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

Enhancement and suppression effects resulting from information structuring in sentences

Information structuring through the use of cleft sentences increases the processing efficiency of references to elements within the scope of focus. Furthermore, there is evidence that putting certain types of emphasis on individual words not only enhances their subsequent processing, but also protects these words from becoming suppressed in the wake of subsequent information, suggesting mechanisms of enhancement and suppression. In Experiment 1, we showed that clefted constructions facilitate the integration of subsequent sentences that make reference to elements within the scope of focus, and that they decrease the efficiency with reference to elements outside of the scope of focus. In Experiment 2, using an auditory text-change-detection paradigm, we showed that focus has similar effects on the strength of memory representations. These results add to the evidence for enhancement and suppression as mechanisms of sentence processing and clarify that the effects occur within sentences having a marked focus structure

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 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

Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease.

F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity

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

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

Relative energetics and structural properties of zirconia using a self-consistent tight-binding model

We describe an empirical, self-consistent, orthogonal tight-binding model for zirconia, which allows for the polarizability of the anions at dipole and quadrupole levels and for crystal field splitting of the cation d orbitals. This is achieved by mixing the orbitals of different symmetry on a site with coupling coefficients driven by the Coulomb potentials up to octapole level. The additional forces on atoms due to the self-consistency and polarizabilities are exactly obtained by straightforward electrostatics, by analogy with the Hellmann-Feynman theorem as applied in first-principles calculations. The model correctly orders the zero temperature energies of all zirconia polymorphs. The Zr-O matrix elements of the Hamiltonian, which measure covalency, make a greater contribution than the polarizability to the energy differences between phases. Results for elastic constants of the cubic and tetragonal phases and phonon frequencies of the cubic phase are also presented and compared with some experimental data and first-principles calculations. We suggest that the model will be useful for studying finite temperature effects by means of molecular dynamics.Comment: to be published in Physical Review B (1 march 2000

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

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 (β-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