Adaptive feedback analysis and control of programmable stimuli for assessment of cerebrovascular function

The assessment of cerebrovascular regulatory mechanisms often requires flexibly controlled and precisely timed changes in arterial blood pressure (ABP) and/or inspired CO2. In this study, a new system for inducing variations in mean ABP was designed, implemented and tested using programmable sequences and programmable controls to induce pressure changes through bilateral thigh cuffs. The system is also integrated with a computer-controlled switch to select air or a CO2/air mixture to be provided via a face mask. Adaptive feedback control of a pressure generator was required to meet stringent specifications for fast changes, and accuracy in timing and pressure levels applied by the thigh cuffs. The implemented system consists of a PC-based signal analysis/control unit, a pressure control unit and a CO2/air control unit. Initial evaluations were carried out to compare the cuff pressure control performances between adaptive and non-adaptive control configurations. Results show that the adaptive control method can reduce the mean error in sustaining target pressure by 99.57 % and reduce the transient time in pressure increases by 45.21 %. The system has proven a highly effective tool in ongoing research on brain blood flow control

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

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

Development of a novel diffuse correlation spectroscopy platform for monitoring cerebral blood flow and oxygen metabolism: from novel concepts and devices to preclinical live animal studies

New optical technologies were developed to continuously measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively through the skull. Methods and devices were created to improve the performance of near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) for use in experimental animals and humans. These were employed to investigate cerebral metabolism and cerebrovascular reactivity under different states of anesthesia and during models of pathological states. Burst suppression is a brain state arising naturally in pathological conditions or under deep general anesthesia, but its mechanism and consequences are not well understood. Electroencephalography (EEG) and cortical hemodynamics were simultaneously measured in rats to evaluate the coupling between cerebral oxygen metabolism and neuronal activity in the burst suppressed state. EEG bursts were used to deconvolve NIRS and DCS signals into the hemodynamic and metabolic response function for an individual burst. This response was found to be similar to the stereotypical functional hyperemia evoked by normal brain activation. Thus, spontaneous burst activity does not cause metabolic or hemodynamic dysfunction in the cortex. Furthermore, cortical metabolic activity was not associated with the initiation or termination of a burst. A novel technique, time-domain DCS (TD-DCS), was introduced to significantly increase the sensitivity of transcranial CBF measurements to the brain. A new time-correlated single photon counting (TCSPC) instrument with a custom high coherence pulsed laser source was engineered for the first-ever simultaneous measurement of photon time of flight and DCS autocorrelation decays. In this new approach, photon time tags are exploited to determine path-length-dependent autocorrelation functions. By correlating photons according to time of flight, CBF is distinguished from superficial blood flow. Experiments in phantoms and animals demonstrate TD-DCS has significantly greater sensitivity to the brain than existing transcranial techniques. Intracranial pressure (ICP) modulates both steady-state and pulsatile CBF, making CBF a potential marker for ICP. In particular, the critical closing pressure (CrCP) has been proposed as a surrogate measure of ICP. A new DCS device was developed to measure pulsatile CBF non-invasively. A novel method for estimating CrCP and ICP from DCS measurement of pulsatile microvascular blood flow in the cerebral cortex was demonstrated in rats.2018-03-08T00:00:00

Using physiological MRI to estimate dynamic cerebral autoregulation metrics: functional MRI feasibility study

Cerebral autoregulation is the homeostatic mechanism that maintains sufficient cerebral circulation despite changes in the perfusion pressure. Dynamic CA refers to the changes that occur in CBF within the first few seconds after an acute MAP change. Assessment of the CA impairment plays important role in the prognosis of many cerebrovascular diseases such as stroke, sub-arachnoid haemorrhage, as well as traumatic brain injury and neurodegenerative disorders. This thesis investigates the feasibility of using physiological MRI to estimate dynamic cerebral autoregulation (dCA) metrics. In particular, this thesis has an emphasis on measuring beat-to-beat arterial blood pressure inside the scanner to provide better understanding of the physiological aspects of dCA. Further, continuous blood pressure (BP) measures in response to different non invasive BP fluctuating methods are acquired to evaluate the reliability of these methods to induce response changes. Blood Oxygen Level Dependent (BOLD) fMRI method was used to estimate the expected variations of tissue oxygenation during induced dCA changes in healthy volunteers. The non invasive arterial blood pressure measurements were acquired using MR compatible arterial blood pressure monitoring device (NIBP-MRI/Caretaker; Biopac®). Further, sudden release of inflated thigh-cuffs (TCR) and inspiratory breath-hold (iBH) methods were used in the scanner to induce dynamic autoregulatory changes. These two methods were investigated in a pilot study, to evaluate the reliability prior to the MR study by comparing BP measurements obtained outside the scanner using non invasive methods. This pilot study included monitoring BP changes in response to four types of non invasive BP fluctuating methods. The reliability of NIBP/MRI Caretaker device was examined by comparing the BP response changes with the simultaneously acquired BP data from Finometer plethysmographic device. The cerebral autoregulation metrics were estimated by calculating the rate of regulation (RoR) following dynamic BP fluctuating events. Rate of regulation defines the rate at which the BOLD signal changes depending on MAP changes at a particular time. Further, the tissue specific regulation parameters were obtained for grey matter (GM), white matter (WM) and water shed areas (WS). The effect of iBH method on cerebral blood flow (CBF) and velocity (CBFV) was explored in a preliminary study by quantitative measures using time resolved 4D PC MRI angiography in two subjects. The mean arterial blood pressure (MAP) changes in response to TCR and iBH method were comparable. The fMRI data demonstrated BOLD signal amplitude change in response to the induced fast MAP changes. The GM and WS areas showed similar rates of regulation, and these were nominally higher than WM RoR in both TCR and iBH methods. Further, the 4D PC MRI data suggested 29% CBF-increase in response to 33% iBH in four minutes acquisition time. The acquired non invasive arterial BP measures concurrent with the BOLD signal amplitude response, allowed deriving the rate of regulation as a metric of dCA. It is not known whether this information is clinically relevant to gauge the haemodynamic risk association to cerebrovascular disease. However, BOLD signal change and CBF changes after iBH are confounded by the extent to which the CO2 gradually accumulate in response to iBH and causes an overshoot in the CBF response-change. In conclusion, the presented study indicates the feasibility of using physiological MRI to measure dCA in response to non-invasively induced MAP changes. Estimation of the dCA metrics could be improved by using advanced data fitting methods as well as controlling for physiological parameters such as PECO2

Using physiological MRI to estimate dynamic cerebral autoregulation metrics: functional MRI feasibility study

Cerebral autoregulation is the homeostatic mechanism that maintains sufficient cerebral circulation despite changes in the perfusion pressure. Dynamic CA refers to the changes that occur in CBF within the first few seconds after an acute MAP change. Assessment of the CA impairment plays important role in the prognosis of many cerebrovascular diseases such as stroke, sub-arachnoid haemorrhage, as well as traumatic brain injury and neurodegenerative disorders. This thesis investigates the feasibility of using physiological MRI to estimate dynamic cerebral autoregulation (dCA) metrics. In particular, this thesis has an emphasis on measuring beat-to-beat arterial blood pressure inside the scanner to provide better understanding of the physiological aspects of dCA. Further, continuous blood pressure (BP) measures in response to different non invasive BP fluctuating methods are acquired to evaluate the reliability of these methods to induce response changes. Blood Oxygen Level Dependent (BOLD) fMRI method was used to estimate the expected variations of tissue oxygenation during induced dCA changes in healthy volunteers. The non invasive arterial blood pressure measurements were acquired using MR compatible arterial blood pressure monitoring device (NIBP-MRI/Caretaker; Biopac®). Further, sudden release of inflated thigh-cuffs (TCR) and inspiratory breath-hold (iBH) methods were used in the scanner to induce dynamic autoregulatory changes. These two methods were investigated in a pilot study, to evaluate the reliability prior to the MR study by comparing BP measurements obtained outside the scanner using non invasive methods. This pilot study included monitoring BP changes in response to four types of non invasive BP fluctuating methods. The reliability of NIBP/MRI Caretaker device was examined by comparing the BP response changes with the simultaneously acquired BP data from Finometer plethysmographic device. The cerebral autoregulation metrics were estimated by calculating the rate of regulation (RoR) following dynamic BP fluctuating events. Rate of regulation defines the rate at which the BOLD signal changes depending on MAP changes at a particular time. Further, the tissue specific regulation parameters were obtained for grey matter (GM), white matter (WM) and water shed areas (WS). The effect of iBH method on cerebral blood flow (CBF) and velocity (CBFV) was explored in a preliminary study by quantitative measures using time resolved 4D PC MRI angiography in two subjects. The mean arterial blood pressure (MAP) changes in response to TCR and iBH method were comparable. The fMRI data demonstrated BOLD signal amplitude change in response to the induced fast MAP changes. The GM and WS areas showed similar rates of regulation, and these were nominally higher than WM RoR in both TCR and iBH methods. Further, the 4D PC MRI data suggested 29% CBF-increase in response to 33% iBH in four minutes acquisition time. The acquired non invasive arterial BP measures concurrent with the BOLD signal amplitude response, allowed deriving the rate of regulation as a metric of dCA. It is not known whether this information is clinically relevant to gauge the haemodynamic risk association to cerebrovascular disease. However, BOLD signal change and CBF changes after iBH are confounded by the extent to which the CO2 gradually accumulate in response to iBH and causes an overshoot in the CBF response-change. In conclusion, the presented study indicates the feasibility of using physiological MRI to measure dCA in response to non-invasively induced MAP changes. Estimation of the dCA metrics could be improved by using advanced data fitting methods as well as controlling for physiological parameters such as PECO2

Effect of Acute Exposure to Hypergravity (Gx vs. Gz) on Dynamic Cerebral Autoregulation

We examined the effects of 30 min of exposure to either +3G(sub x) or +3G(sub z) centrifugation on cerebrovascular responses to 800 head-up tilt (HUT) in 14 healthy individuals. Both before and after +3G(sub x) or +3G(sub z) centrifugation, eye-level blood pressure (BP(sub eye)), end tidal CO2 (P(sub ET)CO2), mean cerebral flow velocity (CFV) in the middle cerebral artery (trans cranial Doppler ultrasound), cerebral vascular resistance (CVR) and dynamic cerebral autoregulatory gain (GAIN) were measured with subjects in the supine position and during subsequent 800 HUT for 30 min. Mean BP(sub eye) decreased with HUT in both the G(sub x) (n= 7) and G(sub z) (n=7) groups (P less than 0.00l), with the decrease being greater after centrifugation only in the G(sub z) group (P less than 0.05). P(sub ET)CO2 also decreased with HUT in both groups (P less than 0.0l), but the absolute level of decrease was unaffected by centrifugation. CFV decreased during HUT more significantly after than before centrifugation in both groups (P less than 0.02). However, these greater decreases were not associated with greater increases in CVR. In the supine position after compared to before centrifugation, GAIN increased in both groups (P less than 0.05, suggesting an autoregulatory deficit), with the change being correlated to a measure of otolith function (the linear vestibulo-ocular reflex) in the G(sub x) group (R=0.76, P less than 0.05) but not in the G(sub z) group (R=0.24, P=0.60). However, GAIN was subsequently restored to pre-centrifugation levels during post-centrifugation HUT (i.e., as BP(sub eye) decreased), suggesting that both types of centrifugation resulted in a leftward shift of the cerebral autoregulation curve. We speculate that this leftward shift may have been due to vestibular activation (especially during +G(sub x)) or potentially to an adaptation to reduced cerebral perfusion pressure during +G(sub z)

The effect of oestrogen on cerebrovascular regulation in eumenorrheic women : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science, Massey University, Wellington, New Zealand

Figures 1 (=Vselja et al., 2014 Fig 1) and 2 (=Ainslie & Duffin, 2009 Fig 2) were removed for copyright reasons. Figure 6 remains for the sake of clarity.Women experience fluctuating sex hormone concentrations throughout their lifetime and while their role in reproduction is well documented, there is little knowledge of the effects of the changing hormone concentrations on women’s cerebrovascular health. Therefore, this study examined dynamic cerebral autoregulation (dCA) in 10 healthy eumenorrheic women (28 ± 7 years) volunteers. The participants dCA was examined at three different phases of the menstrual cycle: early follicular (EF; when oestrogen and progesterone concentrations are low), late follicular (LF; oestrogen concentrations are high, while progesterone remains steady), and mid-luteal (ML; oestrogen and progesterone concentrations are high). The dCA was assessed using the autoregulatory index (AI) of forced changes in blood pressure (BP) and mean middle cerebral blood velocity (MCAv) response, induced during phases of the Valsalva manoeuvre (VM). The VM is a four-phase manoeuvre that produces hyper- and hypotensive changes to blood pressure (BP): phase I (initial increase in BP), phase IIa (initial decrease in BP), phase IIb (stabilisation of BP), phase III (decrease in BP after cessation of breath-hold), and phase IV (overshoot in BP recovery). Resting mean arterial blood pressure (MAP, P= 0.409), MCAv (P= 0.635), and cerebrovascular conductance index (CVCi, P= 0.984) were not different throughout all trials. The partial pressure of endtidal carbon dioxide (PETCO₂) was unchanged between the trials (P = 0.907). The VM induced middle cerebral artery velocity mean (MCAvmean) differences between trials (interaction: P = 0.039), MCAv during mid-luteal (ML; 58 ± 15 cm/s) showed a significant difference to early follicular (EF; 51 ± 14 cm/s, P = 0.013) and late follicular (LF; 49 ± 15 cm/s, P = 0.024) during phase IIb of the VM. There were no differences in MAP (P = 0.233) and CVCi (P = 0.808) during the VM throughout the trials. AI presented no difference during phase II of the VM (P= 0.354), however, phase IV did show a trend (P= 0.086). The results of this study indicate that circulating ovarian hormone concentrations may regulate responses to dynamic cerebrovascular challenges

Can interhemispheric desynchronization of cerebral blood flow anticipate upcoming vasospasm in aneurysmal subarachnoid haemorrhage patients?

BACKGROUND: Asymmetry of cerebral autoregulation (CA) was demonstrated in patients after aneurysmal subarachnoid haemorrhage (aSAH). A classical method for CA assessment requires simultaneous measurement of both arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). In this study, we have proposed a cerebral blood flow asymmetry index based only on CBFV and analysed its association with the occurrence of vasospasm after aSAH. NEW METHOD: The phase shifts (PS) between slow oscillations in left and right CBFV (side-to-side PS) and between ABP and CBFV (CBFV-ABP PS) were estimated using multichannel matching pursuit (MMP) and cross-spectral analysis. RESULTS: We retrospectively analysed data collected from 45 aSAH patients (26 with vasospasm). Data were analysed up to 7th day after aSAH unless the vasospasm was detected earlier. A progressive asymmetry, manifested by a gradual increase in side-to-side PS on consecutive days after aSAH, was observed in patients who developed vasospasm (Radj2 = 0.14, p = 0.009). In these patients, early side-to-side PS was more positive than in patients without vasospasm (2.8° ± 5.6° vs -1.7° ± 5.7°, p = 0.011). No such a difference was found in CBFV-ABP PS. Patients with positive side-to-side PS were more likely to develop vasospasm than patients with negative side-to-side PS (21/7 vs 5/12, p = 0.0047). COMPARISON WITH EXISTING METHOD: MMP, in contrast to the spectral approach, accounts for non-stationarity of analysed signals. MMP applied to the PS estimation reflects the cerebral blood flow asymmetry in aSAH better than the spectral analysis. CONCLUSIONS: Changes in side-to-side PS might be helpful to identify patients who are at risk of vasospasm

Cerebrovascular hemodynamics in older adults: Associations with lifestyle, peripheral vascular health and functional decline

In today’s aging population, cerebrovascular health plays a pivotal role in maintaining independence. The identification of early markers of change might help to plan more appropriate preventative and/or therapeutic measures. Recent focus has been placed on the relationship between peripheral vascular characteristics and cerebral hemodynamics. Given the compliant nature of the cerebral circulation, examination of passive properties, including critical closing pressure (CrCP) and resistance area product (RAP), might provide sensitive information about early functional changes. The purpose of this thesis was to provide a comprehensive view of peripheral vascular and cerebrovascular regulation in community-living older adults. In doing so, the thesis covered a spectrum, ranging from an examination of lifestyle factors, including habitual physical activity and sleep quality, to the impact of cerebrovascular health on functional status, characterized by gait speed. Key findings included the observation that while participants showed the ability to regulate cerebral blood flow (CBF) appropriately in most circumstances, the underlying mechanisms used to achieve this regulation was dependent on baseline vascular tone. During sit-to-stand transitions, individuals with lower baseline resistance relied primarily on fluctuations in RAP, which have been suggested to more closely reflect myogenic pathways. In contrast, individuals with elevated resistance had lower baseline CBF and relied relatively more on fluctuations in CrCP during the dynamic transition. The greater reliance on CrCP might indicate that these individuals were required to tap further into reserve pools to avoid hypoperfusion during the transition. Notably, those who exhibited a smaller dynamic RAP response during the posture change also had slower gait speed and higher occurrence of falls over the past year. These results provide evidence that passive cerebrovascular dynamics are sensitive markers linking peripheral and cerebrovascular properties with functional consequences for brain health in the elderly

Towards clinical assessment of cerebral blood flow regulation using ultrasonography : model applicability in clinical studies

For preservation of its vital functions, the brain is largely dependent of a sufficient delivery of oxygen and nutrients. Blood flow to the brain is essentially regulated by 2 control mechanisms i.e. neurovascular coupling and cerebral autoregulation. Cerebral autoregulation aims for constant adequate blood supply by compensating for blood pressure variations by dilatation or narrowing of the cerebral microvasculature. Neurovascular coupling adjusts blood supply to the local metabolic need. Cerebral perfusion and blood flow regulation are compromised in several pathological conditions. Clinical examination of cerebral blood flow and its regulation may therefore provide helpful diagnostic, predictive and therapeutic information. The work in this thesis was aimed at putting a step forward towards development of reliable and clinically usable parameters for cerebral blood flow regulation assessment using ultrasonography. Regarding early diagnostics, screening and monitoring of cerebral blood flow and its regulation, ultrasonography has major advantages over other imaging tools because of its noninvasiveness, cost-effectiveness, easy usability and its good time resolution. It allows examination of blood flow velocities at multiple locations throughout the extra- and intracranial circulation and evaluation of both control mechanisms by transfer function analysis. For evaluation of cerebral autoregulation, transcranial Doppler blood flow velocities in the large middle cerebral arteries have been recorded simultaneously with plethysmographic (finger) blood pressure. Gain and phase of the pressure-flow transfer function have been determined to obtain quantitative measures for cerebral autoregulation. Neurovascular coupling has been assessed by presenting a visual block stimulus to a subject and simultaneous measurement of the blood flow velocity in the artery exclusively supplying the visual cortex. The obtained visually-evoked blood flow response (VEFR) has been considered as the step response of a linear second order control system model providing patient-specific parameters such as gain and damping as quantitative measures for neurovascular coupling . In chapter 2, a clinical study has been described in which extra- and intracranial blood flow velocities (BFVs), measured at multiple sites in the circulation, have been compared between Alzheimer patients (AD), patients with mild cognitive impairment (MCI) and healthy aging controls (HC). BFVs of AD were significantly lowered at proximal sites but preserved at distal sites for the internal carotid artery and middle and posterior cerebral arteries as compared to those of MCI or HC. This specific pattern can presumably be ascribed to reduced distal diameters resulting from AD pathology. MCI BFV were similar to HC BFV in the extracranial and intracranial posterior circulation, whereas they were intermediate between AD and HC in the intracranial anterior circulation. This suggests that intracranial anterior vessels are most suitable for early detection of pathological alterations resulting from AD. The study findings further indicate that extensive ultrasonographic screening of intra- and extracranial arteries is useful for monitoring BFV decline in the MCI stage. Future follow-up of MCI patients may reveal the predictive value of location-specific BFV for conversion to AD. In the same study cohort, dynamic cerebral autoregulation has been studied as discussed in chapter 3. Cerebral autoregulatory gain and phase values were similar for AD, MCI and HC which implies that the cerebral autoregulatory mechanism is preserved in AD. However, the cerebrovascular resistance index i.e. the ratio between absolute time-averaged blood pressure and flow velocity, was significantly higher in AD as compared to MCI and HC indicating that vessel stiffness is increased in AD. Indeed, it appeared to be a potential biomarker for AD development of MCI. The cerebrovascular resistance increase in AD was furthermore confirmed by windkessel model findings of a significantly elevated peripheral resistance in AD. Arterial resistance and peripheral compliance were equal for all groups. From chapter 4, the focus was shifted to assessment of local blood flow regulation. Visuallyevoked blood flow responses (VEFRs) of formerly (pre-)eclamptic patients and healthy controls have been examined to evaluate neurovascular coupling first in a relative young study population. The aim of the study was to investigate whether possible local (pre)eclampsia-induced endothelial damage was reversible or not. The measured VEFRs have been fitted with the step response of a 2nd order control system model. Although inter-group differences in model parameters were not found, a trend was observed that critical damping (z>1) occurred more frequently in former patients than in controls. Critical damping reflects an atypical VEFR, which is either uncompensated (sluggish, z>1; Tv <20) or compensated by a rise in rate time (intermediate, z>1; Tv > 20). Since these abnormal VEFRs were mainly found in former patients (but not exclusively), these response types were hypothesized to result from pathological disturbances. A revised VEFR analysis procedure to account for reliability and blood pressure dynamics has been proposed in chapter 5. This revised procedure consists of the introduction of a reliability measure for model parameters and of a model extension to consider possible blood pressure contribution to the measured VEFR. The effects of these adjustments on study outcomes have been evaluated by applying both the standard VEFR analysis procedure (applied in chapter 4) and the revised procedure to the AD study cohort. Reliability consideration resulted in about 40% VEFR exclusion, mainly due to the models’ inability to fit critically damped responses. Reliability consideration reduced parameter variability substantially. Regarding the influence of blood pressure variation, a significantly increased damping was found in AD for the standard but not for the revised model. This reversed the study conclusion from altered to normal neurovascular coupling in AD. Considering their influence on obtained parameters, both aspects i.e. reliability and blood pressure variation should be included in VEFR-analysis. Regarding clinical study outcomes, neurovascular coupling seems to be unaffected in AD since the finding of an increased damping may be ascribed to ignorance of blood pressure contribution to VEFR. Study conclusions of earlier chapters (4 and 5) emphasize the need for a model incorporating physiological features. In chapter 6, preliminary results have been reported of the application of a newly developed lumped parameter model of the visual cortex vasculature to the 3 different VEFR types. In the new model, regulatory processes i.e. neurogenic, metabolic, myogenic and shear stress mechanisms, act on smooth muscle tone which inherently leads to adjustment of microcirculatory resistance and compliance. This allows the study of effects of pathological changes on the VEFR. It may be concluded that the model provides an improved link between VEFR and physiology. Preliminary results show that the physiology-based model can describe VEFR type representatives reasonably well obtaining physiologically plausible parameter values. Thus, from a clinical perspective it may be concluded that (Duplex) ultrasonography has great potential as a standard screening tool for MCI patients. It seems worthwhile to examine all future MCI patients on extra- and intracranial blood flow velocity and to determine their cerebrovascular resistance index by simultaneous blood pressure recording. Follow-up of MCI patients will reveal the predictive value of these parameters for future AD development. Furthermore, from a methodological perspective, it can be concluded that the current standard of control system analysis to assess local cerebral blood flow regulation has limitations regarding parameter reliability and VEFR interpretation. Both reliability and interpretation may be improved by optimization and control of data acquisition quality and by use of physiology-based models. Physiological mechanisms influencing VEFR establishment should be incorporated in such a model to possibly explain part of its variance. Efforts should be directed to development and validation of physiology-based models aimed at reliable description of VEFRs by physiologically meaningful parameters