Anatomical And Neuromodulatory Basis Of Arousal Related Large-Scale Functional Connectivity Gradient Dynamics

The brain is a complex network of anatomically connected and functionally interacting neuronal populations.Recent advances in human fMRI connectome have brought an analytic tool,i.e.,large-scale cortical gradients,to capture the intrinsic dimensions of cortical organization.The principal functional gradient in humans is the unimodal-to-transmodal spatial gradient,tracking a functional hierarchy from direct perception and action to integration and abstraction of information.The secondary intrinsic dimension reveals a visual-tosensorimotor gradient which differentiates between the different sensory modalities.The functional gradients provide a novel perspective of how the large-scale functional networks are organized.Although previous evidences have suggested the structural relevance of functional cortical organization,it remains unclear whether the structural connectivity supports the functional connectivity in gradient aspects.Besides the stationary features of functional gradients,it is very likely that the large-scale cortical functional gradients are dynamic across multiple time scales.While many studies have already examined the structural or arousal contribution to resting-state functional connectivity as mentioned above,very few of them directly examined whether and how those factors are related to functional connectivity gradient and its dynamics.Here we developed standardized protocols for imaging awake marmosets,which were implemented across two institutions,the National Institutes of Health(NIH),USA,and the Institute of Neuroscience(ION),China.Then,we achieved a comprehensive resource that integrates the most extensive awake marmoset resting-state fMRI data available to date(39 marmoset monkeys,710 runs,12117 mins)with previously published cellular-level neuronal tracing data(52 marmoset monkeys,143 injections).In this work,we set out to investigate whether and how structural connectivity and ascending neuromodulatory system shapes functional gradients,and ultimately,the dynamic functional gradients,based on multimodal analysis.We systemically characterized the marmoset functional gradients,which resembles the children cortical organization of human,suggesting a potential link between developmental and evolutionary processes.Combined with the marmoset retrograde tracing atlas,we revealed structural gradients strongly shaped the functional gradients.Furthermore,based on the marmoset gene expression atlas,we found a "flood and ebb"-like functional gradients dynamics along with arousal fluctuations,in which structure connectivity and neuromodulatory system exhibited opposing effects.At the two extremes(very drowsy and alert)of arousal fluctuations,neuromodulatory contribution was elevated,while the contribution from structure connectivity was partially suppressed.Finally,we showed that the axes of functional gradients were closely related to spatial patterns of gene expression for specific families of neuromodulatory receptors,which provides a biological substrate for the modulation of large scale functional dynamics.In conclusion,through multimodal analysis of functional,structural and molecular datasets in marmoset monkeys,we revealed the structural basis and arousal modulation of the large-scale functional gradients in the cerebral cortex.Those results provide concrete and specific insights of the global functional organization,and provide a solid foundation for utilizing marmosets for studying large-scale functional dynamics and arousal.The current study also opens a number of new research directions for future work.First,the crossspecies comparison of functional gradients requires further comprehensive investigations.For example,whether the strong coupling of structural and cortical gradients holds for other species,particularly human,remains unclear.Second,with increasingly sophisticated tools available in marmosets,it would be beneficial to extend the current framework to neurological and psychiatric marmoset models,to examine the pathological impacts on the functional gradients and their biological underpinnings.