorders. the STG, , dorsolateral (DLPFC), Three early studies (Adler et al., 1990; Baker et al., 1990; Franks , parietal and cingulate cortexes (Grunwald et al., 2003; et al., 1983) observed abnormal P50 sensory gating that related to Williams et al., 2011). However, we were not able to assess symptom severity only in patients with mania. However, few simultaneously active neuronal generators involved in gating by previous studies have examined sensory gating specific to bipolar MEG. Thus, the neuronal generators of the gating response should patients in the depressive state. The current study failed to find be further investigated by using non-invasive multi-modal neu- any relationship between M50, M100 gating parameters and roimaging techniques, such as functional MRI, standardized low Y. Wang et al. / Journal of Affective Disorders 152-154 (2014) 131–138 137 resolution brain electromagnetic tomography (sLORETA). Four, antipsychotic-free subjects at risk, first-episode, and chronic patients. Biologi- the P50, N100, and P200 evoked responses were thought to reflect cal Psychiatry 64, 376–384. “ ” Cabranes, J.A., Ancín, I., Santos, J.L., Sánchez-Morla, E., García-Jiménez, M.A., Rodríguez- sensory gating-out (Gjini et al., 2010). The gating function Moya, L., et al., 2012. P50 sensory gating is a trait marker of the bipolar spectrum. includes both the ability to inhibit incoming redundant input European Neuropsychopharmacology. (Jul 6. [Epub ahead of print]). 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