Genetic risk for schizophrenia impacts Theory-of-Mind-related brain activation

Abstract

Problems with mentalizing, also called Theory of Mind (ToM), are a hallmark of schizophrenia. Here we show that activation during mentalizing of emotions (green) in healthy controls is modulated by a genetic risk variant for psychosis. A frequent functional single-nucleotide polymorphism in an intron of the ZNF804A gene is the first genetic variant that has been found to be associated with schizophrenia and bipolar disorder on a genomewide significance level. Key areas of the ToM-Network (in red) previously found to be hypoactive in schizophrenia show decreasing ToM-specific activation with the number of risk alleles. For more info on this topic, please refer to the article by Walter et al. on pages 462-470.

ZNF804A Genotype Modulates Neural Activity during Working Memory for Faces

“…The rs1344706 genotype (T = risk allele) is associated with alterations in functional connectivity between prefrontal and inter-hemispheric prefrontal/hippocampal networks in healthy controls during WM [19,20,21], face processing and resting state [22]. The functional effects of the rs134407 variant may extend to a broad range of cognitive phenotypes such as social cognition [23,24] and attentional networks [25,26]. ZNF804A may influence cell adhesion [27] and regulate expression of other genes [28], whereas the rs1344706 variant may have a functional role in the transcription of the ZNF804A gene [29].…”

Effects of ZNF804A on neurophysiologic measures of cognitive control

“…2 Although the physiological function of ZNF804A and its role in schizophrenia risk is currently unclear, the gene has been shown to be associated with psychosis, 3 and several potential intermediate biological phenotypes, such as deficits in executive function 4 and altered cortical connectivity during working memory 5,6 and theory of mind. 7 …”

The role of the amygdala in naturalistic mentalising in typical development and in autism spectrum disorder

“…These disorders involve an aberrant functional profile of the amygdala 42,43 as well as ToM impairments. 8,44,45 Future studies need to investigate whether the relationship between amygdala dysfunction and ToM in naturalistic settings holds true for schizophrenia and borderline personality disorder and if so whether their symptomatology can be mitigated by treatments that focus on mentalising (for example Dimaggio et al 46 and Lysaker & Dimaggio 47 ). In sum, amygdala functioning might represent a biomarker that predicts response to social cognitive treatments in a number of psychiatric conditions characterised by social impairments.…”

“…5 Despite the importance of implicit mentalising for effective social functioning in naturalistic settings, most studies have investigated explicit mentalising processes with abstract and static stimuli such as written stories 6 or cartoon tasks. 7,8 Consequently, such paradigms might lack the sensitivity to detect subtle aberrant behaviour and brain function in individuals with social impairments in real life.…”