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.

Functional abnormalities in the left ventrolateral prefrontal cortex during a semantic fluency task, and their association with thought disorder in patients with schizophrenia.

Thought disorder is one of the primary symptoms in schizophrenia, yet the neural correlates and related semantic processing abnormalities remain unclear. We aimed to investigate the relationship between functional prefrontal abnormalities and thought disorder in schizophrenia using 2 types of verbal fluency tasks: the letter fluency task (LFT) and the category fluency task (CFT). Fifty-six adult patients with schizophrenia and 56 healthy controls matched for age, gender, and IQ participated in the study. During completion of the 2 types of verbal fluency tasks, we measured oxy- and deoxy-hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) signal changes over a wide area of the bilateral prefrontal cortex, using a 52-channel near-infrared spectroscopy (NIRS) system. Thought disorder scores were evaluated using the positive and negative syndrome scale. CFT performance was significantly higher than LFT performance in both groups, while there was no significant difference in any prefrontal NIRS signal changes between the 2 tasks in either group. In both versions of verbal fluency task, healthy controls exhibited a significantly greater NIRS signal change than did patients with schizophrenia. On the CFT only, left ventrolateral prefrontal NIRS [deoxy-Hb] signals were significantly associated with thought disorder scores in patients with schizophrenia. Our results suggest that left ventrolateral prefrontal abnormalities in category fluency might be related to thought disorder in schizophrenia. This could lead to an improved understanding of the neural mechanisms within the left ventrolateral prefrontal cortex involved in mediating semantic processing, as well as the relationship between semantic processing abnormalities and thought disorder in schizophrenia.

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.

Differential spatiotemporal characteristics of the prefrontal hemodynamic response and their association with functional impairment in schizophrenia and major depression.

Recent neuroimaging studies have shown similarities and differences in prefrontal abnormalities between patients with schizophrenia (SZ) and major depressive disorder (MDD). However, the differential spatiotemporal characteristics of these abnormalities and their association with functional impairment remain unclear. To elucidate differential brain pathophysiology in these disorders, we used multichannel near-infrared spectroscopy (NIRS) to measure the spatiotemporal characteristics of prefrontal activation and investigated their association with global functioning levels. The study included 96 individuals: 32 patients with SZ, 32 patients with MDD, and 32 demographically matched healthy subjects. During a verbal fluency task, the changes in oxygenated and deoxygenated hemoglobin ([oxy-Hb] and [deoxy-Hb]) signals over the prefrontal cortex (PFC) were measured using 52-channel NIRS and compared among the 3 groups. Patients with SZ and MDD showed lesser-than-normal [oxy-Hb] activation during the task, whereas the initial slope of [oxy-Hb] activation was steeper for patients with MDD than for patients with SZ. The reduced hemodynamic response was associated with lower global functioning, and the correlative regions were different between the 2 disorders (frontopolar PFC in SZ; dorsolateral and ventrolateral PFC in MDD). The hypofrontality observed in patients with SZ and MDD is consistent with the findings of previous neuroimaging studies. Moreover, the spatiotemporal characteristics and the functional significance of the prefrontal hemodynamic response could differentiate the 2 psychiatric disorders. These results suggest a differential brain pathophysiology between SZ and MDD. Future large-scale studies are needed to determine the practical applicability of these findings for clinical diagnosis and evaluation.

Association between severe dorsolateral prefrontal dysfunction during random number generation and earlier onset in schizophrenia.

OBJECTIVES: Schizophrenia involves impairment in attention, working memory and executive processes associated with prefrontal cortical function, an essential contributor of social functioning. Age at onset is a major factor for predicting social outcome in schizophrenia. In clinical settings, we need an objective assessment tool for evaluating prefrontal function and social outcome. METHODS: Participants included 22 right-handed patients with schizophrenia and 40 gender- and age-matched healthy controls. We used a 52-channel near-infrared spectroscopy (NIRS) instrument to measure oxygenated haemoglobin ([oxy-Hb]) changes over the prefrontal cortex during a random number generation (RNG) task. RESULTS: In healthy controls, we found significant [oxy-Hb] increase in the bilateral dorsolateral (DLPFC; BA9 and BA46) and ventrolateral prefrontal cortex (VLPFC; BA44, 45 and 47). The patients with schizophrenia showed significantly smaller activation than the healthy controls in the same approximate regions. In the patient group, a smaller [oxy-Hb] increase in the right DLPFC region (BA9) was significantly correlated with earlier age at onset. CONCLUSIONS: NIRS can detect prefrontal cortical dysfunction associated with an executive task, which was coupled with earlier age at onset in schizophrenia. SIGNIFICANCE: Multichannel NIRS, a non-invasive and user-friendly instrument, may be useful in evaluating cognitive function and social outcome in clinical settings in psychiatry.

Prefrontal cortex activity during response inhibition associated with excitement symptoms in schizophrenia.

Previous fMRI studies of schizophrenia have shown a prefrontal abnormality during response inhibition. However, the association with the clinical symptoms in schizophrenia remains unclear. The aim of the present study was to clarify the association of psychotic symptoms with the prefrontal function during response inhibition in patients with schizophrenia. We evaluated the prefrontal activity during the Go/NoGo task in 14 patients with schizophrenia and age- and gender-matched 40 healthy controls using multi-channel near-infrared spectroscopy. We also examined the relationship between the prefrontal function during the Go/NoGo task and psychotic symptoms assessed by the PANSS five-factor model in patients with schizophrenia. Subjects in both groups performed well on the task, and the omission and commission error rates in the NoGo condition showed no statistically significant differences. The comparison of prefrontal activation between the Go condition and the NoGo condition in each group revealed that the healthy controls had a significant deactivation during the NoGo condition in the dorsolateral prefrontal cortex (DLPFC), and such changes were not shown in patients with schizophrenia. Furthermore, in patients with schizophrenia, the excitement score of the PANSS five-factor model was positively correlated with the activation in the right prefrontal cortex and frontopolar region. These results suggested that the abnormal prefrontal activity during simple inhibition of response would be associated with excitement symptoms in patients with schizophrenia.

Association between catechol-O-methyltrasferase Val108/158Met genotype and prefrontal hemodynamic response in schizophrenia.

BACKGROUND: "Imaging genetics" studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS). METHODOLOGY/PRINCIPAL FINDINGS: Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls. CONCLUSIONS/SIGNIFICANCE: These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging.

Association between sigma-1 receptor gene polymorphism and prefrontal hemodynamic response induced by cognitive activation in schizophrenia.

The molecular biological role of the sigma-1 receptor (Sig-1R) has attracted much attention. Evidence suggests that the Sig-1R engaged in modulating NMDA and dopamine receptors is involved in the pathophysiology of schizophrenia and the mechanism of psychotropic drug efficacy. However, whether the Sig-1R genotype affects brain function in schizophrenia in vivo remains unknown. We investigated the association between Sig-1R functional polymorphism (Gln2Pro) and brain function in schizophrenia. The subjects were 40 patients with schizophrenia and 60 healthy controls, all right-handed, who gave written informed consent to participate. Signals, detected from prefrontal regions by 52-channel near-infrared spectroscopy (NIRS) during cognitive activation, were compared between two Sig1-R genotype subgroups (Gln/Gln individuals and Pro carriers) matched for age, gender, premorbid IQ and task performance. The prefrontal hemodynamic response of healthy controls during the verbal fluency task was higher than that of patients with schizophrenia. For the patients with schizophrenia, even after controlling the effect of medication, the [oxy-Hb] increase in the prefrontal cortex of the Gln/Gln genotype group was significantly greater than that of the Pro carriers (false discovery rate corrected p<0.05). Clinical symptoms were not significantly different between the two Sig-1R genotype subgroups. These differences were not significant in the healthy controls. This is the first functional imaging genetics study that implicated the association between Sig-1R genotype and prefrontal cortical function in schizophrenia in vivo. Our findings also suggest that the prefrontal hemodynamic response assessed by noninvasive and less demanding NIRS is a useful intermediate phenotype for translational research in schizophrenia.

Gender difference in right lateral prefrontal hemodynamic response while viewing fearful faces: a multi-channel near-infrared spectroscopy study.

Near-infrared spectroscopy (NIRS) has been widely used to non-invasively assess brain function in various psychiatric disorders. Previous NIRS studies have extensively investigated prefrontal activation associated with cognitive tasks; in contrast, NIRS signals from prefrontal cortex in response to emotional stimuli have received little attention. We investigated spatiotemporal characteristics of hemodynamic response during an emotional activation task using fearful facial expression stimuli. We also evaluated gender difference and the relationship with anxiety-related personality traits. Subjects were 10 women and 10 men, all right-handed and matched for age, education and IQ estimated from the adult reading test. NIRS signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions by 52-channel NIRS. Women showed significantly increased [oxy-Hb] change relative to men in the right ventrolateral prefrontal cortex during the latter half of the task period. Frontopolar [deoxy-Hb] response correlated significantly with trait anxiety scores in the whole sample. These results suggest that gender and trait anxiety have an effect on individual variability of NIRS signals in response to emotional stimuli. This observation may help to establish NIRS as a clinical tool for monitoring prefrontal function on an individual basis.

Reduced frontopolar activation during verbal fluency task in schizophrenia: a multi-channel near-infrared spectroscopy study.

Functional neuroimaging studies to date have shown prefrontal dysfunction during executive tasks in schizophrenia. However, relationships between hemodynamic response in prefrontal sub-regions and clinical characteristics have been unclear. The objective of this study is to evaluate prefrontal hemodynamic response related to an executive task in schizophrenia and to assess the relationship between activation in the prefrontal sub-regions and clinical status. Fifty-five subjects with schizophrenia and age- and gender-matched 70 healthy subjects were recruited for this case-control study in a medical school affiliated hospital in the Tokyo metropolitan area, Japan. We measured hemoglobin concentration changes in the prefrontal (dorsolateral, ventrolateral, and frontopolar regions) and superior temporal cortical surface area during verbal fluency test using 52-channel near-infrared spectroscopy, which enables real-time monitoring of cerebral blood volumes in the cortical surface area under a more restraint-free environment than positron emission tomography or functional magnetic resonance imaging. The two groups showed distinct spatiotemporal pattern of oxy-hemoglobin concentration change during verbal fluency test. Schizophrenia patients were associated with slower and reduced increase in prefrontal activation than healthy controls. In particular, reduced activations of the frontopolar region, rather than lateral prefrontal or superior temporal regions, showed significant positive correlations with lower global assessment of functioning scores in the patient group, although task performance was not significantly associated with the scores. These results suggest that reduced frontopolar cortical activation is associated with functional impairment in patients with schizophrenia and that near-infrared spectroscopy may be an efficient clinical tool for monitoring these characteristics.

Season of birth effect on personality in a general population.

Seasonality of births in schizophrenia and other mental disorders has been consistently observed. This may be through effects of unknown environmental factors that seasonally fluctuate on the brain development. The effects may affect cognitive function of the brain and behavioral characteristics that might be correlated with the development of personality not only in patients with mental disorders but also in healthy subjects. We, therefore, investigated the effects of season of birth on personality traits in healthy Japanese adults (n = 397). Personality traits were evaluated using the NEO Personality Inventory-Revised (NEO PI-R). A trend for lower Agreeableness in subjects born during winter (December to February) than other subjects was observed (P = 0.036, after correction for the multiple testing, multiple regression analysis adjusting for age and sex). Other major factors of the NEO PI-R, including Neuroticism, Extraversion, Openness and Conscientiousness, were not affected by season of birth. Further studies may be recommended to confirm the results, considering the relatively limited sample size. Evaluation of cognitive functions and behaviors using other measures including event-related potentials and functional MRI may also help the interpretation of the present result.