Linking resting-state network fluctuations with systems of coherent synaptic density: A multimodal fMRI and 11C-UCB-J PET study

Xiaotian T Fang; Tommaso Volpi; Sophie E Holmes; Irina Esterlis; Richard E Carson; Patrick D Worhunsky

doi:10.3389/fnhum.2023.1124254

Linking resting-state network fluctuations with systems of coherent synaptic density: A multimodal fMRI and ¹¹C-UCB-J PET study

Front Hum Neurosci. 2023 Feb 23:17:1124254. doi: 10.3389/fnhum.2023.1124254. eCollection 2023.

Authors

Xiaotian T Fang¹, Tommaso Volpi¹, Sophie E Holmes², Irina Esterlis^{2

3}, Richard E Carson¹, Patrick D Worhunsky²

Affiliations

¹ Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, United States.
² Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States.
³ Department of Psychology, Yale University, New Haven, CT, United States.

Abstract

Introduction: Resting-state network (RSN) connectivity is a widely used measure of the brain's functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand ¹¹C-UCB-J PET. Methods: Independent component analyses (ICA) were performed on resting-state fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify a priori RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of ¹¹C-UCB-J variability (medial prefrontal, striatal, and medial parietal). Pairwise correlations were performed to examine potential intermodal associations between the fractional amplitude of low-frequency fluctuations (fALFF) of RSNs and subject loadings of ¹¹C-UCB-J source networks both locally and along known anatomical and functional pathways. Results: Greater medial prefrontal synaptic density was associated with greater fALFF of the anterior default-mode, posterior default-mode, and executive-control networks. Greater striatal synaptic density was associated with greater fALFF of the anterior default-mode and salience networks. Post-hoc mediation analyses exploring relationships between aging, synaptic density, and RSN activity revealed a significant indirect effect of greater age on fALFF of the anterior default-mode network mediated by the medial prefrontal ¹¹C-UCB-J source. Discussion: RSN functional connectivity may be linked to synaptic architecture through multiple local and circuit-based associations. Findings regarding healthy aging, lower prefrontal synaptic density, and lower default-mode activity provide initial evidence of a neurophysiological link between RSN activity and local synaptic density, which may have relevance in neurodegenerative and psychiatric disorders.

Keywords: 11C-UCB-J; ICA; PET; SV2A; fMRI; multimodal neuroimaging; resting-state network (RSN).

Abstract

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