Educational challenges for 22q11.2 deletion syndrome in Japan: Findings from a mixed methods survey.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is characterised by a changing pattern of overlapping intellectual, physical, and mental disabilities along the course of one's life. However, the impact of overlapping disorders (multimorbidity) on educational challenges remains unclear. METHOD: A survey was conducted with 88 caregivers of individuals with 22q11DS. A quantitative analysis of educational challenges and support needs divided into age groups (7-12, 13-15, 16-18, and 19 years and over) and a qualitative analysis of the free-text items in the questionnaire was conducted. RESULTS: Caregivers were more interested in comprehensive developmental support when their children were younger, and the emphasis shifted to concerns regarding environments that matched individual characteristics at older ages. Furthermore, when there are multiple disabilities or disorders, support is concentrated on the more obvious disabilities, and the lack of support for the less superficially obvious disabilities associated with multiple difficulties, including mental health problems, can be a challenge for people with 22q11DS and their families. CONCLUSIONS: This study suggests a need for increased focus on multimorbidity and associated disabilities in school education that are difficult to observe because of their mildness or borderline levels if present alone.

Medical, welfare, and educational challenges and psychological distress in parents caring for an individual with 22q11.2 deletion syndrome: A cross-sectional survey in Japan.

Parents of children with 22q11.2 deletion syndrome (22q11DS) experience distress not only due to multimorbidity in the patients, but also due to professionals' lack of understanding about 22q11DS and insufficient support systems. This study investigated relationships between medical, welfare, and educational challenges and parental psychological distress. A cross-sectional survey was conducted on primary caregivers of children with 22q11DS. Participants included 125 parents (114 mothers, 91.2%; average age = 44.3 years) who reported their challenges, psychological distress, and child's comorbidities of 22q11DS. Results showed that the difficulty in going to multiple medical institutions (ß = 0.181, p < 0.05) and lack of understanding by welfare staff and insufficient welfare support systems for 22q11DS (ß = 0.220-0.316, all p < 0.05) were associated with parental psychological distress, even after adjusting for child's comorbidities. In the subsample of parents whose child attended an educational institution, inadequate management in classroom and mismatch between service and users in educational settings were associated with psychological distress (ß = 0.222-0.296, all p < 0.05). This study reveals the importance of assessing not only severity of comorbidities in 22q11DS, but also the medical, welfare, and educational challenges for parental mental health.

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity.

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

Children with special health care needs and mothers' anxiety/depression: Findings from the Tokyo Teen Cohort study.

AIM: Children with special health care needs (CSHCN) are those who require more care for their physical, developmental, or emotional differences than their typically developing peers. Among a wide range of burdens that caregivers of CSHCN experience, the mental burden of caregivers is still not well investigated. This study aimed at examining the relationship between caring for CSHCN and mothers' anxiety/depression. METHODS: This study used data from the Tokyo Early Adolescence Survey, a population-based cross-sectional survey. Using screening questionnaires, we evaluated the prevalence of CSHCN and identified their primary caregivers. Focusing on mothers as caregivers, we analyzed the relationship between having CSHCN and mothers' anxiety/depression, and between the severity of children's condition and mothers' anxiety/depression. We further determined what mediates these relationships using path analyses. RESULTS: Among 4003 participants, we identified 502 CSHCN (12.5%), and 93% of responding caregivers were mothers. We found that mothers with CSHCN were significantly more anxious/depressed than those without CSHCN, which was closely related to the severity of children's condition. The mediation effect of social support on the relation between CSHCN and mothers' anxiety/depression was statistically significant. CONCLUSION: Mothers of CSHCN were more anxious/depressed than other mothers in this study. Social support was indicated to have a significant mediating effect on the relationship between CSHCN and mothers' anxiety/depression. Our results suggest that considering ways to offer social support may effectively relieve the mental stress experienced by mothers of CSHCN.

Social withdrawal and testosterone levels in early adolescent boys.

Social withdrawal may lead to mental health problems and can have a large impact on a life course, particularly among boys. To support adolescents with social withdrawal, an integrative understanding of the biological bases would be helpful. Social dominance, a possible opposite of social withdrawal, is known to have positive associations with testosterone levels. A previous study suggested that social withdrawal has a negative relationship with sexual maturity among adolescent boys. However, the relationship between social withdrawal and testosterone in adolescence is unknown. This study aimed to examine whether social withdrawal was negatively associated with testosterone levels in early adolescent boys. Salivary samples were collected from 159 healthy early adolescent boys (mean age [standard deviation]: 11.5 [0.73]) selected from participants of the "population-neuroscience study of the Tokyo Teen Cohort" (pn-TTC). Social withdrawal and confounding factors, such as the secondary sexual characteristics and their age in months, were evaluated by self-administered questionnaires completed by the primary parents. The degree of social withdrawal was assessed with the Child Behaviour Checklist (CBCL). Levels of salivary testosterone, and cortisol as a control, were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Logistic regression was conducted to examine the association between social withdrawal and testosterone levels. A higher risk of social withdrawal was associated with a lower salivary testosterone level after adjustment for age in months (odds ratio 0.55, 95 % confidence interval 0.33-0.94), and the association remained significant after adjusting for body mass index, the degree of anxiety/depression and pubertal stage. Thus, we found a negative relationship between social withdrawal and testosterone levels in early adolescent boys. These findings may help to clarify the biological foundations of and to develop support for social withdrawal.

Altered expression of microRNA-223 in the plasma of patients with first-episode schizophrenia and its possible relation to neuronal migration-related genes.

Recent studies have shown that microRNAs (miRNAs) play a role as regulators of neurodevelopment by modulating gene expression. Altered miRNA expression has been reported in various psychiatric disorders, including schizophrenia. However, the changes in the miRNA expression profile that occur during the initial stage of schizophrenia have not been fully investigated. To explore the global alterations in miRNA expression profiles that may be associated with the onset of schizophrenia, we first profiled miRNA expression in plasma from 17 patients with first-episode schizophrenia and 17 healthy controls using microarray analysis. Among the miRNAs that showed robust changes, the elevated expression of has-miR-223-3p (miR-223) was validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using another independent sample set of 21 schizophrenia patients and 21 controls. To identify the putative targets of miR-223, we conducted a genome-wide gene expression analysis in neuronally differentiated SK-N-SH cells with stable miR-223 overexpression and an in silico analysis. We found that the mRNA expression levels of four genes related to the cytoskeleton or cell migration were significantly downregulated in miR-223-overexpressing cells, possibly due to interactions with miR-223. The in silico analysis suggested the presence of miR-223 target sites in these four genes. Lastly, a luciferase assay confirmed that miR-223 directly interacted with the 3' untranslated regions (UTRs) of all four genes. Our results reveal an increase in miR-223 in plasma during both the first episode and the later stage of schizophrenia, which may affect the expression of cell migration-related genes targeted by miR-223.

Evaluation of the usefulness of saliva for DNA methylation analysis in cohort studies.

INTRODUCTION: Epigenetic information such as DNA methylation is a useful biomarker that reflects complex gene-environmental interaction. Peripheral tissues such as blood and saliva are commonly collected as the source of genomic DNA in cohort studies. Epigenetic studies mainly use blood, while a few studies have addressed the epigenetic characteristics of saliva. METHODS: The effects of methods for DNA extraction and purification from saliva on DNA methylation were surveyed using Illumina Infinium HumanMethylation450 BeadChip. Using 386 661 probes, DNA methylation differences between blood and saliva from 22 healthy volunteers, and their functional and structural characteristics were examined. CpG sites with DNA methylation levels showing large interindividual variations in blood were evaluated using saliva DNA methylation profiles. RESULTS: Genomic DNA prepared by simplified protocol from saliva showed a similar quality DNA methylation profile to that derived from the manufacturer provided protocol. Consistent with previous studies, the DNA methylation profiles of blood and saliva showed high correlations. Blood showed 1,514 hypomethylated and 2099 hypermethylated probes, suggesting source-dependent DNA methylation patterns. CpG sites with large methylation difference between the two sources were underrepresented in the promoter regions and enriched within gene bodies. CpG sites with large interindividual methylation variations in blood also showed considerable variations in saliva. CONCLUSION: In addition to high correlation in DNA methylation profiles, CpG sites showing large interindividual DNA methylation differences were similar between blood and saliva, ensuring saliva could be a suitable alternative source for genomic DNA in cohort studies. Consideration of source-dependent DNA methylation differences will, however, be necessary.

Auditory Steady State Response; nature and utility as a translational science tool.

The auditory steady-state response (ASSR) has been used to detect auditory processing deficits in patients with psychiatric disorders. However, the methodology of ASSR recording from the brain surface has not been standardized in preclinical studies, limiting its use as a translational biomarker. The sites of maximal ASSR in humans are the vertex and/or middle frontal area, although it has been suggested that the auditory cortex is the source of the ASSR. We constructed and validated novel methods for ASSR recording using a switchable pedestal which allows ASSR recording alternatively from temporal or parietal cortex with a wide range of frequencies in freely moving rats. We further evaluated ASSR as a translational tool by assessing the effect of ketamine. The ASSR measured at parietal cortex did not show clear event-related spectral perturbation (ERSP) or inter-trial coherence (ITC) in any frequency bands or a change with ketamine. In contrast, the ASSR at temporal cortex showed clear ERSP and ITC where 40 Hz was maximal in both gamma-band frequencies. Ketamine exerted a biphasic effect in ERSP at gamma bands. These findings suggest that temporal cortex recording with a wide frequency range is a robust methodology to detect ASSR, potentially enabling application as a translational biomarker in psychiatric and developmental disorders.

Severity-dependent and -independent brain regions of major depressive disorder: A long-term longitudinal near-infrared spectroscopy study.

BACKGROUND: Long-term longitudinal studies are necessary to establish neuroimaging indicators which contribute to the detection of severity changes over time in patients with major depressive disorder (MDD). METHODS: One hundred sixty-five patients with MDD underwent clinical assessments and near-infrared spectroscopy (NIRS) examination at the initial evaluation (T0). After 1.5 years, 45 patients who visited for the follow-up evaluation (T1.5) were included in the analysis. The authors conducted analyses using the 17-item Hamilton Rating Scale for Depression (HAMD) scores and mean oxy-hemoglobin concentration ([oxy-Hb]) changes during a cognitive task in NIRS at T0 (T0_HAMD, T0_[oxy-Hb]) and at T1.5 (T1.5_HAMD, T1.5_[oxy-Hb]), and their intra-individual longitudinal changes (ΔHAMD = T1.5_HAMD - T0_HAMD, Δ[oxy-Hb] = T1.5_[oxy-Hb] - T0_[oxy-Hb]). RESULTS: For severity-dependent regions, the Δ[oxy-Hb] in the right inferior frontal gyrus (IFG) was negatively correlated with the ΔHAMD. For severity-independent regions, the intra-class correlation coefficients between T0_ and T1.5_[oxy-Hb] were moderate in the bilateral middle frontal gyri (MFG). LIMITATIONS: The percentage of patients included in the follow-up examination was relatively small. CONCLUSIONS: Brain activation in the right IFG and the bilateral MFG as measured by NIRS may differentially indicate clinical severity and trait-related abnormalities in MDD.

Population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC): Cohort longitudinal study to explore the neurobiological substrates of adolescent psychological and behavioral development.

AIM: Adolescence is a crucial stage of psychological development and is critically vulnerable to the onset of psychopathology. Our understanding of how the maturation of endocrine, epigenetics, and brain circuit may underlie psychological development in adolescence, however, has not been integrated. Here, we introduce our research project, the population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC), a longitudinal study to explore the neurobiological substrates of development during adolescence. METHODS: Participants in the first wave of the pn-TTC (pn-TTC-1) study were recruited from those of the TTC study, a large-scale epidemiological survey in which 3171 parent-adolescent pairs were recruited from the general population. Participants underwent psychological, cognitive, sociological, and physical assessment. Moreover, adolescents and their parents underwent magnetic resonance imaging (MRI; structural MRI, resting-state functional MRI, and magnetic resonance spectroscopy), and adolescents provided saliva samples for hormone analysis and for DNA analysis including epigenetics. Furthermore, the second wave (pn-TTC-2) followed similar methods as in the first wave. RESULTS: A total of 301 parent-adolescent pairs participated in the pn-TTC-1 study. Moreover, 281 adolescents participated in the pn-TTC-2 study, 238 of whom were recruited from the pn-TTC-1 sample. The instruction for data request is available at: http://value.umin.jp/data-resource.html. CONCLUSION: The pn-TTC project is a large-scale and population-neuroscience-based survey with a plan of longitudinal biennial follow up. Through this approach we seek to elucidate adolescent developmental mechanisms according to biopsychosocial models. This current biomarker research project, using minimally biased samples recruited from the general population, has the potential to expand the new research field of population neuroscience.

Use of human methylation arrays for epigenome research in the common marmoset (Callithrix jacchus).

We examined the usefulness of commercially available DNA methylation arrays designed for the human genome (Illumina HumanMethylation450 and MethylationEPIC) for high-throughput epigenome analysis of the common marmoset, a nonhuman primate suitable for research on neuropsychiatric disorders. From among the probes on the methylation arrays, we selected those available for the common marmoset. DNA methylation data were obtained from genomic DNA extracted from the frontal cortex and blood samples of adult common marmosets as well as the frontal cortex of neonatal marmosets. About 10% of the probes on the arrays were estimated to be useful for DNA methylation assay in the common marmoset. Strong correlations existed between human and marmoset DNA methylation data. Illumina methylation arrays are useful for epigenome research using the common marmoset.

Extracellular elevation of adrenomedullin, a gene associated with schizophrenia, suppresses heat shock protein 1A/1B mRNA.

Several recent gene expression studies on schizophrenia, including one using monozygotic twins discordant for the disease, have reported the upregulation of adrenomedullin (ADM), which was initially identified as a vasodilator hormone. It has been hypothesized that upregulation of ADM may be a susceptibility factor for schizophrenia, although the exact role of ADM in the central nervous system remains unclear. In this study, we used a microarray analysis to investigate the changes in global gene expression induced by the administration of exogenous ADM in SK-N-SH cells, which allowed us to evaluate the effects of elevated ADM on the central nervous system. A quantitative reverse-transcription PCR study showed that the levels of HSPA1A/1B mRNA, another gene that has been associated with schizophrenia, were significantly suppressed after exogenous ADM treatment. These results indicate that elevated ADM may be involved in the etiology of schizophrenia through the regulation of heat shock protein signaling.

Mismatch negativity as a "translatable" brain marker toward early intervention for psychosis: a review.

Recent reviews and meta-analyses suggest that reducing the duration of untreated psychosis leads to better symptomatic and functional outcome in patients with psychotic disorder. Early intervention attenuates the symptoms of individuals at clinical high-risk (HR) for psychosis and may delay or prevent their transition to psychosis. Identifying biological markers in the early stages of psychotic disorder is an important step toward elucidating the pathophysiology, improving prediction of the transition to psychosis, and introducing targeted early intervention for help-seeking individuals aiming for better outcome. Mismatch negativity (MMN) is a component of event-related potentials that reflects preattentive auditory sensory memory and is a promising biomarker candidate for schizophrenia. Reduced MMN amplitude is a robust finding in patients with chronic schizophrenia. Recent reports have shown that people in the early stages of psychotic disorder exhibit attenuation of MMN amplitude. MMN in response to duration deviants and in response to frequency deviants reveals different patterns of deficits. These findings suggest that MMN may be useful for identifying clinical stages of psychosis and for predicting the risk of development. MMN may also be a "translatable" biomarker since it reflects N-methyl-d-aspartte receptor function, which plays a fundamental role in schizophrenia pathophysiology. Furthermore, MMN-like responses can be recorded in animals such as mice and rats. This article reviews MMN studies conducted on individuals with HR for psychosis, first-episode psychosis, recent-onset psychosis, and on animals. Based on the findings, the authors discuss the potential of MMN as a clinical biomarker for early intervention for help-seeking individuals in the early stages of psychotic disorder, and as a translatable neurophysiological marker for the preclinical assessment of pharmacological agents used in animal models that mimic early stages of the disorder.

GluN2B in corticostriatal circuits governs choice learning and choice shifting.

A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2B antagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior.

Hilar mossy cell circuitry controlling dentate granule cell excitability.

Glutamatergic hilar mossy cells of the dentate gyrus can either excite or inhibit distant granule cells, depending on whether their direct excitatory projections to granule cells or their projections to local inhibitory interneurons dominate. However, it remains controversial whether the net effect of mossy cell loss is granule cell excitation or inhibition. Clarifying this controversy has particular relevance to temporal lobe epilepsy, which is marked by dentate granule cell hyperexcitability and extensive loss of dentate hilar mossy cells. Two diametrically opposed hypotheses have been advanced to explain this granule cell hyperexcitability-the "dormant basket cell" and the "irritable mossy cell" hypotheses. The "dormant basket cell" hypothesis proposes that mossy cells normally exert a net inhibitory effect on granule cells and therefore their loss causes dentate granule cell hyperexcitability. The "irritable mossy cell" hypothesis takes the opposite view that mossy cells normally excite granule cells and that the surviving mossy cells in epilepsy increase their activity, causing granule cell excitation. The inability to eliminate mossy cells selectively has made it difficult to test these two opposing hypotheses. To this end, we developed a transgenic toxin-mediated, mossy cell-ablation mouse line. Using these mutants, we demonstrated that the extensive elimination of hilar mossy cells causes granule cell hyperexcitability, although the mossy cell loss observed appeared insufficient to cause clinical epilepsy. In this review, we focus on this topic and also suggest that different interneuron populations may mediate mossy cell-induced translamellar lateral inhibition and intralamellar recurrent inhibition. These unique local circuits in the dentate hilar region may be centrally involved in the functional organization of the dentate gyrus.

Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation.

Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity's net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5-6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation.

Acute psychosis during the postictal period in a patient with idiopathic generalized epilepsy: postictal psychosis or aggravation of schizophrenia? A case report and review of the literature.

Postictal psychoses are common comorbid conditions of temporal lobe epilepsy and are reported to be characterized by affective changes. However, postictal psychoses are rare among patients with idiopathic generalized epilepsy, and the causal relationship between postictal psychoses and idiopathic generalized epilepsy is unknown. Here, we report the case of a man who had idiopathic generalized epilepsy and experienced 4 episodes of schizophrenia-like interictal psychosis before the age of 41 years. At the age of 56 years, he experienced a generalized tonic-clonic seizure for the first time in 15 years and developed psychotic symptoms on the next day. Notably, in addition to the schizophrenia-like symptoms, the patient experienced mania-like symptoms such as elated mood, grandiose delusions, agitation, and pressured speech during the last psychotic episode in the postictal period. It was suspected that postictal neuronal processes and a predisposition to endogenous psychosis both contributed to the psychopathology of this episode.

[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.