Optimising the assessment of cerebral autoregulation from black box models

Cerebral autoregulation (CA) mechanisms maintain blood flow approximately stable despite changes in arterial blood pressure. Mathematical models that characterise this system have been used extensively in the quantitative assessment of function/impairment of CA. Using spontaneous fluctuations in arterial blood pressure (ABP) as input and cerebral blood flow velocity (CBFV) as output, the autoregulatory mechanism can be modelled using linear and non-linear approaches, from which indexes can be extracted to provide an overall assessment of CA. Previous studies have considered a single – or at most a couple of measures, making it difficult to compare the performance of different CA parameters. We compare the performance of established autoregulatory parameters and propose novel measures. The key objective is to identify which model and index can best distinguish between normal and impaired CA. To this end 26 recordings of ABP and CBFV from normocapnia and hypercapnia (which temporarily impairs CA) in 13 healthy adults were analysed. In the absence of a ‘gold’ standard for the study of dynamic CA, lower inter- and intra-subject variability of the parameters in relation to the difference between normo- and hypercapnia were considered as criteria for identifying improved measures of CA. Significantly improved performance compared to some conventional approaches was achieved, with the simplest method emerging as probably the most promising for future studies

Cerebral autoregulation, brain injury, and the transitioning premature infant

Improvements in clinical management of the preterm infant have reduced the rates of the two most common forms of brain injury, such as severe intraventricular hemorrhage and white matter injury, both of which are contributory factors in the development of cerebral palsy. Nonetheless, they remain a persistent challenge and are associated with a significant increase in the risk of adverse neurodevelopment outcomes. Repeated episodes of ischemia–reperfusion represent a common pathway for both forms of injury, arising from discordance between systemic blood flow and the innate regulation of cerebral blood flow in the germinal matrix and periventricular white matter. Nevertheless, establishing firm hemodynamic boundaries, as a part of neuroprotective strategy, has challenged researchers. Existing measures either demonstrate inconsistent relationships with injury, as in the case of mean arterial blood pressure, or are not feasible for long-term monitoring, such as cardiac output estimated by echocardiography. These challenges have led some researchers to focus on the mechanisms that control blood flow to the brain, known as cerebrovascular autoregulation. Historically, the function of the cerebrovascular autoregulatory system has been difficult to quantify; however, the evolution of bedside monitoring devices, particularly near-infrared spectroscopy, has enabled new insights into these mechanisms and how impairment of blood flow regulation may contribute to catastrophic injury. In this review, we first seek to examine how technological advancement has changed the assessment of cerebrovascular autoregulation in premature infants. Next, we explore how clinical factors, including hypotension, vasoactive medications, acute and chronic hypoxia, and ventilation, alter the hemodynamic state of the preterm infant. Additionally, we examine how developmentally linked or acquired dysfunction in cerebral autoregulation contributes to preterm brain injury. In conclusion, we address exciting new approaches to the measurement of autoregulation and discuss the feasibility of translation to the bedside

The best marker for guiding the clinical management of patients with raised intracranial pressure: the RAP index or the mean pulse amplitude?

Raised intracranial pressure is a common problem in a variety of neurosurgical conditions including traumatic brain injury, hydrocephalus and intracranial haemorrhage. The clinical management of these patients is guided by a variety of haemodynamic, biochemical and clinical factors. However to date there is no single parameter that is used to guide clinical management of patients with raised intracranial pressure (ICP). However, the role of ICP indices, specifically the mean pulse amplitude (AMP) and RAP index [correlation coefficient (R) between AMP amplitude (A) and mean ICP pressure (P); index of compensatory reserve], as an indicator of true ICP has been investigated. Whilst the RAP index has been used both as a descriptor of neurological deterioration in TBI patients and as a way of characterising the compensatory reserve in hydrocephalus, more recent studies have highlighted the limitation of the RAP index due to the influence that baseline effect errors have on the mean ICP, which is used in the calculation of the RAP index. These studies have suggested that the ICP mean pulse amplitude may be a more accurate marker of true intracranial pressure due to the fact that it is uninfluenced by the mean ICP and, therefore, the AMP may be a more reliable marker than the RAP index for guiding the clinical management of patients with raised ICP. Although further investigation needs to be undertaken in order to fully assess the role of ICP indices in guiding the clinical management of patients with raised ICP, the studies undertaken to date provide an insight into the potential role of ICP indices to treat raised ICP proactively rather than reactively and therefore help prevent or minimise secondary brain injury

GPS analysis of a team competing at a national Under 18 field hockey tournament

The purpose of this study was to utilise global-positioning system (GPS) technology to quantify the running demands of national Under 18 field hockey players competing in a regional field hockey tournament. Ten male players (mean ± SD; age 17.2 ± 0.4 years; stature 178.1 ± 5.2 cm; body mass 78.8 ± 8.8 kg) wore GPS units while competing in six matches over seven days at the 2018 New Zealand national under 18 field hockey tournament. GPS enabled the measurement of total distance (TD), low-speed activity (LSA; 0 -14.9 km/hr), and high-speed running (HSR; ≥ 15 km/hr) distances. Differences in running demands (TD, LSA, HSR) between positions were assessed using effect size and percent difference ± 90% confidence intervals. Midfielders covered the most TD and LSA per game and strikers the most HSR during the 6 matches. There were “very large” differences between strikers and midfielders for TD and LSA, strikers and defenders for LSA and HSR, and defenders and midfielders for LSA. These results suggest that these playing positions are sufficiently different to warrant specialised position-specific conditioning training leading into a field hockey tournament

The effects of morning preconditioning protocols on testosterone, cortisol and afternoon sprint cycling performance [conference presentation]

Opportunities exist for athletes to undertake morning exercise protocols in an attempt to potentate afternoon performance. Four sub elite track sprint cyclists completed a morning cycling (Cyc) or weights-based protocol (WP) prior to an afternoon cycling time trial (500m) in a repeated measures, counterbalance crossover design. Measured variables included heart rate, blood lactate, cycling peak power, salivary testosterone (T) and cortisol levels along with time trial performance. Standardised differences in means via magnitude-based inferences were calculated using paired samples T-tests in SPSS version 24 with statistical significance set at p < 0.05. The WP produced significantly faster times in the final 250m in comparison to CycP. The anticipated circadian decline of T was observed after the CycP but was however mitigated following the WP. While slight decreases in 500m times were experienced during the WP, they were not significant and were considered within the normal variations experienced between performances by elite athletes. The effect of the WP on the circadian rhythm of T could be linked to a greater recruitment of muscle fibres. Results suggest a morning resistance protocol can positively affect testosterone levels for afternoon performance. Possible gender and individual responses from conducting a W over Cyc protocol were observed and require further investigation

Quantifying variability in dynamic cerebral autoregulation in the human brain

Introduction: The brain is a highly sophisticated system that operates dynamically which is in constant need of a continuous supply of oxygen and glucose via blood flow to sustain functionality and remain healthy. Despite changes in Arterial Blood Pressure (ABP), the blood pressure and flow are maintained at certain levels within the human cranium using a mechanism called dynamic Cerebral Autoregulation (dCA). The major challenge in this research thesis is that the dCA mechanism is a nonstationary process which means that measurements are varying over time. There are determinant physiological factors that make dCA a nonstationary mechanism including Carbon dioxide (CO2), body temperature and Intracranial Pressure (ICP). Aim: This work aims to quantify the variability found in dCA by applying Transfer Function Analysis (TFA) using the MATLAB platform on a univariate scale and multivariate scale. There are several input variables influencing the dCA mechanism and HR input will be included as a measure of sympathetic control in this research. However, CO2 input is widely used in multivariate analysis where HR recordings were used for beat-to-beat averaging or filtering. Also, this thesis aims to examine and quantify the temporal variability of dCA which is found in measurement variability (across multiple recordings) and subject variability (across all recordings) on both univariate and multivariate scales. Methods: The study included 20 subjects recording their vital signs during 5 visits for each subject at 3 conditions (normocapnia, hypercapnia and thigh cuff conditions), forming a dataset of 300 vital signs recordings of ABP, CBv (right and left sides), CO2, and HR as well as mean recordings for ABP and both sides of CBv. Using univariate and multivariate techniques, this study will analyse measurements using the TFA technique. Then, apply reproducibility and covariance analyses where the first will measure ICC levels and the latter will quantify variabilities in measurement and subject variability recordings. Results: For the univariate analysis, the results demonstrate different behaviours in coherence, gain, and phase for normocapnia, hypercapnia, and thigh cuff conditions under different frequency ranges (HF, LF, and VLF). Overall, the thigh cuff condition shows the lowest variation patterns, especially at the LF band. In the HF band, the thigh cuff condition shows low variation in gain and phase but not in coherence. However, the normocapnia condition shows different pattern of variation in the VLF band where normocapnia coherence and gain show narrower measurement variability (the variability between the different visits for each subject for each condition) but larger subject variability (the variability both within each subject 5 recordings, and between the overall subjects recordings for each condition) than hypercapnia and thigh cuff conditions. On the other hand, normocapnia VLF phase variations are significantly narrower in both measurement and subject variabilities compared to the other conditions. Besides, covariance results show that measurement variability are significantly smaller than subject variability in normocapnia, hypercapnia and thigh cuff conditions at all frequency bands. For the multivariate analysis, using 2-inputs and 3-inputs in the TFA significantly increased coherence results compared to the univariate analysis results. Also, ICC results are significantly higher than the ICC results from the univariate analysis where the covariance results show measurement variability significantly smaller than subject variability at all physiological conditions across the frequency spectrum. Conclusion: On a univariate scale, the thigh cuff condition at the LF band exhibits the lowest variation levels among both the right and left sides of the brain compared to the HF and VLF bands. However, the multivariate analysis shows that coherence results appear to improve TFA parameter results as well as ICC values, particularly, when using 3-inputs analysis where covariance results appear to be similar to those found from univariate analysis. Overall, adding HR (Coh ABP+HR = 0.685, ± 0.160, mean, ± Std) to the TFA appears to have more influence than adding CO2 (Coh ABP+CO2 = 0.676, ± 0.137) in increasing coherence results, which has not previously been shown (Coh ABP+CO2+HR = 0.732, ± 0.128)

Magnetic resonance imaging of resting cerebral oxygen metabolism : applications in Alzheimer’s disease

The BOLD contrast employed in functional MRI studies is an ambiguous signal composed of changes in blood flow, blood volume and oxidative metabolism. In situations where the vasculature and metabolism may have been affected, such as in aging and in certain diseases, the dissociation of the more physiologically-specific components from the BOLD signal becomes crucial. The latest generation of calibrated functional MRI methods allows the estimation of both resting blood flow and absolute oxygen metabolism. The work presented here is based on one such proof-of-concept approach, dubbed QUO2, whereby taking into account, within a generalized model, both arbitrary changes in blood flow and blood O2 content during a combination of hypercapnia and hyperoxia breathing manipulations, yields voxel-wise estimates of resting oxygen extraction fraction and oxidative metabolism. In the first part of this thesis, the QUO2 acquisition protocol and data analysis were revisited in order to enhance the temporal stability of individual blood flow and BOLD responses, consequently improving reliability of the model-derived estimates. Thereafter, an assessment of the within and between-subject variability of the optimized QUO2 measurements was performed on a group of healthy volunteers. In parallel, an analysis was performed of the sensitivity of the model to different sources of random and systematic errors, respectively due to errors in measurements and choice of assumed parameters values. Moreover, the various impacts of the oxygen concentration administered during the hyperoxia manipulation were evaluated through a simulation and experimentally, indicating that a mild hyperoxia was beneficial. Finally, the influence of Alzheimer’s disease in vascular and metabolic changes was explored for the first time by applying the QUO2 approach in a cohort of probable Alzheimer’s disease patients and age-matched control group. Voxel-wise and region-wise differences in resting blood flow, oxygen extraction fraction, oxidative metabolism, transverse relaxation rate constant R2* and R2* changes during hypercapnia were identified. A series of limitations along with recommended solutions was given with regards to the delayed transit time, the susceptibility artifacts and the challenge of performing a hypercapnia manipulation in cohorts of elderly and Alzheimer’s patients.Le contraste BOLD employé dans les études d’imagerie par résonance magnétique fonctionnelle (IRMf) provient d’une combinaison ambigüe de changements du flux sanguin cérébral, du volume sanguin ainsi que du métabolisme oxydatif. Dans un contexte où les fonctions vasculaires ou métaboliques du cerveau ont pu être affectées, tel qu’avec l’âge ou certaines maladies, il est crucial d’effectuer une décomposition du signal BOLD en composantes physiologiquement plus spécifiques. La dernière génération de méthodes d’IRMf calibrée permet d’estimer à la fois le flux sanguin cérébral et le métabolisme oxydatif au repos. Le présent travail est basé sur une telle technique, appelée QUantitative O2 (QUO2), qui, via un model généralisé, prend en considération les changements du flux sanguin ainsi que ceux en concentrations sanguine d’O2 durant des périodes d’hypercapnie et d’hyperoxie, afin d’estimer, à chaque voxel, la fraction d’extraction d’oxygène et le métabolisme oxydatif au repos. Dans la première partie de cette thèse, le protocole d’acquisition ainsi que la stratégie d’analyse de l’approche QUO2 ont été revus afin d’améliorer la stabilité temporelle des réponses BOLD et du flux sanguin, conséquemment, afin d’accroître la fiabilité des paramètres estimés. Par la suite, une évaluation de la variabilité intra- et inter-sujet des différentes mesures QUO2 a été effectuée auprès d’un groupe de participants sains. En parallèle, une analyse de la sensibilité du model à différentes sources d’erreurs aléatoires (issues des mesures acquises) et systématiques (dues aux assomptions du model) a été réalisée. De plus, les impacts du niveau d’oxygène administré durant les périodes d’hyperoxie ont été évalués via une simulation puis expérimentalement, indiquant qu’une hyperoxie moyenne était bénéfique. Finalement, l’influence de la maladie d’Alzheimer sur les changements vasculaires et métaboliques a été explorée pour la première fois en appliquant le protocole QUO2 à une cohorte de patients Alzheimer et à un groupe témoin du même âge. Des différences en terme de flux sanguin, fraction d’oxygène extraite, métabolisme oxydatif, et taux de relaxation transverse R2* au repos comme en réponse à l’hypercapnie, ont été identifiées au niveau du voxel, ainsi qu’au niveau de régions cérébrales vulnérables à la maladie d’Alzheimer. Une liste de limitations accompagnées de recommandations a été dressée en ce qui a trait au temps de transit différé, aux artéfacts de susceptibilité magnétique, de même qu’au défi que représente l’hypercapnie chez les personnes âgées ou atteintes de la maladie d’Alzheimer

A simple deep breathing test reveals altered cerebral autoregulation in type 2 diabetic patients

Aims/hypothesis: Patients with diabetes mellitus have an increased risk of stroke and other cerebrovascular complications. The purpose of this study was to evaluate the autoregulation of cerebral blood flow in diabetic patients using a simple method that could easily be applied to the clinical routine screening of diabetic patients. Methods: We studied ten patients with type 2 diabetes mellitus and 11 healthy volunteer control participants. Continuous and non-invasive measurements of blood pressure and cerebral blood flow velocity were performed during deep breathing at 0.1 Hz (six breaths per minute). Cerebral autoregulation was assessed from the phase shift angle between breathing-induced 0.1 Hz oscillations in mean blood pressure and cerebral blood flow velocity. Results: The controls and patients all showed positive phase shift angles between breathing-induced 0.1 Hz blood pressure and cerebral blood flow velocity oscillations. However, the phase shift angle was significantly reduced (p < 0.05) in the patients (48 ± 9°) compared with the controls (80 ± 12°). The gain between 0.1 Hz oscillations in blood pressure and cerebral blood flow velocity did not differ significantly between the patients and controls. Conclusions/interpretation: The reduced phase shift angle between oscillations in mean blood pressure and cerebral blood flow velocity during deep breathing suggests altered cerebral autoregulation in patients with diabetes and might contribute to an increased risk of cerebrovascular disorder

Cerebral Hemodynamic Disturbances in Motor Neuron Disease

An association between motor neuron disease (MND) and dementia was first realized in the late 1800s, yet substantiating research and a description of dementia as part of the clinical syndrome would not appear until the 1990s. In the last two decades, medical imaging has investigated cerebral blood flow changes in the motor and non­ motor cortex to correlate with motor dysfunction and clinical dementia, respectively. The aim of this thesis is to describe early cerebral hemodynamic disturbances with the goal to determine a marker for cognitive decline in MND. Chapter 2 describes the relationship between changes in cerebral hemodynamics and cognition in primary lateral sclerosis (PLS) patients compared to normal controls. Neuropsychological testing revealed subtle frontotemporal changes characterized by executive dysfunction that were associated with global increases in mean transit time (MTT) in grey and white matter, and increased cerebral blood volume (CBV) in the frontotemporal grey matter. Chapter 3 présents a longitudinal clinical study of early cerebral hemodynamic changes in amyotrophie lateral sclerosis (ALS) patients without evidence of cognitive impairment at study onset. This Chapter characterized the relationship between duration ofdiseaseandMTTinthecorticalgreymatter. MTTwasfoundtobethemostsensitive indicator of early cerebral hemodynamic change accompanying disease progression in ALS. Furthermore,thesefindingscorroboratethetrendofincreasedMTTintheabsence of cognitive impairment found in PLS patients in Chapter 2, and may further indicate that hemodynamic changes may occur before the onset of cognitive impairment. iii The aim of Chapter 4 was to elucidate a biological mechanism for increased MTT described in the previous Chapters 2 and 3. A rabbit model of global hypotension was used to demonstrate that MTT is an indicator of cerebral perfusion pressure (CPP). A spectrum of cognitive dysfunction has now been described in MND. The use of sensitive neuropsychological testing has enabled us to identify patients with mild changes in cognitive function from those who are cognitively intact. With the help of this stratification, we were able to show that changes in MTT was associated with disease progression and cognitive impairment. The experimental data presented in this thesis suggest that vascular factors may contribute to cognitive dysfunction in MND