Altered expression of microRNA-223 in the plasma of patients with first-episode schizophrenia and its possible relation to neuronal migration-related genes.

Recent studies have shown that microRNAs (miRNAs) play a role as regulators of neurodevelopment by modulating gene expression. Altered miRNA expression has been reported in various psychiatric disorders, including schizophrenia. However, the changes in the miRNA expression profile that occur during the initial stage of schizophrenia have not been fully investigated. To explore the global alterations in miRNA expression profiles that may be associated with the onset of schizophrenia, we first profiled miRNA expression in plasma from 17 patients with first-episode schizophrenia and 17 healthy controls using microarray analysis. Among the miRNAs that showed robust changes, the elevated expression of has-miR-223-3p (miR-223) was validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using another independent sample set of 21 schizophrenia patients and 21 controls. To identify the putative targets of miR-223, we conducted a genome-wide gene expression analysis in neuronally differentiated SK-N-SH cells with stable miR-223 overexpression and an in silico analysis. We found that the mRNA expression levels of four genes related to the cytoskeleton or cell migration were significantly downregulated in miR-223-overexpressing cells, possibly due to interactions with miR-223. The in silico analysis suggested the presence of miR-223 target sites in these four genes. Lastly, a luciferase assay confirmed that miR-223 directly interacted with the 3' untranslated regions (UTRs) of all four genes. Our results reveal an increase in miR-223 in plasma during both the first episode and the later stage of schizophrenia, which may affect the expression of cell migration-related genes targeted by miR-223.

Severity-dependent and -independent brain regions of major depressive disorder: A long-term longitudinal near-infrared spectroscopy study.

BACKGROUND: Long-term longitudinal studies are necessary to establish neuroimaging indicators which contribute to the detection of severity changes over time in patients with major depressive disorder (MDD). METHODS: One hundred sixty-five patients with MDD underwent clinical assessments and near-infrared spectroscopy (NIRS) examination at the initial evaluation (T0). After 1.5 years, 45 patients who visited for the follow-up evaluation (T1.5) were included in the analysis. The authors conducted analyses using the 17-item Hamilton Rating Scale for Depression (HAMD) scores and mean oxy-hemoglobin concentration ([oxy-Hb]) changes during a cognitive task in NIRS at T0 (T0_HAMD, T0_[oxy-Hb]) and at T1.5 (T1.5_HAMD, T1.5_[oxy-Hb]), and their intra-individual longitudinal changes (ΔHAMD = T1.5_HAMD - T0_HAMD, Δ[oxy-Hb] = T1.5_[oxy-Hb] - T0_[oxy-Hb]). RESULTS: For severity-dependent regions, the Δ[oxy-Hb] in the right inferior frontal gyrus (IFG) was negatively correlated with the ΔHAMD. For severity-independent regions, the intra-class correlation coefficients between T0_ and T1.5_[oxy-Hb] were moderate in the bilateral middle frontal gyri (MFG). LIMITATIONS: The percentage of patients included in the follow-up examination was relatively small. CONCLUSIONS: Brain activation in the right IFG and the bilateral MFG as measured by NIRS may differentially indicate clinical severity and trait-related abnormalities in MDD.

Application of functional near infrared spectroscopy as supplementary examination for diagnosis of clinical stages of psychosis spectrum.

AIM: Research efforts aiming at neuroimaging-aided differential diagnosis for psychiatric disorders have been progressing rapidly. A previous multisite study has developed a supplementary diagnostic system using functional near-infrared spectroscopy (fNIRS) that can be easily applied to clinical settings. However, few neuroimaging biomarkers have been developed for the psychosis spectrum with various clinical stages. METHODS: We employed the fNIRS as a clinical examination device for 143 participants, comprising 47 ultra-high risk for psychosis (UHR) individuals, 30 patients with first-episode psychosis (FEP), 34 patients with chronic schizophrenia (ChSZ), and 33 healthy controls, who were independent of the previous study. A 12-month follow-up measurement was also carried out on 34 UHR individuals (72%), 21 patients with FEP (70%), and 33 controls. The fNIRS algorithm variables used for classification were the intensity and timing of prefrontal activation following the start of the cognitive task as used in the previous multisite study. RESULTS: The discrimination rate by timing of activation was modest but it became acceptable after adjusting confounding factors. Discrimination by intensity of activation was not improved by similar adjustment. A total of 63.8%, 86.7%, and 81.3% patients were classified as UHR, FEP, and ChSZ, respectively; and 85.1%, 86.7%, and 71.9% of patients in these groups, respectively, were classified as being on the psychosis spectrum. In the follow-up measurement, 88.2% of individuals with UHR and 95.0% of patients with FEP were successfully classified into the psychosis spectrum group. CONCLUSION: The fNIRS for supplementary clinical examination could be validly applied to differentiating people with the psychosis spectrum in various clinical stages. The fNIRS is a candidate biological marker for aiding diagnosis of psychosis spectrum in routine clinical settings.

Development of a neurofeedback protocol targeting the frontal pole using near-infrared spectroscopy.

AIM: Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. METHODS: We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. RESULTS: Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). CONCLUSION: The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.

Detection of resting state functional connectivity using partial correlation analysis: A study using multi-distance and whole-head probe near-infrared spectroscopy.

Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.

Association between rostral prefrontal cortical activity and functional outcome in first-episode psychosis: a longitudinal functional near-infrared spectroscopy study.

BACKGROUND: Few biomarkers can be used easily and noninvasively to measure clinical condition and future outcome in patients with first-episode psychosis (FEP). To develop such biomarker using multichannel functional near-infrared spectroscopy (fNIRS), cortical function in the prefrontal cortex was longitudinally measured during a verbal fluency task. METHODS: Sixty-nine fNIRS measurements and 77 clinical assessments were obtained from 31 patients with FEP at baseline, 6-month, and 12-month follow-ups. Sixty measurements were obtained from 30 healthy controls matched for age, sex, and premorbid IQ. We initially tested signal changes for 12 months, and then investigated the relationship between fNIRS signals and clinical assessments. RESULTS: Signal changes from baseline to 12-month follow-up were not evident in any group. Patients with FEP had significant positive correlation coefficients between 6-month fNIRS signals and the 12-month Global Assessment of Functioning (GAF) score in the left middle frontal gyrus (FDR-corrected p=.0016-.0052, r=.65-.59). fNIRS signals at the 12-month follow-up were associated with 12-month GAF score in the bilateral superior and middle frontal gyri (FDR-corrected p=.00085-.018, r=.72-.55), and with the difference between baseline and 12-month GAF scores in the right superior frontal gyrus (FDR-corrected p=.000067-.00012, r=.80-.78). These associations were significant even after controlling for demographic variables. No association between baseline fNIRS signals and later GAF scores was found. DISCUSSION: fNIRS measurement can potentially be used as a biomarker to aid sequential assessment of neuro-clinical conditions through the early stage of psychosis.

Characterizing prefrontal cortical activity during inhibition task in methamphetamine-associated psychosis versus schizophrenia: a multi-channel near-infrared spectroscopy study.

Methamphetamine abuse and dependence, frequently accompanied by schizophrenia-like psychotic symptoms [methamphetamine-associated psychosis (MAP)], is a serious public health problem worldwide. Few studies, however, have characterized brain dysfunction associated with MAP, nor investigated similarities and differences in brain dysfunction between MAP and schizophrenia. We compared prefrontal cortical activity associated with stop-signal inhibitory task in 21 patients with MAP, 14 patients with schizophrenia and 21 age- and gender-matched healthy controls using a 52-channel near-infrared spectroscopy (NIRS) system. Both the MAP and the schizophrenia groups showed significantly reduced activation in the bilateral ventrolateral prefrontal cortex compared with controls; however, only the MAP group showed reduced activation in the frontopolar prefrontal cortex. The MAP group demonstrated significant positive correlations between task performance and hemodynamic responses in the bilateral ventrolateral, polar and left dorsolateral regions of the prefrontal cortex. The MAP and schizophrenia groups demonstrated a significant difference in the relationship of impulsivity to hemodynamic changes in the bilateral premotor cortex. These findings characterize similarities and differences in prefrontal cortical dysfunction between psychosis associated with methamphetamine and schizophrenia. The reduced hemodynamic changes in the bilateral ventrolateral prefrontal cortex suggest a common underlying pathophysiology of MAP and schizophrenia, whereas those in the frontopolar prefrontal cortex point to an impaired state that is either inherent or caused specifically by methamphetamine use.

Concurrent fNIRS-fMRI measurement to validate a method for separating deep and shallow fNIRS signals by using multidistance optodes.

It has been reported that a functional near-infrared spectroscopy (fNIRS) signal can be contaminated by extracerebral contributions. Many algorithms using multidistance separations to address this issue have been proposed, but their spatial separation performance has rarely been validated with simultaneous measurements of fNIRS and functional magnetic resonance imaging (fMRI). We previously proposed a method for discriminating between deep and shallow contributions in fNIRS signals, referred to as the multidistance independent component analysis (MD-ICA) method. In this study, to validate the MD-ICA method from the spatial aspect, multidistance fNIRS, fMRI, and laser-Doppler-flowmetry signals were simultaneously obtained for 12 healthy adult males during three tasks. The fNIRS signal was separated into deep and shallow signals by using the MD-ICA method, and the correlation between the waveforms of the separated fNIRS signals and the gray matter blood oxygenation level-dependent signals was analyzed. A three-way analysis of variance ([Formula: see text]) indicated that the main effect of fNIRS signal depth on the correlation is significant [[Formula: see text], [Formula: see text]]. This result indicates that the MD-ICA method successfully separates fNIRS signals into spatially deep and shallow signals, and the accuracy and reliability of the fNIRS signal will be improved with the method.

Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy.

BACKGROUND: The glutamatergic system is essential for learning and memory through its crucial role in neural development and synaptic plasticity. Genes associated with the glutamatergic system, including metabotropic glutamate receptor (mGluR or GRM) genes, have been implicated in the pathophysiology of schizophrenia. Few studies, however, have investigated a relationship between polymorphism of glutamate-related genes and cortical function in vivo in patients with schizophrenia. We thus explored an association between genetic variations in GRM3 and brain activation driven by a cognitive task in the prefrontal cortex in patients with schizophrenia. MATERIALS AND METHODS: Thirty-one outpatients with schizophrenia and 48 healthy controls participated in this study. We measured four candidate single nucleotide polymorphisms (rs274622, rs2299225, rs1468412, and rs6465084) of GRM3, and activity in the prefrontal and temporal cortices during a category version of a verbal fluency task, using a 52-channel near-infrared spectroscopy instrument. RESULTS AND DISCUSSION: The rs274622 C carriers with schizophrenia were associated with significantly smaller prefrontal activation than patients with TT genotype. This between-genotype difference tended to be confined to the patient group. GRM3 polymorphisms are associated with prefrontal activation during cognitive task in schizophrenia.

Using social epidemiology and neuroscience to explore the relationship between job stress and frontotemporal cortex activity among workers.

Mental health problems, such as depression, are increasingly common among workers. Job-related stresses, including psychological demands and a lack of discretion in controlling one's own work environment, are important causal factors. However, the mechanisms through which job-related stress may affect brain function remain unknown. We sought to identify the relationship between job-related stress and frontotemporal cortex activation using near-infrared spectroscopy. Seventy-nine (45 females, 34 males) Japanese employees, aged 26-51 years, were recruited from respondents to the Japanese Study of Stratification, Health, Income, and Neighborhood survey. Job-related stress was measured using the Japanese version of Job Content Questionnaire, which can index "job demand" and "job control". We found a significant correlation between higher "job demand" and smaller oxygenated hemoglobin [oxy-Hb] changes in the left dorsolateral prefrontal cortex in female (r = -.54 to -.44). Significant correlations between higher "job control" and greater [oxy-Hb] changes in the right temporal cortex were observed among male, and in the combined sample (r = .46-.64). This initial cross-sectional observation suggests that elevated job-related stress is related to decrease frontotemporal cortex activation among workers. Integrating social epidemiology and neuroscience may be a powerful strategy for understanding how individuals' brain functions may mediate between the job-related stress or psychosocial work characteristics and public mental health.

Similar age-related decline in cortical activity over frontotemporal regions in schizophrenia: a multichannel near-infrared spectroscopy study.

OBJECTIVES: Although recent studies have demonstrated that patients with schizophrenia and healthy controls did not differ in the speed of age-related decline in cortical thickness and performances on cognitive tests, hemodynamic changes assessed by functional neuroimaging remain unclear. This study investigated age effects on regional brain cortical activity to determine whether there is similar age-related decline in cortical activity as those observed in cortical thickness and cognitive test performance. METHOD: A total of 109 patients with schizophrenia (age range: 16-59 y) and 106 healthy controls (age range: 16-59 y) underwent near-infrared spectroscopy (NIRS) while performing a verbal fluency test (VFT). Group comparison of cortical activity was examined using 2-tailed t tests, adopting the false discovery rate method. The relationship between age and cortical activity was investigated using correlational and multiple regression analyses, adjusting for potential confounding variables. A 2-way ANOVA was conducted to investigate differences in the age effects between diagnostic groups. RESULTS: The patient group exhibited significantly decreased cortical activity in several regions of the frontotemporal cortices. However, slopes of age-dependent decreases in cortical activity were similar between patients and healthy individuals at the bilateral frontotemporal regions. CONCLUSIONS: Our study showed no significant between-group differences in the age-related decline in cortical activity, as measured by NIRS, over the frontotemporal regions during a VFT. The results of our study may indicate a decrease in cortical activity in a relatively limited period around illness onset rather than continuously progressing over the course of the illness.

Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals.

The early growth response 3 (EGR3) gene is an immediate early gene that is expressed throughout the brain and has been suggested as a potential susceptibility gene for schizophrenia (SZ). EGR3 impairment is associated with various neurodevelopmental dysfunctions, and some animal studies have reported a role for EGR3 function in the prefrontal cortex. Therefore, EGR3 genotype variation may be reflected in prefrontal function. By using multi-channel near-infrared spectroscopy (NIRS) in an imaging genetics approach, we tested for an association between the EGR3 gene polymorphism and prefrontal hemodynamic response during a cognitive task in patients with SZ. We assessed 73 chronic patients with SZ and 73 age-, gender-, and genotype-matched healthy controls (HC) who provided written informed consent. We used NIRS to measure changes in prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task (VFT). Statistical comparisons were performed among EGR3 genotype subgroups (rs35201266, GG/GA/AA). The AA genotype group showed significantly smaller oxyHb increases in the left dorsolateral prefrontal cortex (DLPFC) during the VFT than the GG and GA genotype groups; this was true for both patients with SZ and HC. Our findings provide in vivo human evidence of a significant influence of EGR3 polymorphisms on prefrontal hemodynamic activation level in healthy adults and in patients with SZ. Genetic variation in EGR3 may affect prefrontal function through neurodevelopment. This study illustrates the usefulness of NIRS in imaging genetics investigations on psychiatric disorders.

Distinct effects of duration of untreated psychosis on brain cortical activities in different treatment phases of schizophrenia: a multi-channel near-infrared spectroscopy study.

BACKGROUND: Duration of untreated psychosis (DUP) has been shown to be associated with both poor short-term and long-term outcomes in schizophrenia. Even so, few studies have used functional neuroimaging to investigate DUP in schizophrenia. In the present study, we used near-infrared spectroscopy (NIRS) to investigate the influence of DUP on brain functions during a verbal fluency test (VFT) in patients with schizophrenia. METHODS: A total of 62 patients with schizophrenia were included. They were categorized into either short treatment (≤6months, n=33) or long treatment (>6months, n=29) groups based on their duration of treatment. Hemodynamic changes over the frontotemporal regions during a VFT were measured using multi-channel NIRS. We examined the associations between DUP and hemodynamic changes in each group to explore if there were different effects of DUP on brain cortical activity at different treatment durations. RESULTS: In the long treatment group, we found significant associations between a longer DUP and decreased cortical activity approximately at the left inferior frontal gyrus, left middle frontal gyrus, left postcentral gyrus, right precentral gyrus, bilateral superior temporal gyrus, and bilateral middle temporal gyrus, whereas no associations between DUP and brain cortical activity were observed in the short treatment group. CONCLUSIONS: Our results indicated that longer DUP may be associated with decreased level of cortical activities over the frontotemporal regions in the long-term. Early detection and intervention of psychosis that shortens DUP might help to improve the long-term outcomes in patients with schizophrenia.

Potential biomarker of subjective quality of life: prefrontal activation measurement by near-infrared spectroscopy.

Recently, there has been growing emphasis on enhancing subjective quality of life (QOL), in addition to treating symptoms or extending one's life. However, the neurobiological basis of subjective QOL is unknown. To illuminate the neural substrates that inform subjective QOL, the association between prefrontal function and subjective QOL was explored in 72 healthy volunteers (40 women and 32 men; age, 45.1 ± 20.1 y), using 52-channel near-infrared spectroscopy (NIRS), a portable neuroimaging device that can measure brain function in a less-constrained condition. Results confirmed that subjective QOL was positively correlated with prefrontal hemodynamic response during a cognitive task and that subjective satisfaction regarding social relationships and in the physical domains were cardinal contributors to the association. These findings suggest that subjective QOL has possible involvement in prefrontal function and that NIRS potentially plays a role as a biological marker of subjective QOL.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

A NIRS-fMRI investigation of prefrontal cortex activity during a working memory task.

Near-infrared spectroscopy (NIRS) is commonly used for studying human brain function. However, several studies have shown that superficial hemodynamic changes such as skin blood flow can affect the prefrontal NIRS hemoglobin (Hb) signals. To examine the criterion-related validity of prefrontal NIRS-Hb signals, we focused on the functional signals during a working memory (WM) task and investigated their similarity with blood-oxygen-level-dependent (BOLD) signals simultaneously measured by functional magnetic resonance imaging (fMRI). We also measured the skin blood flow with a laser Doppler flowmeter (LDF) at the same time to examine the effect of superficial hemodynamic changes on the NIRS-Hb signals. Correlation analysis demonstrated that temporal changes in the prefrontal NIRS-Hb signals in the activation area were significantly correlated with the BOLD signals in the gray matter rather than those in the soft tissue or the LDF signals. While care must be taken when comparing the NIRS-Hb signal with the extracranial BOLD or LDF signals, these results suggest that the NIRS-Hb signal mainly reflects hemodynamic changes in the gray matter. Moreover, the amplitudes of the task-related responses of the NIRS-Hb signals were significantly correlated with the BOLD signals in the gray matter across participants, which means participants with a stronger NIRS-Hb response showed a stronger BOLD response. These results thus provide supportive evidence that NIRS can be used to measure hemodynamic signals originating from prefrontal cortex activation.