Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLDFC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLDFC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Automated summary

By studying asymptomatic patients with arterial stenosis and healthy controls, this study demonstrates a negative association between homotopic BOLD-FC and capillary transit time heterogeneity (CTH) differences, suggesting that increasing CTH differences lead to BOLD-FC reductions. Simulations also show that increasing CTH corresponds to broadened and delayed CBF responses to ongoing neuronal activity.