A Nonlinear Dynamic Approach Reveals a Long-Term Stroke Effect on Cerebral Blood Flow Regulation at Multiple Time Scales

Abstract

Cerebral autoregulation (CA) is an important vascular control mechanism responsible for relatively stable cerebral blood flow despite changes of systemic blood pressure (BP). Impaired CA may leave brain tissue unprotected against potentially harmful effects of BP fluctuations. It is generally accepted that CA is less effective or even inactive at frequencies >∼0.1 Hz. Without any physiological foundation, this concept is based on studies that quantified the coupling between BP and cerebral blood flow velocity (BFV) using transfer function analysis. This traditional analysis assumes stationary oscillations with constant amplitude and period, and may be unreliable or even invalid for analysis of nonstationary BP and BFV signals. In this study we propose a novel computational tool for CA assessment that is based on nonlinear dynamic theory without the assumption of stationary signals. Using this method, we studied BP and BFV recordings collected from 39 patients with chronic ischemic infarctions and 40 age-matched non-stroke subjects during baseline resting conditions. The active CA function in non-stroke subjects was associated with an advanced phase in BFV oscillations compared to BP oscillations at frequencies from ∼0.02 to 0.38 Hz. The phase shift was reduced in stroke patients even at > = 6 months after stroke, and the reduction was consistent at all tested frequencies and in both stroke and non-stroke hemispheres. These results provide strong evidence that CA may be active in a much wider frequency region than previously believed and that the altered multiscale CA in different vascular territories following stroke may have important clinical implications for post-stroke recovery. Moreover, the stroke effects on multiscale cerebral blood flow regulation could not be detected by transfer function analysis, suggesting that nonlinear approaches without the assumption of stationarity are more sensitive for the assessment of the coupling of nonstationary physiological signals. Cerebral autoregulation is an important mechanism that regulates blood supply to brain tissue to match metabolic demands during daily activities. Impaired cerebral autoregulation increases the dependence of cerebral blood flow on systemic blood pressure, and is associated with fatal outcomes in patients after brain injury and acute ischemic stroke. Reliable and noninvasive assessment of cerebral autoregulation is still a major challenge in medical diagnostics and clinic studies, mainly because blood pressure and flow are intrinsically nonstationary (possessing complex oscillations/fluctuations with varying amplitude and frequency) while traditional methods for assessment of the pressure-flow dependence assume stationary signals. We propose a new computational technique that is based on nonlinear theories without the assumption of stationary signals. This technique allows us to detect the degradation of cerebral autoregulation in patients with mild ischemic stroke even at >6 months after the insult. The degradation was present in both stroke and non-stroke sides and was accompanied by an altered pressure-flow interaction over a wide range of frequencies from 0.02–0.38 Hz. Our results challenges the traditionally accepted functional region of autoregulation (<∼0.1 Hz). The observed long-term influences of stroke highlight the importance of reliable monitoring of cerebral blood flow regulation for the management and daily care of stroke patients.