Modeling the impact of neurovascular coupling impairments on BOLD-based functional connectivity at rest.

Functional magnetic resonance imaging (fMRI) of blood oxygenation level dependent (BOLD) signals during the resting-state is widely used to study functional connectivity (FC) of slowly fluctuating ongoing brain activity (BOLD-FC) in humans with and without brain diseases. While physiological impairments, e.g. aberrant perfusion or vascular reactivity, are common in neurological and psychiatric disorders, their impact on BOLD-FC is widely unknown and ignored. The aim of our simulation study, therefore, was to investigate the influence of impaired neurovascular coupling on resting-state BOLD-FC. Simulated BOLD signals comprising intra- and extravascular contributions were derived from an adjusted balloon model, which allows for independent definitions of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO) responses, being elicited by a synthetic oscillatory input signal with low frequency (0.05 ​Hz) amplitude modulations. BOLD-FC was then defined by correlations between physiological reference BOLD time curves (seeds of seed-based BOLD-FC) and the test BOLD time curves (targets of BOLD-FC) featuring altered physiological variables (CMRO, CBF, cerebral blood volume (CBV)). Impact of impaired neurovascular coupling on BOLD-FC was investigated for three different scenarios with independent changes in (1) CBF and CMROamplitudes, (2) CBF and CMROdelays, and (3) coupling between CBF and CBV. For scenario 1, we found 'linear' influences of CMRO and CBF amplitudes on BOLD-FC: for a given CMRO amplitude, BOLD-FC changes from negative to positive FC with increasing CBF amplitude, and increasing CMRO amplitude simply shifts this dependence linearly. For scenario 2, CMRO and CBF delays had a complex 'non-linear' effect on BOLD-FC: for small CMRO delays, we found that BOLD-FC changes from positive to negative BOLD-FC with increasing CBF delays, but for large CMRO delays positive BOLD-FC simply diminishes with increasing CBF delay. For scenario 3, changes in CBF-CBV coupling have almost no effect on BOLD-FC. All these changes were not critically influenced by both signal-to-noise-ratio and temporal resolution modulations. Our results demonstrate the importance of alterations in neurovascular coupling for aberrant resting-state BOLD-FC. Based on our data, we suggest to complement BOLD-FC studies, at least of at-risk patient populations, with perfusion and oxygenation sensitive MRI. In cases where this is not available, we recommend careful interpretation of BOLD-FC results considering previous findings about hemodynamic-metabolic changes. In the future, accurate modeling of the hemodynamic-metabolic context might improve both our understanding of the crucial interplay between vascular-hemodynamic-neuronal components of intrinsic BOLD-FC and the evaluation of aberrant BOLD-FC in brain diseases with vascular-hemodynamic impairments.