In comparison with adult patients, childhood onset patients have a greater number of prepsychotic developmental disorders. One third have earlier forms of autism spectrum disorder, and one third have motor, speech, language, attentional or impulse related developmental disorders (Rapoport et al. 2009)(Driver et al submitted). Cognitive studies have begun within this protocol to obtain prospective measures of working memory, attention and learning for young full siblings of the childhood onset schizophrenia patients. It is hypothesized that some attention related earlier cognitive relative deficits will be ameliorated in parallel with temporal and frontal cortical brain/development(Gogtay et al. 2007; Mattai et al. 2011). Studies of anatomic hippocampal development in the healthy siblings showed no deviance from that seen for the healthy controls however a study in collaboration with colleagues at the University of Chicago show anterior hippocampal shape deviation in COS, similar to that seen for adult onset subjects, which are also shared, more subtly, by healthy COS siblings(Johnson et al. Submitted). Similarly, recent analyses also show that COS probands and their sibling show overlapping developmental deficits in insula compared to matched controls(Moran et al. submitted). We have increased our focus on studying the neurocircuitry development and abnormal connectivity in COS patients and their healthy siblings. Such analyses, particularly in healthy siblings may highlight the resilience factors or circuits in the brain that may be relevant to psychosis. A new functional MRI study in collaboration with Dr Karen Berman, NIMH, is studying functional response during an N Back working memory task for probands, healthy siblings and controls. Very preliminary data suggest that probands and to a lesser extend healthy siblings demonstrate increased recruitment in several brain regions including the right DLPFC and parietal circuits suggesting a subtle but perhaps more sensitive functional endophenotype. A recent study explored the small world networks properties using resting state fMRI data in COS patients which suggested loss of shorter connections while the longer connections were relatively preserved(Alexander-Bloch et al. 2012). These findings are now being extended to healthy COS siblings. We are actively recruiting younger siblings for these fMRI studies to see whether deficits in activation or (dys)connectivity relate to regions under greatest developmental change with respect to synaptic development. Several genetic studies are ongoing. Individual case studies from our cohort indicate that exome sequencing studies are likely to be informative as we are already finding unique variants in selected cases (Addington et al. 2011; Lee et al. 2012). While a previous report had indicated higher rate of rare copy number variants (CNVs), a reanalysis of array data updated to include 121 probands, involving 75 proband/sib pairs, and access to the current Database of Genomic Variation of over 26,000 individuals- A total of 8% of COS probands carry a rare, disease related CNV including 5 cases with the 22q11 deletion. This represents a significantly higher incidence compared to that seen for healthy controls ( p<.05) (Kwangmi et al. submitted). To better understand the heritability of schizenia, and to identify de novo gene mutations, collaborators at the University of Montreal (Dr. Guy Roulleau) are conducting targeted sequencing of 5,000 brain development-related genes from 30 trios, comprising affected children with schizophrenia and their parents. Using the trios, we are also probing rare variants that may be associated with the disease. An ongoing collaborative study with Dr. Ricardo Dolmetsch, Stanford University and the Allen Brain Institute, is studying neuronal activation and neurite development from iPS derived neurons from our childhood onset schizophrenia patients. Patients with and without rare disease associated copy number variants (CNVs) are included. Contrast groups will include unrelated healthy controls, and healthy and affected family members (some healthy carriers of risk CNVs). Finally, we continue to explore novel treatment strategies for this severely psychotic and treatment refractory population. Two inpatient treatment trials are currently ongoing; both with two week, double blind, placebo-controlled, parallel designs. The first trial explores the efficacy of trans-cranial direct current stimulation (TDCS) to (a) improve cognitive deficits by application of anodal current to bilateral DLPFC and (b) improve hallucinations by applying cathodal current to temporal cortex bilaterally. The second trial, which was just approved by the IRB, explores the efficacy of twice-daily intranasal oxytocin for enhancement of emotional cognition in COS and its effects on amygdalar-frontal emotional circuitry.