Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings

Abstract

IMPORTANCE Abnormalities in structural brain connectivity have been observed in patients with schizophrenia. Mapping these abnormalities longitudinally and understanding their genetic risk via sibship studies will provide crucial insight into progressive developmental changes associated with schizophrenia.OBJECTIVES To identify corticocortical connections exhibiting an altered developmental trajectory in adolescents with childhood-onset schizophrenia (COS) and to determine whether similar alterations are found in patients' unaffected siblings. DESIGN, SETTING, AND PARTICIPANTS Using prospective structural brain magnetic resonance imaging, large-scale corticocortical connectivity was mapped from ages 12 to 24 years in 109 patients with COS (272 images), 86 of their unaffected siblings (184 images), and 102 healthy controls (262 images) over a 20-year period beginning January 1, 1991, through April 30, 2011, as part of the ongoing COS study at the National Institute of Mental Health. MAIN OUTCOMES AND MEASURESStructural connectivity between pairs of cortical regions was estimated using a validated technique based on across-subject covariation in magnetic resonance imaging-derived cortical thickness measurements.RESULTS Compared with normally developing controls, significant left-hemisphere occipitotemporal deficits in cortical thickness correlations were found in patients with COS as well as their healthy siblings (P < .05). Deficits in siblings normalized by mid-adolescence, whereas patients with COS showed significantly longer maturational delays, with cortical thickness correlations between the left temporal lobe and left occipital cortex not showing evidence of development until early adulthood. The normalization of deficits with age in patients with COS correlated with improvement in symptoms. Compared with controls, left-hemisphere occipitotemporal thickness correlations in a subgroup of patients with high positive symptoms were significantly reduced from age 14 to 18 years (P < .05); however, other patients with low positive symptoms showed no significant deficits.CONCLUSIONS AND RELEVANCE Delayed maturation of occipitotemporal connectivity appears to be a trait marker in patients with COS, with a milder endophenotype in unaffected siblings associated with resilience to developing schizophrenia. These findings indicate genetically influenced and connection-specific developmental abnormalities in the schizophrenia connectome, and lead to the hypothesis that visual hallucinations in patients with COS may be because of delayed development of the inferior longitudinal fasciculus, a prominent occipitotemporal fiber.

Generative network models identify biological mechanisms of altered structural brain connectivity in schizophrenia

“…Converging evidence supports the notion that wiring disruptions of brain networks may partially underlie these abnormalities (5)(6)(7). Indeed, previous studies have found marked differences in the brain network architecture in schizophrenia (8,9) and delineated alterations in their structural development (10). More generally, human brain networks show a complex architecture favoring topologically advantageous properties while still being sparsely connected, in line with the proposal that the developmental architecture of the human brain connectome results from an economic trade-off between minimizing wiring costs and allowing adaptively valuable topological features (11).…”

Adolescent Tuning of Association Cortex in Human Structural Brain Networks

“…In humans, the differential variance contained within cortical morphology and structural network architecture could be investigated through further within-population comparisons of these measures, in (1) their ability to discriminate between case–control populations, (2) their association to behavioral and cognitive measures, and (3) their heritability. For example, patients with childhood-onset schizophrenia have shown differences in adolescent trajectories of both cortical thinning (Alexander-Bloch et al 2014) and structural correlation (Zalesky et al 2015) relative to healthy controls, but the measures have not been explicitly compared.…”

Cognitive intervention in early psychosis — preserving abilities versus remediating deficits

“…This derives from the notion that individuals at heightened risk for a schizophrenia-spectrum disorder (but who do not develop the illness) show a normalisation of abnormalities as they mature into adulthood. This is evidenced in studies examining trajectories of brain development in the unaffected siblings of childhood schizophrenia cases [60][61][62] (for discussion: 10,11,16]). Specifically, abnormalities found in childhood and early adolescence normalise during adolescence, including evidence of increased brain volumes and brain connectivity.…”