Yukika Nishimura

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.

Associations between psychotic-like experiences and mental health status and other psychopathologies among Japanese early teens

Psychotic-like experiences (PLEs) are considered predictive of mental health problems later in life. However, little has been known about the mental health status and psychopathological distress in adolescents with PLEs in the general population. To investigate the associations between PLEs and mental health status or psychopathologies in a community sample of adolescents in a school-based cross-sectional fashion, PLEs were studied using a self-rating questionnaire in 5073 Japanese junior-high school students aged 12-15 years. Mental health status was evaluated using the 12-item General Health Questionnaire (GHQ-12). Psychopathologies, lifestyle, victimization, and interpersonal and help-seeking attitudes were also studied using a self-rating questionnaire. Fifteen percent of the students reported definitely having experienced at least one PLE. A dose-response relationship between the severity of PLEs and the prevalence of poor mental health status was observed. PLEs were also significantly associated with psychopathologies (strong anxiety in the classroom: OR = 1.4, 95% CI 1.2-1.6; suicidal ideation: OR = 2.1, 95% CI 1.8-2.4; self-harm behaviors: OR = 1.4, 95% CI 1.0-1.9; difficulty falling asleep due to hypersensitivity to environmental noise: OR = 1.7, 95% CI 1.4-2.0; difficulty concentrating due to hypersensitivity to environmental noise: OR = 1.5, 95% CI 1.3-1.8; physically assaulting others: OR = 1.3, 95% CI 1.0-1.5; bullying others, OR = 1.3, 95% CI 1.1-1.5; irritability when exchanging e-mails: OR = 1.3, 95% CI 1.0-1.6). Adolescents with PLEs in the community suffer from a wide range of psychopathological problems during crucial developmental periods [corrected]

Genome-wide association study of panic disorder in the Japanese population.

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Although a number of association studies have been conducted, no gene has been identified as a susceptibility locus. In this study, we conducted a genome-wide association study of PD in 200 Japanese patients and the same number of controls, using the GeneChip Human Mapping 500 K Array Set. Genotypes were determined using the Bayesian Robust Linear Model with Mahalanobis (BRLMM) genotype calling algorithm. The genotype data were data-cleaned using criteria for SNP call rate (⩾95%), Hardy–Weinberg equilibrium (P⩾0.1%) and minor allele frequency (⩾5%). The significance level of the allele P-value was set at 1.0 × 10−6, to make false discovery rate (FDR) <0.05. As a result, seven SNPs were significantly associated with PD, which were located in or adjacent to genes including PKP1, PLEKHG1, TMEM16B, CALCOCO1, SDK2 and CLU (or APO-J). Studies with other samples are required to confirm the results.

Psychotic-like experiences are associated with suicidal feelings and deliberate self-harm behaviors in adolescents aged 12-15 years

Nishida A, Sasaki T, Nishimura Y, Tanii H, Hara N, Inoue K, Yamada T, Takami T, Shimodera S, Itokawa M, Asukai N, Okazaki Y. Psychotic‐like experiences are associated with suicidal feelings and deliberate self‐harm behaviors in adolescents aged 12–15 years.

Different hemodynamic response patterns in the prefrontal cortical sub-regions according to the clinical stages of psychosis.

BACKGROUND Symptomatic and functional outcomes in schizophrenia are associated with the duration of untreated psychosis. However, no candidate biomarkers have been adopted in clinical settings. Multichannel near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the prefrontal cortex, is a candidate instrument for clinical use. AIMS We intended to explore prefrontal dysfunction among individuals at different clinical stages, including ultra-high-risk (UHR), first-episode psychosis (FEP), and chronic schizophrenia (ChSZ), compared to healthy subjects. METHOD Twenty-two UHR subjects, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects participated. We measured hemodynamic changes during a block-designed letter fluency task using multichannel NIRS instruments. RESULTS We found that the activations of the bilateral ventrolateral prefrontal cortex, and the fronto-polar and anterior parts of the temporal cortical regions in the UHR group were lower than those of the controls, but similar to those of the FEP and ChSZ groups. However, the activations in the bilateral dorsolateral prefrontal cortex regions decrease with advancing clinical stage. CONCLUSIONS To the best of our knowledge, this is the first study directly comparing differences in hemodynamic changes with respect to the 3 clinical stages of psychosis. Furthermore, this study also demonstrates different patterns of impairment according to the progression of clinical stages using NIRS instruments. NIRS measurements for UHR and FEP individuals may be candidate biomarkers for the early detection of the clinical stages of psychosis.

Meta-analysis of genome-wide association studies for panic disorder in the Japanese population

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10−5, odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10−4). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

Intrasubject reproducibility of prefrontal cortex activities during a verbal fluency task over two repeated sessions using multi‐channel near‐infrared spectroscopy

Aim:  To determine whether intrasubject reproducibility could be observed in the frontal cortex and to assess the mental‐health status of subjects in each session.

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.

Frontal dysfunction during a cognitive task in drug-naive patients with panic disorder as investigated by multi-channel near-infrared spectroscopy imaging

The present study investigated oxygenated ([oxy-Hb]) and deoxygenated ([deoxy-Hb]) hemoglobin concentration changes during the performance of a word fluency task in the frontal region of five drug-naive patients with panic disorder with or without agoraphobia and in 33 age-, sex-, and task performance-matched healthy volunteers by using multi-channel near-infrared spectroscopy (NIRS). The left inferior frontal [oxy-Hb] changes during performance of the task in patients with panic disorder were significantly smaller than those of healthy controls. This pilot study suggests the possibility that the left frontal lobe, required for cognitive function, is impaired in patients with panic disorder.

A multimodal approach to investigate biomarkers for psychosis in a clinical setting: The integrative neuroimaging studies in schizophrenia targeting for early intervention and prevention (IN-STEP) project

Longitudinal clinical investigations and biological measurements have determined not only progressive brain volumetric and functional changes especially around the onset of psychosis but also the abnormality of developmental pathways based on gene-environment interaction model. However, these studies have contributed little to clinical decisions on their diagnosis and therapeutic choices because of subtle differences between patients and healthy controls. A multi-modal approach may resolve this limitation and is favorable to explore the pathophysiology of psychosis. The integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is a research project aimed at exploring the pathophysiological features of the onset of psychosis and investigating possible predictive biomarkers for the clinical treatment of psychosis. Since 2008, we have adopted blood sampling, neurocognitive batteries, neurophysiological assessment, structural imaging, and functional imaging longitudinally for help-seeking ultra-high-risk (UHR) individuals and patients with first-episode psychosis (FEP). Here, we intend to introduce the IN-STEP research study protocol and present preliminary clinical findings. Thirty-seven UHR individuals and 30 patients with FEP participated in this study. Six months later, there was no difference in objective and subjective scores between the groups, which suggests that young people having symptoms and functional deficits should be cared for regardless of their history of psychosis according to their clinical stages. The rate of transition to psychosis was 7.1%, 8.0%, and 35.3% (at 6, 12, and 24months, respectively). Through this research project, we expect to clarify the pathophysiological features around the onset of psychosis and improve the prognosis of psychosis through clinical application.