The role of T-lymphocytes in central nervous system diseases.

The central nervous system (CNS) has been considered an immunologically privileged site. In the past few decades, research on inflammation in CNS diseases has mostly focused on microglia, innate immune cells that respond rapidly to injury and infection to maintain CNS homeostasis. Discoveries of lymphatic vessels within the dura mater and peripheral immune cells in the meningeal layer indicate that the peripheral immune system can monitor and intervene in the CNS. This review summarizes recent advances in the involvement of T lymphocytes in multiple CNS diseases, including brain injury, neurodegenerative diseases, and psychiatric disorders. It emphasizes that a deep understanding of the pathogenesis of CNS diseases requires intimate knowledge of T lymphocytes. Aiming to promote a better understanding of the relationship between the immune system and CNS and facilitate the development of therapeutic strategies targeting T lymphocytes in neurological diseases.

A Shared Multivariate Brain-Behavior Relationship in a Transdiagnostic Sample of Adolescents.

BACKGROUND: Internalizing and externalizing psychopathology typically present in early childhood and can have negative implications on general functioning and quality of life. Prior work has linked increased psychopathology symptoms with altered brain structure. Multivariate analysis such as partial least squares correlation can help identify patterns of covariation between brain regions and psychopathology symptoms. This study examined the relationship between gray matter volume (GMV) and psychopathology symptoms in adolescents with various psychiatric diagnoses. METHODS: Structural magnetic resonance imaging data were collected from 490 participants with various internalizing and externalizing diagnoses (197 female/293 male; age = 14.68 ± 2.35 years; IQ = 104.05 ± 13.11). Cortical and subcortical volumes were parcellated using the Desikan-Killiany atlas. Partial least squares correlation was used to identify multivariate linear relationships between GMV and the Strength and Difficulties Questionnaire difficulties domains (emotional, peer, conduct, and hyperactivity issues). Resampling approaches were used to determine significance (permutation test), stability (bootstrap resampling), and reproducibility (split-half resampling) of identified relationships. RESULTS: We found a significant, stable, and largely reproducible dimension that linked lower Strength and Difficulties Questionnaire scores (less impairment) across all difficulties domains with greater widespread GMV (singular value = 1.17, accounts for 87.1% of the covariance; p < .001). This dimension emphasized the relationship between lower conduct problems and greater GMV in frontotemporal regions. CONCLUSIONS: Our results indicate that the most significant and stable brain-behavior relationship in a transdiagnostic sample is a domain-general relationship, linking lower psychopathology symptom scores to greater global GMV. This finding suggests that a shared brain-behavior relationship may be present across adolescents with and without clinically significant psychopathology symptoms.

Reduced volume of the left cerebellar lobule VIIb and its increased connectivity within the cerebellum predict more general psychopathology one year later via worse cognitive flexibility in children.

Predicting the risk for general psychopathology (the p factor) requires the examination of multiple factors ranging from brain to cognitive skills. While an increasing number of findings have reported the roles of the cerebral cortex and executive functions, it is much less clear whether and how the cerebellum and cognitive flexibility (a core component of executive function) may be associated with the risk for general psychopathology. Based on the data from more than 400 children aged 6-12 in the Children School Functions and Brain Development (CBD) Project, this study examined whether the left cerebellar lobule VIIb and its connectivity within the cerebellum may prospectively predict the risk for general psychopathology one year later and whether cognitive flexibility may mediate such predictions in school-age children. The reduced gray matter volume in the left cerebellar lobule VIIb and the increased connectivity of this region to the left cerebellar lobule VI prospectively predicted the risk for general psychopathology and was partially mediated by worse cognitive flexibility. Deficits in cognitive flexibility may play an important role in linking cerebellar structure and function to the risk for general psychopathology.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Assistência à saúde nos transtornos mentais no período de puerpério: revisão integrativa / Health care in mental disorders in the period of puerperium: Integrative Review / Atención sanitaria en los trastornos mentales en el puerpério: Revisión integradora

No puerpério, a mulher passa por intensas mudanças de ordem familiar e social, como também de adaptações psicológicas e biológicas, que são marcadas por alterações metabólicas e hormonais complexas, sendo a fase de maior risco para o desenvolvimento de algum transtorno mental. Objetivo:Realizar uma revisão da literatura paraidentificar a assistência à saúde nos transtornos mentais no período de puerpério. Metodologia:Estudo descritivo na modalidade revisão integrativa, realizado com artigos originais disponíveis nas línguas portuguesa, inglesa e espanhola, publicados nas bases de dados Scientific Electronic LibraryOnline (SCIELO) e Literatura Latino-Americana em Ciências da Saúde (LILACS), no período de 2015 a 2021 com os seguintes descritores: assistência de enfermagem, transtornos mentais e períodopós-parto. Resultados:Foram encontrados 58artigos, dos quais 17foram selecionados ao final do processo. 10 trabalhos evidenciaram fatores associados com transtorno mental, 4 trabalhos descreveram medidas de proteção e 3 abordaram ações assistenciais de saúde na intervenção dos transtornos mentais no puerpério. Conclusões:Após análise da literatura, observa-seque o baixo suporte social e familiar se mostraram como principais fatores de risco associados aos transtornos mentais para a puérpera. Já os fatores de proteção foram relacionados com aumento do apoio familiar e assistencial por meio dos serviços de saúde, bem como a importância da enfermagem na implementação de estratégias preventivas para os transtornos mentais no puerpério (AU).

In the puerperium, women undergoes intense changes of family and social order, as well as psychological and biological adaptations, which are marked by complex metabolic and hormonal alterations, being the phase of greatest risk for the development of somemental disorder. Objective: Conduct a review of the literature to identify health care in mental disorders in the postpartum period.Methodology:Descriptive study in the integrative review modality, carried out with original articles available in Portuguese, English and Spanish, published in the scientific electronic library online (SCIELO) and Latin American literature in health sciences (LILACS) databases, from 2015 to 2021 with the following descriptors: nursing care, mental disorders and postpartum period.Results:Fifty-eight articles were found, of which 17 were selected at the end of the process. 10 studies showed factors associated with mental disorder, 4 studies described protective measures and 3 addressed health care actions in the intervention of mental disorders in the puerperium.Conclusions:After analyzing the literature, we observed that low social and family support were shown to be the main risk factors associated with mental disorders for the puerperal. On the other hand, the protective factors were related to increased family and care support through health services, as well as the importance of nursing in the implementation of preventive strategies for mental disorders in the puerperium (AU).

En el puerperio, la mujer sufre intensos cambios de orden familiar y social, así como adaptaciones psicológicas y biológicas, que se caracterizan por complejas alteraciones metabólicas y hormonales, siendo la fase de mayor riesgo para el desarrollo de algún trastorno mental.Objetivo:Realizar una revisión de la literatura para identificar la atención médica en los trastornos mentales en el período posparto. Metodología: Estudio descriptivo en la modalidad de revisión integradora, realizado con artículos originales disponibles en portugués, inglés y español, publicados en las bases de datos de la biblioteca científica electrónica en línea (SCIELO) y de la literatura latinoamericana en ciencias de la salud (LILACS), de 2015 a 2021 con los siguientes descriptores: cuidados de enfermería, trastornos mentales y puerperio.Resultados: Se encontraron cincuenta y ocho artículos, de los cuales 17 fueron seleccionados al final del proceso. 10 estudios mostraron factores asociadosal trastorno mental, 4 estudios describieron medidas de protección y 3 abordaron acciones de atención sanitaria en la intervención de los trastornos mentales en el puerperio.Conclusiones: Después de analizar la literatura, observamos que el bajo apoyo social y familiar demostró ser el principal factor de riesgo asociado a los trastornos mentales para el puerperal. Por otro lado, los factores protectores se relacionaron con el aumento del apoyo familiar y asistencial a través de los servicios de salud, asícomo la importancia de la enfermería en la implementación de estrategias preventivas para los trastornos mentales en el puerperio (AU).

Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Youth.

OBJECTIVE: Associations between psychiatric problems and white matter (WM) microstructure have been reported in youth. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations in youth. METHOD: In this observational study, we leveraged the world's largest single- and multi-site cohorts of neurodevelopment: the Generation R (GenR) and Adolescent Brain Cognitive Development Studies (ABCD) (total n scans = 11,400; total N = 5,700). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band internalizing and externalizing scales, and as syndrome scales (eg, Anxious/Depressed). We quantified WM with diffusion tensor imaging (DTI), globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation. RESULTS: We did not identify any longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses) before, and after multiple testing corrections. We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses). Some cross-sectional associations surpassed multiple testing corrections in ABCD, but not in GenR. CONCLUSION: Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms were not robustly identified. We have proposed several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected. STUDY REGISTRATION INFORMATION: Bidirectionality Brain Function and Psychiatric Symptoms; https://doi.org/10.17605/OSF.IO/PNY92.

A fatal alliance: Glial connexins, myelin pathology and mental disorders.

Mature oligodendrocytes are myelin forming glial cells which are responsible for myelination of neuronal axons in the white matter of the central nervous system. Myelin pathology is a major feature of severe neurological disorders. Oligodendrocyte-specific gene mutations and/or white matter alterations have also been addressed in a variety of mental disorders. Breakdown of myelin integrity and demyelination is associated with severe symptoms, including impairments in motor coordination, breathing, dysarthria, perception (vision and hearing), and cognition. Furthermore, there is evidence indicating that myelin sheath defects and white matter pathology contributes to the affective and cognitive symptoms of patients with mental disorders. Oligodendrocytes express the connexins GJC2; mCx47 [human (GJC2) and mouse (mCx47) connexin gene nomenclature according to Söhl and Willecke (2003)], GJB1; mCx32, and GJD1; mCx29 in both white and gray matter. Preclinical findings indicate that alterations in connexin expression in oligodendrocytes and astrocytes can induce myelin defects. GJC2; mCx47 is expressed at early embryonic stages in oligodendrocyte precursors cells which precedes central nervous system myelination. In adult humans and animals GJC2, respectively mCx47 expression is essential for oligodendrocyte function and ensures adequate myelination as well as myelin maintenance in the central nervous system. In the past decade, evidence has accumulated suggesting that mental disorders can be accompanied by changes in connexin expression, myelin sheath defects and corresponding white matter alterations. This dual pathology could compromise inter-neuronal information transfer, processing and communication and eventually contribute to behavioral, sensory-motor, affective and cognitive symptoms in patients with mental disorders. The induction of myelin repair and remyelination in the central nervous system of patients with mental disorders could help to restore normal neuronal information propagation and ameliorate behavioral and cognitive symptoms in individuals with mental disorders.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Advancing preclinical models of psychiatric disorders with human brain organoid cultures.

Psychiatric disorders are often distinguished from neurological disorders in that the former do not have characteristic lesions or findings from cerebrospinal fluid, electroencephalograms (EEGs), or brain imaging, and furthermore do not have commonly recognized convergent mechanisms. Psychiatric disorders commonly involve clinical diagnosis of phenotypic behavioral disturbances of mood and psychosis, often with a poorly understood contribution of environmental factors. As such, psychiatric disease has been challenging to model preclinically for mechanistic understanding and pharmaceutical development. This review compares commonly used animal paradigms of preclinical testing with evolving techniques of induced pluripotent cell culture with a focus on emerging three-dimensional models. Advances in complexity of 3D cultures, recapitulating electrical activity in utero, and disease modeling of psychosis, mood, and environmentally induced disorders are reviewed. Insights from these rapidly expanding technologies are discussed as they pertain to the utility of human organoid and other models in finding novel research directions, validating pharmaceutical action, and recapitulating human disease.

Implicaciones del estigma hacia losproblemas de salud mental en elriesgo de suicidio en personas conproblemas de salud mental: unarevisión sistemática / Implications of stigma towards mental health problems on suicide risk in people with mental health problems: a systematic review

Introducción: El estigma asociado a los problemas psicológicos es una cuestión preocupante que afecta negativamente a las personas que conviven con diferentes sintomatologías, en ocasiones con graves consecuencias para susalud. El objetivo principal de este trabajo fue realizar unarevisión sistemática actualizada para explorar la relación entre el estigma asociado a los problemas de salud mental y elriesgo de suicidio en la población clínica, así como estudiarlas variables implicadas en esta relación.Método. Se realizó una búsqueda en las bases de datosPsycInfo, Pubmed y Scopus, utilizando palabras clave relacionadas con el estigma, el suicidio, y limitando los estudiosa muestras clínicas. La búsqueda incluyó artículos en inglés yespañol desde enero de 2012 hasta diciembre de 2020.Resultados. Un total de 12 artículos cumplieron los criterios de inclusión y fueron seleccionados para el análisis. Losresultados sugieren que el aumento del auto estigma hacialos problemas de salud mental se asocia con un mayor riesgo de suicidio en población clínica. Asimismo, se sugierenvariables implicadas en esta relación, como la depresión, ladesesperanza, la pérdida de sentido vital, el desempleo o ladisminución de las redes de apoyo. (AU)

Background: Stigma associated with psychological problems is a major concern that negatively affects people living with different symptomatology, sometimes with seriousconsequences for their health. The principal purpose of thispaper was to carry out an updated systematic review to explore the relationship between the stigma associated withmental health problems and the risk of suicide in the clinicalpopulation, as well as to study the variables involved in thisrelationship.Method. A search was carried out in the PsycInfo, Pubmed and Scopus databases, using keywords related to stigma, suicide, and limiting the studies to clinical samples. Thesearch included articles in English and Spanish from January2012 to December 2020.Results. A total of 12 articles met the inclusion criteriaand were selected for analysis. The results suggest that increased self-stigma toward mental health problems is associated with increased risk of suicide in clinical population.Also, variables involved in this relationship are suggested,such as depression, hopelessness, loss of vital sense, unemployment or decrease of support networks. (AU)

Shared Transdiagnostic Neuroanatomical Signatures Across First-episode Patients with Major Psychiatric Diseases and Individuals at Familial Risk.

BACKGROUND: Nowadays, increasing evidence has found transdiagnostic neuroimaging biomarkers across major psychiatric disorders (MPDs). However, it remains to be known whether this transdiagnostic pattern of abnormalities could also be seen in individuals at familial high-risk for MPDs (FHR). We aimed to examine shared neuroanatomical endophenotypes and protective biomarkers for MPDs. METHODS: This study examined brain grey matter volume (GMV) of individuals by voxel-based morphometry method. A total of 287 individuals were included, involving 100 first-episode medication-naive MPDs, 87 FHR, and 110 healthy controls (HC). They all underwent high-resolution structural magnetic resonance imaging (MRI). RESULTS: At the group level, we found MPDs were characterized by decreased GMV in the right fusiform gyrus, the right inferior occipital gyrus, and the left anterior and middle cingulate gyri compared to HC and FHR. Of note, the GMV of the left superior temporal gyrus was increased in FHR relative to MPDs and HC. At the subgroup level, the comparisons within the FHR group did not return any significant difference, and we found GMV difference among subgroups within the MPDs group only in the opercular part of the right inferior frontal gyrus. CONCLUSION: Together, our findings uncover common structural disturbances across MPDs and substantial changes in grey matter that may relate to high hereditary risk across FHR, potentially underscoring the importance of a transdiagnostic way to explore the neurobiological mechanisms of major psychiatric disorders.

Neurobiological Highlights of Cognitive Impairment in Psychiatric Disorders.

This review is focused on several psychiatric disorders in which cognitive impairment is a major component of the disease, influencing life quality. There are plenty of data proving that cognitive impairment accompanies and even underlies some psychiatric disorders. In addition, sources provide information on the biological background of cognitive problems associated with mental illness. This scientific review aims to summarize the current knowledge about neurobiological mechanisms of cognitive impairment in people with schizophrenia, depression, mild cognitive impairment and dementia (including Alzheimer's disease).The review provides data about the prevalence of cognitive impairment in people with mental illness and associated biological markers.

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets.

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

Reaching into the toolbox: Stem cell models to study neuropsychiatric disorders.

Recent advances in genetics, molecular biology, and stem cell biology have accelerated our understanding of neuropsychiatric disorders, like autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). This progress highlights the incredible complexity of both the human brain and mental illnesses from the biochemical to the cellular level. Contributing to the complexity of neuropsychiatric disorders are their polygenic nature, cellular and brain region interconnectivity, and dysregulation of human-specific neurodevelopmental processes. Here, we discuss available tools, including CRISPR-Cas9, and the applications of these tools to develop cell-based two-dimensional (2D) models and 3D brain organoid models that better represent and unravel the intricacies of neuropsychiatric disorder pathophysiology.

Multidimensional brain-age prediction reveals altered brain developmental trajectory in psychiatric disorders.

Brain-age prediction has emerged as a novel approach for studying brain development. However, brain regions change in different ways and at different rates. Unitary brain-age indices represent developmental status averaged across the whole brain and therefore do not capture the divergent developmental trajectories of various brain structures. This staggered developmental unfolding, determined by genetics and postnatal experience, is implicated in the progression of psychiatric and neurological disorders. We propose a multidimensional brain-age index (MBAI) that provides regional age predictions. Using a database of 556 individuals, we identified clusters of imaging features with distinct developmental trajectories and built machine learning models to obtain brain-age predictions from each of the clusters. Our results show that the MBAI provides a flexible analysis of region-specific brain-age changes that are invisible to unidimensional brain-age. Importantly, brain-ages computed from region-specific feature clusters contain complementary information and demonstrate differential ability to distinguish disorder groups (e.g., depression and oppositional defiant disorder) from healthy controls. In summary, we show that MBAI is sensitive to alterations in brain structures and captures distinct regional change patterns that may serve as biomarkers that contribute to our understanding of healthy and pathological brain development and the characterization and diagnosis of psychiatric disorders.

Evaluating brain structure traits as endophenotypes using polygenicity and discoverability.

Human brain structure traits have been hypothesized to be broad endophenotypes for neuropsychiatric disorders, implying that brain structure traits are comparatively "closer to the underlying biology." Genome-wide association studies from large sample sizes allow for the comparison of common variant genetic architectures between traits to test the evidence supporting this claim. Endophenotypes, compared to neuropsychiatric disorders, are hypothesized to have less polygenicity, with greater effect size of each susceptible SNP, requiring smaller sample sizes to discover them. Here, we compare polygenicity and discoverability of brain structure traits, neuropsychiatric disorders, and other traits (91 in total) to directly test this hypothesis. We found reduced polygenicity (FDR = 0.01) and increased discoverability (FDR = 3.68 × 10-9 ) of cortical brain structure traits, as compared to aggregated estimates of multiple neuropsychiatric disorders. We predict that ~8 M individuals will be required to explain the full heritability of cortical surface area by genome-wide significant SNPs, whereas sample sizes over 20 M will be required to explain the full heritability of depression. In conclusion, our findings are consistent with brain structure satisfying the higher power criterion of endophenotypes.

Neuroimaging studies within Cognitive Genetics Collaborative Research Organization aiming to replicate and extend works of ENIGMA.

Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta- and mega-analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta-analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega-analysis. Furthermore, a schizophrenia-specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega-analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings.

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research.

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.