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Major depressive disorder (MDD) and bipolar disorder (BD) are two major mood disorders with partly overlapped symptoms but different treatments. However, their misdiagnosis and mistreatment are common based on the DSM-V criteria, lacking objective and quantitative indicators. This study aimed to develop a novel approach that accurately classifies MDD and BD based on their resting-state magnetoencephalography (MEG) signals during euthymic phases. A revisited 3D CNN model, Semi-CNN, that could automatically detect brainwave patterns in spatial, temporal, and frequency domains was implemented to classify wavelet-transformed MEG signals of normal controls and MDD and BD patients. The model achieved a test accuracy of 96.05% and an average of 95.71% accuracy for 5-fold cross-validation. Furthermore, saliency maps of the model were estimated using Grad-CAM++ to visualize the proposed classification model and highlight disease-specific brain regions and frequencies. Clinical Relevance - Our model provides a stable pipeline that accurately classifies MDD, BD, and healthy individuals based on resting-state MEG signals during the euthymic phases, opening the potential for quantitative and accurate brain-based diagnosis for the highly misdiagnosed MDD/BD patients.

Objectives: Bipolar I disorder (BD) is a highly heritable disorder characterized by mood swings between high-energy and low-energy states. Amygdala hyperactivity and cortical inhibitory hypoactivity [e.g., of the dorsolateral prefrontal cortex (dlPFC)] have been found in patients with BD, as evidenced by their abnormal resting-state functional connectivity (FC) and glucose utilization (GU). However, it has not been determined whether functional abnormalities of the dlPFC-amygdala circuit exist in unaffected, healthy siblings of the patients with BD (BDsib)., Methods: Twenty euthymic patients with BD, 20 unaffected matching BDsib of the patient group, and 20 well-matched healthy control subjects were recruited. We investigated seed-based FC (seeds: dlPFC) with resting-state functional magnetic resonance imaging and GU in the regions of interest (e.g., dlPFC and amygdala) using (18) F-fluorodeoxyglucose positron emission tomography., Results: The FC in the dlPFC (right)-amygdala circuit was statistically abnormal in patients with BD and BDsib, but only the patients with BD demonstrated hypoactive GU bilaterally in the dlPFC and hyperactive GU bilaterally in the amygdala. Facilitating differentiation between the BD groups, the altered FC between dlPFC (right) and amygdala (left) was even more prominent in the patients with BD (p < 0.05)., Conclusions: There was a dysfunctional connection with intact GU in the dlPFC-amygdala circuit of the BDsib, which highlights the vulnerability in families with BD. Diminished top-down control from the bilateral dlPFC, which prevents adequate inhibition of limbic hyperactivity, might mediate the development of BD., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bipolar disorder (BD) is highly heritable and associated with dysregulation of brain glucose utilizations (GU). The mitochondrial DNA (mtDNA) 10398A polymorphism, as a reported BD risk factor, leads to deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular calcium levels. However, whether mtDNA-10398A has functional effects on the brain and how our body responds remain elusive. We compared peripheral and central glucose-utilizing patterns between mtDNA A10398G polymorphisms in BD and their unaffected siblings (BDsib). Since siblings carry identical mtDNA, we hypothesized that certain characteristics co-segregate in BD families. We recruited twenty-seven pairs of non-diabetic BD patients and their BDsib and 30 well-matched healthy control subjects (HC). The following were investigated: mtDNA, fasting plasma glucose/insulin, cognitive functions including Montreal Cognitive Assessment (MoCA), and brain GU at rest. Insulin resistance was rechecked in sixty-one subjects (19-BD, 18-BDsibib, and 24-HC) six months later. We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting glucose, even after controlling for many covariates. BD-pairs had abnormally lower dorso-prefrontal-GU and higher cerebellar-GU, but only BD demonstrated lower medio-prefrontal-GU and MoCA. Subjects carrying mtDNA-10398A had significantly lower prefrontal-GU (FWE-corrected p<0.05). An abnormal inverse pattern of insulin-GU and insulin-MoCA correlation was found in BD-pairs. The insulin-MoCA correlation was particularly prominent in those carrying mtDNA-10398A. mtDNA-10398A predicted insulin resistance 6 months later. In conclusion, mtDNA-10398A was associated with impaired prefrontal-GU. An up-regulation of glucose utilizations was found in BD-pairs, probably compensating for mtDNA-10398A-related energy loss., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to investigate the relationship between resting brain glucose metabolism and cognitive profiles in patients with remitted bipolar I disorder (BD-I) and bipolar II disorder (BD-II). We hypothesized that BD-I patients (compared to BD-II patients) would perform worse on tests of cognitive function because of abnormal metabolism in the prefrontal cortex and other mood-related brain areas., Methods: Thirty-four patients with remitted bipolar disorder (BD) (BD-I = 17, BD-II = 17) under treatment and 17 well-matched healthy controls received both fluorodeoxyglucose ((18) F-FDG) positron emission tomography (PET) and neuropsychological tests of attention, memory, and executive function., Results: Clinical features in patients with BD-I and BD-II were comparable. Executive function, as indicated by performance on the Wisconsin Card Sorting Test, was significantly worse (i.e., higher percentage of errors, lower percentage of conceptual level responses, and fewer categories completed) in BD-I patients than in BD-II patients and healthy subjects. No difference in attention and memory tests was found among these three groups. Brain PET analysis showed that BD-I patients (compared to BD-II patients) had significantly lower glucose uptake in the bilateral anterior cingulum, insula, striatum, and part of the prefrontal cortex, and higher glucose uptake in the left parahippocampus. Further analyses revealed significant correlations between poor executive function and abnormal glucose uptake in other brain areas in BD-I patients., Conclusions: There are neurobiological differences between subtypes of BD. BD-I is associated with more impaired fronto-limbic circuitry, which might account for reduced executive function in BD-I patients during remission., (© 2012 John Wiley and Sons A/S.)

This study investigates the distinct patterns of local and long-range gamma oscillations between patients with bipolar disorder (BD) and major depressive disorder (MDD). Twenty BD patients, twenty MDD patients, and twenty normal controls participated in this study. For each participant, the event-related magnetoencephalographic responses while performing an implicit emotional task were recorded and processed with time-frequency analysis. Compared to normal controls, the BD patients exhibited the gamma power decease at the right frontal and prefrontal regions and yet gamma power increase at the right posterior temporal region. The abnormal long-range gamma oscillation between the right frontal and parietal-occipital region was also found. These results indicate that the BD patients may have hyperactivity in perceptual binding of emotional features and tend to be oversensitive to facial features. On the other hand, MDD patients displayed increased early gamma activity at the left anterior temporal region, which may imply their hyperactivated binding process of emotional features at corticolimbic regions. The distinct alterations of gamma patterns between the BD and MDD patients implicate that their impairments of binding processes are located at different regions. Gamma activity in the parietal and left posterior temporal regions may be a potential index to differentiate BD patients from MDD patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Although patients with bipolar I and II disorders exhibit heterogeneous clinical presentations and cognitive functions, it remains unclear whether these two subtypes have distinct neural substrates. This study aimed to differentiate the fiber abnormalities between bipolar I and II patients using diffusion tensor images., Method: Fourteen bipolar I patients, thirteen bipolar II patients, and twenty-one healthy subjects were recruited. Fractional anisotropy (FA) values calculated from diffusion tensor images were compared among groups using two-sample t-test analysis in a voxel-wise manner. Correlations between the mean FA value of each survived area and the clinical characteristics as well as the scores of neuropsychological tests were further analyzed., Results: Patients of both subtypes manifested fiber impairments in the thalamus, anterior cingulate, and inferior frontal areas, whereas the bipolar II patients showed more fiber alterations in the temporal and inferior prefrontal regions. The FA values of the subgenual anterior cingulate cortices for both subtypes correlated with the performance of working memory. The FA values of the right inferior frontal area of bipolar I and the left middle temporal area of bipolar II both correlated with executive function. For bipolar II patients, the left middle temporal and inferior prefrontal FA values correlated with the scores of YMRS and hypomanic episodes, respectively., Conclusions: Our findings suggest distinct neuropathological substrates between bipolar I and II subtypes. The fiber alterations observed in the bipolar I patients were majorly associated with cognitive dysfunction, whereas those in the bipolar II patients were related to both cognitive and emotional processing., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Bipolar disorder (BD) and major depressive disorder (MDD) have distinct pathophysiologies but similar depressive appearances. The present study aimed at the differentiation of the brain responses between BD and MDD patients. We hypothesized that different affective disorder patients may have distinct patterns of oscillatory cortical activities in response to negative emotional stimuli., Methods: Twenty BD patients, twenty MDD patients, and twenty age- and gender-matched healthy normal subjects were recruited. We adopted an implicit emotional task with facial image stimuli. The acquired event-related magnetoencephalographic signals were processed by the time-frequency analysis and beamformer-based source imaging techniques followed by statistical inference., Results: We found that there were gamma oscillation decreases in the frontal regions of both BD and MDD patients, gamma oscillation increases in the bilateral temporal regions of MDD, and alpha-beta rhythm increases in BD patients. Relative to the cortical activation in the control group, the BD patients displayed more widely increased oscillatory activities over the fronto-parieto-occipital regions than MDD patients., Conclusions: Our results demonstrate the distinct neuropathological patterns of emotional responses in BD and MDD patients. The findings suggest that the dysfunction of emotion regulation in BD may result from the increased sensitivity to emotionally salient information, implicating the potential cause of the emotion lability. The present study also suggests that the implicit emotional task is an effective approach to differentiate bipolar from unipolar disorders and their distinct neuropathological patterns to emotional stimuli may provide objective and quantitative measures for potential diagnostic significance., (Copyright 2009 Elsevier B.V. All rights reserved.)

Recent functional imaging studies demonstrated that brain exhibit coherent, synchronized activities during resting state and the dynamics may be impaired in various psychiatric illnesses. In order to investigate the change of neural dynamics in bipolar disorder, we used a new nonlinear measurement "similarity index" to analyze the magnetoencephalography (MEG) recordings and test the hypothesis that there are synchronization changes within different frequency bands in the frontal cortex of patients with bipolar disorder. Ten patients with bipolar I disorder during euthymic phase and ten normal controls underwent 2min eye-closed resting recording with a whole-head 306-channel MEG system. Eleven channels of MEG data from frontal area were selected for analysis. Synchronization level in the delta (2-4Hz), theta (4-8Hz), alpha (8-12Hz) and beta (12-24Hz) bands was calculated for each subject and compared across group. The results showed that significant dynamic changes in bipolar patients can be characterized by increased synchronization of slow frequency oscillations (delta) and decreased synchronization of fast frequency oscillations (beta). Furthermore, the positive correlation between beta synchronization level and preservative errors in Wisconcin card sorting task was found which would implicate the deficit of executive function in bipolar patients. Our findings indicate that analysis of spontaneous MEG recordings at resting state using nonlinear dynamic approaches may disclose the subtle regional changes of neural dynamics in BD.

Bipolar disorder (BD) is a common affective disorder. In morphometric brain imaging studies, BD subjects have atrophic gray matter, especially in the prefrontal area. These structural abnormalities could involve the change of cortical shape. Gyrification index (GI) is a useful metric to measure the degree of cortical complexity. This work aims to compare the cortical development between bipolar patients and healthy controls using GI. No significant difference was detected between two groups. However, we found asymmetry pattern of cortical complexity was increased in limbic lobe on bipolar patients. Significant negative correlation was also observed between rating scores and asymmetry coefficients in frontal lobe.