Angela S. M. Salinet

Does hypercapnia-induced impairment of cerebral autoregulation affect neurovascular coupling? A functional TCD study

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.

The longitudinal evolution of cerebral blood flow regulation after acute ischaemic stroke.

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.

Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation.

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.

Reproducibility of cerebral and peripheral haemodynamic responses to active, passive and motor imagery paradigms in older healthy volunteers: a fTCD study.

Cerebral blood flow velocity (CBFv) changes to sensorimotor and cognitive paradigms have been used to assess the integrity of haemodynamic responses, though the reproducibility of these responses has not been properly assessed. Continuous recordings of blood pressure, end-tidal CO(2), heart rate and bilateral CBFv were obtained during 60s of active, passive and mental imagined paradigms on two different occasions over a 1-week period in 13 healthy subjects. The correlation coefficient, standard error of measurement (SEM), intra-class correlation (ICC) and its 95% CI (confidence intervals) for each variable were calculated at the beginning and end of each paradigm. The temporal patterns of haemodynamic responses revealed substantial reproducibility. For the CBFv response, the SEM ranged from 2.4 to 5.5% for the different manoeuvres, whilst the ICC ranged from 0.5 to 0.8 with better reproducibility occurring at the beginning of the paradigm. These findings have important implications for the design of studies of the natural history of haemodynamic changes following ageing and disease.

Effects of active, passive and motor imagery paradigms on cerebral and peripheral hemodynamics in older volunteers: a functional TCD study.

This study aimed to compare the response of metabolic-induced cerebral hemodynamic changes measured using transcranial Doppler (TCD) ultrasonography during passive, active and motor imagery paradigms, and associated peripheral hemodynamic responses. Continuous recordings of bilateral cerebral blood flow velocity (CBFv), blood pressure, heart rate and end-tidal CO(2) were performed in 12 right-handed subjects (aged ≥45 y) before, during and after 60 s of active, passive and mental-imagined paradigms. The results revealed no significant difference in CBFv responses between the paradigms and, furthermore, the temporal patterns of the hemodynamic responses showed some degree of similarity. Moreover, significant changes were seen in cerebral and peripheral hemodynamic responses for all paradigms. Our results suggest that active, passive and motor imagery paradigms can be used interchangeably to assess hemodynamic responses. This will enable more detailed noninvasive assessment in patients, where voluntary movement is not possible, but where abnormalities of cerebral hemodynamic control mechanisms can be anticipated.

Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity

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.

A systematic review of cerebral hemodynamic responses to neural activation following stroke

The aim of this study was to systematically review CBF studies, assess their methodological quality, and identify trends in the association between task-related brain activation patterns and CBF changes in ischemic stroke (IS) patients. We searched the MEDLINE, EMBASE, CINAHL, and Web of Sciences databases for studies of functional recovery with quantification of CBF responses to brain activation paradigms after IS. Titles, abstracts and full text of articles were scrutinised according to pre-defined selection criteria. Two independent reviewers (AS, VH) undertook the methodological quality screening and data extraction of the included studies. Sixteen of the 1,521 identified studies were relevant. Studies showed weaknesses in key methodological criteria (e.g. population size, discussion of limitations), and only seven studies compared responses with a control population. Overall, there was no agreement between CBF responses in either the affected or unaffected hemisphere and prediction of post-IS recovery. Some studies have shown a higher CBF increase in the unaffected hemisphere when the affected hemisphere was stimulated compared to the healthy control responses. However, CBF responses in the affected hemisphere were inconsistent. Many post-IS CBF studies are of poor methodological quality, and do not demonstrate a consistent response post-IS or a relationship with recovery. Further longitudinal studies assessing the natural history of CBF responses to brain paradigms following IS should be undertaken to determine prognostic significance, and to inform future therapeutic strategies.

Active, passive, and motor imagery paradigms: component analysis to assess neurovascular coupling

The association between neural activity and cerebral blood flow (CBF) has been used to assess neurovascular coupling (NVC) in health and diseases states, but little attention has been given to the contribution of simultaneous changes in peripheral covariates. We used an innovative approach to assess the contributions of arterial blood pressure (BP), PaCO2, and the stimulus itself to changes in CBF velocities (CBFv) during active (MA), passive (MP), and motor imagery (MI) paradigms. Continuous recordings of CBFv, beat-to-beat BP, heart rate, and breath-by-breath end-tidal CO2 (EtCO2) were performed in 17 right-handed subjects before, during, and after motor-cognitive paradigms performed with the right arm. A multivariate autoregressive-moving average model was used to calculate the separate contributions of BP, EtCO2, and the neural activation stimulus (represented by a metronome on-off signal) to the CBFv response during paradigms. Differences were found in the bilateral CBFv responses to MI compared with MA and MP, due to the contributions of stimulation (P < 0.05). BP was the dominant contributor to the initial peaked CBFv response in all paradigms with no significant differences between paradigms, while the contribution of the stimulus explained the plateau phase and extended duration of the CBFv responses. Separating the neural activation contribution from the influences of other covariates, it was possible to detect differences between three paradigms often used to assess disease-related NVC. Apparently similar CBFv responses to different motor-cognitive paradigms can be misleading due to the contributions from peripheral covariates and could lead to inaccurate assessment of NVC, particularly during MI.

Contribution of arterial blood pressure and PaCO2 to the cerebrovascular responses to motor stimulation

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.

Statistical criteria for estimation of the cerebral autoregulation index (ARI) at rest.

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 (Welchs 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 Tiecks 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.