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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.

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.

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.

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.

Sleep disturbances in psychiatric disease have long been reported. However, research on sleep disturbances in child and adolescent psychiatric disorders is limited. We examined the relationship of sleep disturbance to clinical severity and co-morbid diagnoses (e.g. anxiety), for a population with childhood-onset schizophrenia (COS). Sixty-one COS patients underwent a medication-free inpatient observation period as part of an NIMH study of COS. Sleep quantity during the last 5-7 days of a patient's medication-free period was measured using safety records and daily nursing notes. Subjects were divided into two groups: "good sleepers" (>6 h) and "poor sleepers" (

Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). Methods: Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. Results: COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. Conclusions: Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the GABAergic inhibitory system shows protracted development and GABAergic deficits are widely replicated in post-mortem schizophrenia studies. We examined expression of several interneuron markers across postnatal human development and in schizophrenia to determine whether protracted development of certain interneuron subpopulations may make them particularly vulnerable in schizophrenia. Method: RNA was extracted from the dorsolateral prefrontal cortex of individuals (n=68) at developmental ages from 6 weeks to 49 years, and from a cohort consisting of controls and schizophrenia subjects (n=37 pairs). Expression levels of parvalbumin, cholecystokinin, somatostatin, neuropeptide Y, calretinin, calbindin, and vasoactive intestinal peptide were measured by quantitative reverse transcriptase-polymerase chain reaction. Western blots were used to examine changes in parvalbumin and calretinin protein levels. Results: Interneuron marker genes followed one of three general expressionprofiles, either increasing (parvalbumin, cholecystokinin) or decreasing (somatostatin, calretinin, neuropeptide Y) in expression over postnatal life with themost dramatic changes seenwithin the first decade of life before reaching a plateau; or a dynamic pattern increasing topeakexpressionat toddler age, thendecreasing (calbindin, vasoactive intestinal peptide). Expressionof all interneuronmarker genes,with the exception of calbindin (which increased), showed a significant reduction (between 8 31%) in schizophrenia. Somatostatin showed the most dramatic reduction (31%) in schizophrenia. Conclusions: Developmental changes in interneuron marker mRNAs extends well into school age suggesting that the inhibitory system takes years to mature in humans. It appears that a developmentally heterogeneous population of interneurons is affected in schizophrenia. Further studies will be required to determine if specific interneuron subpopulations are altered in schizophrenia or if common or distinct upstream pathways are responsible for the interneuron deficits in schizophrenia.