Thalamic connectivity measured with fMRI is associated with a polygenic index predicting thalamo-prefrontal gene co-expression.

The functional connectivity between thalamic medio-dorsal nucleus (MD) and cortical regions, especially the dorsolateral prefrontal cortex (DLPFC), is implicated in attentional processing and is anomalous in schizophrenia, a brain disease associated with polygenic risk and attentional deficits. However, the molecular and genetic underpinnings of thalamic connectivity anomalies are unclear. Given that gene co-expression across brain areas promotes synchronous interregional activity, our aim was to investigate whether coordinated expression of genes relevant to schizophrenia in MD and DLPFC may reflect thalamic connectivity anomalies in an attention-related network including the DLPFC. With this aim, we identified in datasets of post-mortem prefrontal mRNA expression from healthy controls a gene module with robust overrepresentation of genes with coordinated MD-DLPFC expression and enriched for schizophrenia genes according to the largest genome-wide association study to date. To link this gene cluster with imaging phenotypes, we computed a Polygenic Co-Expression Index (PCI) combining single-nucleotide polymorphisms predicting module co-expression. Finally, we investigated the association between PCI and thalamic functional connectivity during attention through fMRI Independent Component Analysis in 265 healthy participants. We found that PCI was positively associated with connectivity strength of a thalamic region overlapping with the MD within an attention brain circuit. These findings identify a novel association between schizophrenia-related genes and thalamic functional connectivity. Furthermore, they highlight the association between gene expression co-regulation and brain connectivity, such that genes with coordinated MD-DLPFC expression are associated with coordinated activity between the same brain regions. We suggest that gene co-expression is a plausible mechanism underlying biological phenotypes of schizophrenia.

Association of familial risk for schizophrenia with thalamic and medial prefrontal functional connectivity during attentional control.

Anomalies in behavioral correlates of attentional processing and related brain activity are crucial correlates of schizophrenia and associated with familial risk for this brain disorder. However, it is not clear how brain functional connectivity during attentional processes is key for schizophrenia and linked with trait vs. state related variables. To address this issue, we investigated patterns of functional connections during attentional control in healthy siblings of patients with schizophrenia, who share with probands genetic features but not variables related to the state of the disorder. 356 controls, 55 patients with schizophrenia on stable treatment with antipsychotics and 40 healthy siblings of patients with this brain disorder underwent the Variable Attentional Control (VAC) task during fMRI. Independent Component Analysis (ICA) is allowed to identify independent components (IC) of BOLD signal recorded during task performance. Results indicated reduced connectivity strength in patients with schizophrenia as well as in their healthy siblings in left thalamus within an attentional control component and greater connectivity in right medial prefrontal cortex (PFC) within the so-called Default Mode Network (DMN) compared to healthy individuals. These results suggest a relationship between familial risk for schizophrenia and brain functional networks during attentional control, such that this biological phenotype may be considered a useful intermediate phenotype in order to link genes effects to aspects of the pathophysiology of this brain disorder.

Effects of emotional contexts on cerebello-thalamo-cortical activity during action observation.

Several studies investigated the neural and functional mechanisms underlying action observation in contexts with objects. However, actions seen in everyday life are often embedded in emotional contexts. The neural systems integrating emotion cues in action observation are still poorly understood. Previous findings suggest that the processing of both action and emotion information recruits motor control areas within the cerebello-thalamo-cortical pathways. It is therefore hard to determine whether social emotional contexts influence action processing via a direct modulation of motor representations coding for the observed action or via the affective state and implicit motor preparedness elicited in observers in response to emotional contexts. Here we designed a novel fMRI task to identify neural networks engaged by the affective appraisal of a grasping action seen in two different emotional contexts, while keeping the action kinematics constant. Results confirmed that observing the same acts of grasping but in different emotional contexts modulated activity in supplementary motor area, ventrolateral thalamus, anterior cerebellum. Moreover, changes in functional connectivity between left supplementary motor area and parahippocampus in different emotional contexts suggested a direct neural pathway through which emotional contexts may drive the neural motor system. Taken together, these findings shed new light on the malleability of motor system as a function of emotional contexts.