Emmanuel Katsogridakis

Embolus Trajectory Through a Physical Replica of the Major Cerebral Arteries

Background and Purpose— The observed distribution of cerebral infarcts varies markedly from expectations based on blood-flow volume or Doppler embolus detection. In this study, we used an in vitro model of the cerebral arteries to test whether embolus microspheres encountering the circle of Willis are carried proportionally to volume flow or express a preferred trajectory related to arterial morphology or embolus size. Methods— Our model consisted of a patient-specific silicone replica of the cerebral macrocirculation featuring physiologically realistic pulsatile flow of a blood-mimicking fluid at approximately 1000 mL/min and an input pressure of approximately 150/70 mm Hg. Particles of 200, 500, and 1000 &mgr;m diameter with equivalent density to thrombus were introduced to the carotid arteries and counted on exiting the model outlets. Results— The middle cerebral arteries (MCAs) of the replica attracted a disproportionate number of emboli compared with the anterior cerebral arteries; 98%±3% of 1000 &mgr;m and 93%±2% of 500 &mgr;m emboli entered the MCA compared with 82%±5% of the flow. The observed distribution of large emboli was consistent with the ratio of MCA:anterior cerebral artery infarcts, approximately 95% of which occur in territories supplied by the MCA. With decreasing embolus size, the distribution of emboli approaches that of the flow (approximately 89% of 200 &mgr;m emboli took the MCA). Conclusions— Embolus trajectory through the cerebral arteries is dependent on embolus size and strongly favors the MCA for large emboli. The 70:30 ratio of MCA:anterior cerebral artery emboli observed by Doppler ultrasound is consistent with the trajectories of small emboli that tend to be asymptomatic.

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% CO2 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.

The Leicester cerebral haemodynamics database: normative values and the influence of age and sex

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 min stabilisation, and a 5 min 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.

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.

Signal-to-noise ratio of bilateral nonimaging transcranial Doppler recordings of the middle cerebral artery is not affected by age and sex.

Differences between transcranial Doppler ultrasonography (TCD) recordings of symmetrical vessels can show true physiologic differences, but can also be caused by measurement error and other sources of noise. The aim of this project was to assess the influence of noise on estimates of dynamic cerebral autoregulation (dCA), and of age, sex and breathing manoeuvres on the signal-to-noise ratio (SNR). Cerebral blood flow (CBF) was monitored in 30 young (<40 years) and 30 older volunteers (age >60 years) during baseline conditions, breath-holding and hyperventilation. Noise was defined as the difference between beat-to-beat values of the two mean CBF velocity (CBFV) signals. Magnitude squared coherence estimates of noise vs. ABP and ABP vs. CBFV were obtained and averaged. A similar approach was adopted for the CBFV step response. The effect of age and breathing manoeuvre on the SNR was assessed using a two-way analysis of variance (ANOVA), whilst the effect of sex was investigated using a Students t test. No significant differences were observed in SNR (baseline 6.07 ± 3.07 dB and 7.33 ± 3.84 dB, breath-hold: 13.53 ± 3.93 dB and 14.64 ± 4.52 dB, and hyperventilation: 14.69 ± 4.04 dB and 14.84 ± 4.05 dB) estimates between young and old groups, respectively. The use of breathing manoeuvres significantly improved the SNR (p < 10(-4)) without a significant difference between manoeuvres. Sex does not appear to have an effect on SNR (p = 0.365). Coherence estimates were not influenced by the SNR, but significant differences were found in the amplitude of the CBFV step response.

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.

Tracking instantaneous pressure-to-flow dynamics of cerebral autoregulation induced by CO2 reactivity

In this work, we proposed a novel method to investigate the underlying rapid pressure-to-flow dynamics induced by changes of arterial CO2. Autoregulation was modeled as a multivariate system. The instantaneous effect of CO2 to cerebral blood flow velocity (CBFV) was removed adaptively by the recursive least square (RLS) method from CBFV. The residue CBFV and arterial blood pressure (ABP) were then filtered by a Gaussian-modulated sinusoidal pulse filter, in order to optimize the time and frequency resolution when estimating the instantaneous phase difference between the signals using Hilbert transform (HT). The results indicate that the effect of CO2 on dynamic autoregulation is slower than on CBFV.

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.

Assessing Inter-subject Variability in Cerebral Blood Flow Control Measurements

The aim of this study is to assess inter-individual variability and repeatability in measures assessing blood flow control in the brain during spontaneous and enhanced fluctuations in blood pressure. There is clear evidence of inter-individual difference during enhanced blood pressure variability, but not at rest. This difference exceeds the within-individual variability by factor of 2.73.

Non-linear models for the detection of impaired cerebral blood flow autoregulation.

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model’s derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired.