Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Shared network-level functional alterations across substance use disorders: A multi-level kernel density meta-analysis of resting-state functional connectivity studies.

An increasing number of neuroimaging studies indicate functional alterations in cortico-striatal loops in individuals with substance use disorders (SUD). Dysregulations in these circuits may contribute to drug-seeking and drug-consuming behaviour by impeding inhibitory control, habit formation, and reward processing. Despite evidence of network-level changes in SUD, a shared pattern of functional alterations within and between spatially distributed brain networks has not been systematically investigated. The present meta-analytic investigation aims at identifying common alterations in resting-state functional connectivity patterns across different SUD, including stimulant, heroin, alcohol, cannabis, and nicotine use. To this aim, seed-based whole-brain connectivity maps for different functional networks were extracted and subjected to multi-level kernel density analysis to identify dysfunctional networks in individuals with SUD compared with healthy controls. In addition, an exploratory analysis examined substance-specific effects as well as the influence of drug use status on the main findings. Our findings indicate a hypoconnectivity pattern for the limbic, salience, and frontoparietal networks in individuals with SUD as compared with healthy controls. The default mode network additionally exhibited a complex pattern of hypo- and hyperconnectivity across the studies. The observed disrupted connectivity between networks in SUD may associate with deficient inhibitory control mechanisms that are thought to contribute to excessive craving and automatic drug-related behaviour as well as failure in substance use cessation. The identified network-based alterations in SUD represent potential treatment targets for neuromodulation, for example, network-based real-time functional magnetic resonance imaging (fMRI) neurofeedback. Such interventions can evaluate the behavioural relevance of the identified neural circuits.

Population variability in social brain morphology for social support, household size and friendship satisfaction.

The social brain hypothesis proposes that the complexity of human brains has coevolved with increasing complexity of social interactions in primate societies. The present study explored the possible relationships between brain morphology and the richness of more intimate 'inner' and wider 'outer' social circles by integrating Bayesian hierarchical modeling with a large cohort sample from the UK Biobank resource (n = 10 000). In this way, we examined population volume effects in 36 regions of the 'social brain', ranging from lower sensory to higher associative cortices. We observed strong volume effects in the visual sensory network for the group of individuals with satisfying friendships. Further, the limbic network displayed several brain regions with substantial volume variations in individuals with a lack of social support. Our population neuroscience approach thus showed that distinct networks of the social brain show different patterns of volume variations linked to the examined social indices.