Cerebral blood flow (CBF) regulation can be impaired in acute ischemic stroke but the combined effects of dynamic cerebral autoregulation (CA), CO2 cerebrovascular reactivity (CVR), and neurovascular coupling (NVC), obtained from simultaneous measurements, have not been described. CBF velocity in the middle cerebral artery (MCA) (CBFv, transcranial Doppler), blood pressure (BP, Finometer), and end-tidal Pco2 (PetCO2 , infrared capnography) were recorded during a 1-min passive movement of the arm in 27 healthy controls [mean age (SD) 61.4 (6.0) yr] and 27 acute stroke patients [age 63 (11.7) yr]. A multivariate autoregressive-moving average model was used to separate the contributions of BP, arterial Pco2 (PaCO2 ), and the neural activation to the CBFv responses. CBFv step responses for the BP, CO2, and stimulus inputs were also obtained. The contribution of the stimulus to the CBFv response was highly significant for the difference between the affected side [area under the curve (AUC) 104.5 (4.5)%] and controls [AUC 106.9 (4.3)%; P = 0.008]. CBFv step responses to CO2 [affected hemisphere 0.39 (0.7), unaffected 0.55 (0.8), controls 1.39 (0.9)%/mmHg; P = 0.01, affected vs. controls; P = 0.025, unaffected vs. controls] and motor stimulus inputs [affected hemisphere 0.20 (0.1), unaffected 0.22 (0.2), controls 0.37 (0.2) arbitrary units; P = 0.009, affected vs. controls; P = 0.02, unaffected vs. controls] were reduced in the stroke group compared with controls. The CBFv step responses to the BP input at baseline and during the paradigm were not different between groups (P = 0.07), but PetCO2 was lower in the stroke group (P < 0.05). These results provide new insights into the interaction of CA, CVR, and NVC in both health and disease states.

We aimed to assess cerebral autoregulation (CA) and neurovascular coupling (NVC) in stroke patients of differing severity comparing responses to healthy controls and explore the association between CA and NVC with functional outcome. Patients admitted with middle cerebral artery (MCA) stroke and healthy controls were recruited. Stroke severity was defined by the National Institutes of Health Stroke Scale (NIHSS) scores: ≤4 mild, 5-15 moderate and ≥16 severe. Transcranial Doppler ultrasound and Finometer recorded MCA cerebral blood flow velocity (CBFv) and blood pressure, respectively, over 5 min baseline and 1 min passive movement of the elbow to calculate the autoregulation index (ARI) and CBFv amplitude responses to movement. All participants were followed up for three months. A total of 87 participants enrolled in the study, including 15 mild, 27 moderate and 13 severe stroke patients, and 32 control subjects. ARI was lower in the affected hemisphere (AH) of moderate and severe stroke groups. Decreased NVC was seen bilaterally in all stroke groups. CA and NVC correlated with stroke severity and functional outcome. CBFv regulation is significantly impaired in acute stroke, and further compromised with increasing stroke severity. Preserved CA and NVC in the acute period were associated with improved three-month functional outcome.

Background: Acute stroke is known to impair cerebral blood flow (CBF) regulation, but the longitudinal changes of these effects have been poorly reported. The main CBF regulatory mechanisms [cerebral autoregulation (CA) and neurovascular coupling (NVC)] were assessed over 3 months after acute ischaemic stroke. Methods: Recordings of CBF velocity (CBFv), blood pressure (BP), and end-tidal CO₂ were performed during 5 min baseline and 1 min passive movement of the elbow. Stroke patients were assessed <72 h of stroke onset, and at 2 weeks, 1 and 3 months after stroke. Results: Fifteen acute stroke subjects underwent all 4 sessions and were compared to 22 control subjects. Baseline recordings revealed a significantly lower CBFv in the affected hemisphere within 72 h after stroke compared to controls (p = 0.02) and a reduction in CA index most marked at 2 weeks (p = 0.009). CBFv rise in response to passive arm movement was decreased bilaterally after stroke, particularly in the affected hemisphere (p < 0.01). Both alterations in CA and NVC returned to control levels during recovery. Conclusion: The major novel finding of this study was that both CA and NVC regulatory mechanisms deteriorated initially following stroke onset, but returned to control levels during the recovery period. These findings are relevant to guide the timing of interventions to manipulate BP and potentially for the impact of intensive rehabilitation strategies that may precipitate acute physiological perturbations but require further exploration in a larger population that better reflects the heterogeneity of stroke. Further, they will also enable the potential influence of stroke subtype to be investigated.

The autoregulation index (ARI) can reflect the effectiveness of cerebral blood flow (CBF) control in response to dynamic changes in arterial blood pressure (BP), but objective criteria for its validation have not been proposed. Monte Carlo simulations were performed by generating 5 min long random input/output signals that mimic the properties of mean beat-to-beat BP and CBF velocity (CBFV) as usually obtained by non-invasive measurements in the finger (Finometer) and middle cerebral artery (transcranial Doppler ultrasound), respectively. Transfer function analysis (TFA) was used to estimate values of ARI by optimal fitting of template curves to the output (or CBFV) response to a step change in input (or BP). Two-step criteria were adopted to accept estimates of ARI as valid. The 95% confidence limit of the mean coherence function (0.15-0.25 Hz) ([Formula: see text]) was estimated from 15 000 runs, resulting in [Formula: see text]  =  0.190 when using five segments of data, each with 102.4 s (512 samples) duration (Welch's method). This threshold for acceptance was dependent on the TFA settings and increased when using segments with shorter duration (51.2 s). For signals with mean coherence above the critical value, the 5% confidence limit of the normalised mean square error (NMSEcrit) for fitting the step response to Tieck's model, was found to be approximately 0.30 and independent of the TFA settings. Application of these criteria to physiological and clinical sets of data showed their ability to identify conditions where ARI estimates should be rejected, for example due to CBFV step responses lacking physiological plausibility. A larger number of recordings were rejected from acute ischaemic stroke patients than for healthy volunteers. More work is needed to validate this procedure with different physiological conditions and/or patient groups. The influence of non-stationarity in BP and CBFV signals should also be investigated.

Neurovascular coupling (NVC) and dynamic cerebral autoregulation (dCA) are both impaired in the acute phase of ischemic stroke, but their reciprocal interactions are difficult to predict. To clarify these aspects, the present study explored NVC in a healthy volunteer population during a surrogate state of impaired dCA induced by hypercapnia. This study aimed to test whether hypercapnia leads to a depression of NVC through an impairment of dCA. Continuous recordings of middle cerebral arteries cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 were performed in 19 right-handed subjects (aged >45 yr) before, during, and after 60 s of a passive paradigm during normocapnia and hypercapnia. The CBFv response was broken down into subcomponents describing the relative contributions of BP (VBP), critical closing pressure (VCrCP), and resistance area product (VRAP). VRAP reflects myogenic activity in response to BP changes, whereas VCrCP is more indicative of metabolic control. The results revealed that hypercapnia significantly affected NVC, with significant reductions in the relative contribution of VCrCP to the paradigm-induced increase in CBFv. The present study suggests that hypercapnia impairs both dCA and NVC, probably acting through an impairment of the metabolic component of CBF control.

Normative values of physiological parameters hold significance in modern day clinical decision-making. Lack of such normative values has been a major hurdle in the translation of research into clinical practice. A large database containing uniform recordings was constructed to allow more robust estimates of normative ranges and also assess the influence of age and sex.Doppler recordings were performed on healthy volunteers in the same laboratory, using similar protocols and equipment. Beat-to-beat blood pressure, heart-rate, electrocardiogram, and end-tidal CO2 were measured continuously. Bilateral insonation of the middle cerebral arteries (MCAs) was performed using TCD following a 15-minute stabilisation, and a 5-minute baseline recording.Good quality Doppler recordings for both MCAs were obtained in 129 participants (57 female) with a median age of 57 years (range 20-82). Age was found to influence baseline haemodynamic and transfer function analysis parameters. Cerebral blood flow velocity and critical closing pressure were the only sex-related differences found, which was significantly higher in females than males.Normative values for cerebral haemodynamic parameters have been defined in a large, healthy population. Such age/sex-defined normal values can be used to reduce the burden of collecting additional control data in future studies, as well as to identify disease-associated changes. Key wordsCerebral haemodynamics, cerebral autoregulation, ageing, sex differences, cerebral blood

Motor stimulation induces a neurovascular response that can be detected by continuous measurement of cerebral blood flow (CBF). Simultaneous changes in arterial blood pressure (ABP) and Pa(CO(2)) have been reported, but their influence on the CBF response has not been quantified. Continuous bilateral recordings of CBF velocity (CBFV), ABP, and end-tidal CO(2) (ET(CO(2))) were obtained in 10 healthy middle-aged subjects at rest and during 60 s of repetitive, metronome-controlled (1 Hz) elbow flexion. A multivariate autoregressive-moving average model was adopted to quantify the relationship between beat-to-beat changes in ABP, breath-by-breath ET(CO(2)), and the motor stimulus, represented by the metronome on-off signal (inputs), and the CBFV response to stimulation (output). All three inputs contributed to explain CBFV variance following stimulation. For the ipsi- and contralateral hemispheres, ABP explained 20.3 ± 17.3% (P = 0.0007) and 19.5 ± 17.2% (P = 0.01) of CBFV variance, respectively. Corresponding values for ET(CO(2)) and metronome signals were 22.0 ± 24.2% (P = 0.008), 24.0 ± 24.1% (P = 0.037), 32.7 ± 22.5% (P = 0.0015), and 43.2 ± 25.1% (P = 0.013), respectively. Synchronized population averages suggest that the initial sudden change in CBFV was largely due to ABP, while the influence of ET(CO(2)) was more erratic. The component due to elbow flexion showed a well-defined pattern, with rise time slower than the main CBFV change but reaching a stable plateau after 15 s of stimulation. Identifying and removing the influences of ABP and Pa(CO(2)) to motor-induced changes in CBF should lead to more robust estimates of neurovascular coupling and better understanding of its physiological covariates.

PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end‐tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive‐moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P <0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P <0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics.