Elsevier

Journal of Affective Disorders

Volume 190, 15 January 2016, Pages 800-806
Journal of Affective Disorders

Research paper
Differentiation between major depressive disorder and bipolar disorder by auditory steady-state responses

https://doi.org/10.1016/j.jad.2015.11.034Get rights and content

Highlights

  • We examined the auditory steady-state response (ASSR) in major depressive disorder.

  • Major depressive disorder patients showed larger ASSR than bipolar disorders.

  • Major depressive disorders showed more phase-locked ASSR than bipolar disorders.

  • 40 Hz-ASSRs may be a potential biomarker for differentiation of two disorders.

Abstract

Background

The auditory steady-state response (ASSR) elicited by gamma band neural oscillations has received considerable interest as a biomarker of psychiatric disorders. Although recent ASSR studies have reported that patients with bipolar disorder (BD) show altered ASSRs, little is known about ASSRs in patients with major depressive disorder (MDD). The aim of this study was to evaluate whether ASSRs in MDD subjects differed from those in BD subjects or normal controls (NC).

Method

We analyzed ASSRs in 14 MDD patients, 19 BD patients, and 29 normal control subjects. We used whole-head 306-channel magnetoencephalography to evaluate ASSR power and phase-locking factors (PLF) elicited by 20-, 30-, 40-, and 80-Hz click trains. We determined optimal sensitivity and specificity of ASSR power and PLF for the diagnosis of MDD or BD via receiver operating characteristic (ROC) curve analysis using a nonparametric approach.

Results

MDD patients exhibited no significant differences in ASSR power or PLF compared with NC subjects, while BD patients showed deficits on the ASSR measures. MDD patients showed significantly larger ASSR power and PLF for 30-, 40-, and 80-Hz stimuli compared with BD patients. The area under the curve (AUC) for the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66–0.96, p=0.003] concerning 40-Hz ASSR power.

Limitations

We could not exclude the effect of medication and the sample size of the current study is relatively small.

Conclusions

We could differentiate between MDD and BD subjects in terms of gamma band ASSR. Our data suggest that the 40-Hz ASSR may be a potential biomarker for differentiation between MDD and BD patients.

Introduction

Major depressive disorder (MDD) is one of the most common psychiatric diseases, and is a serious public health issue. A systemic review of populations in Europe, Asia, and North America indicated that MDD has a 12-month prevalence of 4.1% and a lifetime prevalence of 6.7% (Waraich et al., 2004). Psychiatric nosology since the development of the DSM-III has classified MDD separately from bipolar disorder (BD). Indeed, the correct differentiation between MDD and BD in patients who present with symptoms of depression is critical for providing appropriate treatment and improving patient outcome. Despite clear phenomenological criteria, the differential diagnosis between MDD and BD remains a clinical challenge. The first symptom of BD typically constitutes depression with non-specific features (Perugi et al., 2000, Howes et al., 2011), and so there is often a substantial delay to diagnosis. In one study, the interval between the first major mood episode and initial treatment with a mood stabilizer was found to be 9.6 years (Drancourt et al., 2013). Other study reported that between 3.3% and 21.6% of primary care patients with MDD may have an undiagnosed BD (Smith et al., 2011). Several studies have described demographic and clinical characteristics that could help to distinguish between MDD and BD (Hirschfeld, 2014). However, MDD is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no clear pathophysiological mechanism (Belmaker and Agam, 2008); therefore, objective biological indices are needed. Several neuroimaging approaches have identified biomarkers that can be used to differentiate between MDD and BD. For example, in one structural MRI study, the authors were able to differentiate MDD from BD with depressive features (Redlich et al., 2014). Hemodynamic patterns from near-infrared spectroscopy have also been used to distinguish between MDD and BD or schizophrenia with depressive symptoms (Takizawa et al., 2014).

Neurophysiological approaches that employ magnetoencephalography (MEG) have the potential to be very beneficial because MEG can be used to measure direct consequences of the electrical activity of neurons with a high temporal resolution. Additionally, multimodal approaches are useful in the development of biomarkers. Neural oscillations in the gamma band (30–100 Hz) have received considerable interest as a biomarker of psychiatric disorders. Furthermore, MEG is suitable for noninvasively recording high-frequency neural oscillations (Brealy et al., 2015). The generation of gamma band activity is critically dependent upon several neurotransmitters, such as those in the GABAergic, glutamatergic, and cholinergic systems (Bartos et al., 2007, Goddard et al., 2012, Sullivan et al., 2015). Gamma oscillations have been associated with perceptual organization, attention, memory, consciousness, language processing, and motor coordination (Uhlhaas et al., 2008).

The auditory steady-state response (ASSR) is one of the most widely investigated responses with respect to gamma band neural oscillations (Onitsuka et al., 2013a, Onitsuka et al., 2013b). Periodic auditory click stimulation elicits an ASSR that synchronizes to both the phase and frequency of the click stimulus, and the ASSR is particularly prominent at rates near 40 Hz (Picton et al., 2003). The ASSR may reflect the efficiency of GABA inhibitory interneuron activity, which controls the timing of pyramidal neurons in layer II/III of the cortex (Gonzalez-Burgos and Lewis, 2008, Brenner et al., 2009). In addition, N-methyl-d-aspartate receptor (NMDAR) activities are associated with ASSR because NMDAR antagonists lead to ASSR deficits in animals (Sullivan et al., 2015, Leishman et al., 2015). Recent ASSR studies have reported that patients with schizophrenia and bipolar disorder show an altered ASSR for 40-Hz click stimuli (O’Donnell et al., 2004, Spencer et al., 2008, Reite et al., 2009, Rass et al., 2010, Tsuchimoto et al., 2011, Oda et al., 2012), indicating that both patients may have GABAergic and/or glutamatergic dysfunction. However, little is known about ASSR in MDD patients.

In the current study, we investigated beta (ASSR for 20-Hz click trains), low (ASSR for 30- and 40-Hz click trains), and high gamma (ASSR for 80-Hz click trains) ASSRs in healthy controls, MDD patients, and BD patients. We sought to evaluate whether ASSRs in MDD subjects were different from those in BD or NC individuals. Moreover, we explored how ASSRs might be useful in differentiating between MDD and BD.

Section snippets

Subjects

We analyzed MEG data from 14 MDD, 19 BD, and 29 normal control (NC) subjects in the present series. We collected new data for 14 MDD, 5 BD, and 4 NC subjects, and used data from our previous study regarding 14 of the 19 BD and 25 of the 29 NC subjects (Oda et al., 2012), who were chosen because they had demographic data that were consistent with that of the new participant group. All participants had normal hearing, were aged 20–60 years, and were right-handed, as assessed via the Edinburgh

Demographic characteristics

The demographic data of the subjects are shown in Table 1. We found no significant group differences between the two disorders in terms of neuroleptic or benzodiazepine dose [t(31)=−0.90, p=0.37 for neuroleptics; t(31)=1.26, p=0.22 for benzodiazepine]. To exclude the effects of transient gamma band responses, we analyzed the ASSR using a 200–500 ms window. We found no significant correlations between the dose of neuroleptics, benzodiazepine or lithium and ASSR power or PLF in both the MDD and BD

Discussion

We investigated the MEG-ASSR elicited by click trains of 20, 30, 40, and 80 Hz in patients with MDD. Our major findings were: (1) MDD patients were not significantly different from the NC group in terms of ASSR power and PLF; (2) MDD patients showed significantly larger ASSR power and PLF for the 30-, 40-, and 80-Hz stimuli compared with BD patients; (3) The area under the curve (AUC) of the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66–0.96, p=0.003] concerning 40-Hz ASSR power.

To the best of

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (B25293252 to S.K., C23591712 to T.O., B22791129 and 15K09836 to Y.H.) and Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (S2208 to S.K. and T.O.); a Research Grant from Mitsubishi Pharma Research Foundation to T.O.; the Health and Labour Sciences Research Grants for Comprehensive

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