Separating vascular and neuronal effects of age on fMRI BOLD signals.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.This work is supported by the British Academy (PF160048), the Guarantors of Brain (G101149), the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400; and SUAG/046 G101400), European Union’s Horizon 2020 (732592) and the Cambridge NIHR Biomedical Research Centre

Optimisation, evaluation and application of cerebrovascular reactivity measurement using magnetic resonance imaging in patients with cerebral small vessel disease

Small vessel disease (SVD) is a common cause of strokes and dementia. Currently, there are no treatments; therefore, developing and validating early biomarkers of disease progression and treatment response is important for future drug trials. Though SVD pathogenesis is not well understood, findings from previous studies suggest that blood-brain barrier dysfunction and impaired cerebrovascular reactivity (CVR) contribute to the disease. The latter can be measured in vivo using a vasoactive stimulus in parallel with magnetic resonance imaging (MRI) techniques sensitive to blood flow, such as blood oxygen level dependent (BOLD) contrast, and has frequently been assessed in patients with steno-occlusive diseases. However, it is unclear if the technique is reliable when investigating cerebrovascular health in deep structures of the brain where SVD is prevalent. Therefore, this thesis aimed to assess and optimise the reliability of CVR measurements and deepen our understanding of its role in SVD pathogenesis. A systematic review was performed to provide a detailed overview of CVR MRI methodologies and clinical applications, including SVD, present in the literature, which identified several acquisition and analysis methods, a need for greater standardisation and lack of data on reliability. Specifically in SVD research, there was limited application of CVR MRI in SVD populations, little optimisation and reliability assessment of CVR in deep brain structures relevant to SVD, such as in white and subcortical grey matter. Following those findings, the effects of voxel- and region-based analysis approaches on reliability of CVR estimates were investigated using simulations and test-retest data from healthy volunteers. Voxel-based CVR magnitude estimates in tissues with high noise levels were prone to bias, whereas biases in region-based estimates were independent of noise level, but consistently underestimated CVR magnitude relative to the ground-truth mean. Furthermore, the test-retest study confirmed the repeatability of CVR estimates from a BOLD-CVR experiment with fixed inhaled stimulus, although a systematic, but small, bias was detected due to habituation to the gas challenge. The data from healthy volunteers were further used to conduct a proof-of-concept and investigate the feasibility of extracting cerebral pulsatility from BOLD-CVR data. Small-to-moderate correlations with pulsatility from phase-contrast MRI were found depending on the regions considered. CVR pulsatility was also computed in a small cohort of SVD patients: it was higher than in healthy volunteers, but no associations were found with SVD burden. It was concluded that further optimisation and validation of the technique is needed before being suitable for clinical research. Following the optimisation of the CVR MRI technique, relationships between CVR and SVD neuroimaging features, cognition, stroke severity and outcome were investigated cross-sectionally and longitudinally in a cohort of patients with mild stroke. In the cross-sectional analysis, CVR impairment in normal-appearing and damaged tissues was associated with worse SVD burden and cognition deficit. Furthermore, the longitudinal analysis showed that baseline CVR impairment predicted worsening of white matter hyperintensity and perivascular space volumes after one year. In conclusion, assessment of CVR in the brain and its deeper structures was successfully conducted in healthy volunteers and patients with SVD using MRI. However, this required appropriate optimisation of processing strategy as the latter can affect accuracy of CVR parameters and inter-study comparability. Importantly, applying the technique in a cohort of SVD patients led to the findings that CVR impairment was related to worse SVD burden and is a potential marker of SVD severity and progression

A practical modification to a resting state fMRI protocol for improved characterization of cerebrovascular function

Available online 24 June 2021.Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO 2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemo- dynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural ac- tivity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting- state data segments, and in data segments which added a 2–3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO 2 pressure: a breath-hold task to induce hypercapnia (CO 2 increase) and a cued deep breathing task to induce hypocapnia (CO 2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO 2 by systematically shifting the CO 2 regressor in time to optimize the model fit. This optimization inher- ently increases gray matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO 2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemody- namic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation.This research was supported by the Eunice Kennedy Shriver Na- tional Institute of Child Health and Human Development of the Na- tional Institutes of Health under award number K12HD073945. The pediatric dataset and cerebral palsy dataset were collected with sup- port of National Institutes of Health award R03 HD094615–01A1. The authors would like to acknowledge Marie Wasielewski and Carson Ingo for their support in acquiring these data. K.Z. was supported by an NIH-funded training program (T32EB025766). S.M. was supported by the European Union’s Horizon 2020 research and innovation pro- gram (Marie Sk ł odowska-Curie grant agreement No. 713673), a fel- lowship from La Caixa Foundation (ID 100010434, fellowship code LCF/BQ/IN17/11620063) and C.C.G was supported by the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Fellowship, RYC-2017- 21845), the Basque Government (BERC 2018–2021 and PIBA_2019_104) and the Spanish Ministry of Science, Innovation and Universities (MICINN; PID2019–105520GB-100)

Hybrid Optical System for Studying the Dynamic Regulation of Blood Flow/Metabolism in the Adult Brain

Cerebral blood flow (CBF) and oxygen delivery are tightly controlled to meet neuronal energy demands; however, studying dynamic neurovascular coupling in the human brain is challenging due to the lack of methods that can measure rapid changes in CBF and tissue oxygenation. This report presents an in-house-developed hybrid time-resolved near-infrared spectroscopy/diffuse correlation spectroscopy (TR-NIRS/DCS) device and its use to track dynamic CBF and tissue oxygen saturation (StO2) responses simultaneously with sub-second resolution following a vasodilatory stimulus (i.e., a hypercapnic challenge). Cerebrovascular reactivity (CVR) experiments were performed on 10 healthy participants (mean age: 27 years) using a computer-controlled gas delivery system to manipulate breath-to-breath inspired CO2 levels. TR-NIRS and DCS data were acquired continuously at a sampling frequency of 3 Hz to capture dynamic CBF and oxygenation responses. CVR measurements derived from oxyhemoglobin and deoxyhemoglobin concentrations were 3.4 ± 2.6 and 3.0 ± 1.9 %/mmHg, respectively. Their dynamic component, a fitted exponential coefficient that defines the speed of the response as per the hemodynamic response function, was estimated to be 32 ± 16 and 33 ± 28 seconds. The corresponding CVR value and dynamic component derived from CBF was 3.5 ± 3.6 %/mmHg and 33 ± 18 seconds. These experiments demonstrated that the optical system had sufficient temporal resolution to capture the dynamics of the oxygenation and CBF responses to a vasodilatory stimulus

Dependence of resting-state-based cerebrovascular reactivity (CVR) mapping on spatial resolution

Cerebrovascular reactivity (CVR) is typically assessed with a carbon dioxide (CO2) stimulus combined with BOLD fMRI. Recently, resting-state (RS) BOLD fMRI has been shown capable of generating CVR maps, providing a potential for broader CVR applications in neuroimaging studies. However, prior RS-CVR studies have primarily been performed at a spatial resolution of 3–4 mm voxel sizes. It remains unknown whether RS-CVR can also be obtained at high-resolution without major degradation in image quality. In this study, we investigated RS-CVR mapping based on resting-state BOLD MRI across a range of spatial resolutions in a group of healthy subjects, in an effort to examine the feasibility of RS-CVR measurement at high resolution. Comparing the results of RS-CVR with the maps obtained by the conventional CO2-inhalation method, our results suggested that good CVR map quality can be obtained at a voxel size as small as 2 mm isotropic. Our results also showed that, RS-CVR maps revealed resolution-dependent sensitivity. However, even at a high resolution of 2 mm isotropic voxel size, the voxel-wise sensitivity is still greater than that of typical task-evoked fMRI. Scan duration affected the sensitivity of RS-CVR mapping, but had no significant effect on its accuracy. These findings suggest that RS-CVR mapping can be applied at a similar resolution as state-of-the-art fMRI studies, which will broaden the use of CVR mapping in basic science and clinical applications including retrospective analysis of previously collected fMRI data

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

Imaging alterations in the hemodynamic response in the SHRSP: A model of cerebral small vessel disease

Cerebral small vessel disease (SVD) is associated with various pathological and neurological processes that affect perforating arterioles, capillaries and venules. The characteristic features of cerebral SVD include small lacunar subcortical infarcts, white matter hyperintensities, microbleeds and cortical microinfarcts. The underlying pathology of cerebral SVD is not fully known, owing to the difficulty of studying the disease in humans. Small lacunar infarcts are rarely fatal and often asymptomatic. In cases where death occurs, autopsy tissue is often difficult to interpret since multiple pathological changes have occurred at this late-stage in disease pathology. Spontaneously hypertensive stroke prone rats (SHRSPs) are an accepted and validated model of cerebral SVD, demonstrating many of the features observed in the human condition. Arteriosclerosis, thickening of the vessel wall, narrowing of the arterial lumen, endothelial dysfunction and a loss of vessel reactivity have all been reported in SHRSPs. Given these pathologic cerebrovascular changes, the hemodynamic response in these animals may be sensitive to such changes and therefore provide a marker of cerebrovascular health and an indicator of therapeutic effect. Blunted BOLD responses have been observed in patients with SVD but no study has assessed whether SHRSPs demonstrate a similar reduction in the stimulus-evoked BOLD response. Therefore, the main aim of this thesis was to evaluate whether differences in the hemodynamic response could be detected in between SHRSPs compared to age-matched WKYs. Prior to performing the study described above, we deemed it necessary to evaluate the ability to non-invasively monitor PaCO2¬, by measuring end-tidal CO2 using side-stream capnography. Baseline and stimulus-evoked cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) responses are sensitive to changes in the partial pressure of arterial carbon dioxide (PaCO2). Therefore, it is important that PaCO2 is monitored and kept within normal physiological values to avoid introducing confounds into the data. Blood gas analysis remains the gold standard for assessing PaCO2 and other blood gases, however these measurements are invasive and discrete, only providing a measure of PaCO2 for a short time following withdrawal and analysis of the blood sample. The ability to continuously and non-invasively assess PaCO2 using side-stream capnography would be beneficial for preclinical fMRI studies, particularly longitudinal studies, as it could minimise/eliminate any invasive surgery/procedure required to periodically take blood samples for blood gas analysis and provide a continuous measurement. However, the combination of the rat’s small tidal volume, long sample lines, and large sample volumes required by most capnographs complicate the accurate assessment of PaCO2 using ETCO2¬ ¬in these small animals. Therefore, an aim of this thesis was to assess the ability of micro-sampling side stream capnography to non-invasively assess PaCO2 by comparing ETCO2 measurements with PaCO2 measurements obtained by blood gas analysis. Despite the smaller sample volumes require by micro sampling capnographs, our findings indicate that a large variability still exists between ETCO2 and PaCO2 values when long sampling lines are used, as would be required for use in an fMRI experiment. Therefore, side-stream capnography was not implemented in any of the other studies described in this thesis. However, the use of shorter lines for bench top experiments may hold promise with some opimisation. It was also deemed necessary to explore the effects of varying forelimb stimulation parameters on stimulus-evoked BOLD, CBF and neural responses under combined medetomidine-isoflurane anaesthesia. Anesthesia is known to have various effects on CBF and neural activity, depending on the anesthetic being used, which can subsequently affect stimulus-evoked hemodynamic and neural responses. Therefore, there is a general consensus that stimulus parameters should be optimised to the anaesthetic being utilised, especially in cases where a novel anaesthetic is being used or if no stimulus optimisation is currently provided in the literature. Since no study has previously characterised the effects of varying stimulus parameters on the hemodynamic and neural responses under this anaesthetic protocol, the effect of varying the stimulus intensity, stimulus frequency and pulse duration on the stimulus-evoked BOLD, CBF and neural responses was subsequently investigated using fMRI, laser speckle contrast imaging and electrophysiology, respectively. The aim of these experiments was to identify the optimal stimulus parameters that evoked the largest response. Tested parameters were selected based on commonly used values in the literature. We observed that frequency had the largest impact on the resultant hemodynamic or neural measurements, with higher frequencies generally evoking larger peak responses. However, analysis of the SEPs revealed that at higher frequencies there was a periodic loss of the SEP response and the overall amplitude of the SEPs declined over the course of stimulation. Stimulus intensity had a modest effect on the hemodynamic response with larger responses generally being observed >4 mA. Ultimately, the optimal parameters were selected as 6 mA, 0.3 ms and 3 Hz. These parameters were subsequently used for the fMRI study in SHRSPs. The findings in this thesis represent one of the few preclinical studies assessing the hemodynamic response in SHRSPs. Several studies have assessed the hemodynamic response in patients with cerebral SVD and observed blunted BOLD responses to stimulation. However, to our knowledge, this has not been assessed in the SHRSP. Given the role of the endothelium in mediating the hemodynamic response, and that dysfunction of the endothelium has been reported in the SHRSP and patients with cerebral SVD, assessing the hemodynamic response may provide a biomarker of cerebrovascular health and therapeutic effect. Several clinical trials have already assessed cerebrovascular reactivity by evaluating changes in the BOLD response to a hypercapnic challenge as a primary endpoint, suggesting this assessment is clinically relevant. Characterising the hemodynamic response in SHRSPs could further support their use as a model of cerebral SVD and allow consistent assessments to be performed in preclinical and clinical stages, which could aid in drug identification and development. Therefore, the main aim of this study was to characterise any differences between the stimulus-evoked BOLD and CBF responses to forelimb stimulation in the SHRSP, including any differences between young and old animals and aged-matched WKYs. The hemodynamic response was found to differ between older SHRSPs and young and older WKYs, with the stimulus-evoked BOLD and CBF responses being larger in the old SHRSPs. This observation opposes the findings of other studies that assess the hemodynamic response in patients with SVD, but aligns with fMRI findings in the SHR parent strain. It will be important for future studies to characterise this difference of responses between preclinical and clinical populations to confirm whether it is underpinned by a biological and pathologic mechanism or whether it has been artificially created by some of the requirements for preclinical studies i.e. anaesthesia

Cerebral Autoregulation-Based Blood Pressure Management In The Neuroscience Intensive Care Unit: Towards Individualizing Care In Ischemic Stroke And Subarachnoid Hemorrhage

The purpose of this thesis is to review the concept of cerebral autoregulation, to establish the feasibility of continuous bedside monitoring of autoregulation, and to examine the impact of impaired autoregulation on functional and clinical outcomes following subarachnoid hemorrhage and ischemic stroke. Autoregulation plays a key role in the regulation of brain blood flow and has been shown to fail in acute brain injury. Disturbed autoregulation may lead to secondary brain injury as well as worse outcomes. Furthermore, there exist several methodologies, both invasive and non-invasive, for the continuous assessment of autoregulation in individual patients. Resultant autoregulatory parameters of brain blood flow can be harnessed to derive optimal cerebral perfusion pressures, which may be targeted to achieve better outcomes. Multiple studies in adults and several in children have highlighted the feasibility of individualizing mean arterial pressure in this fashion. The thesis herein argues for the high degree of translatability of this personalized approach within the neuroscience intensive care unit, while underscoring the clinical import of autoregulation monitoring in critical care patients. In particular, this document recapitulates findings from two separate, prospectively enrolled patient groups with subarachnoid hemorrhage and ischemic stroke, elucidating how deviation from dynamic and personalized blood pressure targets associates with worse outcome in each cohort. While definitive clinical benefits remain elusive (pending randomized controlled trials), autoregulation-guided blood pressure parameters wield great potential for constructing an ideal physiologic environment for the injured brain. The first portion of this thesis discusses basic autoregulatory physiology as well as various tools to interrogate the brain’s pressure reactivity at the bedside. It then reviews the development of the optimal cerebral perfusion pressure as a biological hemodynamic construct. The second chapter pertains to the clinical applications of bedside neuromonitoring in patients with aneurysmal subarachnoid hemorrhage. In this section, the personalized approach to blood pressure monitoring is discussed in greater detail. Finally, in the third chapter, a similar autoregulation-oriented blood pressure algorithm is applied to a larger cohort of patients with ischemic stroke. This section contends that our novel, individualized strategy to hemodynamic management in stroke patients represents a better alternative to the currently endorsed practice of maintaining systolic blood pressures below fixed and static thresholds

Neurocognitive impairment across the continuum of critical illness: exploration of acute insults, functional risk factors, and clinical monitoring tools.

Critically ill patients of all ages suffer from high burden of neurocognitive impairment during (i.e. delirium) and following (i.e. long term cognitive impairment) critical illness that is associated with worse patient and healthy system outcomes. Ischemia has emerged as a plausible mechanism given the high prevalence of hypotension and shock, ischemic injury on neuroimaging, and impairment of cerebral autoregulation in these patients. However, the burden of ischemic insults during critical illness and mechanisms responsible for these insults are poorly described. Furthermore, while baseline impairment in cerebrovascular function can render patients more vulnerable to ischemia, such baseline functional assessments in patients with high risk of critical illness have not been considered. Finally, the operational limitations of existing cognitive batteries preclude routine linkage of ischemic insults and baseline impairment in cerebrovascular function with neurocognitive outcomes. In this work we carried out three studies to address these knowledge gaps. In the first study, we showed that critically ill patients with respiratory failure or shock experience deviations in cerebral blood flow velocity consistent with ischemia or hyperemia for 17-24% of the observation time. These deviations occurred irrespective of the state of cerebral autoregulation and were not explained by concurrent changes in blood pressure or CO2. These deviations represent a plausible ischemic insult that may explain high prevalence of ischemic injury in previous neuroimaging and histopathologic studies, and warrants further research to understand the underlying mechanism and link with neurocognitive outcomes. In the second study, we showed that hemodialysis patients have baseline impairment in cerebrovascular function prior to onset of critical illness, which may render them more vulnerable to ischemic injury during critical illness as a result of perturbation in cerebral blood flow shown in our first study. In our third study, we optimized an existing comprehensive web-based cognitive battery for monitoring cognitive outcomes in ICU patients, which should enable future linkage of ischemic insults and baseline impairment in cerebrovascular function from our first two studies with neurocognitive outcomes, as well enable routine clinical monitoring of cognitive recovery in ICU survivors

Dynamic Assessment of Cerebral Metabolic Rate of Oxygen (cmro2) With Magnetic Resonance Imaging

The brain is almost entirely dependent on oxidative metabolism to meet its energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) is a direct measure of brain energy use. CMRO2 provides insight into brain functional architecture and has demonstrated potential as a clinical tool for assessing many common neurological disorders. Recent developments in magnetic resonance imaging (MRI)-based CMRO2 quantification have shown promise in spatially resolving CMRO2 in clinically feasible scan times. However, brain energy requirements are both spatially heterogeneous and temporally dynamic, responding to rapid changes in oxygen supply and demand in response to physiologic stimuli and neuronal activation. Methods for dynamic quantification of CMRO2 are lacking, and this dissertation aims to address this gap. Given the fundamental tradeoff between spatial and temporal resolution in MRI, we focus initially on the latter. Central to each proposed method is a model-based approach for deriving venous oxygen saturation (Yv) – the critical parameter for CMRO2 quantification – from MRI signal phase using susceptometry-based oximetry (SBO). First, a three-second-temporal-resolution technique for whole-brain quantification of Yv and CMRO2 is presented. This OxFlow method is applied to measure a small but highly significant increase in CMRO2 in response to volitional apnea. Next, OxFlow is combined with a competing approach for Yv quantification based on blood T2 relaxometry (TRUST). The resulting interleaved-TRUST (iTRUST) pulse sequence greatly improves T2-based CMRO2 quantification, while allowing direct, simultaneous comparison of SBO- and T2-based Yv. iTRUST is applied to assess the CMRO2 response to hypercapnia – a topic of great interest in functional neuroimaging – demonstrating significant biases between SBO- and T2-derived Yv and CMRO2. To address the need for dynamic and spatially resolved CMRO2 quantification, we explore blood-oxygen-level-dependent (BOLD) calibration, introducing a new calibration model and hybrid pulse sequence combining OxFlow with standard BOLD/CBF measurement. Preliminary results suggest Ox-BOLD provides improved calibration “M-maps” for converting BOLD signal to CMRO2. Finally, OxFlow is applied clinically to patients with obstructive sleep apnea (OSA). A small clinical pilot study demonstrates OSA-associated reductions in CMRO2 at baseline and in response to apnea, highlighting the potential utility of dynamic CMRO2 quantification in assessing neuropathology