Alternative representation of neural activation in multivariate models of neurovascular coupling in humans

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and $$, rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO₂ (EtCO₂) with capnography. The simultaneous effects of neural stimulation, BP, and $$ on CBFV were expressed with a dynamic multivariate model, using BP, EtCO₂, and stimulation [s(t)] as inputs. Two versions of s(t) were considered: a gate function [s(t)] or an orthogonal decomposition [s(t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO₂ reactivity [vasomotor reactivity step response (VMR_SR)], and NVC [stimulus step response (STIM_SR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated s(t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10^-5) and was correlated with the CBFV change (r = 0.73, P = 0.0001). The s(t) explained a greater fraction of CBFV variance (~50%) than s(t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for s(t), and 6.9 and 7.4 for s(t), respectively. No differences between DH and NDH were observed for VMR_SR or STIM_SR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO₂ in response to sensorimotor stimulation_, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO₂ reactivity, and NVC in humans.NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO₂ ($$) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or $$. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, $$ and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO₂ reactivity and other contributions.