Testing the null hypothesis of uncoupling between mean arterial pressure and mean cerebral blood velocity in health and pathology via different surrogate strategies.

Active standing (STAND) deteriorates dynamic cerebral autoregulation (dCA) in healthy controls (HCs).

• Study included 26 healthy controls (age: 43 ± 11 yr, 13 males, 13 females).
• Active standing from supine resting (REST) was used as a physiological challenge to dCA.
• The state space correspondence method based on model-free cross-predictability was used to estimate the degree of MCBv dependence on MAP.
• Deterioration of dCA during STAND was detected in the HC group.

In severe aortic valve stenosis (SAVR) patients, active standing does not affect dCA either before or after surgery.

• Study included 48 SAVR patients (age: 62 ± 14 yr; 35 males, 13 females) assessed before and after surgical aortic valve replacement.
• Unlike healthy controls, SAVR patients showed no significant change in dCA with STAND either pre- or post-surgery.
• Analyses compared REST and STAND conditions across both time points (pre- and post-surgery).

SAVR patients exhibit a pre-surgery activation of the flow-to-pressure link at REST.

• The flow-to-pressure pathway (MCBv dependence driving MAP) was found to be activated at REST in SAVR patients before surgery.
• This pre-surgery activation was not observed in healthy controls under the same REST condition.
• The directional analysis separated the dependence of MAP on MCBv from that over the reverse (pressure-to-flow) pathway.
• This finding highlights pathophysiological differences in the closed-loop MCBv-MAP relationship in aortic valve stenosis.

In healthy controls, preserving nonlinear dynamics when testing the significance of the pressure-to-flow link provides results different from those obtained while maintaining exclusively linear dynamics.

• Two different types of surrogate strategies were used: one destroying nonlinear components and one preserving them as much as possible.
• Results from nonlinear-preserving surrogates differed from those based on linear-only surrogates specifically for the pressure-to-flow (MAP-to-MCBv) link in HCs.
• This difference was found specifically in the HC group, underscoring the physiological relevance of nonlinear mechanisms in dCA.
• The findings suggest that conclusions about dCA significance testing depend on the surrogate strategy adopted.

The study employed a model-free, state space correspondence method based on cross-predictability to assess directional coupling in the closed-loop MCBv-MAP relationship.

• The approach estimates the degree of MCBv dependence on MAP and MAP dependence on MCBv separately.
• Two surrogate types were applied: surrogates that destroy nonlinear components and surrogates that preserve nonlinear dynamics as much as possible.
• The methodology was applied across four experimental conditions: HCs at REST and STAND, and SAVR patients at REST and STAND both pre- and post-surgery.
• The closed-loop framework was explicitly designed to disentangle the pressure-to-flow (dCA) and flow-to-pressure pathways.

The study found pathophysiological relevance of applying a nonlinear directional approach to disentangle the closed-loop MCBv-MAP relationship.

• The authors stress that 'conclusions might depend on the strategy adopted to generate surrogates.'
• Nonlinear mechanisms were found to be relevant specifically in healthy controls for the pressure-to-flow direction.
• The presence of a myriad of nonlinear mechanisms in dCA is acknowledged, operating in association with the flow-to-pressure pathway.
• The results highlight that using only linear surrogates may miss important aspects of cerebrovascular regulation.