Genetic changes linked to altered default mode network in psychosis

Researchers have identified biological processes likely to underlie altered activity in the resting-state default mode network (DMN) in patients with psychosis.

The study involved 1305 participants who underwent functional magnetic resonance imaging. They included 324 mentally healthy controls, 296 patients with schizophrenia and 179 of their unaffected first-degree relatives, and 300 patients with psychotic bipolar disorder and 206 of their unaffected first-degree relatives.

Lead study author Shashwath Meda (Institute of Living at Hartford Hospital, Connecticut, USA) and team identified three DMNs in these participants: an anterior, inferior-posterior, and superior-posterior DMN.

All three DMNs showed hypoconnectivity in the psychosis patients compared with controls, and this correlated with symptom measures including Positive and Negative Syndrome Scale scores. However, there were no areas of hyperconnectivity, as has been reported in some previous studies.

The superior-posterior DMN differentiated schizophrenia patients from bipolar patients, with the former having significantly more pronounced hypoconnectivity than the latter. Also, in the anterior DMN, the hypoconnectivity seen in schizophrenia patients extended to their relatives.

This confirms the role of the DMN in psychosis, say the researchers in the Proceedings of the National Academy of Sciences USA. And they add: “Most importantly we were able to dissect the underlying biological/molecular pathways and processes that might mediate genetic risk of psychosis via a valuable, noninvasive imaging marker.”

A subset of 549 patients and controls underwent genetic analysis in parallel with the imaging. This revealed clusters of genes that had significant associations with connectivity in five sub-DMNs, two in the anterior, one in the inferior-posterior and two in the superior-posterior DMN.

For example, one of the associations in the anterior DMN involved a subnetwork encompassing the anterior cingulate and medial prefrontal cortex, the connectivity of which correlated with 454 single nucleotide polymorphisms in 386 genes.

Across the five phenotype–genotype associations, the most heavily represented pathways included N-methyl-D-aspartate–dependent postsynaptic long-term potentiation, protein kinase A signalling and interleukin-15 signalling. Process networks included axonal guidance and synaptic contact, and metabolic networks included ceramides and N-acyl-sphingosine pathways.

Meda et al say that such pathways have been directly linked to psychotic diagnoses. By contrast, their study provides a link with a recognised, measurable intermediate phenotype, rather than with psychiatric diagnoses that are “based on clinical phenomenology and lack biological validity”.

They conclude: “Having measurable phenotypes and knowing their molecular underpinnings in a transdiagnostic, multivariate-context suggest novel strategies for drug targeting and customization in these serious disorders.”

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