Abstract
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 [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 () 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.
Highlights
Neural stimulation, induced by cognitive or sensorimotor paradigms, leads to increases in cerebral blood flow (CBF), through a cascade of complex interactions, encapsulated in the concept of neurovascular coupling (NVC; Girouard and Iadecola 2006)
Human studies of NVC have been performed with noninvasive techniques for measuring CBF such as magnetic resonance imaging (MRI), near infrared spectroscopy, and, increasingly, with transcranial Doppler ultrasound (TCD)
In previous studies of NVC, involving both sensorimotor and cognitive paradigms, we have addressed the problem of blood pressure (BP) and PaCO2 interference with the use of multivariate modeling, where the CBF velocity (CBFV) response is represented as the output of a linear model, having BP, end-tidal CO2 (EtCO2), and a neural stimulation signal, s(t), as inputs (Maggio et al 2014; Panerai et al 2012a, 2012b)
Summary
Neural stimulation, induced by cognitive or sensorimotor paradigms, leads to increases in cerebral blood flow (CBF), through a cascade of complex interactions, encapsulated in the concept of neurovascular coupling (NVC; Girouard and Iadecola 2006). If the cross-sectional area of the insonated vessel remains constant, changes in CBFV will reflect changes in absolute CBF. For this reason, most studies of fTCD adopt the CBFV response to neural stimulation as a metric of NVC integrity and efficiency (Azevedo et al 2011; Claassen and Zhang 2011; Deppe et al 2004; Fritzsch et al 2010; Kelley et al 1992; Martens et al 2009; Silvestrini et al 1993; Stroobant and Vingerhoets 2001; Wolf 2015). One key limitation of focusing only on the CBFV response is the parallel physiological changes that take place with stimulation in important determinants of CBFV, such as arterial blood pressure www.jn.org
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