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. 2013). 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. 2013). Similarly, recent analyses also show that COS probands and their sibling show overlapping developmental deficits in insula compared to matched controls (Moran et al. 2013a);and that sibling brain developmental defects tend to be age limited, (Moran et al 2013b). 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 resilience factors or circuits in the brain that are relevant to early psychosis. A new functional MRI study in collaboration with Dr Karen Berman, NIMH, is studying functional response during two working memory tasks 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. 2013). 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. There is a higher rate of rare copy number variants (CNVs), with 126 probands, involving 75 proband/sib pairs, and access to the current Database of Genomic Variation of over 26,000 individuals. A total of 12% 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 and to that for adult onset schizophrenia patients (p<.05) (Ahn et al. 2013). To better understand the heritability of COS, exomic sequesting of 73 trios is being completed in collaboration with Matthew State, MD, (Yale). We are also finding an increased rate of rare CNVs for a group of our patients with severe early onset non-schizophrenic disorders indicating the non-specifity of CNV risk. 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). Evidence from 4 iPSC derived neurons 22q11 subjects indicated reduced L-type voltage gated calcium responses in pyramidal neurons (Dolmetsch in preparation). 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 (David et al. 2013). 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. We continue to advise on use of clozapine for COS and to establish guidelines for monitoring its use (Maher et al 2013) (Merikangas et al 2013). These studies are of particular importance given the dearth of new treatments in child psychiatry (Merikangas et al 2013) (Rapoport et al 2013).

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Ambalavanan, Amirthagowri; Girard, Simon L; Ahn, Kwangmi et al. (2016) De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet 24:944-8
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