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.

Objective Cortical gray matter (GM) abnormalities in patients with childhood-onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to “normalize” by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls. Method Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval–matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. Results As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17. Conclusions Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings.

Introduction: Multivariate machine learning methods can be used to classify groups of schizophrenia patients and controls using structural magnetic resonance imaging (MRI). However, machine learning methods to date have not been extended beyond classification and contemporaneously applied in a meaningful way to clinical measures. We hypothesized that brain measures would classify groups, and that increased likelihood of being classified as a patient using regional brain measures would be positively related to illness severity, developmental delays, and genetic risk. Methods: Using 74 anatomic brain MRI sub regions and Random Forest (RF), a machine learning method, we classified 98 childhood onset schizophrenia (COS) patients and 99 age, sex, and ethnicity-matched healthy controls. We also used RF to estimate the probability of being classified as a schizophrenia patient based on MRI measures. We then explored relationships between brain-based probability of illness and symptoms, premorbid development, and presence of copy number variation (CNV) associated with schizophrenia. Results: Brain regions jointly classified COS and control groups with 73.7% accuracy. Greater brain-based probability of illness was associated with worse functioning (p = 0.0004) and fewer developmental delays (p = 0.02). Presence of CNV was associated with lower probability of being classified as schizophrenia (p = 0.001). The regions that were most important in classifying groups included left temporal lobes, bilateral dorsolateral prefrontal regions, and left medial parietal lobes. Conclusion: Schizophrenia and control groups can be well classified using RF and anatomic brain measures, and brain-based probability of illness has a positive relationship with illness severity and a negative relationship with developmental delays/problems and CNV-based risk.

Objective Previous anatomic studies have established a reduction in hippocampal volume in schizophrenia, but few have investigated the progressive course of these changes and whether they are trait markers. In the present study, the authors examined hippocampal volumes in relation to age for patients with childhood-onset schizophrenia, their nonpsychotic healthy siblings, and healthy comparison subjects. Method Anatomic brain magnetic resonance scans were obtained in childhood-onset schizophrenia probands (N=89, 198 scans), their nonpsychotic full siblings (N=78, 172 scans), and matched healthy comparison subjects (N=79, 198 scans) between the ages of 10 and 29 years. Total, left, and right hippocampal volumes were measured using FreeSurfer software and analyzed using a linear mixed-model regression covarying for sex and intracranial volume. Results Childhood-onset schizophrenia probands had a fixed reduction in hippocampal volumes (total, left, and right) relative to both nonpsychotic siblings and healthy comparison subjects, whereas there were no significant volumetric or trajectory differences between nonpsychotic siblings and healthy comparison subjects. Conclusions Fixed hippocampal volume loss seen in childhood-onset schizophrenia, which is not shared by healthy siblings, appears to be related to the illness. Decreased hippocampal volume is not strong ly genetically related but represents an important intermediate disease phenotype.

Context Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. Objective To study WM growth differences in non-psychotic siblings of patients with COS. Design Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. Setting National Institutes of Health Clinical Center, Bethesda, Maryland. Participants Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1[5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9[5.3] years; 29 male, 28 female). Intervention Magnetic resonance imaging. Main Outcome Measure White matter growth rates. Results We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P =.004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. Conclusions In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

Background Neuroanatomic studies have not yet addressed how subtle phenotypic distinctions in psychosis alter the underlying brain changes, and whether there is evidence for psychosis as a dimensional construct. We explored the relationship of cortical GM thickness to psychotic phenotypes in children. Methods Cross-sectional comparison of anatomic brain imaging between patients referred as childhood-onset schizophrenia (COS) but ruled out after a drug free inpatient observation. Groups included: patients with no evidence of psychosis (n=22) after drug free observation, patients with psychosis not otherwise specified (PNOS; total n=29) further divided into those without other axis I diagnoses (n=13) and those with other axis I comorbidities (n=16), age/sex matched COS patients (n=48), and 51 matched healthy controls. GM cortical thickness was compared between the groups, and regressed on patients’ SAPS, SANS and GAS scores. Results Patients with no evidence of psychosis showed no cortical GM deficits. Presence of psychosis (PNOS with or without co-morbidities) showed some areas of temporal and prefrontal deficits, more subtle compared to the extensive bilateral cortical deficits seen for COS. GAS SAPS and SANS scores showed a relationship with cortical GM thickness although it did not survive adjustment for multiple comparisons. Conclusions These results highlight the need for careful phenotypic characterization, as subtle diagnostic distinctions appear to reflect distinct underlying patterns of brain deficits. The incremental nature of cortical deficits from no psychosis to PNOS to COS may further support dimensional model for psychosis.

Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children.