Psychosis brain subtypes validated in first-episode cohorts and related to illness remission: results from the PHENOM consortium.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups-a 'lower brain volume' subgroup (SG1) and an 'higher striatal volume' subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership ('None'), and mixed SG1 + SG2 subgroups ('Mixed'). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of 'lower brain volume' in SG1 and 'higher striatal volume' (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

Multisite Machine Learning Analysis Provides a Robust Structural Imaging Signature of Schizophrenia Detectable Across Diverse Patient Populations and Within Individuals.

Past work on relatively small, single-site studies using regional volumetry, and more recently machine learning methods, has shown that widespread structural brain abnormalities are prominent in schizophrenia. However, to be clinically useful, structural imaging biomarkers must integrate high-dimensional data and provide reproducible results across clinical populations and on an individual person basis. Using advanced multi-variate analysis tools and pooled data from case-control imaging studies conducted at 5 sites (941 adult participants, including 440 patients with schizophrenia), a neuroanatomical signature of patients with schizophrenia was found, and its robustness and reproducibility across sites, populations, and scanners, was established for single-patient classification. Analyses were conducted at multiple scales, including regional volumes, voxelwise measures, and complex distributed patterns. Single-subject classification was tested for single-site, pooled-site, and leave-site-out generalizability. Regional and voxelwise analyses revealed a pattern of widespread reduced regional gray matter volume, particularly in the medial prefrontal, temporolimbic and peri-Sylvian cortex, along with ventricular and pallidum enlargement. Multivariate classification using pooled data achieved a cross-validated prediction accuracy of 76% (AUC = 0.84). Critically, the leave-site-out validation of the detected schizophrenia signature showed accuracy/AUC range of 72-77%/0.73-0.91, suggesting a robust generalizability across sites and patient cohorts. Finally, individualized patient classifications displayed significant correlations with clinical measures of negative, but not positive, symptoms. Taken together, these results emphasize the potential for structural neuroimaging data to provide a robust and reproducible imaging signature of schizophrenia. A web-accessible portal is offered to allow the community to obtain individualized classifications of magnetic resonance imaging scans using the methods described herein.

Physical Fitness and Metabolic Syndrome in Children with Repaired Congenital Heart Disease Compared with Healthy Children.

OBJECTIVE: To determine whether children who underwent surgery for congenital heart disease (CHD) are as fit as their peers. STUDY DESIGN: We studied 66 children (6-14 years) who underwent surgery for ventricular septal defect (n = 19), coarctation of aorta (n = 10), tetralogy of Fallot (n = 15), and transposition of great arteries (n = 22); and 520 healthy children (6-12 years). All children performed physical fitness tests: cardiorespiratory fitness, muscular strength, balance, flexibility, and speed. Metabolic score was assessed through z-score standardization using 4 components: waist circumference, blood pressure, blood lipids, and insulin resistance. Assessment also included self-reported and accelerometer-measured physical activity. Linear regression analyses with group (CHD vs control) as a predictor were adjusted for age, body mass index, physical activity, and parental education. RESULTS: Measured physical activity level, body mass index, cardiorespiratory fitness, flexibility, and total metabolic score did not differ between children with CHD and controls, whereas reported physical activity was greater in the CHD group than control group. Boys with CHD were less strong in upper muscular strength, speed, and balance, whereas girls with CHD were better in lower muscular strength and worse in balance. High-density lipoprotein was greater in boys and girls with CHD, whereas boys with CHD showed unhealthier glucose homeostasis. CONCLUSION: Appropriate physical fitness was achieved in children after surgery for CHD, especially in girls. Consequently, children with CHD were not at increased total metabolic risk. Lifestyle counseling should be part of every patient interaction.

Neurodevelopment and behavior after transcatheter versus surgical closure of secundum type atrial septal defect.

OBJECTIVE: To assess the neuropsychological and behavioral profiles of school-aged children treated for atrial septal defect, secundum type (ASD-II) with open-heart surgery or catheterization. STUDY DESIGN: Patients (n = 48; mean age, 9 years, 3 months) and a matched healthy group (mean age, 9 years, 2 months) were evaluated with a shortened intelligence scale (Wechsler Intelligence Scale for Children, third edition, Dutch version) and a developmental neuropsychological test battery (Developmental Neuropsychological Assessment, second edition, Dutch version). Parents completed behavioral checklists (Achenbach Child Behavior Checklist for Children aged 6-18). Hospitalization variables were retrieved from medical files for studying associations with long-term neurodevelopment. RESULTS: Compared with the healthy matched controls, patients treated for ASD-II had significantly lower scores on subtasks underlying such Developmental Neuropsychological Assessment, second edition, Dutch version domains as Attention and Executive Functioning, Language, Working Memory, Sensorimotor Functioning, Social Cognition, and Visuospatial Information Processing. Only subtle differences, mainly in Visuospatial Information Processing, were found between the surgical repair and transcatheter repair groups. Socioeconomic status, longer hospital stay, and larger defect size were associated with neurocognitive outcome measures. Parents of patients reported more thought problems, posttraumatic stress problems, and lower school performance compared with parents of healthy peers. CONCLUSION: After treatment for ASD-II, children display a range of neuropsychologic difficulties that may increase their risk for learning problems and academic underachievement. Differences related to treatment were not found. Our results suggest that neurodevelopmental and behavioral follow-up at school age is warranted in this group.

Neuropsychological performance in school-aged children with surgically corrected congenital heart disease.

OBJECTIVE: As surgical management of children with congenital heart disease (CHD) advanced, developmental outcome became the main focus of contemporary research. In this study, we specify the cognitive profile of children with CHD, 6 to 12 years postoperatively. STUDY DESIGN: Patients with CHD (n = 43, mean age 8 years, 8 months) and healthy controls (n = 43, mean age 8 years, 11 months), were examined with an abbreviated intelligence scale (Wechsler Intelligence Scale for Children-3rd edition, Dutch version) and a developmental neuropsychological assessment battery (NEPSY [a developmental NEuroPSYchological assessment]). RESULTS: We identified significantly lower scores for the CHD group on Estimated Full Scale IQ (P < .01). Neuropsychological assessment revealed lower scores for the CHD group on the cognitive domains of Sensorimotor Functioning (P < .001), Language (P < .001), Attention and Executive Functioning (P < .05), and Memory (P < .05). Children with CHD displayed more impulsive test behavior than healthy peers. No differences on IQ or cognitive domains were found between the cyanotic and the acyanotic CHD group. CONCLUSIONS: Six to 12 years postoperatively, children with CHD display a neuropsychological profile with mainly mild motor deficits and subtle difficulties with language tasks. Attention/executive functioning and memory also appear involved but to a lesser degree. Long-term follow-up of children with surgically corrected CHD, even when hemodynamically successful, is warranted, as they are at risk for neurodevelopmental delay at school age.

Left ventricular outflow obstruction in rhabdomyoma of infancy: meta-analysis of the literature.

Primary heart tumors are exceptional in infants and children. Most common is the rhabdomyoma, often associated with tuberous sclerosis (Bourneville's disease). This tumor is generally believed to have no hemodynamic effects in the majority of cases. Recently, severe obstruction of the left ventricular outflow tract by a solitary tumor was diagnosed during pregnancy and emergency surgery was needed soon after birth.

QTc interval prolongation and QTc dispersion in children and adolescents with type 1 diabetes.

OBJECTIVES: To evaluate whether QT interval, QT interval corrected for heart rate (QTc), and QTc dispersion changes are already present in children and adolescents with diabetes. STUDY DESIGN: QT interval, QTc, and QTc dispersion were measured on a 12-lead surface electrocardiogram in 60 children and adolescents with stable type 1 diabetes and in 63 sex- and age-matched control subjects. Differences were evaluated by using the Kolmogorov-Smirnov Z test. The number of patients with QTc > 440 ms was compared in the two groups. The possible influence of age, sex, diabetes duration, and glycosylated hemoglobin (HbA(1c)) was examined by using Spearman correlation analysis. RESULTS: Diabetic children had significantly longer QTc intervals and a significantly larger QTc dispersion. The number of individuals with a QTc >440 ms was significantly higher in the diabetic group (14/60) than in the control group (2/63). The effect of age on R-R interval and QTc dispersion in healthy children was less pronounced in children with diabetes. HbA(1C) values did not significantly correlate with any of the parameters. CONCLUSIONS: QTc prolongation and a larger QTc dispersion are already present in a significant proportion of children and adolescents with diabetes.