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.

Association Between Adherence to Glasses Wearing During Amblyopia Treatment and Improvement in Visual Acuity.

IMPORTANCE: Occlusion dose monitors have helped establish that better adherence to occlusion is associated with improved visual outcomes in patients undergoing amblyopia treatment. However, the role of adherence to glasses wearing is unknown. OBJECTIVES: To establish the feasibility and reliability of objectively monitoring adherence to glasses wearing using age-based norms, establish the association between adherence to glasses wearing and improvement in visual acuity (VA) after optical treatment and occlusion therapy, and analyze the effect of age, sex, refractive errors, type of amblyopia, and adherence to glasses wearing on improvement in VA. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, nonmasked, cohort study was conducted between June 8, 2008, and June 30, 2013, among patients at a pediatric ophthalmology clinic of a tertiary care hospital who were newly diagnosed with anisometropic and/or strabismic amblyopia and had not undergone previous treatment. The study consisted of a glasses phase (18 weeks) and a patching phase (glasses and occlusion for 10 hours per day for 12 weeks). Reliability of the glasses monitors was assessed by comparing diary entries and monitor recordings in adults. INTERVENTIONS: Objective monitoring of glasses wearing and occlusion. MAIN OUTCOMES AND MEASURES: Adherence to glasses wearing (hours per day) and effect on VA. RESULTS: Among 20 children with anisometropia (mean [SD] age, 6.20 [2.16] years; 11 boys and 9 girls) and 20 with strabismic or mixed amblyopia (mean [SD] age, 4.90 [1.36] years; 10 boys and 10 girls), adherence to glasses wearing was successfully monitored in all but 1 patient. Agreement between diaries and monitored times wearing glasses in adults was high (intraclass correlation coefficient, 1.00; 95% CI, 0.999-1.00). Median (SD) adherence to glasses wearing was 70% (25.3%). A moderate correlation was observed between adherence to glasses wearing and percentage improvement in VA during the glasses phase (r = 0.462; P = .003). Multiple regression revealed that age (ß = -0.535; P = .001), type of amblyopia (ß = -0.347; P = .02), and adherence to glasses wearing (ß = 0.287; P = .04) were independently associated with improvement in VA after the glasses phase and explained 42% of the variability (F3,35 = 8.457; P < .001). A strong correlation between glasses wearing and occlusion adherence was observed (r = 0.719; P < .001). CONCLUSIONS AND RELEVANCE: The results suggest that adherence to glasses wearing is less than optimal and highly variable but is important in achieving good VA. This study emphasizes the importance of encouraging children to not only have good adherence to occlusion therapy but also to glasses wearing.

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.

An educational intervention to improve adherence to high-dosage patching regimen for amblyopia: a randomised controlled trial.

BACKGROUND: Previous reports suggest that adherence to patching is a major issue in amblyopia treatment. We tested with an unmasked randomised controlled clinical trial whether an intense educational/motivational intervention improves adherence when a high-dose regime is prescribed. METHODS: 62 children with newly diagnosed amblyopia were randomly allocated into two treatment arms with and without educational/motivational intervention material. Both were prescribed patching 10 h/day, 6 days/week for a fixed period of 12 weeks. The intervention arm received an educational/motivational intervention before patching which included information booklets, video, a cartoon story book, sticker charts and a dedicated session with a researcher. The control arm received the usual clinical information. The primary outcome measure was adherence measured using electronic occlusion dose monitors where a success/failure binary outcome was used to account for participants who dropped out of the study defined as patching >4 h/day. Visual outcome, expressed as percentage visual deficit, was measured as secondary outcome. RESULTS: The intervention increased adherence success rate from 45.2% in the control group to 80.6% in the intervention group (p=0.0027). However, visual outcome was not significantly better in the intervention group (p=0.190). CONCLUSIONS: Our study shows that an intense educational/motivational intervention can improve adherence to patching to high prescribed doses although no significant improvement in visual outcome was observed. TRIALS REGISTRATION NUMBER: ISRCTN05346737 (International Standard Randomised Controlled Trial Number Register).

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.

Doppler ultrasound detection of side-vessel occlusion: an in vitro study.

BACKGROUND AND PURPOSE: Small-vessel knock is a recently reported Doppler ultrasound finding that has been identified in patients with cerebral ischemia. It has been hypothesized that knock-type signals are linked to the presence of either small-vessel occlusion or wall motion. The aim of this study was to investigate the origins of "knock-type" signals by reproducing occlusion of a peripheral artery model in vitro. METHODS: Synthetic bifurcations were fabricated from glass and latex and placed in a flow-rig mimicking physiological blood-flow conditions. The glass model permitted study of fluid flow in the absence of wall motion, whereas the latex model also produced wall motion effects. Vessels were artificially obstructed to examine Doppler signal characteristics associated with blood flow and wall motion. RESULTS: Complete obstruction of the peripheral branch of the glass model revealed discrete (<100 ms) knock-type signals caused by local fluid flow in the occluded branch. Imaging of the obstructed vessel using color Doppler revealed forward and reflected flow. The walls produced periodic bidirectional knock-type signals, which occurred during systole and were not related to the presence of an obstruction. CONCLUSIONS: In our laboratory model, transcranial Doppler ultrasound was found to be capable of detecting knock signals produced by circulating fluid within an occluded branch. However, because similar signals are also generated by nonpathological wall motion, these results cannot be directly translated to a clinical setting. Clinicians should be careful to avoid casual overinterpretation of transcranial Doppler ultrasound data.