Aberrant Monoaminergic System in Thyroid Hormone Receptor-ß Deficient Mice as a Model of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Thyroid hormone receptors are divided into 2 functional types: TRα and TRß. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans. METHODS: Here we examined behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupted (TRα (0/0) ) and TRß-deficient (TRß (-/-) ) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured. RESULTS: TRß (-/-) mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TRα (0/0) mice showed normal exploratory activity. The biochemical profiles of dopamine and 5-hydroxytryptamine showed significantly low dopamine metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-hydroxytryptamine metabolic rates in TRß (-/-) mice, but not in TRα (0/0) mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TRß (-/-) mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system. CONCLUSIONS: These findings suggest that TRß deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.

Comparison of pervasive developmental disorder and schizophrenia by the Japanese version of the National Adult Reading Test.

OBJECTIVE: In adults, it is sometimes difficult to discriminate between pervasive developmental disorder (PDD) and schizophrenia (SCH) when positive symptoms are not outstanding. We examined whether the Japanese version of the National Adult Reading Test (JART), is a valid scale for evaluating pre-morbid intelligence quotient (IQ) in patients with SCH, and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) are useful for helping to discriminate between PDD and SCH. METHODS: Sixteen patients with adult PDD and 16 age-, education- and sex-matched patients with SCH participated in the present study. In addition, two groups were matched for JART and GAF scores. All subjects were scored on the JART and WAIS-R after informed consent on the aim of this study. Examiners who were blind to the diagnoses measured JART and WAIS-R. RESULTS: Significant diagnosis-by-IQ examination interactions were found (F[1,30] = 10.049, P = 0.003). Furthermore, WAIS-R scores of the PDD group were higher than those of the SCH group (P = 0.002) considering two groups were matched for JART. CONCLUSIONS: The comparison of IQ in the PDD group and in the SCH group by JART and WAIS-R might be an easy and useful method for helping to discriminate between PDD and SCH.

Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions.

Paroxysmal kinesigenic dyskinesia (PKD (MIM128000)) is a neurological disorder characterized by recurrent attacks of involuntary movements. Benign familial infantile convulsion (BFIC) is also one of a neurological disorder characterized by clusters of epileptic seizures. The BFIC1 (MIM601764), BFIC2 (MIM605751) and BFIC4 (MIM612627) loci have been mapped to chromosome 19q, 16p and 1p, respectively, while BFIC3 (MIM607745) is caused by mutations in SCN2A on chromosome 2q24. Furthermore, patients with BFIC have been observed in a family concurrently with PKD. Both PKD and BFIC2 are heritable paroxysmal disorders and map to the same region on chromosome 16. Recently, the causative gene of PKD, the protein-rich transmembrane protein 2 (PRRT2), has been detected using whole-exome sequencing. We performed mutation analysis of PRRT2 by direct sequencing in 81 members of 17 families containing 15 PKD families and two BFIC families. Direct sequencing revealed that two mutations, c.649dupC and c.748C>T, were detected in all members of the PKD and BFIC families. Our results suggest that BFIC2 is caused by a truncated mutation that also causes PKD. Thus, PKD and BFIC2 are genetically identical and may cause convulsions and involuntary movements via a similar mechanism.

Changed preference for sweet taste in adulthood induced by perinatal exposure to bisphenol A-A probable link to overweight and obesity.

BACKGROUND: The preference of obesity has risen dramatically worldwide over the past decades. Some latest reports showed significant increase of obesity in men compared to women. Implication of environmental endocrine disruptors has been focused more and more. Numerous studies in vitro and vivo implied metabolic actions of bisphenol A (BPA), however much less consideration is given to the possibility of BPA exposure-induced change in gender-specific behaviors which result in obesity and overweight. OBJECTIVES: To examine whether perinatal exposure to BPA at relative dose to environmental levels can influence sweet preference of male and female rats and consequently lead to alteration in bodyweight. METHODS: Rats perinatally exposed to BPA at doses of 0.01, 0.1 and 1.0 mg/L were tested sweet preference for 0.25%, 0.5% saccharin and 15% sucrose by two-bottle choice (water vs. saccharin/sucrose). The food intake, liquid consumption and bodyweight of each rat were monitored daily. At the end of the test, the fat percentage and tail blood pressure were measured. RESULTS: Significant sex difference of preference for 0.25% and 0.5% saccharin was shown in control and all BPA-treated groups (p < 0.001, female vs. male). 0.1 and 1.0 mg/L BPA treatment induced the increase of preference for 0.25% saccharin solution in males, but not in females. 0.1 mg/L BPA treatment increased sucrose preference in males at postnatal day (PND) 70 and 140 (p < 0.05 and p < 0.001, compared to control respectively) but decreased sucrose preference in females at PND 140 (p < 0.05, compared to control). The males treated by BPA showed overweight (p < 0.001), high fat percentage (p < 0.001) and tail blood pressure (p < 0.05) than control at PND 140. CONCLUSION: Perinatal exposure to a low dose of BPA could increase sweet preference of male rats. Calorie intake may be programmed during early life, leading to changes of body weight depending on the gender. Although further researches concerning the mechanism are required, the results of the present study are particularly important with regards to the more significant increasing prevalence of obesity in men and the environmental endocrine disruptors.

Effects of osmotic-release methylphenidate in attention-deficit/hyperactivity disorder as measured by event-related potentials.

AIM: Attention-deficit/hyperactivity disorder (ADHD) is a relatively common central nervous system disorder in school-age children, which may involve a specific disorder in cognition and/or information processing. Event-related potentials (ERP) are commonly used as physiological measures of cognitive function as they are easily measured and non-invasive. Thus, in the present study, we examined the effects of osmotic-release methylphenidate (MPH) (Concerta), a common treatment for childhood attention-deficit/hyperactivity disorder (ADHD), in ADHD children as measured by ERP. METHODS: Ten ADHD children participated after giving consent. Based on the guidelines for evoked potential measurement, mismatch negativity (MMN) and P300 were obtained by auditory odd-ball tasks. We measured both MMN and P300 in the drug-naive condition and after intake of osmotic-release MPH. RESULTS: The MMN amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Pz and C4. The P300 amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Cz and Pz. CONCLUSION: MMN and P300 are sensitive tools for measuring the pharmacological effects of osmotic-release MPH in ADHD children.

[Autism spectrum disorders--recent advances in the research on the impairment in social communication].

Since the discovery of early infantile autism (1943), the etiology of the disease has for long been a matter of dispute-from a form of innate schizophrenia, maltreatment by 'refrigerator mother', to dysfunction of speech development. After the re-discovery of Asperger syndrome by Wing (1981), the concept of this diverse syndrome complex has merged to pervasive developmental disorders (PDD) or autism spectrum disorders (ASD). People suffering from Asperger syndrome do not show impairments in speech development, in fact, they have good linguistic abilities. They can explain their own psychopathology, which helps in the understanding of classical autism with profound mental retardation. Currently, ASD is prevalent in 1 of 150 births with strong genetic inheritance. ASD is therefore thought a psychiatric common disease. Asperger syndrome has frequently been the subject of neuroimaging studies,since social communication is an important characteristic of human behavior. This review encompasses a historical and clinical overview of ASD and puts force the current perspectives on the researches in animal models,genetic studies of animal and human samples,and neuroimaging studies. Our current focus is the possible role of oxytocin,which was recently found to have an effect on empathy,in the etiology of ASD.

Tai Chi exercise versus rehabilitation for the elderly with cerebral vascular disorder: a single-blinded randomized controlled trial.

BACKGROUND: Cerebral vascular disorder (CVD) might result in a quantifiable decrease in quality of life, which is determined not only by the neurological deficits but also by impairment of cognitive functions. There are few studies that report on the cognitive effect of Tai Chi exercise (Tai Chi) on the elderly with CVD. The purpose of the present study was to examine the cognitive effect of Tai Chi on the elderly with CVD using P300 measurement, in addition to the General Health Questionnaire (GHQ) and Pittsburgh Sleep Quality Index (PSQI). METHODS: A total of 34 patients with CVD were recruited from outpatient Akistu-Kounoike Hospital and randomly assigned to receive Tai Chi (n= 17) or rehabilitation (n= 17) in group sessions once a week for 12 weeks. To examine the time courses of each score (P300 amplitude, P300 latency, GHQ score and PSQI score), repeated-measures analysis of variance was carried out with groups and time as factors. RESULTS: For the time courses of P300 amplitudes and latencies, there were no significant effects of interaction between group and time. However, significant time-by-group interactions were found for Sleep Quality (P= 0.006), GHQ total score (P= 0.005), anxiety/insomnia score (P= 0.034), and severe depression score (P= 0.020). CONCLUSIONS: Tai Chi might therefore be considered a useful non-pharmacological approach, along with rehabilitation, for the maintenance of cognitive function in the elderly with CVD and might be a more useful non-pharmacological approach for the improvement of sleep quality and depressive symptoms in the elderly with CVD than rehabilitation.

Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice.

BACKGROUND: Dysmyelination is hypothesized to be one of the causes of schizophrenic symptoms. Supporting this hypothesis, demyelination induced by cuprizone was recently shown to cause schizophrenia-like symptoms in adult rodents [Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, et al. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry 2008;13:697-708]. The present study asked if the timing of demyelination (i.e., juvenile period or adulthood) influenced abnormal behavior. METHODS: B57BL/6 mice were fed with 0.2% cuprizone either from postnatal day 29 (P29) to P56 (early demyelination group) or from P57 to P84 (late demyelination group), and then returned to normal mouse chow until P126, when the behavioral analysis was initiated. RESULTS: In both groups, the intake of cuprizone for 28 days produced massive demyelination in the corpus callosum by the end of the treatment period, and subsequent normal feeding restored myelination by P126. In a Y-maze test, the spatial working memory was impaired in both groups right after the cuprizone feeding ceased, consistent with previous studies, whereas only the early demyelination group exhibited impaired working memory after remyelination took place. In an open field test, social interactions were decreased in the early demyelination group, but not in the late group. Novel cognition and anxiety-related behaviors were comparable between the two groups. CONCLUSIONS: Our findings suggest that the timing of demyelination has substantial impacts on behaviors of adult mice.

Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia.

The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

Paroxysmal kinesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with benign familial infantile convulsions.

Paroxysmal kinesigenic choreoathetosis (PKC) is presently clearly designated as a familial movement disorder with autosomal dominant inheritance. We identified a family of PKC, in which 6 out of 23 members were affected, and 4 of the affected members had a history of infantile convulsions. Thus, this family was also considered as a case of infantile convulsions with paroxysmal choreoathetosis (ICCA). Video-EEG monitoring of two affected members suggested that PKC is less likely to be a form of reflex epilepsy, despite the existence of a history of infantile convulsions. Linkage analysis on eight Japanese families, including this family, defined the locus of PKC within the pericentromeric region of chromosome 16. ICCA and a form of autosomal dominant benign familial infantile convulsions (BFIC) were both mapped to the same or nearby region for PKC on chromosome 16. Additionally and quite unexpectedly, the locus of wet/dry ear wax (cerumen) was found to be located in the same region. Lastly, it was pointed out that the priority of the first discovery of PKC in the world should go to a Japanese psychiatrist, Shuzo Kure (1865-1932), who published the first detailed and almost complete description of a male patient with PKC in a Japanese medical journal in 1892.

Review of animal models for autism: implication of thyroid hormone.

Autism is a behaviorally defined disorder associated with characteristic impairments in social interactions and communication, as well as restricted and repetitive behaviors and interest. Its prevalence was once thought to be 2/10,000, but recently several large autism prevalence reviews revealed that the rate of occurrence was roughly 30/10,000. While it has been considered a developmental disorder, little is certain about its etiology. Neuroanatomical studies at the histological level in the brains of autistic patients provide many arguments in the etiology of autism. Results from postmortem and imaging studies have implicated many major structures of the brain including the limbic system, cerebellum, corpus callosum, basal ganglia and brainstem. There is no single biological or clinical marker for autism. While several promising candidate genes have been presented, the critical loci are yet unknown. Environmental influences such as rubella virus, valproic acid, and thalidomide exposure during pregnancy are also considered important, as concordance in monozygotic twins is less than 100% and the phenotypic expression of the disorder varies widely. It is thus hypothesized that non-genetic mechanisms contribute to the onset of autistic syndrome. In light of these ambiguities, hope is held that an animal model of autism may help elucidate matters. In this article, we overview most of the currently available animal models for autism, and propose the rat with mild and transient neonatal hypothyroidism as a novel model for autism.

Activation of the prefrontal cortex to trauma-related stimuli measured by near-infrared spectroscopy in posttraumatic stress disorder due to terrorism.

To develop a noninvasive method for psychophysiological assessment of posttraumatic stress disorder (PTSD), 34 victims of the Tokyo Subway Sarin Attack in 1995 including 8 diagnosed as PTSD and 12 controls were examined by a multichannel near-infrared spectroscopy (NIRS) system. Hemodynamic response in the prefrontal cortex was monitored during the presentation of trauma-related and control stimuli by video images. Skin conductance response (SCR) was also examined. Oxygenated hemoglobin significantly increased during the trauma-related image in the victims with or without PTSD. Deoxygenated hemoglobin significantly decreased only in victims with PTSD. No significant alteration was found in controls. Significantly enhanced SCR was also observed in the victims with PTSD during trauma-related stimuli. The findings suggest that measurement of cerebral hemodynamic response by NIRS is useful for psychophysiological assessment of PTSD.

Hypoactivation of the prefrontal cortex during verbal fluency test in PTSD: a near-infrared spectroscopy study.

Several studies have suggested that there is frontal dysfunction in subjects with posttraumatic stress disorder (PTSD). We investigated the relationship between alterations of the hemodynamic response of the prefrontal cortex during a cognitive task (verbal fluency task; VFT) and memory function measured using the Wechsler Memory Scale-Revised (WMS-R). The subjects were victims of the Tokyo Subway Sarin attack with (n = 8) or without (n = 26) PTSD. Hemodynamic response in the prefrontal cortex was measured using a 24-channel near-infrared spectroscopy (NIRS) system. Subjects with PTSD had a significantly smaller response of oxygenated hemoglobin and total hemoglobin during the VFT compared with those without PTSD, although there was no significant difference in performance on the VFT. Subjects with PTSD had significantly lower scores on attention and concentration in the WMS-R, which was positively correlated with the increase of total hemoglobin during the VFT. The 'frontal dysfunction' observed in subjects with PTSD may be a secondary phenomenon to reduced attentional capacity.

Mapping of the wet/dry earwax locus to the pericentromeric region of chromosome 16.

Human earwax is a one-gene trait comprising two phenotypically distinct forms--wet and dry. This trait is attributed to secretory products of the ceruminous apocrine glands, and frequencies of phenotypes vary between ethnic groups. We did linkage analysis of eight Japanese families segregating earwax dimorphism. We assigned the earwax locus within a approximately 7.42-cM region between the loci D16S3093 and D16S3080 on chromosome 16p11.2-16q12.1, with a maximum two-point LOD score of 11.15 (theta;=0.00) at the locus D16S3044. Identification of the earwax locus could contribute to further anthropogenetic studies and physiological and pathological understanding of the apocrine-gland development.