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.

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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.

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.

Childhood-onset schizophrenia (COS) is a rare severe form of schizophrenia that may have greater salient genetic risk. Despite evidence for high heritability, conclusive genetic causes of schizophrenia remain elusive. Recent genomic technologies in concert with large case-control cohorts, have led to several associations of highly penetrant rare copy number variants (CNVs) and schizophrenia. We previously reported two patients with COS who carried a microduplication disrupting the PXDN and MYT1L genes at 2p25.3. This is a significantly higher rate of duplications within our COS population (N=92) when compared to 2,026 healthy controls (p=0.002). As a replication, we report a meta-analysis of four recently published studies that together provide strong evidence for association between variably-sized microduplications involving the MYT1L gene and schizophrenia. None have reported this separately. Altogether, among 5,325 cases and 9,279 controls, 10 microduplications were observed; 9 in cases and 1 in a control (OR=15.7, p=0.001). Further, the 2% rate observed in our COS patients is also significantly higher than the rate in adult onset cases (0.14%, OR=16.6, p=0.01). This report adds to the growing body of literature implicating rare CNVs as risk factors for schizophrenia, and that some risk CNVs are more common among extreme early-onset cases.