Search

Climate change is a major global public mental health crisis that is expected to increase the need for mental health services. Psychiatrists and other mental health care providers must address workforce needs through recruitment, training and education, prevention and intervention, public policy and advocacy, and direct efforts to reduce climate change. This column discusses concrete steps for the psychiatric workforce to take to prepare for growing mental health needs associated with climate change.

The clinical severity, impact on development, and poor prognosis of childhood-onset schizophrenia may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis, and hallucinations are more often multimodal. In healthy children and children with a variety of other psychiatric illnesses, hallucinations are not uncommon and diagnosis should not be based on these alone. Childhood-onset schizophrenia is an extraordinarily rare illness that is poorly understood but seems continuous with the adult-onset disorder. Once a diagnosis is confirmed, aggressive medication treatment combined with family education and individual counseling may prevent further deterioration.

SummaryHuman brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genesGPR139, DACH1andAPOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.

Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity.A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS.Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P0.05, corrected) for both patient groups.A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is state-related.

Structural brain changes that occur during development and ageing are related to mental health and general cognitive functioning. Individuals differ in the extent to which their brain volumes change over time, but whether these differences can be attributed to differences in their genotypes has not been widely studied. Here we estimate heritability (h2) of changes in global and subcortical brain volumes in five longitudinal twin cohorts from across the world and in different stages of the lifespan (N = 861). Heritability estimates of brain changes were significant and ranged from 16% (caudate) to 42% (cerebellar gray matter) for all global and most subcortical volumes (with the exception of thalamus and pallidum). Heritability estimates of change rates were generally higher in adults than in children suggesting an increasing influence of genetic factors explaining individual differences in brain structural changes with age. In children, environmental influences in part explained individual differences in developmental changes in brain structure. Multivariate genetic modeling showed that genetic influences of change rates and baseline volume significantly overlapped for many structures. The genetic influences explaining individual differences in the change rate for cerebellum, cerebellar gray matter and lateral ventricles were independent of the genetic influences explaining differences in their baseline volumes. These results imply the existence of genetic variants that are specific for brain plasticity, rather than brain volume itself. Identifying these genes may increase our understanding of brain development and ageing and possibly have implications for diseases that are characterized by deviant developmental trajectories of brain structure.

The clinical severity, impact on development, and poor prognosis of childhood-onset schizophrenia may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis, and hallucinations are more often multimodal. In healthy children and children with a variety of other psychiatric illnesses, hallucinations are not uncommon and diagnosis should not be based on these alone. Childhood-onset schizophrenia is an extraordinarily rare illness that is poorly understood but seems continuous with the adult-onset disorder. Once a diagnosis is confirmed, aggressive medication treatment combined with family education and individual counseling may prevent further deterioration.

Objective This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS). Method A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings. Results Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers. Conclusion The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype.

Background There is evidence suggesting neuropsychiatric disorders share genomic, cognitive and clinical features. Here, we ask if autism-spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and schizophrenia share neuroanatomical variations. Methods First, we used measures of cortical anatomy to estimate spatial overlap of neuroanatomical variation using univariate methods. Next, we developed a novel methodology to determine whether cortical deficits specifically target or are "enriched" within functional resting-state networks. Results We found cortical anomalies were preferentially enriched across functional networks rather than clustering spatially. Specifically, cortical thickness showed significant enrichment between patients with ASD and those with ADHD in the default mode network, between patients with ASD and those with schizophrenia in the frontoparietal and limbic networks, and between patients with ADHD and those with schizophrenia in the ventral attention network. Networks enriched in cortical thickness anomalies were also strongly represented in functional MRI results (Neurosynth; r = 0.64, p = 0.032). Limitations We did not account for variable symptom dimensions and severity in patient populations, and our cross-sectional design prevented longitudinal analyses of developmental trajectories. Conclusion These findings suggest that common deficits across neuropsychiatric disorders cannot simply be characterized as arising out of local changes in cortical grey matter, but rather as entities of both local and systemic alterations targeting brain networks.

Childhood-onset schizophrenia is a rare pediatric onset psychiatric disorder continuous with and typically more severe than its adult counterpart. Neuroimaging research conducted on this population has revealed similarly severe neural abnormalities. When taken as a whole, neuroimaging research in this population shows generally decreased cortical gray matter coupled with white matter connectivity abnormalities, suggesting an anatomical basis for deficits in executive function. Subcortical abnormalities are pronounced in limbic structures, where volumetric deficits are likely related to social skill deficits, and cerebellar deficits that have been correlated to cognitive abnormalities. Structures relevant to motor processing also show a significant alteration, with volumetric increase in basal ganglia structures likely due to antipsychotic administration. Neuroimaging of this disorder shows an important clinical image of exaggerated cortical loss, altered white matter connectivity, and differences in structural development of subcortical areas during the course of development and provides important background to the disease state.

There are varying, often conflicting, reports with respect to altered striatal volume and morphometry in the major psychoses due to the influences of antipsychotic medications on striatal volume. Thus, disassociating disease effects from those of medication become exceedingly difficult. For the first time, using a longitudinally studied sample of structural magnetic resonance images from patients with childhood onset schizophrenia (COS; neurobiologically contiguous with the adult onset form of schizophrenia), their nonpsychotic siblings (COSSIBs), and novel shape mapping algorithms that are volume independent, we report the familial contribution of striatal morphology in schizophrenia. The results of our volumetric analyses demonstrate age-related increases in overall striatal volumes specific only to COS. However, both COS and COSSIBs showed overlapping shape differences in the striatal head, which normalized in COSSIBs by late adolescence. These results mirror previous studies from our group, demonstrating cortical thickness deficits in COS and COSSIBs as these deficits normalize in COSSIBs in the same age range as our striatal findings. Finally, there is a single region of nonoverlapping outward displacement in the dorsal aspect of the caudate body, potentially indicative of a response to medication. Striatal shape may be considered complimentary to volume as an endophenotype, and, in some cases may provide information that is not detectable using standard volumetric techniques. Our striatal shape findings demonstrate the striking localization of abnormalities in striatal the head. The neuroanatomical localization of these findings suggest the presence of abnormalities in the striatal-prefrontal circuits in schizophrenia and resilience mechanisms in COSSIBs with age dependent normalization.

Background Schizophrenia is a disorder of brain connectivity and altered neurodevelopmental processes. Cross-sectional case-control studies in different age groups have suggested that deficits in cortical thickness in childhood-onset schizophrenia may normalize over time, suggesting a disorder-related difference in cortical growth trajectories. Methods We acquired magnetic resonance imaging scans repeated over several years for each subject, in a sample of 106 patients with childhood-onset schizophrenia and 102 age-matched healthy volunteers. Using semiparametric regression, we modeled the effect of schizophrenia on the growth curve of cortical thickness in ~80,000 locations across the cortex, in the age range 8 to 30 years. In addition, we derived normative developmental modules composed of cortical regions with similar maturational trajectories for cortical thickness in typical brain development. Results We found abnormal nonlinear growth processes in prefrontal and temporal areas that have previously been implicated in schizophrenia, distinguishing for the first time between cortical areas with age-constant deficits in cortical thickness and areas whose maturational trajectories are altered in schizophrenia. In addition, we showed that when the brain is divided into five normative developmental modules, the areas with abnormal cortical growth overlap significantly only with the cingulo-fronto-temporal module. Conclusions These findings suggest that abnormal cortical development in schizophrenia may be modularized or constrained by the normal community structure of developmental modules of the human brain connectome.

The clinical severity, impact on development, and poor prognosis of Childhood Onset Schizophrenia (COS) may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis and hallucinations are more often multi modal. Both in healthy children, as well as in children with a variety of other psychiatric illnesses, hallucinations are not uncommon [1] and diagnosis should not be based on these alone. COS is an extraordinarily rare illness which is poorly understood but appears continuous with the adult onset disorder. Additionally, as seen in other areas of medicine, early onset populations have more prominent progressive brain changes, and genetic risk factors [2].

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development.

The corpus callosum (CC) has been implicated in the pathogenesis of schizophrenia, and CC deficits have been reported in adults with schizophrenia. We explored the developmental trajectory of the corpus callosum in childhood-onset schizophrenia (COS) patients, their healthy siblings (SIB) and healthy volunteers. We obtained 235 anatomic brain magnetic resonance imaging (MRI) scans from 98 COS patients, 153 scans from 71 of their healthy siblings, and 253 scans from 100 age- and gender-matched healthy volunteers, across ages 9–30 years. The volumes of five sub-regions of the CC were calculated using FreeSurfer, and summed to give the total volume. Longitudinal data were examined using mixed model regression analysis. There were no significant differences for the total or sub-regional CC volumes between the three groups. There were also no significant differences between the groups for developmental trajectory (slope) of the CC. This is the largest longitudinal study of CC development in schizophrenia and the first COS study of the CC to include healthy siblings. Overall, CC volume and growth trajectory did not differ between COS patients, healthy siblings, or healthy volunteers. These results suggest that CC development, at least at a macroscopic level, may not be a salient feature of schizophrenia.

Human brain functional networks are embedded in anatomical space and have topological properties—small-worldness, modularity, fat-tailed degree distributions—that are comparable to many other complex networks. Although a sophisticated set of measures is available to describe the topology of brain networks, the selection pressures that drive their formation remain largely unknown. Here we consider generative models for the probability of a functional connection (an edge) between two cortical regions (nodes) separated by some Euclidean distance in anatomical space. In particular, we propose a model in which the embedded topology of brain networks emerges from two competing factors: a distance penalty based on the cost of maintaining long-range connections; and a topological term that favors links between regions sharing similar input. We show that, together, these two biologically plausible factors are sufficient to capture an impressive range of topological properties of functional brain networks. Model parameters estimated in one set of functional MRI (fMRI) data on normal volunteers provided a good fit to networks estimated in a second independent sample of fMRI data. Furthermore, slightly detuned model parameters also generated a reasonable simulation of the abnormal properties of brain functional networks in people with schizophrenia. We therefore anticipate that many aspects of brain network organization, in health and disease, may be parsimoniously explained by an economical clustering rule for the probability of functional connectivity between different brain areas.

Background In recent years, transcranial direct current stimulation (tDCS) has been used to study and treat many neuropsychiatric conditions. However, information regarding its tolerability in the pediatric population is lacking. Objective This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population. Methods Twelve participants with COS completed this inpatient study. Participants were assigned to one of two groups: bilateral anodal dorsolateral prefrontal cortex (DLPFC) stimulation (n = 8) or bilateral cathodal superior temporal gyrus (STG) stimulation (n = 5). Patients received either 2 mA of active treatment or sham treatment (with possibility of open active treatment) for 20 minutes, for a total of 10 sessions (2 weeks). Results tDCS was well tolerated in the COS population with no serious adverse events occurring during the study. Conclusions This is the first study to demonstrate that a 20-minute duration of 2 mA of bilateral anodal and bilateral cathodal DC polarization to the DLPFC and STG was well tolerated in a pediatric population.

We explored regional and total volumetric cerebellar differences in probands and their unaffected full siblings relative to typically developing participants. Participants included 94 (51 males) patients diagnosed with childhood onset schizophrenia (COS), 80 related non-psychotic siblings (37 males) and 110 (64 males) typically developing participants scanned longitudinally. The sample mean age was 16.87(S.D.=4.7; range 6.5 to 29). We performed mixed model regressions to examine group differences in trajectory and volume. The COS group had smaller bilateral anterior lobes and anterior and total vermis volumes than controls. The COS group diverged from controls over time in total, left, right, and bilateral posterior inferior cerebellum. Siblings did not have any fixed volumetric differences relative to controls but differed from controls in developmental trajectories of total and right cerebellum, left inferior posterior, left superior posterior, and superior vermis. Results are consistent with previous COS findings and several reports of decreased cerebellar volume in adult onset schizophrenia. Sibling trajectories may represent a trait marker, although the effect size for volumetric differences in early adulthood may be small.

Many of the major neuropsychiatric illnesses, including schizophrenia, have a typical age of onset in late adolescence. Late adolescence may reflect a critical period in brain development making it particularly vulnerable for the onset of psychopathology. Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. In this review, we examine the evidence from 2 unique longitudinal cohorts that span the ages from early childhood through young adulthood; a study of childhood-onset schizophrenia where patients and siblings are followed from ages 6 through to their early twenties, and an ultra-high risk study where subjects (mean age of 19 years) are studied before and after the onset of psychosis. From the available evidence, we make an argument that subtle, regionally specific, and genetically influenced alterations during developmental age windows influence the course of psychosis and the resultant brain phenotype. The importance of examining trajectories of development and the need for future combined approaches, using multimodal imaging together with molecular studies is discussed.

Structural brain abnormalities have become an established feature of schizophrenia and increasing evidence points towards the progressive nature of these abnormalities. The brain abnormalities are most profound in early onset cases, which have a severe, treatment refractory phenotype and more salient genetic features. Unique insights could thus be gained in schizophrenia pathology from studying the earliest manifestations of the illness. This paper reviews and updates the findings on anatomic brain development in patients with very early onset schizophrenia while showing preliminary data from ongoing studies. Collectively, our studies demonstrate that childhood-onset schizophrenia (COS) subjects show progressive loss of gray matter, delayed/disrupted white matter (WM) growth, and a progressive decline in cerebellar volume, some of which are shared by their healthy siblings. The developmental patterns or the ‘trajectories’ of brain development are often more striking than anatomic brain differences at any one point in time; highlighting the importance of longitudinal studies. The sibling findings of partially shared gray matter (GM) deficits which appear to normalize with age, along with other genetic analyses, provide evidence that the brain developmental ‘patterns/trajectories’ for several regions at particular ages could be useful endophenotypes (trait markers).

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating “movies” of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with “masculinization” of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

[FR] L’objectif du présent article est de passer en revue les études longitudinales évaluant des changements cérébraux évolutifs chez des patients souffrant de psychose précoce. Comprendre les trajectoires développementales des processus moléculaires et cellulaires du développement normal, et les différences entre le développement normal et anormal, est essentiel pour l’interprétation des études d’imagerie clinique, et pour la recherche d’une physiopathologie différentielle dans les affections psychiatriques liées au neurodéveloppement. Par conséquent, compte tenu de l’objectif de cet article, nous présenterons un bref sommaire des résultats d’études d’imagerie à résonnance magnétique (IRM) chez des sujets à développement cérébral normal. Nous présenterons ensuite un bref sommaire d’études longitudinales portant sur des psychoses précoces. Étant donné que la schizophrénie à début très précoce et la schizophrénie débutant à l’adolescence semblent se caractériser par des précurseurs et une évolution différents, et que l’expression génique diffère dans les différents groupes d’âge, nous diviserons les données en 2 groupes : début précoce et début à l’adolescence. Les résultats d’études longitudinales portant sur d’autres psychoses précoces seront examinés également afin d’évaluer la spécificité des résultats pour la schizophrénie, comparativement à d’autres maladies précoces avec symptômes psychotiques. Le sommaire des résultats sera suivi par des facteurs cliniques corrélés, et par une discussion des implications. Enfin, on soumettra des recommandations pour la recherche future., [EN] Progressive losses of cortical grey-matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in non-schizophrenia early onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research., [ES] Se han observado en la adolescencia unas pérdidas progresivas de volúmenes de sustancia gris y unos crecimientos ventriculares en pacientes con esquizofrenias de la niñez. Estudios longitudinales demuestran que en la adolescencia el ritmo de pérdida cortical observado en las esquizofrenias con inicios muy tempranos (COS) se estabiliza en los jóvenes adultos. Los pacientes en quienes el primer episodio sobreviene en la adolescencia presentan cambios evolutivos menos marcados, a pesar del reducido número de estudios en esta población. Ciertos estudios demuestran que unos cambios evolutivos menos marcados aparecen también en las psicosis no esquizofrénicas tempranas. La mayor pérdida de tejido cerebral observada en las esquizofrenias muy tempranas, aun varios años tras el primer episodio en comparación con las esquizofrenias de la adolescencia o la edad adulta podría estar vinculada con unas variables tales como el muestreo sesgado (enfermedad más severa; muestreo de pacientes con esquizofrenia temprana, refractarios al tratamiento), índole específica de la evolución en la adolescencia de las COS, efectos diferenciales de tratamientos medicamentosos en esta población, desenlace clínico, o interacción entre estas variables. Los resultados de estudios transversales en pacientes tras un primer episodio, así como estudios longitudinales sobre las COS y las esquizofrenias con inicio en la adolescencia, afianzan la idea que la esquizofrenia temprana es una afección del neurodesarrollo evolutiva, con anomalías del desarrollo tempranas y tardías. Los fururos estudios deberían buscar factores relacionados a nivel celular, y explicaciones patofisiolológicas para los cambios de volumen en estas poblaciones. La asociación de genes con crecimiento del riesgo en los circuitos neuronales vinculados con la esquizofrenia en relación con las trayectorias del desarrollo es otra pista prometedora para las investigaciones del porvenir., Cette recherche est soutenue en partie par CIBER de Salud Mental, ISCIII, Espagne.

Background Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset illness, with more salient neurobiological causes. Previous cross-sectional structural neuroimaging research has suggested that normal cortical asymmetry patterns [(R − L)/( R + L )] may be altered in adult schizophrenia, although these findings were not well replicated. Recent studies show dynamic changes in brain asymmetry during childhood and adolescence. We hypothesized that COS patients would show a lack of normal development of asymmetry and decreased overall asymmetry. Methods Prospective structural magnetic resonance scans were obtained at baseline and at two-year follow-up visits in 49 right-handed COS patients (mean baseline age: 14.72 ± 2.63, 117 scans) and 50 age and sex-matched, right-handed healthy controls (mean baseline age: 15.15 ± 3.37, 125 scans). Cortical thickness was calculated at 40,962 homologous points across each cerebral hemisphere using a fully automated, validated method. Differences in developmental asymmetry patterns across the cortical surface were analyzed using a linear mixed effects regression model. Results No significant asymmetry differences were found either for cross-sectional comparisons of COS and healthy controls across the lateral and medial cortical surfaces or with respect to timing of developmental changes in asymmetry. Conclusions The present findings do not support asymmetry differences for this severe, early form of schizophrenia.

Objective To highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS). Method Clinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed. Results In the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism. Conclusions Biological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.

Objective Few studies have examined prediction of schizophrenia outcome in relation to brain magnetic resonance imaging measures. In this study, remission status at the time of discharge was examined in relation to admission cortical thickness for childhood-onset schizophrenia probands. We hypothesized that total, frontal, temporal, and parietal gray matter thickness would be greater in patients who subsequently remit. Method The relation between admission cortical brain thickness on magnetic resonance imaging and remission status at the time of discharge an average of 3 months later was examined for 56 individuals (32 males) ages 6 to 19 diagnosed with childhood-onset schizophrenia. Cortical thickness was measured across the cerebral hemispheres at admission. Discharge remission criteria were adapted from the 2005 Remission in Schizophrenia Working Group criteria. Results Patients remitted at discharge ( n = 16 [29%]) had thicker regional cortex in left orbitofrontal, left superior, and middle temporal gyri and bilateral postcentral and angular gyri ( p ≤ .008). Conclusions Our results provide neuroanatomic correlates of clinical remission in schizophrenia and evidence that response to treatment may be mediated by these cortical brain regions. J. Am. Acad. Child Adolesc. Psychiatry , 2008;47(10):1133–1140.

Advances in neuroimaging allow prospective study of human brain development. Studies on pediatric populations are particularly informative because they explore the pathophysiological processes that are tied to important periods of brain development. Furthermore, childhood-onset counterparts of typical adult-onset illnesses usually show a more severe phenotype, one that is less likely to be influenced by environmental factors and more likely to show genetic influences. Such samples thus provide an opportunity to study the illness in its relatively pure form and that may also increase the likelihood of identifying causal genetic events. A study of childhood-onset schizophrenia (COS) has been ongoing at the NIMH since 1990. The diagnosis is made using unmodified DSM-III-R/IV criteria and, in most cases, after a drug-free inpatient observation. The COS cases (N = 102 to date) clinically resemble poor outcome adult-onset schizophrenia (AOS) cases, in that all phenomenological, family, and neurobiological studies in COS show similar findings as in AOS, suggesting continuity between these two forms of the illness. Structuralbrainabnormalitiesareanestablishedfeature of AOS, characterized by reduced gray matter (GM) volumes in the cortex, hippocampus, and amygdala, which is subtly progressive over time. The majority of neuroimaging studies in COS have come from the NIMH sample. Earlier COS studies, consistent with findings from AOS studies, showed increased lateral ventricular volume, decreased total and regional GM volumes, and increased basal ganglia volumes that progressed during adolescence.

Background: Although the role of clozapine is well established for treatment-resistant schizophrenia, it is rarely used in pediatric populations, mainly due to its potentially serious adverse effects. Objective: To summarize practical aspects of use of clozapine in treating children with schizophrenia and management of associated adverse effects. Methods: Available studies in the literature using clozapine in the pediatric population are summarized and the NIMH experience in treating refractory childhood-onset schizophrenia cases with clozapine is discussed. Conclusion: Despite a higher incidence of adverse effects in children, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia.

Childhood-onset schizophrenia (COS; defined as onset by age 12 years) is rare, difficult to diagnose, and represents a severe and chronic phenotype of the adult-onset illness. A study of childhood-onset psychoses has been ongoing at the National Institute of Mental Health (NIMH) since 1990, where children with COS and severe atypical psychoses (provisionally labeled "multidimensionally impaired" or MDI by the NIMH team) are studied prospectively along with all first-degree relatives. COS subjects have robust cortical gray matter (GM) loss during adolescence, which appears to be an exaggeration of the normal cortical GM developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults. These cortical GM changes in COS are diagnostically specific and seemingly unrelated to the effects of medications. Furthermore, the cortical GM loss is also shared by healthy full siblings of COS probands suggesting a genetic influence on the abnormal brain development.

Noninvasive brain imaging permits longitudinal studies of anatomic brain development in healthy and psychiatrically ill children. The time course for gray matter maturation varies by region and parallels earlier histological studies, indicating dynamic patterns of overproduction and regression. Developmental trajectories vary in relation to gender, intelligence, and overall functioning. Twin studies show high heritability for brain volumes, which varies with region and with age. Diagnostically specific, illness-related changes as well as outcome-associated plastic response are observed as illustrated for two pediatric populations, childhood-onset schizophrenia and attention-deficit/hyperactivity disorder, conditions which may be, in part, disorders of brain plasticity.

Background: There are, to date, no pre-post onset longitudinal imaging studies of bipolar disorder at any age. We report the first prospective study of cortical brain development in pediatric bipolar illness for 9 male children, visualized before and after illness onset. Method: We contrast this pattern with that observed in a matched group of healthy children as well as in a matched group of 8 children with ‘atypical psychosis’ who had similar initial presentation marked by mood dysregulation and transient psychosis (labeled as ‘multi-dimensionally impaired’ (MDI)) as in the bipolar group, but have not, to date, developed bipolar illness. Results: Dynamic maps, reconstructed by applying novel cortical pattern matching algorithms, for the children who became bipolar I showed subtle, regionally specific, bilaterally asymmetrical cortical changes. Cortical GM increased over the left temporal cortex and decreased bilaterally in the anterior (and sub genual) cingulate cortex. This was seen most strikingly after the illness onset, and showed a pattern distinct from that seen in childhood onset schizophrenia. The bipolar neurodevelopmental trajectory was generally shared by the children who remained with MDI diagnosis without converting to bipolar I, suggesting that this pattern of cortical development may reflect affective dysregulation (lability) in general. Conclusions: These dynamic trajectories of cortical development may explain age-related disparate findings from cross-sectional studies of bipolar illness, and suggest the importance of mood disordered non-bipolar control group in future studies. Keywords: Pediatric, bipolar, MRI, mapping, gray, matter. Bipolar disorder is a common psychiatric illness that is characterized by severe mood fluctuations and recent studies suggest that the lifetime prevalence of bipolar I disorder in the US is about 3.3% (Grant

Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research., Supported in part by CIBER de Salud Mental, ISCIII, Spain.

Prior cross-sectional anatomic brain imaging studies of the hippocampus in schizophrenia have generally shown loss in total hippocampal volume although the progressive course of these changes remains unknown. We report the first prospective sub-regional maps of hippocampal development in childhood onset schizophrenia (COS), reconstructed from serial brain MRI scans of 29 children with COS scanned every 2 years (87 scans) and compared to 31 controls matched for age, sex, and scan interval (94 scans). As expected, the COS subjects showed significant bilateral deficits (9-10%) in total hippocampal volume which remained consistent between age 9 and 26. However sub-regional maps showed heterogeneous changes with loss of hippocampal volume in both anterior as well as posterior ends while the body of the hippocampus gained in volume suggesting that hippocampal subunits are differentially affected in schizophrenia.

Abnormalities in structural brain connectivity have been observed in patients with schizophrenia. Mapping these abnormalities longitudinally and understanding their genetic risk via sibship studies will provide crucial insight into progressive developmental changes associated with schizophrenia.To identify corticocortical connections exhibiting an altered developmental trajectory in adolescents with childhood-onset schizophrenia (COS) and to determine whether similar alterations are found in patients' unaffected siblings.Using prospective structural brain magnetic resonance imaging, large-scale corticocortical connectivity was mapped from ages 12 to 24 years in 109 patients with COS (272 images), 86 of their unaffected siblings (184 images), and 102 healthy controls (262 images) over a 20-year period beginning January 1, 1991, through April 30, 2011, as part of the ongoing COS study at the National Institute of Mental Health.Structural connectivity between pairs of cortical regions was estimated using a validated technique based on across-subject covariation in magnetic resonance imaging-derived cortical thickness measurements.Compared with normally developing controls, significant left-hemisphere occipitotemporal deficits in cortical thickness correlations were found in patients with COS as well as their healthy siblings (P .05). Deficits in siblings normalized by mid-adolescence, whereas patients with COS showed significantly longer maturational delays, with cortical thickness correlations between the left temporal lobe and left occipital cortex not showing evidence of development until early adulthood. The normalization of deficits with age in patients with COS correlated with improvement in symptoms. Compared with controls, left-hemisphere occipitotemporal thickness correlations in a subgroup of patients with high positive symptoms were significantly reduced from age 14 to 18 years (P .05); however, other patients with low positive symptoms showed no significant deficits.Delayed maturation of occipitotemporal connectivity appears to be a trait marker in patients with COS, with a milder endophenotype in unaffected siblings associated with resilience to developing schizophrenia. These findings indicate genetically influenced and connection-specific developmental abnormalities in the schizophrenia connectome, and lead to the hypothesis that visual hallucinations in patients with COS may be because of delayed development of the inferior longitudinal fasciculus, a prominent occipitotemporal fiber.

Detailed descriptions of cortical anatomy in youth with Down syndrome (DS), the most common genetic cause of intellectual disability (ID), are scant. Thus, the current study examined deviations in cortical thickness (CT) and surface area (SA), at high spatial resolution, in youth with DS, to identify focal differences relative to typically developing (TD) youth. Participants included 31 youth with DS and 45 age- and sex-matched TD controls (mean age ∼16 years; range = 5-24 years). All participants completed T1-weighted ASSET-calibrated magnetization prepared rapid gradient echo scans on a 3-T magnetic resonance imaging scanner. Replicating prior investigations, cortical volume was reduced in DS compared with controls. However, a novel dissociation for SA and CT was found-namely, SA was reduced (predominantly in frontal and temporal regions) while CT was increased (notably in several regions thought to belong to the default mode network; DMN). These findings suggest that reductions in SA rather than CT are driving the cortical volume reductions reported in prior investigations of DS. Moreover, given the link between DMN functionality and Alzheimer's symptomatology in chromosomally typical populations, future DS studies may benefit from focusing on the cortex in DMN regions, as such investigations may provide clues to the precocious onset of Alzheimer's disease in this at-risk group.

BackgroundFixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients.MethodWe prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume).ResultsFewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043).ConclusionsThese results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

Childhood onset schizophrenia (COS), with onset of psychosis before age 13, is a rare form of schizophrenia that represents a more severe and chronic form of the adult onset illness. In this review we examine structural and functional magnetic resonance imaging (MRI) studies of COS and non-psychotic siblings of COS patients in the context of studies of schizophrenia as a whole. Studies of COS to date reveal progressive loss of gray matter volume and cortical thinning, ventricular enlargement, progressive decline in cerebellar volume and a significant but fixed deficit in hippocampal volume. COS is also associated with a slower rate of white matter growth and disrupted local connectivity strength. Sibling studies indicate that non-psychotic siblings of COS patients share many of these brain abnormalities, including decreased cortical thickness and disrupted white matter growth, yet these abnormalities normalize with age. Cross-sectional and longitudinal neuroimaging studies remain some of the few methods for assessing human brain function and play a pivotal role in the quest for understanding the neurobiology of schizophrenia as well as other psychiatric disorders. Parallel studies in non-psychotic siblings provide a unique opportunity to understand both risk and resilience in schizophrenia.

Long-term outcomes in children with atypical psychosis have been poorly studied. Four to 6 weeks of inpatient observation and up to 11 years (mean, 4.0 +/- 1.3 years) of follow- up have afforded us some experience with this probably heterogeneous group of transiently psychotic patients commonly mislabeled as schizophrenic. Despite severe preadmission morbidity, some patients have successfully remained neuroleptic-free since discharge. Predictors of good versus poor outcome were sought.Of roughly 150 patients admitted with the presumptive diagnosis of schizophrenia, 32 patients were discharged meeting criteria for psychosis not otherwise specified (NOS), otherwise labeled by the NIMH team as "multidimensionally impaired" (MDI). Admission and biannual follow-up data included a semistructured clinical interview with the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS), IQ testing, clinical rating scales (e.g., Clinical Global Impression Scale (CGI), Children's Global Assessment Scale (C-GAS), Brief Psychiatric Rating Scale (BPRS), Scales for the Assessment Negative and Positive Symptoms (SANS and SAPS), and Bunney-Hamburg (B-H)). At follow-up (as of February 2005) 38% of patients (12 of 32) met criteria for bipolar 1 disorder, 12% (4 of 23) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free ("good outcome," n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy ("poor outcome," n = 10) at follow-up.Good-outcome patients had a significantly higher baseline level of functioning (on admission and on medications). This was demonstrated by better scores on CGI (3.5 +/- 0.6 versus 4.8 +/- 0.8; p = 0.03) and C-GAS (66.3 +/- 6.3 versus 38.6 +/- 11.5; p = 0.01). Groups were otherwise comparable in demographic data (gender, race, socioeconomic status, age at onset), months of neuroleptic exposure, severity of psychotic symptoms, and level of premorbid functioning.C-GAS (which correctly classified 85.7% of good-outcome subjects) and CGI at baseline appear to predict outcome. On other variables, MDI subgroups were remarkably similar.

Background Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. Aims To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). Method Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. Results COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. Conclusions Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. Declaration of interest The study was done at the National Institutes of Health.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

The administration of psychostimulants to children with psychotic symptoms is controversial. This study reports the stimulant drug response of 5 children, aged 8-15 years, with childhood-onset schizophrenia (COS) and comorbid attention deficit hyperactivity disorder (ADHD). Four COS inpatients were given stimulants for comorbid ADHD after stabilization of psychosis on antipsychotic medication. A fifth COS inpatient received stimulants while still actively psychotic, despite concurrent neuroleptic treatment. Data from the 10-item Brief Conners Teachers Ratings Scale (BCTRS) were examined the week before, and the week after, stimulant addition. A paired t test, conducted using Conners Teachers data from these 4 subjects, indicated significant improvement in ADHD symptoms (p = 0.02). Data obtained from a retrospective chart review indicated no significant worsening of psychosis. The 2 subjects treated with mixed salts of dextroamphetamine sulfate and amphetamine sulfate remained on that medication at 6 months and at the 2-year follow-up. Our results suggest that ADHD comorbid with COS may be safely treated with a stimulant, once the psychosis is stabilized. A systematic investigation of this question may be warranted.

Background Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. Methods Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). Results Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD ( n = 12) than for the non-PDD ( n = 27) subgroup (−19.5 ± 11.3 mL/year vs. −9.6 ± 15.3 mL/year; p = .05). None of eight candidate genes for autism were associated with COS or COS-PDD. Conclusions Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.

Diffusion tensor imaging is a neuroimaging method that quantifies white matter (WM) integrity and brain connectivity based on the diffusion of water in the brain. White matter has been hypothesized to be of great importance in the development of schizophrenia as part of the dysconnectivity model. Childhood-onset schizophrenia (COS), is a rare, severe form of the illness that resembles poor outcome adult-onset schizophrenia. We hypothesized that COS would be associated with WM abnormalities relative to a sample of controls.To evaluate WM integrity in this population 39 patients diagnosed with COS, 39 of their healthy (nonpsychotic) siblings, and 50 unrelated healthy volunteers were scanned using a diffusion tensor imaging (DTI) sequence during a 1.5 T MRI acquisition. Each DTI scan was processed via atlas-based analysis using a WM parcellation map, and diffeomorphic mapping that shapes a template atlas to each individual subject space. Fractional anisotropy (FA), a measure of WM integrity was averaged over each of the 46 regions of the atlas. Eleven WM regions were examined based on previous reports of WM growth abnormalities in COS.Of those regions, patients with COS, and their healthy siblings had significantly lower mean FA in the left and right cuneus as compared to the healthy volunteers (P.005). Together, these findings represent the largest DTI study in COS to date, and provide evidence that WM integrity is significantly impaired in COS. Shared deficits in their healthy siblings might result from increased genetic risk.

Objective: Among children 90%, overall accuracy>77%, and areas under the curve (AUCs)>86%. Conclusions: COS can be distinguished from alternate disorders with psychosis in children and adolescents; greater levels of positive and negative symptoms and lower levels of depression combine to make COS more likely. We include a worksheet so that clinicians in the community and academic centers can predict the probability that a young patient may be schizophrenic, using only two ratings.