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

Abstract

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and [Formula: see text], 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 [Formula: see text] 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 [ sG( t)] or an orthogonal decomposition [ sO( 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 (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO( 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 sO( t) explained a greater fraction of CBFV variance (~50%) than sG( 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 sG( t), and 6.9 and 7.4 for sO( t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. 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 ([Formula: see text]) 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 [Formula: see text]. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, [Formula: see text] 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.