Yoshio Minabe

Publications of Yoshio Minabe

• Spatiotemporal frequency characteristics of cerebral oscillations during the perception of fundamental frequency contour changes in one-syllable intonation.

  Authors: Sanae Ueno, Eiichi Okumura, Gerard B Remijn, Yuko Yoshimura, Mitsuru Kikuchi, Kiyomi Shitamichi, Kikuko Nagao, Masayuki Mochiduki, Yasuhiro Haruta, Norio Hayashi, Toshio Munesue, Tsunehisa Tsubokawa, Manabu Oi, Hideo Nakatani, Haruhiro Higashida, Yoshio Minabe

  Neuroscience letters. 03/2012;

  Accurate perception of fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker's intonation, and consequently also his/her attitude. In this study, weAccurate perception of fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker's intonation, and consequently also his/her attitude. In this study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese one-syllable interjection "ne" in 21 native-Japanese listeners. A passive oddball paradigm was applied in which "ne" with a high falling F0 contour, used when urging a reaction from the listener, was randomly presented as a rare deviant among a frequent "ne" syllable with a flat F0 contour (i.e., meaningless intonation). We applied an adaptive spatial filtering method to the neuromagnetic time course recorded by whole-head magnetoencephalography (MEG) and estimated the spatiotemporal frequency dynamics of event-related cerebral oscillatory changes in the oddball paradigm. Our results demonstrated a significant elevation of beta band event-related desynchronization (ERD) in the right temporal and frontal areas, in time windows from 100 to 300 and from 300 to 500ms after the onset of deviant stimuli (high falling F0 contour). This is the first study to reveal detailed spatiotemporal frequency characteristics of cerebral oscillations during the perception of intonational (not lexical) F0 contour changes in the human voice. The results further confirmed that the right hemisphere is associated with perception of intonational F0 contour information in the human voice, especially in early time windows.

• Social memory, amnesia, and autism: Brain oxytocin secretion is regulated by NAD(+) metabolites and single nucleotide polymorphisms of CD38.

  Authors: Haruhiro Higashida, Shigeru Yokoyama, Jian-Jun Huang, Li Liu, Wen-Jie Ma, Shirin Akther, Chiharu Higashida, Mitsuru Kikuchi, Yoshio Minabe, Toshio Munesue

  Neurochemistry international. 02/2012;

  Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which isPreviously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C>A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials.

• Language performance and auditory evoked fields in 2- to 5-year-old children.

  Authors: Yuko Yoshimura, Mitsuru Kikuchi, Kiyomi Shitamichi, Sanae Ueno, Gerard B Remijn, Yasuhiro Haruta, Manabu Oi, Toshio Munesue, Tsunehisa Tsubokawa, Haruhiro Higashida, Yoshio Minabe

  The European journal of neuroscience. 02/2012; 35(4):644-50.

  Language development progresses at a dramatic rate in preschool children. As rapid temporal processing of speech signals is important in daily colloquial environments, we performedLanguage development progresses at a dramatic rate in preschool children. As rapid temporal processing of speech signals is important in daily colloquial environments, we performed magnetoencephalography (MEG) to investigate the linkage between speech-evoked responses during rapid-rate stimulus presentation (interstimulus interval < 1 s) and language performance in 2- to 5-year-old children (n = 59). Our results indicated that syllables with this short stimulus interval evoked detectable P50m, but not N100m, in most participants, indicating a marked influence of longer neuronal refractory period for stimulation. The results of equivalent dipole estimation showed that the intensity of the P50m component in the left hemisphere was positively correlated with language performance (conceptual inference ability). The observed positive correlations were suggested to reflect the maturation of synaptic organisation or axonal maturation and myelination underlying the acquisition of linguistic abilities. The present study is among the first to use MEG to study brain maturation pertaining to language abilities in preschool children.

• Oxytocin attenuates feelings of hostility depending on emotional context and individuals' characteristics.

  Authors: Tetsu Hirosawa, Mitsuru Kikuchi, Haruhiro Higashida, Eiichi Okumura, Sanae Ueno, Kiyomi Shitamichi, Yuko Yoshimura, Toshio Munesue, Tsunehisa Tsubokawa, Yasuhiro Haruta, Hideo Nakatani, Takanori Hashimoto, Yoshio Minabe

  Scientific reports. 01/2012; 2:384.

  In humans, oxytocin (OT) enhances prosocial behaviour. However, it is still unclear how the prosocial effects of OT are modulated by emotional features and/or individuals' characteristics. In aIn humans, oxytocin (OT) enhances prosocial behaviour. However, it is still unclear how the prosocial effects of OT are modulated by emotional features and/or individuals' characteristics. In a placebo-controlled design, we tested 20 healthy male volunteers to investigate these behavioural and neurophysiological modulations using magnetoencephalography. As an index of the individuals' characteristics, we used the empathy quotient (EQ), the autism spectrum quotient (AQ), and the systemising quotient (SQ). Only during the perception of another person's angry face was a higher SQ a significant predictor of OT-induced prosocial change, both in the behavioural and neurophysiological indicators. In addition, a lower EQ was only a significant predictor of OT-induced prosocial changes in the neurophysiological indicators during the perception of angry faces. Both on the behavioural and the neurophysiological level, the effects of OT were specific for anger and correlated with a higher SQ.

• Lateralized theta wave connectivity and language performance in 2- to 5-year-old children.

  Authors: Mitsuru Kikuchi, Kiyomi Shitamichi, Yuko Yoshimura, Sanae Ueno, Gerard B Remijn, Tetsu Hirosawa, Toshio Munesue, Tsunehisa Tsubokawa, Yasuhiro Haruta, Manabu Oi, Haruhiro Higashida, Yoshio Minabe

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 10/2011; 31(42):14984-8.

  Recent neuroimaging studies support the view that a left-lateralized brain network is crucial for language development in children. However, no previous studies have demonstrated a clear link betweenRecent neuroimaging studies support the view that a left-lateralized brain network is crucial for language development in children. However, no previous studies have demonstrated a clear link between lateralized brain functional network and language performance in preschool children. Magnetoencephalography (MEG) is a noninvasive brain imaging technique and is a practical neuroimaging method for use in young children. MEG produces a reference-free signal, and is therefore an ideal tool to compute coherence between two distant cortical rhythms. In the present study, using a custom child-sized MEG system, we investigated brain networks while 78 right-handed preschool human children (32-64 months; 96% were 3-4 years old) listened to stories with moving images. The results indicated that left dominance of parietotemporal coherence in theta band activity (6-8 Hz) was specifically correlated with higher performance of language-related tasks, whereas this laterality was not correlated with nonverbal cognitive performance, chronological age, or head circumference. Power analyses did not reveal any specific frequencies that contributed to higher language performance. Our results suggest that it is not the left dominance in theta oscillation per se, but the left-dominant phase-locked connectivity via theta oscillation that contributes to the development of language ability in young children.

• Effects of brain amyloid deposition and reduced glucose metabolism on the default mode of brain function in normal aging.

  Authors: Mitsuru Kikuchi, Tetsu Hirosawa, Masamichi Yokokura, Shunsuke Yagi, Norio Mori, Etsuji Yoshikawa, Yujiro Yoshihara, Genichi Sugihara, Kiyokazu Takebayashi, Yasuhide Iwata, Katsuaki Suzuki, Kazuhiko Nakamura, Takatoshi Ueki, Yoshio Minabe, Yasuomi Ouchi

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 08/2011; 31(31):11193-9.

  Brain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's disease. Many recent brain imaging studies have focused on areasBrain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's disease. Many recent brain imaging studies have focused on areas deactivated during cognitive tasks [the default mode network (DMN), i.e., medial frontal gyrus/anterior cingulate cortex and precuneus/posterior cingulate cortex], where the strength of functional coordination was more or less affected by cerebral Aβ deposits. In the present positron emission tomography study, to investigate whether regional glucose metabolic alterations and Aβ deposits seen in nondemented elderly human subjects (n = 22) are of pathophysiological importance in changes of brain hemodynamic coordination in DMN during normal aging, we measured cerebral glucose metabolism with [(18)F]FDG, Aβ deposits with [(11)C]PIB, and regional cerebral blood flow during control and working memory tasks by H(2)(15)O on the same day. Data were analyzed using both region of interest and statistical parametric mapping. Our results indicated that the amount of Aβ deposits was negatively correlated with hemodynamic similarity between medial frontal and medial posterior regions, and the lower similarity was associated with poorer working memory performance. In contrast, brain glucose metabolism was not related to this medial hemodynamic similarity. These findings suggest that traceable Aβ deposition, but not glucose hypometabolism, in the brain plays an important role in occurrence of neuronal discoordination in DMN along with poor working memory in healthy elderly people.

• Frontal areas contribute to reduced global coordination of resting-state gamma activities in drug-naïve patients with schizophrenia.

  Authors: Mitsuru Kikuchi, Takanori Hashimoto, Tatsuya Nagasawa, Tetsu Hirosawa, Yoshio Minabe, Masafumi Yoshimura, Werner Strik, Thomas Dierks, Thomas Koenig

  Schizophrenia research. 06/2011; 130(1-3):187-94.

  Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attractedSchizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30-50 Hz) and below-gamma (1.5-30 Hz) bands in drug-naïve patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naïve patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity.

• Hemodynamic responses to visual stimuli in cortex of adults and 3- to 4-year-old children.

  Authors: Gerard B Remijn, Mitsuru Kikuchi, Yuko Yoshimura, Kiyomi Shitamichi, Sanae Ueno, Kikuko Nagao, Toshio Munesue, Haruyuki Kojima, Yoshio Minabe

  Brain research. 02/2011; 1383:242-51.

  In this study we used near-infrared spectroscopy (NIRS) to measure relative changes in cortical hemodynamics from 19 adult and 19 preschool children (aged 3-4 years old), while they watched epochs ofIn this study we used near-infrared spectroscopy (NIRS) to measure relative changes in cortical hemodynamics from 19 adult and 19 preschool children (aged 3-4 years old), while they watched epochs of static and motion pictures extracted from TV programs. The spatio-temporal characteristics of oxygenated and deoxygenated hemoglobin volumes (oxy- and deoxy-Hb) of both subject groups were described and compared where appropriate for five regions of interest (ROIs). These were striate, left and right middle temporal, and left and right temporo-parietal areas. Over these areas, deoxy-Hb volumes did not differ between both groups. Preschool data showed significant increases in oxy-Hb over striate, middle temporal and temporo-parietal areas in response to visual motion stimuli. Static stimuli caused a significant oxy-Hb increase over striate and left middle temporal areas. Surprisingly, changes in adult oxy-Hb were not profound and did not show a significant oxy-Hb increase in striate and middle temporal areas in response to the motion stimuli, warranting further research. In spite of oxy-Hb volume differences, oxy-Hb recovery to baseline followed a similar pattern in both groups in response to both static and motion stimuli. Together, the results suggest that near-infrared spectroscopy is a viable method to investigate cortical development of preschool children by monitoring their hemodynamic response patterns.

• EEG microstate analysis in drug-naive patients with panic disorder.

  Authors: Mitsuru Kikuchi, Thomas Koenig, Toshio Munesue, Akira Hanaoka, Werner Strik, Thomas Dierks, Yoshifumi Koshino, Yoshio Minabe

  PloS one. 01/2011; 6(7):e22912.

  Patients with panic disorder (PD) have a bias to respond to normal stimuli in a fearful way. This may be due to the preactivation of fear-associated networks prior to stimulus perception. Based onPatients with panic disorder (PD) have a bias to respond to normal stimuli in a fearful way. This may be due to the preactivation of fear-associated networks prior to stimulus perception. Based on EEG, we investigated the difference between patients with PD and normal controls in resting state activity using features of transiently stable brain states (microstates). EEGs from 18 drug-naive patients and 18 healthy controls were analyzed. Microstate analysis showed that one class of microstates (with a right-anterior to left-posterior orientation of the mapped field) displayed longer durations and covered more of the total time in the patients than controls. Another microstate class (with a symmetric, anterior-posterior orientation) was observed less frequently in the patients compared to controls. The observation that selected microstate classes differ between patients with PD and controls suggests that specific brain functions are altered already during resting condition. The altered resting state may be the starting point of the observed dysfunctional processing of phobic stimuli.

• Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: implication of fatty acid-binding proteins (FABP) and G protein-coupled receptor 40 (GPR40) in adult neurogenesis.

  Authors: Nadezhda B Boneva, Mitsuru Kikuchi, Yoshio Minabe, Tetsumori Yamashima

  Journal of pharmacological sciences. 01/2011; 116(2):163-72.

  Adult neurogenesis in the mammalian brain is well-known to occur in the subgranular zone of the hippocampus. As the hippocampus is related to learning, memory, and emotions, adult hippocampalAdult neurogenesis in the mammalian brain is well-known to occur in the subgranular zone of the hippocampus. As the hippocampus is related to learning, memory, and emotions, adult hippocampal neurogenesis possibly contributes to these functions. Adult neurogenesis is modulated by polyunsaturated fatty acids (PUFA) such as docosahexaenoic and arachidonic acids that are essential for normal brain development, maintenance, and function. They are reported to improve spatial learning and memory in rodents and cognitive functions in humans. However, detailed mechanisms of PUFA effects still remain obscure. PUFA are functionally linked with chaperons called fatty acid-binding proteins (FABP). FABP uptake and transport PUFA to different intracellular organelles. Intriguingly, PUFA were determined as ligands for G protein-coupled receptor 40 (GPR40), a cell membrane receptor abundantly expressed in the brain and the pancreas of primates. While the role of GPR40 in pancreatic β-cells is associated with insulin secretion, its role in the brain is not yet clarified presumably because of its absence in the rodent brain. The purpose of this review is to discuss the role of PUFA in adult neurogenesis, considering the role of GPR40 and FABP in the hippocampal neurogenic niche. Here, the authors would like to introduce a PUFA-GPR40 signaling pathway that is specific for the primate brain.

• CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism.

  Authors: Haruhiro Higashida, Shigeru Yokoyama, Toshio Munesue, Mitsuru Kikuchi, Yoshio Minabe, Olga Lopatina

  Biological & pharmaceutical bulletin. 01/2011; 34(9):1369-72.

  Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in theOxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38(-/-)) produced impairment of maternal behavior and male social recognition in mice, similar to the behavior observed in Oxt and OXT receptor (Oxtr) gene knockout (Oxt(-/-) and Oxtr(-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalization (USV) calls was lower in Cd38(-/-) than Cd38(+/+) pups. These phenotypes seemed to be caused by the high plasma OXT levels during development from neonates to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of differentiating plasma OXT. Contribution by breastfeeding was an important exogenous source for regulating plasma OXT before weaning by the presence of OXT in milk and the dam's mammary glands. The dissimilarity of Cd38(-/-) infant behaviour to Oxt(-/-) or Oxtr(-/-) mice can be explained partly by this exogenous source of OXT. These results suggest that secretion of OXT into the brain in a CD38-dependent manner may play an important role in the development of social behavior, and mice with OXT signalling deficiency, including Cd38(-/-), Oxt(-/-) and Oxtr(-/-) mice are good animal models for developmental disorders, such as autism.

• Neurovascular coupling in the human somatosensory cortex: a single trial study.

  Authors: Mitsuru Kikuchi, Kiyomi Shitamichi, Sanae Ueno, Yuko Yoshimura, Gerard B Remijn, Kikuko Nagao, Toshio Munesue, Koichi Iiyama, Tsunehisa Tsubokawa, Yasuhiro Haruta, Yoshihiro Inoue, Katsumi Watanabe, Takanori Hashimoto, Haruhiro Higashida, Yoshio Minabe

  Neuroreport. 12/2010; 21(17):1106-10.

  Oscillations in the higher frequency range are closely related to regional brain hemodynamic changes. Here we investigated this neurovascular coupling in humans in response to electrical stimulationOscillations in the higher frequency range are closely related to regional brain hemodynamic changes. Here we investigated this neurovascular coupling in humans in response to electrical stimulation of the right median nerve. In a single-trial study, we simultaneously recorded hemodynamic fluctuations in the somatosensory cortex by near infrared spectroscopy and brain neuronal oscillations by whole-head magnetoencephalography (MEG). The results from six volunteers showed that neural fluctuations at β or γ-band power were correlated with hemodynamic fluctuation during stimulus conditions. These correlations were prominent with a time delay of 5-7 s. This study provides new direct evidence that hemodynamic onset lags specific neural oscillations in the order of seconds in human awake conditions using noninvasive methods.

• Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.

  Authors: Toshio Munesue, Shigeru Yokoyama, Kazuhiko Nakamura, Ayyappan Anitha, Kazuo Yamada, Kenshi Hayashi, Tomoya Asaka, Hong-Xiang Liu, Duo Jin, Keita Koizumi [......] Minako Hashii, Sarwat Amina, Fabio Malavasi, Eric J Huang, Jiasheng Zhang, Nobuaki Shimizu, Takeo Yoshikawa, Akihiro Matsushima, Yoshio Minabe, Haruhiro Higashida

  Neuroscience research. 06/2010; 67(2):181-91.

  The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play aThe neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.

• Heart rate variability in drug-naïve patients with panic disorder and major depressive disorder.

  Authors: Mitsuru Kikuchi, Akira Hanaoka, Tomokazu Kidani, Gerard Bastiaan Remijn, Yoshio Minabe, Toshio Munesue, Yoshifumi Koshino

  Progress in neuro-psychopharmacology & biological psychiatry. 09/2009;

  Power spectral analysis of electrocardiogram (ECG) R-R intervals is useful for the detection of autonomic dysfunction in various clinical disorders. Although both panic disorder (PD) and majorPower spectral analysis of electrocardiogram (ECG) R-R intervals is useful for the detection of autonomic dysfunction in various clinical disorders. Although both panic disorder (PD) and major depressive disorder (MDD) are known to have effects on the cardiac autonomic nervous system, no previous study has tested this among drug-naïve (i.e. no history of treatment) patients with MDD and PD in the same study. The purpose of this study was to compare cardiac autonomic functions among drug-naive patients with MDD and PD and those of healthy controls. Subjects were 17 drug-naïve PD patients, 15 drug-naïve MDD patients and 15 normal controls. ECGs were recorded under both supine resting and supine deep-breathing conditions (10-12 breaths/minute; 0.17-0.20 Hz). We measured the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. As expected, deep breathing induced an increase in HF power and a decrease in the LF/HF ratio in healthy controls. Compared to these controls, however, the MDD group had a lower response to regular deep breathing in LF power and in LF/HF ratio. PD patients showed intermediate results between normal controls and MDD patients. The results indicate that the reactivity to deep breathing revealed diminished cardiac autonomic reactivity in drug-naïve MDD patients.

• Preliminary genome-wide association study of bipolar disorder in the Japanese population.

  Authors: Eiji Hattori, Tomoko Toyota, Yuichi Ishitsuka, Yoshimi Iwayama, Kazuo Yamada, Hiroshi Ujike, Yukitaka Morita, Masafumi Kodama, Kenji Nakata, Yoshio Minabe [......] Makoto Arai, Masahiro Nankai, Toshiya Inada, Sumiko Yoshida, Hiroshi Kunugi, Michiko Nakamura, Yoshimi Iijima, Yuji Okazaki, Teruhiko Higuchi, Takeo Yoshikawa

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 03/2009;

  Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide associationRecent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary. (c) 2009 Wiley-Liss, Inc.

• Decreased serum levels of platelet-endothelial adhesion molecule (PECAM-1) in subjects with high-functioning autism: a negative correlation with head circumference at birth.

  Authors: Kenji J Tsuchiya, Kenji Hashimoto, Yasuhide Iwata, Masatsugu Tsujii, Yoshimoto Sekine, Genichi Sugihara, Hideo Matsuzaki, Shiro Suda, Masayoshi Kawai, Kazuhiko Nakamura, Yoshio Minabe, Atsuko Yagi, Masaomi Iyo, Nori Takei, Norio Mori

  Biological psychiatry. 12/2007; 62(9):1056-8.

  BACKGROUND: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation.BACKGROUND: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls. METHODS: Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured. RESULTS: Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-1 showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects. CONCLUSIONS: These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.

• Decreased serum levels of epidermal growth factor in adult subjects with high-functioning autism.

  Authors: Katsuaki Suzuki, Kenji Hashimoto, Yasuhide Iwata, Kazuhiko Nakamura, Masatsugu Tsujii, Kenji J Tsuchiya, Yoshimoto Sekine, Shiro Suda, Genichi Sugihara, Hideo Matsuzaki, Toshiro Sugiyama, Masayoshi Kawai, Yoshio Minabe, Nori Takei, Norio Mori

  Biological psychiatry. 08/2007; 62(3):267-9.

  BACKGROUND: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a roleBACKGROUND: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism. METHODS: We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects. RESULTS: The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p < .001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism. CONCLUSIONS: This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.

• Disruption of reelin signaling attenuates methamphetamine-induced hyperlocomotion.

  Authors: Hideo Matsuzaki, Yoshio Minabe, Kazuhiko Nakamura, Katsuaki Suzuki, Yasuhide Iwata, Yoshimoto Sekine, Kenji J Tsuchiya, Genichi Sugihara, Shiro Suda, Nori Takei, Daiichiro Nakahara, Kenji Hashimoto, Angus C Nairn, Norio Mori, Kohji Sato

  The European journal of neuroscience. 07/2007; 25(11):3376-84.

  To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found thatTo clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

• Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder.

  Authors: Chihiro Kakiuchi, Mizuho Ishiwata, Shinichiro Nanko, Hiroshi Kunugi, Yoshio Minabe, Kazuhiko Nakamura, Norio Mori, Kumiko Fujii, Kazuo Yamada, Takeo Yoshikawa, Tadafumi Kato

  Neuroscience letters. 06/2007; 417(3):316-21.

  Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5,Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.

• Decreased serum levels of hepatocyte growth factor in male adults with high-functioning autism.

  Authors: Genichi Sugihara, Kenji Hashimoto, Yasuhide Iwata, Kazuhiko Nakamura, Masatsugu Tsujii, Kenji J Tsuchiya, Yoshimoto Sekine, Katsuaki Suzuki, Shiro Suda, Hideo Matsuzaki, Masayoshi Kawai, Yoshio Minabe, Atsuko Yagi, Nori Takei, Toshiro Sugiyama, Norio Mori

  Progress in neuro-psychopharmacology & biological psychiatry. 03/2007; 31(2):412-5.

  BACKGROUND: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a roleBACKGROUND: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. RESULTS: The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. CONCLUSIONS: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.