Background: Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. Methods: We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Results: Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849–0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Conclusions: Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD.

Near-infrared spectroscopy (NIRS) is an optimal imaging modality used to examine spontaneous brain activity because it can quietly measure blood flow changes with less physical restriction during the resting state. Here, NIRS was used at rest to measure spontaneous activity in the medial prefrontal cortex (mPFC), a main locus of default mode network. Consistent with previous fMRI studies, magnitude of the spontaneous activity in this region declined with increasing age in healthy subjects. The magnitude reduced in the mPFC of patients with schizophrenia. Additionally, in the mPFC of patients with schizophrenia, the spontaneous activity did not show any age-related decline; the activity was already low in younger patients. Further analysis using fractional amplitude of low-frequency fluctuations confirmed the reduction of spontaneous activity in the mPFC of patients with schizophrenia, consistent with the findings of fMRI studies. Our findings demonstrate the ability of NIRS to evaluate the spontaneous activity in the mPFC of patients with schizophrenia, particularly younger patients. Considering the safety and ease of the NIRS measurements, the current NIRS study of the resting-state activity indicates its utility for clinical applications to schizophrenia, which may facilitate chronological assessment of larger cohorts of patients with schizophrenia in further studies.

In applications of near-infrared spectroscopy (NIRS) in clinical psychiatry settings in Japan, a phonemic verbal fluency test (VFT) that includes “switching” (the ability to shift efficiently to a new word subcategory) to assess phonemic fluency is employed to capture disease-specific hemodynamic changes in the prefrontal cortex (PFC). In this study, to extend the specific features of this test, the VFT was repeated to examine an activation change in NIRS measurements in 20 healthy males. Without task performance change, the hemodynamic activation induced by the VFT was significantly attenuated in the left PFC through repetition of the task. These findings suggest that the left PFC is involved in processing of the VFT. Further, it may be possible to extend the current VFT using this repetition to provide a more sensitive examination of the left PFC, whose dysfunction has been reported in several psychiatric diseases such as major depression, bipolar disorder, and schizophrenia.

in functional imaging, accumulating evidence suggests that spontaneous activity decreases during the resting state in the core brain regions of the default-mode network [e.g. medial prefrontal cortex (mPFC)] in schizophrenia. However, the significance of this decreased activity has not been clarified in relation to its clinical symptoms. in this study, near-infrared spectroscopy (niRS), which is a simple imaging modality suitable for resting state paradigm, was used to evaluate the intensity of the spontaneous activity during the resting state in chronic schizophrenia. Consistent with previous findings of fMRi studies, spontaneous activity decreased in the mpfc of patients with schizophrenia. in addition, the decreased spontaneous activity was associated with severe hallucinations in this region where reality monitoring is fundamentally engaged. these results may encourage additional application of niRS with the resting state paradigm into daily clinical settings for addressing the broad phenotypes and unstable course of schizophrenia. Since default-mode activity was termed for the brain regional activity that is enhanced during the resting state 1,2 , numerous research fields have been opened up to identify the significance of this activity in human brains and brain diseases 3-5. The default-mode activity is characterized by spontaneous low-frequency (<0.1 Hz) fluctuations of the brain blood flow 6. Such fluctuations are synchronized among specific brain regions called the default-mode network whose core regions consist of the medial prefrontal cortex (mPFC) and PCC/precuneus 1,4. While most of the recent studies about disturbances of this activity have examined the impact on the network changes in psychiatric illnesses, less attention has been paid to quantify the intensity of this activity, which may provide an additional valid marker for mental illnesses. An index to measure the intensity of the resting-state activity in functional MRI (fMRI) is the amplitude of low-frequency fluctuations (ALFF), which appear dominantly in the core regions of the default-mode network 7,8. The ALFF indicates the sum of the power across low-frequency range (0.01-0.08 Hz) fluctuations of the brain blood flow, whereas the fractional ALFF (fALFF) indicates the ratio of the ALFF to the total power. Although previous fMRI studies have shown that both the ALFF and fALFF have reliable signals from the grey matter of the brain, the ALFF is believed to be more sensitive to the differences among groups and individuals owing to its higher test-retest reliability 8. On the other hand, the fALFF is reported to generate lesser noise from physiological sources 7,8. Therefore, it is recommended to use both analyses to maximize the reliability of examining spontaneous regional brain activity during the resting state 8. Several lines of evidence using fMRI suggest that the ALFF or fALFF is decreased during the resting state in the core regions of the default-mode network in schizophrenia 9-16. However, the extended analysis to explore the releva...