Differential patterns of age-related cortical and subcortical functional connectivity in 6-to-10 year old children: A connectome-wide association study

Introduction: Typical brain development is characterized by specific patterns of maturation of functional networks. Cortico-cortical connectivity generally increases, whereas subcortico-cortical connections often decrease. Little is known about connectivity changes amongst different subcortical regions in typical development. Methods: This study examined age- and gender-related differences in functional connectivity between and within cortical and subcortical regions using two different approaches. The participants included 411 six- to ten-year-old typically developing children sampled from the population-based Generation R study. Functional connectomes were defined in native space using regions of interest from subject-specific FreeSurfer segmentations. Connections were defined as: (a) the correlation between regional mean time-series; and (b) the focal maximum of voxel-wise correlations within FreeSurfer regions. The association of age and gender with each functional connection was determined using linear regression. The preprocessing included the exclusion of children with excessive head motion and scrubbing to reduce the influence of minor head motion during scanning. Results: Cortico-cortical associations echoed previous findings that connectivity shifts from short to long-range with age. Subcortico-cortical associations with age were primarily negative in the focal network approach but were both positive and negative in the mean time-series network approach. Between subcortical regions, age-related associations were negative in both network approaches. Few connections had significant associations with gender. Conclusions: The present study replicates previously reported age-related patterns of connectivity in a relatively narrow age-range of children. In addition, we extended these findings by demonstrating decreased connectivity within the subcortex with increasing age. Lastly, we show the utility of a more focal approach that challenges the spatial assumptions made by the traditional mean time series approach

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia

Short circuit : how brain connectivity and disconnectivity relate to brain function

The brain is like a super computer: it is a collection of interconnected computational units which work together to enable both basic functions, such as regulation of breathing, as well as higher functions, such as cognition, thought and emotion. The computational units, or regions, are located in the grey matter (i.e. the cortical surface and in the subcortex), whereas the connections between them, or tracts, are found in the white matter. The development and maintenance of both grey and white matter is essential to brain function. When either tissue type becomes compromised, so too does function. Brain connectivity can non-invasively be derived fro