Inter-subject analysis of transfer function coherence in studies of dynamic cerebral autoregulation.

OBJECTIVE: The gain and phase of the arterial blood pressure (BP)-cerebral blood flow velocity (CBFV) relationship, assessed by transfer function analysis (TFA), are widely used dynamic cerebral autoregulation (CA) metrics, but their reliability depend on the statistical significance of the magnitude squared coherence (MSC) function. We tested a new approach, based on inter-subject data, to estimate the confidence limits of MSC. APPROACH: Five minute beat-to-beat time series of mean arterial BP (MAP, Finometer) and CBFV (transcranial Doppler) were used for intra-subject (MAP and CBFV from same subject) and inter-subject (BP and CBFV swapped between subjects) estimates of MSC. The 95% confidence limit of MSC was obtained by non-parametric methods for the cases of single frequency harmonics in the range (0.02-0.50 Hz), and also from the mean value of all possible frequency intervals in this range. MAIN RESULTS: Intra-subject estimates of MSC were obtained from 100 healthy subjects (48 female, age range: 21-82 years old) allowing calculation of 9900 inter-subject estimates, with 95% confidence limits in excellent agreement with classical values derived from surrogate random data. Confidence limits of MSC, derived from mean values, decreased asymptotically to around 0.16 with the increasing number of harmonics averaged. SIGNIFICANCE: Replacing estimates of MSC at a single frequency harmonic by the mean calculated over the range (0.02-0.30 Hz) could lead to more robust studies of dynamic CA with greater acceptance of recordings, an important consideration in clinical studies where measurements tend to be more susceptible to noise and artefacts.

How many squat-stand manoeuvres to assess dynamic cerebral autoregulation?

PURPOSE: Squat-stand manoeuvres (SSMs) have been used to induce blood pressure (BP) changes for the reliable assessment of dynamic cerebral autoregulation. However, they are physically demanding and thus multiple manoeuvres can be challenging for older subjects. This study aimed to determine the minimum number of SSMs required to obtain satisfactory coherence, thus minimising the subjects' workload. METHOD: 20 subjects performed SSMs at a frequency of 0.05 Hz. End-tidal CO2, cerebral blood flow velocity, heart rate, continuous BP and the depth of the squat were measured. 11 subjects returned for a repeat visit. The time points at which subjects had performed 3, 6, 9, 12 and 15 SSMs were determined. Transfer function analysis was performed on files altered to the required length to obtain estimates of coherence and the autoregulation index (ARI). RESULTS: After three SSMs, coherence (0.05 Hz) was 0.93 ± 0.05, and peaked at 0.95 ± 0.02 after 12 manoeuvres. ARI decreased consecutively with more manoeuvres. ARI was comparable across the two visits (p = 0.92), but coherence was significantly enhanced during the second visit (p < 0.01). The intra-subject coefficients of variation (CoV) for ARI remained comparable as the number of manoeuvres varied. CONCLUSIONS: This analysis can aid those designing SSM protocols, especially where participants are unable to tolerate a standard 5-min protocol or when a shorter protocol is needed to accommodate additional tests. We emphasise that fewer manoeuvres should only be used in exceptional circumstances, and where possible a full set of manoeuvres should be performed. Furthermore, these results need replicating at 0.10 Hz to ensure their applicability to different protocols.

Reproducibility of task activation using the Addenbrooke's cognitive examination in healthy controls: A functional Transcranial Doppler ultrasonography study.

INTRODUCTION: Cerebral blood flow velocity (CBFv) changes occurring with cognitive stimulation can be measured by Transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the reproducibility of CBFv changes to the Addenbrooke's cognitive examination (ACE-III). NEW METHOD: 13 volunteers underwent bilateral TCD (middle cerebral artery), continuous heart rate (HR, 3-lead ECG, Finometer), beat-to-beat mean arterial pressure (MAP, Finometer), and end-tidal CO2 (ETCO2, capnography). After 5min baseline, all ACE-III tasks were performed in 3 domains (A/B/C). Data presented are population CBFv peak normalised changes and area under the curve (AUC). Statistical analysis was by 2-way repeated measures (ANOVA), intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). RESULTS: 12 bilateral data sets were obtained (10 right hand dominant, 6 female). Baseline parameters (MAP, HR, ETCO2) did not differ between visits. All tasks increased CBFv. Only domain A on AUC analysis differed significantly on ANOVA, and one task on post hoc testing (p <0.05). ICC values were poor (<0.4) for most tasks, but 3 tasks produced more consistent results on AUC and peak CBFv analysis (range ICC: 0.15-0.73, peak CV: 16.2-56.1(%), AUC CV: 23.2-60.2(%), peak SEM: 2.5-6.0 (%), AUC SEM: 21.8-135.8 (%*s). COMPARISON WITH EXISTING METHODS: This is the first study to examine reproducibility of CBFv changes to a complete cognitive assessment tool. CONCLUSIONS: Reproducibility of CBFv measurements to the ACE-III was variable. AUC may provide more reliable estimates than peak CBFv responses. These data need validating in patient populations.

Transcranial Doppler ultrasonography in the assessment of neurovascular coupling responses to cognitive examination in healthy controls: A feasibility study.

BACKGROUND: We tested the hypothesis that paradigms from the Addenbrooke's Cognitive Examination (ACE-III), including those that had not been studied using TCD previously (novel) versus those which had been (established), would elicit changes in CBF velocity (CBFv). NEW METHOD: Healthy subjects were studied with bilateral transcranial Doppler (TCD), beat-to-beat blood pressure (Finapres), continuous electrocardiogram (ECG), and end-tidal CO2 (nasal capnography). After a 5-min baseline recording, cognitive tests of the ACE-III were presented to subjects, covering attention (SUB7, subtracting 7 from 100 sequentially), language (REP, repeating words and phrases), fluency (N-P, naming words), visuospatial (DRAW, clock-drawing), and memory (MEM, recalling name and address). An event marker noted question timing. RESULTS: Forty bilateral data sets were obtained (13 males, 37 right-hand dominant) with a median age of 31 years (IQR 22-52). Population normalized mean peak CBFv% in the dominant and non-dominant hemispheres, respectively, were: SUB7 (11.3±9.6%, 11.2±10.5%), N-P (12.7±11.7%, 11.5±12.0%), REP (12.9±11.7%, 11.6±11.6%), DRAW (13.3±11.7%, 13.2±15.4%) and MEM (13.2±10.3%, 12.0±10.1%). There was a significant difference between the dominant and non-dominant CBFv responses (p<0.008), but no difference between the amplitude of responses. COMPARISON WITH EXISTING METHODS: For established paradigms, our results are in excellent agreement to what has been found previously in the middle cerebral artery. CONCLUSIONS: Cognitive paradigms derived from the ACE-III led to significant lateralised changes in CBFv that were not distinct for novel paradigms. Further work is needed to assess the potential of paradigms to improve the interpretation of cognitive assessments in patients at risk of mild cognitive impairment.

Cerebral blood flow autoregulation in ischemic heart failure.

Patients with ischemic heart failure (iHF) have a high risk of neurological complications such as cognitive impairment and stroke. We hypothesized that iHF patients have a higher incidence of impaired dynamic cerebral autoregulation (dCA). Adult patients with iHF and healthy volunteers were included. Cerebral blood flow velocity (CBFV, transcranial Doppler, middle cerebral artery), end-tidal CO2 (capnography), and arterial blood pressure (Finometer) were continuously recorded supine for 5 min at rest. Autoregulation index (ARI) was estimated from the CBFV step response derived by transfer function analysis using standard template curves. Fifty-two iHF patients and 54 age-, gender-, and BP-matched healthy volunteers were studied. Echocardiogram ejection fraction was 40 (20-45) % in iHF group. iHF patients compared with control subjects had reduced end-tidal CO2 (34.1 ± 3.7 vs. 38.3 ± 4.0 mmHg, P < 0.001) and lower ARI values (5.1 ± 1.6 vs. 5.9 ± 1.0, P = 0.012). ARI <4, suggestive of impaired CA, was more common in iHF patients (28.8 vs. 7.4%, P = 0.004). These results confirm that iHF patients are more likely to have impaired dCA compared with age-matched controls. The relationship between impaired dCA and neurological complications in iHF patients deserves further investigation.

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 (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.