Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia

Abstract

The symptoms of schizophrenia imply disruption to brain systems supporting higher-order cognitive activity, but whether these systems are impacted differentially against a background of diffuse cortical gray-matter deficit remains ambiguous. Some unaffected first-degree relatives of schizophrenics also manifest cortical gray-matter deficits, but it is unclear whether these changes are isomorphic with those in patients, and the answer is critical to understanding the neurobiological conditions necessary for disease expression given a predisposing genotype. Here we report three-dimensional cortical surface maps (probabilistic atlases matching subjects' anatomy point by point throughout cortex) in monozygotic (MZ) and dizygotic (DZ) twins discordant for chronic schizophrenia along with demographically matched control twins. A map encoding the average differences between schizophrenia patients and their unaffected MZ co-twins revealed deficits primarily in dorsolateral prefrontal cortex, superior temporal gyrus, and superior parietal lobule. A map encoding variation associated with genetic proximity to a patient (MZ co-twins > DZ co-twins > control twins) isolated deficits primarily in polar and dorsolateral prefrontal cortex. In each case, the statistical significance was confirmed through analysis of 10,000 Monte Carlo permutations, and the remaining cortex was shown to be significantly less affected by contrast analysis. The disease-related deficits in gray matter were correlated with measures of symptom severity and cognitive dysfunction but not with duration of illness or antipsychotic drug treatment. Genetic and disease-specific influences thus affect gray matter in partially nonoverlapping areas of predominantly heteromodal association cortex, changes that may act synergistically in producing overt behavioral features of the disorder.

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

“…People at high risk of psychosis show qualitatively similar volumetric abnormalities to patients with schizophrenia. Cortical brain abnormalities have been found in genetically defined high-risk populations such as first-degree relatives and co-twins of patients with schizophrenia, as well in people with ARMS [13,[68][69][70][71][72][73][74][75][76][77][78][79][80]. Previous longitudinal MRI studies in this group found that the subset of patients who developed psychosis showed a longitudinal reduction in GM in the orbito-frontal, temporal lobe, parietal lobe and cerebellum [79,81,82].…”

Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia

“…Nevertheless, studies indicate that cortical surface parameters are linked to neurodevelopmental processes that undergo only partial reshaping across the lifespan (Wienberger and McClure, 2002;Mangin et al, 2010). Surface parameters can be viewed as promising endophenotypes (Cannon et al, 2002;Goghari et al, 2007;Goldman et al, 2009;Qiu et al, 2010). Methods for characterizing cortical surface morphology, for example, by folding patterns, continue to emerge.…”

Cortical mapping of genotype–phenotype relationships in schizophrenia

“…Disease-specific deficits correlated with symptom severity and working and episodic memory impairment, but not with illness duration or treatment. (b) Significance map of genetic liability-related deficits: Gray matter deficits correlated with genetic proximity to a patient in polar and superior prefrontal cortex [Cannon et al 2002]. (c) Callosal surface averages mapped in groups defined by biological risk for schizophrenia.…”

“…To investigate the topography of genetically encoded deficits in cortical gray matter in schizophrenia, we created the first three-dimensional cortical surface maps of intrapair differences in MZ and DZ twins discordant for SZ (10 discordant pairs of each zygosity), along with 10 pairs of demographically matched control twins of each zygosity [Cannon et al, 2002] (Fig. 3).…”