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Duplication of chromosome 15q11-13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11-13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.
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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.
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Síndrome de DiGeorge , Discapacidad Intelectual , Niño , Humanos , Síndrome de DiGeorge/epidemiología , Japón , Escolaridad , Encuestas y CuestionariosRESUMEN
Aim: The 22q11.2 deletion syndrome (22q11DS) is associated with a high prevalence of mental health comorbidities. However, not enough attention has been paid to the elevated prevalence of high trait anxiety that begins early in life and may be enduring. We sought to identify specific medical, welfare, or educational difficulties associated with high trait anxiety in 22q11DS. Methods: A questionnaire-based survey was conducted for the parents of 22q11DS individuals (N = 125). First, a multiple regression analysis was conducted to confirm the hypothesis that high trait anxiety in individuals with 22q11DS would be associated with parents' psychological distress. This was based on 19 questionnaire options regarding what difficulties the parents currently face about their child's disease, characteristics, and traits. Next, we explored what challenges faced in medical, welfare, and educational services would be associated with the trait anxiety in their child. Results: The multiple regression analysis confirmed that the high trait anxiety was significantly associated with parental psychological distress (ß = 0.265, p = 0.018) among the 19 clinical/personal characteristics of 22q11DS. Furthermore, this characteristic was associated with various difficulties faced in the medical care, welfare, and education services, and the parent-child relationship. Conclusion: To our knowledge, this is the first study to clarify quantitatively how the characteristic of high anxiety level in 22q11DS individuals is related to the caregivers' perceived difficulties in medical, welfare, and educational services. These results suggest the necessity of designing service structures informed of the fact that high trait anxiety is an important clinical feature of the syndrome.
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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.
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Síndrome de DiGeorge , Distrés Psicológico , Adulto , Niño , Estudios Transversales , Síndrome de DiGeorge/epidemiología , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicología , Humanos , Japón/epidemiología , Padres/psicologíaRESUMEN
Aim: Adverse childhood experiences (ACEs) are highly prevalent in the general population, and their lifelong impact on physical and mental health is profound. In assessing ACEs, it is vital to consider the pathways and modalities by which an individual internalizes events as an adverse experience and its effects on their biological, psychological, and social function. However, conventional assessments of ACEs are inadequate in that they do not comprehensively assess the source of the adverse event and the pathway and mode of its impact on the individual. Methods: This study developed an original scale for ACEs that classifies the source of the event and the pathway and mode of its impact on the individual from a retrospective review of medical charts. We also used this scale to investigate the ACEs in 536 patients with psychiatric disorders (depression, bipolar disorder, and schizophrenia). Results: This scale consisted of 28 items, and its reliability and validity were sufficient. We also found that 45.9% of the patients studied had at least one ACE, ranging from 43.5% to 51.5% for all disorders. Psychological trauma (bullying) from peers was the most common cause at 27.2%. Conclusion: We developed a retrospective chart review-based assessment tool for ACEs which enables the examination of the source of the events of ACEs and the pathways and modalities of their impact on the individual. The frequency of ACEs is high regardless of the type of psychiatric disorder, and horizontal trauma (bullying victimization) is as frequent as vertical trauma (parental maltreatment).
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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.
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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.
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Ansiedad , Depresión , Niños con Discapacidad , Madres/psicología , Adolescente , Adulto , Ansiedad/epidemiología , Niño , Estudios de Cohortes , Estudios Transversales , Depresión/epidemiología , Niños con Discapacidad/estadística & datos numéricos , Femenino , Humanos , Masculino , Madres/estadística & datos numéricos , Tokio/epidemiologíaRESUMEN
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.
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Conducta del Adolescente/fisiología , Conducta Infantil/fisiología , Pubertad/fisiología , Conducta Social , Testosterona/metabolismo , Adolescente , Niño , Cromatografía Liquida , Estudios de Cohortes , Humanos , Hidrocortisona/metabolismo , Masculino , Pubertad/metabolismo , Saliva/metabolismo , Espectrometría de Masas en TándemRESUMEN
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.
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Movimiento Celular/genética , MicroARNs/sangre , Neurogénesis/genética , Esquizofrenia/sangre , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Adulto JovenRESUMEN
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.
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Islas de CpG , Metilación de ADN , Saliva , Adulto , Epigénesis Genética , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
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.
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Corteza Auditiva/fisiopatología , Encéfalo/fisiopatología , Trastornos Mentales/fisiopatología , Esquizofrenia/fisiopatología , Estimulación Acústica/efectos adversos , Adulto , Animales , Corteza Auditiva/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Potenciales Evocados Auditivos/efectos de los fármacos , Potenciales Evocados Auditivos/fisiología , Humanos , Ketamina/farmacología , Trastornos Mentales/diagnóstico por imagen , Trastornos Mentales/tratamiento farmacológico , Ratas , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Investigación Biomédica TraslacionalRESUMEN
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.
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Conducta del Adolescente/fisiología , Desarrollo del Adolescente/fisiología , Síntomas Conductuales/fisiopatología , Encéfalo/diagnóstico por imagen , Electroencefalografía , Epigénesis Genética/genética , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Adolescente , Conducta del Adolescente/psicología , Síntomas Conductuales/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Padres , Saliva , Tokio/epidemiologíaRESUMEN
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 (ΔHAMDâ¯=â¯T1.5_HAMDâ¯-â¯T0_HAMD, Δ[oxy-Hb]â¯=â¯T1.5_[oxy-Hb]â¯-â¯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.
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Trastorno Depresivo Mayor/patología , Índice de Severidad de la Enfermedad , Lóbulo Temporal/patología , Adulto , Trastorno Depresivo Mayor/psicología , Femenino , Lóbulo Frontal , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Corteza Prefrontal/patología , Escalas de Valoración Psiquiátrica , Espectroscopía Infrarroja CortaRESUMEN
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.
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Metilación de ADN , Epigénesis Genética , Epigenómica/métodos , Animales , Callithrix , Epigenómica/instrumentación , Humanos , Masculino , Especificidad de la EspecieRESUMEN
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.
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Adrenomedulina/metabolismo , Líquido Extracelular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/genética , ARN Mensajero/metabolismo , Adrenomedulina/farmacología , Línea Celular Tumoral , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica , Proteínas de Choque Térmico/metabolismo , Humanos , Neuroblastoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
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.
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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.