Abnormal asymmetries in subcortical brain volume in schizophrenia.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Comparison of the symptoms of menopause and symptoms of thyroid disease in Japanese women aged 35-59 years.

OBJECTIVE: In this study, we surveyed thyroid function abnormalities and menopausal symptoms in young as well as in menopausal women. METHODS: We conducted a random survey among outpatients at our facility from September 2008 to June 2011. The study included 853 women aged 35-59 years. We assessed the subjects according to the Simplified Menopause Index, menstrual status, thyroid hormone measurements (thyroid stimulating hormone, free thyroxine, free triiodothyronine), the presence of Hashimoto's disease antibodies (anti-thyroid peroxidase antibody or anti-thyroglobulin antibody), the presence of Grave's disease (anti-TSH receptor antibody), markers of thyroid tumor (high thyroglobulin), and thyroid ultrasonography studies. The data were analyzed by means of the statistical program JMP version 8.0. RESULTS: 'Facial flushing', 'sweating', and 'thyroid tumor' were all positively related with age and menstrual status. 'Breathlessness and palpitations' were positively related to Grave's disease. Moreover, 'sweating', 'irritability', and 'stiff shoulders, low back pain, and joint pain' were related to thyroid tumors. 'Insomnia' decreased with age. Patients with Hashimoto's disease were very rare because they were usually treated at other hospitals that specialize in thyroid disease. CONCLUSION: The symptoms of thyroid function abnormalities were shown to be very similar to menopausal symptoms and were found to occur in younger women before the onset of menopause. This study shows the need to differentiate menopausal symptoms from those of thyroid diseases.

The relationship between psychosocial problems including depression and behavioural trends among middle-aged menopausal women in a cohort study.

OBJECTIVE: We investigated the association of psychosocial problems, menopausal symptoms such as hot flushes, and trends of smoking and use of cosmetics in our previous study. In this follow-up study, we researched psychiatric disorders and psychosocial problems in menopausal women. METHODS: We designed a cohort study with 577 Japanese women aged 30-64 years. Subjects were selected randomly from among women who visited the department of gender-specific medicine at Tokyo Women's Medical University East Medical Center between June 2010 and September 2011. We analysed trends such as smoking, using cosmetics, and menopausal symptoms and their association with the first lifetime episode of severe depression and anxiety using structured clinical interviews for the DSM-IV (structured clinical interview for DSM-IV, outpatient version [SCID]), the Center for Epidemiological Studies Depression Scale (CES-D) and the State-Trait Anxiety Inventory (STAI). RESULTS: Significant associations were observed between hot flushes, smoking and the frequency of using cosmetics. Furthermore, the trends in cosmetic use and smoking affected not only psychosocial problems, but also physical problems. Younger women suffered from psychosocial problems more than twice the rate of post-menopausal women. Those who reported their first severe depression episode were also affected by severe anxiety disorders and physical problems. CONCLUSION: By self-checking the frequency of using cosmetics is up to date knowledge of psychosocial mood problems and improving women's quality of life.

The psychosocial influence to habit using make-up of women aged 40 to 59 years menopausal Japanese women.

We conducted a survey to elucidate the psychosocial influence of menopausal symptoms on the habit of using make-up. This study included 420 Japanese women (age, 40-59 years) who were examined for the first time in a specialized women's outpatient clinic of our institution from June 2010 to September 2011. Using the Menopause-Specific Quality of Life questionnaire (MENQOL), we analysed the scores in relation to menopausal symptoms and whether and how frequently the subject used make-up (including foundation, lip rouge and eyebrow brushing). JMP version 9.0 software was used to statistically analyse the data. Significant results were observed for psychosocial symptoms (P = 0.0002) but not for vasomotor symptoms. Psychosocial symptoms tended to be more severe in women with climacteric <5 years previously. Furthermore, the frequency of make-up use was positively correlated with menopausal symptoms (P = 0.0251). There were strong relationships between psychological symptoms and make-up use in menopausal women. Psychological condition and the frequency of make-up use were inversely correlated, especially in women with climacteric <5 years previously.

A study of menopausal symptoms in relation to habits of smoking and make-up using in Japanese women aged 35-59.

We conducted a survey to elucidate the influence with menopause symptoms and the impact of not only smoking but also using make-up among for Japanese women, included ages above and below the menopausal generation. The subjects of this study were 335 Japanese women from 35 to 59 years of age who were examined for the first time in the specialized women's outpatient clinic of our institution from July 2010 to June 2011 for 1 year period. We used the items of the Menopause-Specific Quality of Life Questionnaire. Similarly, we analysed the scores in relation to menopausal symptoms and whether the subject smoked, whether the subject used make-up depend on women (including foundation, lip rouge, brush one's eyebrows), how frequently she used make-up. The JMP version 9.0 software program was used to statistically analyse the score data. Significant associations were observed in psychosocial (P = 0.0196), tended to be more severe in women before menopause and after climacteric. Furthermore, the frequency of using make-up were negative relations with menopause symptoms (P = 0.0251) after climacteric. Smoking had made worse for physical symptoms (P < 0.001). Menopause symptoms are already experienced by younger women, especially, psychological symptoms. Also, physical conditions were influenced by smoking. Using make-up frequently was often seen after climacteric because of appearance changes by oestrogen dynamic decline.

Differences in the pharmacokinetics of Cyp3a substrates in TSOD and streptozotocin-induced diabetic mice.

The pharmacokinetics of drugs can change in diabetes mellitus and even among diabetics. They may differ between type I diabetes (T1DM) and type 2 diabetes (T2DM). As triazolam was administered orally to Tsumura, Suzuki, obese, diabetes (TSOD) mice and streptozotocin (STZ) mice, clearance per body (CL/F) in TSOD mice did not differ compared with Tsumura, Suzuki, non-obesity (TSNO) mice. In STZ mice, CL/F was greater than in control mice. Small intestinal cytochrome P450 (Cyp) 3a expression in TSOD mice was significantly lower than in TSNO mice. No significant difference existed in small intestinal Cyp3a expression between STZ mice and control mice. In insulin-treated mice, small intestinal Cyp3a expression was significantly lower than in control mice. These results suggested that the differences in changes in small intestinal Cyp3a expression between T1DM and T2DM may be due to differences in plasma insulin concentrations. This may be a factor in the difference in the drug pharmacokinetics between T2DM and T1DM patients.

Variability of 128 schizophrenia-associated gene variants across distinct ethnic populations.

Schizophrenia is a common polygenetic disease affecting 0.5-1% of individuals across distinct ethnic populations. PGC-II, the largest genome-wide association study investigating genetic risk factors for schizophrenia, previously identified 128 independent schizophrenia-associated genetic variants (GVs). The current study examined the genetic variability of GVs across ethnic populations. To assess the genetic variability across populations, the 'variability indices' (VIs) of the 128 schizophrenia-associated GVs were calculated. We used 2504 genomes from the 1000 Genomes Project taken from 26 worldwide healthy samples comprising five major ethnicities: East Asian (EAS: n=504), European (EUR: n=503), African (AFR: n=661), American (AMR: n=347) and South Asian (SAS: n=489). The GV with the lowest variability was rs36068923 (VI=1.07). The minor allele frequencies (MAFs) were 0.189, 0.192, 0.256, 0.183 and 0.194 for EAS, EUR, AFR, AMR and SAS, respectively. The GV with the highest variability was rs7432375 (VI=9.46). The MAFs were 0.791, 0.435, 0.041, 0.594 and 0.508 for EAS, EUR, AFR, AMR and SAS, respectively. When we focused on the EAS and EUR population, the allele frequencies of 86 GVs significantly differed between the EAS and EUR (P<3.91 × 10-4). The GV with the highest variability was rs4330281 (P=1.55 × 10-138). The MAFs were 0.023 and 0.519 for the EAS and EUR, respectively. The GV with the lowest variability was rs2332700 (P=9.80 × 10-1). The MAFs were similar between these populations (that is, 0.246 and 0.247 for the EAS and EUR, respectively). Interestingly, the mean allele frequencies of the GVs did not significantly differ between these populations (P>0.05). Although genetic heterogeneities were observed in the schizophrenia-associated GVs across ethnic groups, the combination of these GVs might increase the risk of schizophrenia.

Structural alterations of the superior temporal gyrus in schizophrenia: Detailed subregional differences.

BACKGROUND: Reduced gray matter volumes in the superior temporal gyrus (STG) have been reported in patients with schizophrenia. Such volumetric abnormalities might denote alterations in cortical thickness, surface area, local gyrification or all of these factors. The STG can be anatomically divided into five subregions using automatic parcellation in FreeSurfer: lateral aspect of the STG, anterior transverse temporal gyrus of Heschl gyrus (HG), planum polare (PP) of the STG, planum temporale (PT) of the STG and transverse temporal sulcus. METHODS: We acquired magnetic resonance imaging (MRI) 3T scans from 40 age- and sex-matched patients with schizophrenia and 40 healthy subjects, and the scans were automatically processed using FreeSurfer. General linear models were used to assess group differences in regional volumes and detailed thickness, surface area and local gyrification. RESULTS: As expected, patients with schizophrenia had significantly smaller bilateral STG volumes than healthy subjects. Of the five subregions in the STG, patients with schizophrenia showed significantly and marginally reduced volumes in the lateral aspect of the STG and PT of the STG bilaterally compared with healthy subjects. The volumetric alteration in bilateral lateral STG was derived from both the cortical thickness and surface area but not local gyrification. There was no significant laterality of the alteration in the lateral STG between patients and controls and no correlation among the structures and clinical characteristics. CONCLUSIONS: These findings suggest that of five anatomical subregions in the STG, the lateral STG is one of the most meaningful regions for brain pathophysiology in schizophrenia.

DEGS2 polymorphism associated with cognition in schizophrenia is associated with gene expression in brain.

A genome-wide association study of cognitive deficits in patients with schizophrenia in Japan found association with a missense genetic variant (rs7157599, Asn8Ser) in the delta(4)-desaturase, sphingolipid 2 (DEGS2) gene. A replication analysis using Caucasian samples showed a directionally consistent trend for cognitive association of a proxy single-nucleotide polymorphism (SNP), rs3783332. Although the DEGS2 gene is expressed in human brain, it is unknown how DEGS2 expression varies during human life and whether it is affected by psychiatric disorders and genetic variants. To address these questions, we examined DEGS2 messenger RNA using next-generation sequencing in postmortem dorsolateral prefrontal cortical tissue from a total of 418 Caucasian samples including patients with schizophrenia, bipolar disorder and major depressive disorder. DEGS2 is expressed at very low levels prenatally and increases gradually from birth to adolescence and consistently expressed across adulthood. Rs3783332 genotype was significantly associated with the expression across all subjects (F3,348=10.79, P=1.12 × 10(-)(3)), particularly in control subjects (F1,87=13.14, P=4.86 × 10(-4)). Similar results were found with rs715799 genotype. The carriers of the risk-associated minor allele at both loci showed significantly lower expression compared with subjects homozygous for the non-risk major allele and this was a consistent finding across all diagnostic groups. DEGS2 expression showed no association with diagnostic status after correcting for multiple testing (P>0.05). Our findings demonstrate that a SNP showing genome-wide association study significant association with cognition in schizophrenia is also associated with regulation of DEGS2 expression, implicating a molecular mechanism for the clinical association.

Imaging genetics and psychiatric disorders.

Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol-Omethyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of largescale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders.

The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study.

Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.

Chronic administration of tricyclic antidepressants suppresses hypothalamo-pituitary-adrenocortical activity in male rats.

The effect of chronic administration of the clinically effective antidepressants, imipramine, clomipramine and desipramine, on corticosterone (CS) release in male rats was investigated. Chronic administration of imipramine, clomipramine and desipramine at a dose of 20 mg/kg b.w./day, but not at a dose of 2 mg/kg b.w./day, suppressed blood CS concentration at 2000h and abolished its circadian rhythm. The normal circadian rhythm of CS release resumed seven days after the termination of imipramine injection. The acute administration of imipramine (20 mg/kg b.w./day) at 0800h but not at 2000h elevated CS concentrations. Chronic administration of imipramine (20 mg/kg b.w./day) tended to increase the inhibitory effect of dexamethasone on CS release. Adrenocortical sensitivity to exogenous adrenocorticotropic hormone tended to be decreased by chronic administration of imipramine (20 mg/kg b.w./day). These results indicate that antidepressants have effects on the hypothalamo-pituitary-adrenocortical axis which may confound psychoneuroendocrinological tests, such as the dexamethasone suppression test, for the diagnosis of affective disorders.

Facilitation of agonist motoneurons upon initiation of rapid and slow voluntary movements in man.

The time course of facilitation of the agonist motoneurons upon initiation of voluntary ankle dorsiflexion was investigated in eight healthy subjects. The H-reflex and visually guided tracking methods were used for testing the excitability of the motoneuron pool and for controlling the initiation of movement as well as speed and force. Since the onset of voluntary EMG activity (EMG reaction time: EMGvRT) was delayed and/or obscured by test H-reflexes which were evoked very close to the behavioral responses, the subject was instructed to make response movements bilaterally, and EMGvRT was measured on the side without stimulation. In every subject, the EMGvRT was invariably longer in the ramp movement than in the step movement. The onset of H-reflex facilitation prior to EMG onset, which was regarded as indicating the arrival time of the descending motor command to the motoneuron pool, always started earlier in the ramp movement than in the step movement. The difference in facilitation onset between the two tasks was smaller than that in EMGvRT. Since the amplitude of the H-reflex at the onset of the voluntary EMG was equivalent in both movements, the development of H-reflex towards the behavioral EMG onset was more gradual in the ramp movement than in the step movement. The present results demonstrate that the longer reaction time in the slow ramp task depends on 2 factors: delay in the arrival of descending facilitatory impulses to the agonist motoneuron pool, and its slow recruitment thereafter.

Effects of test H-reflex size on reciprocal inhibition in forearm muscles.

We studied effects of test H-reflex size on reciprocal Ia inhibition in forearm muscles. In both healthy control subjects and hemiplegic patients, the amount of Ia inhibition decreased as the test H-reflex size increased. It is possible that forearm reciprocal Ia inhibition in hemiplegics reported previously might be underestimated due to larger test H-reflexes used in the hemiplegics than in the controls.

Development of circadian rhythms in rats with lesions of serotonergic system.

In order to assess the role of the serotonergic system in the development of overt circadian rhythms in the rat, serotonin neurons in the brain were destroyed either by thermocoagulation of the median raphe (MRL) or by an intracerebroventricular injection of the neurotoxin, 5,7-dihydroxytryptamine (DHT). The reductions in serotonin content induced by two manipulations with MRL and DHT were 41% and 100% in the striatum, 40% and 66% in the hypothalamus, and 62% and 88% in the hippocampus, respectively. Neither manipulation eliminated the expression of circadian rhythms in corticosterone (CS) secretion, locomotor activity and drinking behavior, and changed the phase relationship in the overt CS rhythm. Also, 5,7-DHT treatments did not significantly affect the free-running period in locomotor activity. However, the emergence of CS circadian rhythm was delayed for one week in both MRL and DHT groups compared to the intact control ones. These results suggested that a serotonergic system would not be essential for the generation of the endogenous rhythm and the photoentrainment of overt circadian rhythms, but seems to participate in the only development of CS rhythms during the early stage of life.

Free-access to a running wheel shortens the period of free-running rhythm in blinded rats.

The period of free-running rhythm was measured with two different devices, Automex and running wheel, in blinded female rats. The period was significantly shorter when measured with a running wheel than with an Automex. After transfer between the two devices, all 13 rats examined showed the same direction of change in the free-running period and that transfer from the Automex to running wheel shortened the period, while transfer from the running wheel to Automex elongated it, with the exception of two rats who did not show any significant change in the period even when they were transferred twice. These results indicate that free access to a running wheel shortens the free-running period in female blinded rats.

Stress adaptation and hypersensitivity in 5-HT neuronal systems after repeated foot shock.

The relationship between adaptation to stress and change in sensitivity of the 5-hydroxytryptamine (5-HT) neuronal system was studied in rats exposed to repeated foot shock stress for up to 10 days. Although hypolocomotion, freezing behavior and loss of weight were observed after in the initial stress, relief from these behavioral changes developed by the 3rd and persisted for another 7 days, indicating the development of stress adaptation. Following an IP injection of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), rats exposed to the stress for 10 days, but not for 5 days, displayed enhanced forepaw treading, tremor and Straub tail compared to control rats. These results suggest that the hypersensitivity of the 5-HT system after repeated stress may be in part related to the neuronal mechanism of stress adaptation. However, since hypersensitivity was not observed after exposure for 5 days, when adaptation was maximal, it is proposed that the 5-HT system may participate in the maintenance of adaptation rather than its development. On the other hand, no change in 5-HT1, 5-HT1a and 5-HT2 receptor binding assays was found after chronic stress, suggesting that the hypersensitivity of 5-HT system may not be accompanied with changes in the numbers of 5-HT receptor binding sites. The results of beta-adrenergic receptor binding determined simultaneously were also discussed with reference to previous reports of stress-induced reduction in beta-adrenergic receptor density.

Circadian fluctuations in pain responsiveness and brain Met-enkephalin-like immunoreactivity in the rat.

The 24-hour patterns of pain responsiveness and brain Met-enkephalin-like immunoreactivity (MLI) were determined in male Wistar rats housed under a 12-hour light and dark cycle (lights on from 0700 hr to 1900 hr). A circadian rhythm was observed in latencies to hot plate test (55 degrees C), showing the peak level near the onset of the dark phase (2000 hr). Pretreatment with naloxone (5 mg/kg, subcutaneously) decreased the highest latency (2000 hr), but did not change the lowest latency (1100 hr). In the mesolimbic area and the striatum, MLI had a negative correlation with the circadian fluctuation in pain sensitivity. MLI at 2000 hr was reduced significantly compared to that at 1100 hr in the basal ganglia, the frontal cortex and the substantia nigra. These results suggest that the circadian variation in hot plate latencies follows a circadian change in the activity of the endogenous opioid peptides system, and that Met-enkephalin may participate in the enhancement of the opioid system in the brain.

[A case of chronic, motor, axonal polyneuropathy successfully treated by immunoadsorption].

We reported a 61-year-old male with chronic, motor, axonal polyneuropathy. Neurological examination revealed severe muscle weakness in the proximal parts of the four limbs. Sensory examination was normal. The cerebrospinal fluid protein was elevated to 74 mg/dl, and the cell count was normal. The serum antibodies to GM1, GD1a, GD1b, and GQ1b were all negative. Electrophysiological studies showed reduced compound muscle action potentials (CMAPs) suggesting axonal neuropathy, and the nerve conduction velocity was only mildly reduced. After treatment with plasmapheresis (PP) by the immunoadsorption method, his symptoms significantly improved in three weeks, and the cerebrospinal fluid protein, and CMAPs also improved. Only a few studies have been reported regarding patients with chronic, motor dominant, axonal polyneuropathy that responded to immunosuppressive therapies or PP. It remains to be determined whether chronic, dominantly motor, axonal polyneuropathy as seen in the present case is a subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or a primary axonal immune-mediated neuropathy that is different from CIDP. At present we are not able to answ what kind of clinical or laboratory markers other than an elevated cerebrospinal fluid protein level may help to predict a positive response to immunosuppressive therapy or PP.