Diverging functional connectivity timescales: Capturing distinct aspects of cognitive performance in early psychosis.

Background: Psychosis spectrum disorders (PSDs) are marked by cognitive impairments, the neurobiological correlates of which remain poorly understood. Here, we investigate the entropy of time-varying functional connectivity (TVFC) patterns from resting-state fMRI (rfMRI) as potential biomarker for cognitive performance in PSDs. By combining our results with multimodal reference data, we hope to generate new insights into the mechanisms underlying cognitive dysfunction in PSDs. We hypothesized that low-entropy TVFC patterns (LEN) would be more behaviorally informative than high-entropy TVFC patterns (HEN), especially for tasks that require extensive integration across diverse cognitive subdomains. Methods: rfMRI and behavioral data from 97 patients in the early phases of psychosis and 53 controls were analyzed. Positron-Emission Tomography (PET) and magnetoencephalography (MEG) data were taken from a public repository (Hansen et al., 2022). Multivariate analyses were conducted to examine relationships between TVFC patterns at multiple spatial scales and cognitive performance in patients. Results: Compared to HEN, LEN explained significantly more cognitive variance on average in PSD patients, driven by superior encoding of information on psychometrically more integrated tasks. HEN better captured information in specific subdomains of executive functioning. Nodal HEN-LEN transitions were spatially aligned with neurobiological gradients reflecting monoaminergic transporter densities and MEG beta power. Exploratory analyses revealed a close statistical relationship between LEN and positive PSD symptoms. Conclusion: Our entropy-based analysis of TVFC patterns dissociates distinct aspects of cognition in PSDs. By linking topographies of neurotransmission and oscillatory dynamics with cognitive performance, it enhances our understanding of the mechanisms underlying cognitive deficits in PSDs. CRediT Authorship Contribution Statement: Fabian Hirsch: Conceptualization, Methodology, Software, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Visualization; Ângelo Bumanglag: Methodology, Software, Formal analysis, Writing - Review & Editing; Yifei Zhang: Methodology, Software, Formal analysis, Writing - Review & Editing; Afra Wohlschlaeger: Methodology, Writing - Review & Editing, Supervision, Project administration.

Subcortical influences on the topology of cortical networks align with functional processing hierarchies.

fMRI of the human brain reveals spatiotemporal patterns of functional connectivity (FC), forming distinct cortical networks. Lately, subcortical contributions to these configurations are receiving renewed interest, but investigations rarely focus explicitly on their effects on cortico-cortical FC. Here, we employ a straightforward multivariable approach and graph-theoretic tools to assess subcortical impact on topological features of cortical networks. Given recent evidence showing that structures like the thalamus and basal ganglia integrate input from multiple networks, we expect increased segregation between cortical networks after removal of subcortical effects on their FC patterns. We analyze resting state data of young and healthy participants (male and female; N = 100) from the human connectome project. We find that overall, the cortical network architecture becomes less segregated, and more integrated, when subcortical influences are accounted for. Underlying these global effects are the following trends: 'Transmodal' systems become more integrated with the rest of the network, while 'unimodal' networks show the opposite effect. For single nodes this hierarchical organization is reflected by a close correspondence with the spatial layout of the principal gradient of FC (Margulies et al., 2016). Lastly, we show that the limbic system is significantly less coherent with subcortical influences removed. The findings are validated in a (split-sample) replication dataset. Our results provide new insight regarding the interplay between subcortex and cortical networks, by putting the integrative impact of subcortex in the context of macroscale patterns of cortical organization.

Quantification of Kuramoto Coupling Between Intrinsic Brain Networks Applied to fMRI Data in Major Depressive Disorder.

Organized patterns of system-wide neural activity adapt fluently within the brain to adjust behavioral performance to environmental demands. In major depressive disorder (MD), markedly different co-activation patterns across the brain emerge from a rather similar structural substrate. Despite the application of advanced methods to describe the functional architecture, e.g., between intrinsic brain networks (IBNs), the underlying mechanisms mediating these differences remain elusive. Here we propose a novel complementary approach for quantifying the functional relations between IBNs based on the Kuramoto model. We directly estimate the Kuramoto coupling parameters (K) from IBN time courses derived from empirical fMRI data in 24 MD patients and 24 healthy controls. We find a large pattern with a significant number of Ks depending on the disease severity score Hamilton D, as assessed by permutation testing. We successfully reproduced the dependency in an independent test data set of 44 MD patients and 37 healthy controls. Comparing the results to functional connectivity from partial correlations (FC), to phase synchrony (PS) as well as to first order auto-regressive measures (AR) between the same IBNs did not show similar correlations. In subsequent validation experiments with artificial data we find that a ground truth of parametric dependencies on artificial regressors can be recovered. The results indicate that the calculation of Ks can be a useful addition to standard methods of quantifying the brain's functional architecture.