Does the Variability of Evoked Tympanic Membrane Displacement Data (V m) Increase as the Magnitude of the Pulse Amplitude Increases?

OBJECTIVES: Evoked tympanic membrane displacement (TMD) measurements, quantified by V m, record small volume changes in the ear canal following stimulation of the acoustic reflex. V m shows a correlation with intracranial pressure (ICP) and has been proposed as an option to non-invasively measure ICP. The spontaneous pulsing of the tympanic membrane, driven by the cardiovascular pulse, may contaminate the recordings and contribute to high measurement variability in some subjects. This study hypothesised that the larger the spontaneous vascular pulse, the larger the variability in V m. MATERIALS AND METHODS: Spontaneous and evoked TMD data from each ear in the sitting and supine position were recorded from 100 healthy volunteers using the MMS-14 CCFP analyser. ECG was also recorded to identify each heartbeat. Using bespoke software written in Matlab, spontaneous data were analysed to produce average pulse amplitude (PA) waveforms and evoked data were analysed to calculate average V m and its standard deviation. Averaged spontaneous PA was plotted against V m variability and Pearson's correlation coefficient was calculated to test for a significant linear relationship. RESULTS: There was a strong positive correlation between PA and V m variability in all conditions: left sitting, r = 0.758; left supine, r = 0.665; right sitting, r = 0.755; right supine, r = 0.513. All were significant at p < 0.001. CONCLUSION: This study shows that large V m variability is associated with a large spontaneous vascular pulse. This suggests that efforts to reduce vascular pulsing from recordings, either by a subtraction technique during post-processing or ECG-gating of the evoking stimulus, may improve reliability of the V m measurement.

Haptoglobin, alpha-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania.

Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (ß-coefficient -16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35-0·8] & RRR = 0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.

A randomized controlled trial of prophylactic intra-aortic balloon counterpulsation in high-risk aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: To assess whether prophylactic postoperative intraaortic balloon counterpulsation (IABC) reduces the risk of poor outcome because of vasospasm following aneurysmal subarachnoid haemorrhage relative to conventional hypervolemic therapy (HT). METHODS: This was a single-center, parallel group randomized controlled trial. Patients suffering a subarachnoid hemorrhage at high risk of vasospasm were eligible. Patients were randomly allocated to receive prophylactic IABC (n=35) or HT (n=36). The primary end point was Glasgow Outcome and SF-36 scores assessed at 6 months by a blinded and independent observer and analyzed by intention to treat. Secondary analysis of physiological parameters was by treatment performed. RESULTS: Twenty-seven patients in each arm had a good outcome (P=0.55). There was no statistical difference in mean SF-36 score (t=0.39, P=0.70). There were no long-term complications secondary to IABC. There were no differences in preload (pulmonary artery wedge pressure, P=0.97) or afterload (mean arterial pressure, P=0.97). IABC was associated with a lower cardiac output (P=0.002) and higher systemic vascular resistance (P=0.005), although for both groups mean cardiac output was >6 L/min. Cerebral blood flow was not different between groups: HT=41.5 (SD 7.2), IABP=44.9 (SD 8.6) mL/100 g/min (P=0.14). CONCLUSIONS: In this study, prophylactic IABC did not improve perfusion indices or confer any clinical benefit following subarachnoid haemorrhage in patients with normal cardiac function. The study was small, however, and cannot be extrapolated to patients with cardiac failure and medically refractory symptomatic cerebral vasospasm. Clinical Trial Registration- This trial was not registered because enrolment began prior to July 1, 2005.

Pulsatile tympanic membrane displacement is associated with cognitive score in healthy subjects.

To test the hypothesis that pulsing of intracranial pressure has an association with cognition, we measured cognitive score and pulsing of the tympanic membrane in 290 healthy subjects. This hypothesis was formed on the assumptions that large intracranial pressure pulses impair cognitive performance and tympanic membrane pulses reflect intracranial pressure pulses. 290 healthy subjects, aged 20-80 years, completed the Montreal Cognitive Assessment Test. Spontaneous tympanic membrane displacement during a heart cycle was measured from both ears in the sitting and supine position. We applied multiple linear regression, correcting for age, heart rate, and height, to test for an association between cognitive score and spontaneous tympanic membrane displacement. Significance was set at P < 0.0125 (Bonferroni correction.) A significant association was seen in the left supine position (p = 0.0076.) The association was not significant in the right ear supine (p = 0.28) or in either ear while sitting. Sub-domains of the cognitive assessment revealed that executive function, language and memory have been primarily responsible for this association. In conclusion, we have found that spontaneous pulses of the tympanic membrane are associated with cognitive performance and believe this reflects an association between cognitive performance and intracranial pressure pulses.

Estimating confidence intervals for cerebral autoregulation: a parametric bootstrap approach.

Cerebral autoregulation (CA) refers to the ability of the brain vasculature to control blood flow in the face of changing blood pressure. One of the methods commonly used to assess cerebral autoregulation, especially in participants at rest, is the analysis of phase derived from transfer function analysis (TFA), relating arterial blood pressure (ABP) to cerebral blood flow (CBF). This and other indexes of CA can provide consistent results when comparing groups of subjects (e.g. patients and healthy controls or normocapnia and hypercapnia) but can be quite variable within and between individuals. The objective of this paper is to present a novel parametric bootstrap method, used to estimate the sampling distribution and hence confidence intervals (CIs) of the mean phase estimate in the low-frequency band, in order to optimise estimation of measures of CA function and allow more robust inferences on the status of CA from individual recordings. A set of simulations was used to verify the proposed method under controlled conditions. In 20 healthy adult volunteers (age 25.53.5 years), ABP and CBF velocity (CBFV) were measured at rest, using a Finometer device and Transcranial Doppler (applied to the middle cerebral artery), respectively. For each volunteer, five individual recordings were taken on different days, each approximately 18 min long. Phase was estimated using TFA. Analysis of recorded data showed widely changing CIs over the duration of recordings, which could be reduced when noisy data and frequencies with low coherence were excluded from the analysis (Wilcoxon signed rank testp= 0.0065). The TFA window-lengths of 50s gave smaller CIs than lengths of 100s (p< 0.001) or 20s (p< 0.001), challenging the usual recommendation of 100s. The method adds a much needed flexible statistical tool for CA analysis in individual recordings.

Vasomotion Drives Periarterial Drainage of Aß from the Brain.

In this issue of Neuron, van Veluw et al. (2020) show that elimination of solutes from the brain along arterial walls is driven by low-frequency arteriolar oscillations and suggest that age-related reduction of this vasomotion may contribute to impaired clearance of Aß.

Refining non-invasive techniques to measure intracranial pressure: comparing evoked and spontaneous tympanic membrane displacements.

OBJECTIVE: Tympanic membrane displacements (TMDs) are used to non-invasively gauge inner-ear fluid pressure. Inner-ear fluid pressure equalizes with intracranial pressure (ICP) via the cochlear aqueduct and therefore TMDs can indirectly evaluate ICP. We studied the relationship between two TMD modalities, evoked and spontaneous. Evoked TMD is a reflex response to an auditory stimulus and the established stapes-footplate mechanism explains how evoked TMDs change with ICP. Spontaneous TMD refers to a pulsatile TMD waveform expressed in the form of pulse amplitudes (TMD-PAs), the origins of which are poorly understood. We investigated whether both modalities respond similarly to an ICP change, suggesting a common mechanism. APPROACH: ICP was manipulated in 20 healthy volunteers by a postural change from sitting (lower ICP) to supine (higher ICP). Differences between paired sitting and supine TMD results generated ΔEvoked and ΔSpontaneous values. MAIN RESULTS: Evoked TMDs became more inward on lying supine while spontaneous TMDs became more outward. There was no evidence of a correlation between ΔEvoked and ΔSpontaneous (Right ears: r = -0.38, p = 0.10, 95% CI -0.75 to 0.21; Left ears: r = 0.34, p = 0.16, 95% CI -0.17 to 0.75). SIGNIFICANCE: This suggests the stapes-footplate mechanism is not the primary mechanism explaining how spontaneous TMDs respond to changing ICP.

Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement.

OBJECTIVE: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. APPROACH: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1-5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. MAIN RESULTS: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. SIGNIFICANCE: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies-respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD.

Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure.

OBJECTIVE: Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. APPROACH: Measurements were made in 154 healthy adults. Results were quantified by V m, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. MAIN RESULTS: The range in which 95% of scores fall is -283 to 722 nl (M = 132 nl) left sitting, -232 to 623 nl (M = 97 nl) right sitting, -543 to 717 nl (M = 37 nl) left supine and -584 to 504 nl (M = -15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. SIGNIFICANCE: We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for V m. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use.

Sympathetic peripheral vasoconstriction may be measured using an artifact of the Finapres volume clamp technique.

OBJECTIVES: The objective of this work was to test the hypothesis that the Finapres underestimates blood pressure during sympathetic peripheral vasoconstriction. METHODS: Measurements were made simultaneously with two Finapres devices and one radial artery tonometer during the onset of periodic lower body negative pressure in healthy volunteers. The Finapres is believed to underestimate blood pressure during sympathetic peripheral vasoconstriction, but tonometry is not considered to be influenced. A lower blood pressure recording was therefore expected from the Finapres during the induced sympathetic vasoconstriction. To test the association with autonomic activity the time course of the difference between the two measurement techniques was compared with the induced change in heart rate. RESULTS: In averaged results from 10 volunteers the Finapres and tonometer both showed a drop in blood pressure with the vacuum onset. A significantly larger drop was recorded by the Finapres. The result is consistent with an underestimate of blood pressure by the Finapres during the autonomic stimulation. The time course of the difference between the two measures of blood pressure follows the induced changes in heart rate, providing further evidence that the differences relate to autonomic activity. CONCLUSION: Measurement of the difference may be a convenient method for monitoring the neurological component of peripheral vasoactivity. It is argued that the difference is insensitive to peripheral vasoactivity mediated by local endothelial or myogenic mechanisms.

At what data length do cerebral autoregulation measures stabilise?

OBJECTIVE: Cerebral autoregulation is commonly assessed through mathematical models that use non-invasive measurements of arterial blood pressure and cerebral blood flow velocity. There is no agreement in the literature as to what is the minimum length of data needed for the cerebral autoregulation coefficients to stabilise. APPROACH: We introduce a simple empirical tool for studying the minimum length of time series needed to parameterise three popular cerebral autoregulation coefficients ARI, Mx and Phase (in the low frequency range [0.07-0.2] Hz), which can be easily applied in a more general context. We use our recently collected data, from which we select high quality (absence of non-physiological artefacts), baseline ABP-CBFV time series (16 min each). The data were beat-to-beat averaged and downsampled at 10 Hz. MAIN RESULT: On average, ARI exhibits greater variability than Mx and Phase, when calculated for short intervals; however, it stabilises fastest. SIGNIFICANCE: Our results show that values of ARI, Mx and Phase calculated on intervals shorter than 3 min (1800 samples), 6 min (3600 samples) and 5 min (3000 samples), respectively, may be very sensitive to changes in the length of data interval.

Increased blood pressure variability upon standing up improves reproducibility of cerebral autoregulation indices.

Dynamic cerebral autoregulation, that is the transient response of cerebral blood flow to changes in arterial blood pressure, is currently assessed using a variety of different time series methods and data collection protocols. In the continuing absence of a gold standard for the study of cerebral autoregulation it is unclear to what extent does the assessment depend on the choice of a computational method and protocol. We use continuous measurements of blood pressure and cerebral blood flow velocity in the middle cerebral artery from the cohorts of 18 normotensive subjects performing sit-to-stand manoeuvre. We estimate cerebral autoregulation using a wide variety of black-box approaches (including the following six autoregulation indices ARI, Mx, Sx, Dx, FIR and ARX) and compare them in the context of reproducibility and variability. For all autoregulation indices, considered here, the intra-class correlation was greater during the standing protocol, however, it was significantly greater (Fisher's Z-test) for Mx (p < 0.03), Sx (p < 0.003) and Dx (p < 0.03). In the specific case of the sit-to-stand manoeuvre, measurements taken immediately after standing up greatly improve the reproducibility of the autoregulation coefficients. This is generally coupled with an increase of the within-group spread of the estimates.

Coherent averaging of pseudorandom binary stimuli: is the dynamic cerebral autoregulatory response symmetrical?

OBJECTIVE: Previous studies on cerebral autoregulation have shown the existence of hemispheric symmetry, which may be altered in stroke and traumatic brain injury. There is a paucity of data however on whether the response is symmetrical between those disturbances that cause cerebral hyperperfusion, to those that cause hypoperfusion. Our aim was to investigate whether the responses of cerebral autoregulation to haemodynamic stimuli of different directions are symmetrical. APPROACH: Using a previously described assessment method, we employed coherent averaging of the cerebral blood flow velocity (CBFV) responses to thigh cuff inflation and deflation, as driven by pseudorandom binary sequences, whilst simultaneously altering the inspired CO2. The symmetry of the autoregulatory response was assessed with regards to two parameters, its speed and gain. Using the first harmonic method, critical closing pressure (CrCP) and resistance area product (RAP) were estimated, and the gain of the autoregulatory response was calculated by performing linear regression between the coherent averages of arterial blood pressure (ABP) and CBFV, ABP and CrCP and finally ABP and RAP. A two-way repeated measures ANOVA was used to assess for the effect of the direction of change in ABP and the method of CO2 administration. MAIN RESULTS: Our results suggest that whilst the direction of ABP change does not have a significant effect, the effect of CO2 administration method is highly significant (p < 10-4). SIGNIFICANCE: This is the first report to demonstrate the symmetry of the autoregulatory response to stimuli of different directions as well as the short term dynamics of RAP and CrCP under intermittent and constant hypercapnia. As haemodynamic stimulus direction does not appear to have an influence, our findings validate previous work done using different assessment methods.

Revisiting the frequency domain: the multiple and partial coherence of cerebral blood flow velocity in the assessment of dynamic cerebral autoregulation.

Despite advances in modelling dynamic autoregulation, only part of the variability of cerebral blood flow velocity (CBFV) in the low frequency range has been explained. We investigate whether a multivariate representation can be used for this purpose. Pseudorandom sequences were used to inflate thigh cuffs and to administer 5% CO2. Multiple and partial coherence were estimated, using arterial blood pressure (ABP), end-tidal CO2 (EtCO2) and resistance area product as input and CBFV as output variables. The inclusion of second and third input variables increased the amount of CBFV variability that can be accounted for (p < 10(-4) in both cases). Partial coherence estimates in the low frequency range (<0.07 Hz) were not influenced by the use of thigh cuffs, but CO2 administration had a statistically significant effect (p < 10(-4) in all cases). We conclude that the inclusion of additional inputs of a priori known physiological significance can help account for a greater amount of CBFV variability and may represent a viable alternative to more conventional non-linear modelling. The results of partial coherence analysis suggest that dynamic autoregulation and CO2 reactivity are likely to be the result of different physiological mechanisms.

Assessing cerebral blood flow control from variability in blood pressure and arterial CO2 levels.

Blood flow to the brain is controlled by a number of physiological mechanisms that respond to changes in arterial blood pressure, arterial CO2 levels and many other factors. Assessing the integrity of this control system is a major challenge. We report on repeatability of measures based on single and multiple input models during spontaneous and enhanced fluctuations in blood pressure.

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.

Detection of impaired cerebral autoregulation improves by increasing arterial blood pressure variability.

Although the assessment of dynamic cerebral autoregulation (CA) based on measurements of spontaneous fluctuations in arterial blood pressure (ABP) and cerebral blood flow (CBF) is a convenient and much used method, there remains uncertainty about its reliability. We tested the effects of increasing ABP variability, provoked by a modification of the thigh cuff method, on the ability of the autoregulation index to discriminate between normal and impaired CA, using hypercapnia as a surrogate for dynamic CA impairment. In 30 healthy volunteers, ABP (Finapres) and CBF velocity (CBFV, transcranial Doppler) were recorded at rest and during 5% CO(2) breathing, with and without pseudo-random sequence inflation and deflation of bilateral thigh cuffs. The application of thigh cuffs increased ABP and CBFV variabilities and was not associated with a distortion of the CBFV step response estimates for both normocapnic and hypercapnic conditions (P=0.59 and P=0.96, respectively). Sensitivity and specificity of CA impairment detection were improved with the thigh cuff method, with the area under the receiver-operator curve increasing from 0.746 to 0.859 (P=0.031). We conclude that the new method is a safe, efficient, and appealing alternative to currently existing assessment methods for the investigation of the status of CA.

Random perturbations of arterial blood pressure for the assessment of dynamic cerebral autoregulation.

The assessment of cerebral autoregulation (CA) relies mostly on methods that modulate arterial blood pressure (ABP). Despite advances, the gold standard of assessment remains elusive and clinical practicality is limited. We investigate a novel approach of assessing CA, consisting of the intermittent application of thigh cuffs using square wave sequences. Our aim was to increase ABP variability whilst minimizing volunteer discomfort, thus improving assessment acceptability. Two random square wave sequences and two maximum pressure settings (80 and 150 mmHg) were used, corresponding to four manoeuvres that were conducted in random order after a baseline recording. The intermittent application of thigh cuffs resulted in an amplitude dependent increase in ABP (p = 0.001) and cerebral blood flow velocity (CBFV) variability (p = 0.026) compared to baseline. No statistically significant differences in mean heart rate or heart rate variability were observed (p = 0.108 and p = 0.350, respectively), suggesting that no significant sympathetic response was elicited. No significant differences in the CBFV step response were observed, suggesting no distortion of autoregulatory parameters resulted from the use of thigh cuffs. We conclude that pseudorandom binary sequences are an effective and safe alternative for increasing ABP variability. This new approach shows great promise as a tool for the robust assessment of CA.