Modeling of dynamic cerebrovascular reactivity to spontaneous and externally induced CO2 fluctuations in the human brain using BOLD-fMRI

In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels

Modeling the dynamics of cerebrovascular reactivity to carbon dioxide in fMRI under task and resting-state conditions

Conventionally, cerebrovascular reactivity (CVR) is estimated as the amplitude of the hemodynamic response to vascular stimuli, most commonly carbon dioxide (CO(2)). While the CVR amplitude has established clinical utility, the temporal characteristics of CVR (dCVR) have been increasingly explored and may yield even more pathology-sensitive parameters. This work is motivated by the current need to evaluate the feasibility of dCVR modeling in various experimental conditions. In this work, we present a comparison of several recently published/utilized model-based deconvolution (response estimation) approaches for estimating the CO(2) response function h(t), including maximum a posteriori likelihood (MAP), inverse logit (IL), canonical correlation analysis (CCA), and basis expansion (using Gamma and Laguerre basis sets). To aid the comparison, we devised a novel simulation framework that incorporates a wide range of SNRs, ranging from 10 to -7 dB, representative of both task and resting-state CO(2) changes. In addition, we built ground-truth h(t) into our simulation framework, overcoming the conventional limitation that the true h(t) is unknown. Moreover, to best represent realistic noise found in fMRI scans, we extracted noise from in-vivo resting-state scans. Furthermore, we introduce a simple optimization of the CCA method (CCA(opt)) and compare its performance to these existing methods. Our findings suggest that model-based methods can accurately estimate dCVR even amidst high noise (i.e. resting-state), and in a manner that is largely independent of the underlying model assumptions for each method. We also provide a quantitative basis for making methodological choices, based on the desired dCVR parameters, the estimation accuracy and computation time. The BEL method provided the highest accuracy and robustness, followed by the CCA(opt) and IL methods. Of the three, the CCA(opt) method has the lowest computational requirements. These findings lay the foundation for wider adoption of dCVR estimation in CVR mapping

The spatiotemporal dynamics of cerebral autoregulation in functional magnetic resonance imaging

The thigh-cuff release (TCR) maneuver is a physiological challenge that is widely used to assess dynamic cerebral autoregulation (dCA). It is often applied in conjunction with Transcranial Doppler ultrasound (TCD), which provides temporal information of the global flow response in the brain. This established method can only yield very limited insights into the regional variability of dCA, whereas functional MRI (fMRI) has the ability to reveal the spatial distribution of flow responses in the brain with high spatial resolution. The aim of this study was to use whole-brain blood-oxygenation-level-dependent (BOLD) fMRI to characterize the spatiotemporal dynamics of the flow response to the TCR challenge, and thus pave the way toward mapping dCA in the brain. We used a data driven approach to derive a novel basis set that was then used to provide a voxel-wise estimate of the TCR associated haemodynamic response function (HRFTCR). We found that the HRFTCR evolves with a specific spatiotemporal pattern, with gray and white matter showing an asynchronous response, which likely reflects the anatomical structure of cerebral blood supply. Thus, we propose that TCR challenge fMRI is a promising method for mapping spatial variability in dCA, which will likely prove to be clinically advantageous

Physiological and motion signatures in static and time-varying functional connectivity and their subject identifiability

Human brain connectivity yields significant potential as a noninvasive biomarker. Several studies have used fMRI-based connectivity fingerprinting to characterize individual patterns of brain activity. However, it is not clear whether these patterns mainly reflect neural activity or the effect of physiological and motion processes. To answer this question, we capitalize on a large data sample from the Human Connectome Project and rigorously investigate the contribution of the aforementioned processes on functional connectivity (FC) and time-varying FC, as well as their contribution to subject identifiability. We find that head motion, as well as heart rate and breathing fluctuations, induce artifactual connectivity within distinct resting-state networks and that they correlate with recurrent patterns in time-varying FC. Even though the spatiotemporal signatures of these processes yield above-chance levels in subject identifiability, removing their effects at the preprocessing stage improves identifiability, suggesting a neural component underpinning the inter-individual differences in connectivity

Towards a better understanding of the impact of heart rate on the BOLD signal: a new method for physiological noise correction and its applications

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level-dependent (BOLD) contrast allows non-invasive examination of brain activity and is widely used in the neuroimaging field. The BOLD contrast mechanism reflects hemodynamic changes resulting from a complex interplay of blood flow, blood volume, and oxygen consumption. Heart rate (HR) variations are the most intriguing and less understood physiological processes affecting the BOLD signal, as they are the result of a wide variety of interacting factors. The use of the response function that best models HR-induced signal changes, called cardiac response function (CRF), is an effective method to reduce HR noise in fMRI. However, current models of physiological noise correction based on CRF, i.e. canonical and individual, either do not take into account variations in HR between subjects, and are thus inadequate for cohorts with varying HR, or require time-consuming quality control of individual physiological recordings and derived CRFs. By analyzing a large cohort of healthy individuals, the results presented in this thesis show that different HRs influence the BOLD signal and their corresponding spectra differently. A further finding is that HR plays an essential role in determining the shape of the CRF. Slower HRs produce a smoothed CRF with a single well-defined maximum, while faster HRs cause a second maximum. Taking advantage of this dependence of the CRF on HR, a novel method is proposed to model HR-induced fluctuations in the BOLD signal more accurately than current approaches of physiological noise correction. This method, called HR-based CRF, consists of two CRFs: one for HRs below 68 bpm and one for HRs above this value. HR-based CRFs can be directly applied to the fMRI data without the time-consuming task of deriving a CRF for each subject while accounting for inter-subject variability in HR response

Brain connectivity studied by fMRI: homologous network organization in the rat, monkey, and human

The mammalian brain is composed of functional networks operating at different spatial and temporal scales — characterized by patterns of interconnections linking sensory, motor, and cognitive systems. Assessment of brain connectivity has revealed that the structure and dynamics of large-scale network organization are altered in multiple disease states suggesting their use as diagnostic or prognostic indicators. Further investigation into the underlying mechanisms, organization, and alteration of large-scale brain networks requires homologous animal models that would allow neurophysiological recordings and experimental manipulations. My current dissertation presents a comprehensive assessment and comparison of rat, macaque, and human brain networks based on evaluation of intrinsic low-frequency fluctuations of the blood oxygen-level-dependent (BOLD) fMRI signal. The signal fluctuations, recorded in the absence of any task paradigm, have been shown to reflect anatomical connectivity and are presumed to be a hemodynamic manifestation of slow fluctuations in neuronal activity. Importantly, the technique circumvents many practical limitations of other methodologies and can be compared directly between multiple species. Networks of all species were found underlying multiple levels of sensory, motor, and cognitive processing. Remarkable homologous functional connectivity was found across all species, however network complexity was dramatically increased in primate compared to rodent species. Spontaneous temporal dynamics of the resting-state networks were also preserved across species. The results demonstrate that rats and macaques share remarkable homologous network organization with humans, thereby providing strong support for their use as an animal model in the study of normal and abnormal brain connectivity as well as aiding the interpretation of electrophysiological recordings within the context of large-scale brain networks

Quantitative methods to assess cerebral haemodynamics

In this thesis methods for the assessment of cerebral haemodynamics using 7 T Magnetic Resonance Imaging (MRI) are described. The measurement of haemodynamic parameters, such as cerebral blood flow (CBF), is an important clinical tool. Arterial Spin Labelling (ASL) is a non-invasive technique for CBF measurement using MRI. ASL methodology for ultra high field (7 T) MRI was developed, including investigation of the optimal readout strategy. Look-Locker 3D-EPI is demonstrated to give large volume coverage improving on previous studies. Applications of methods developed to monitor functional activity, through flow or arterial blood volume, in healthy volunteers and in patients with low grade gliomas using Look-Locker ASL are described. The effect of an increased level of carbon dioxide in the blood (hypercapnia) was studied using ASL and functional MRI; hypercapnia is a potent vasodilator and has a large impact on haemodynamics. These measures were used to estimate the increase in oxygen metabolism associated with a simple motor task. To study the physiology behind the hypercapnic response, magnetoencephalography was used to measure the impact of hypercapnia on neuronal activity. It was shown that hypercapnia induces widespread desynchronisation in a wide frequency range, up to ~ 50 Hz, with peaks in the sensory-motor areas. This suggests that hypercapnia is not iso-metabolic, which is an assumption of calibrated BOLD. A Look-Locker gradient echo sequence is described for the quantitative monitoring of a gadolinium contrast agent uptake through the change in longitudinal relaxation rate. This sequence was used to measure cerebral blood volume in Multiple Sclerosis patients. Further development of the sequence yielded a high resolution anatomical scan with reduced artefacts due to field inhomogeneities associated with ultra high field imaging. This allows whole head images acquired at sub-millimetre resolution in a short scan time, for application in patient studies

Functional connectivity of the ageing brain

This thesis investigated the impact of advancing age on modifying the functional connectivity (FC) of both typical cortical resting-state networks and subcortical structures in the human brain. Furthermore, it explored how any differences in FC may be associated with changes in sleep quality, also thought to be affected by age, and how such interactions may contribute to typical cognitive disruption associated with older age. The results suggest that older age is associated with the heterogeneous, spatially specific re-organisation of resting-state networks (RSNs), as well as indicating gender-specific spatial re-organisation. Investigation of thalamic FC revealed that older adults exhibited greater thalamo-sensory and thalamo-hippocampal FC, which was related to cognitive performance on RT and memory tasks, respectively. Investigation into participant’s sleep patterns provided evidence that sleep quality was more variable amongst the older participants. Furthermore, older adults that slept the longest each night were found to exhibit patterns of thalamic FC which were associated with better cognitive performance, than seen in older shorter sleepers. These results provide preliminary evidence that sleep may be associated with more ‘preferable’ patterns of FC in older adults which may be beneficial for cognitive function

A multi-measure approach for assessing the performance of fMRI preprocessing strategies in resting-state functional connectivity

It is well established that head motion and physiological processes (e.g. cardiac and breathing activity) should be taken into consideration when analyzing and interpreting results in fMRI studies. However, even though recent studies aimed to evaluate the performance of different preprocessing pipelines there is still no consensus on the optimal strategy. This is partly due to the fact that the quality control (QC) metrics used to evaluate differences in performance across pipelines have often yielded contradictory results. Furthermore, preprocessing techniques based on physiological recordings or data decomposition techniques (e.g. aCompCor) have not been comprehensively examined. Here, to address the aforementioned issues, we propose a framework that summarizes the scores from eight previously proposed and novel QC metrics to a reduced set of two QC metrics that reflect the signal-to-noise ratio and the reduction in motion artifacts and biases in the preprocessed fMRI data. Using this framework, we evaluate the performance of three commonly used practices on the quality of data: 1) Removal of nuisance regressors from fMRI data, 2) discarding motion-contaminated volumes (i.e., scrubbing) before regression, and 3) low-pass filtering the data and the nuisance regressors before their removal. Using resting-state fMRI data from the Human Connectome Project, we show that the scores of the examined QC metrics improve the most when the global signal (GS) and about 17% of principal components from white matter (WM) are removed from the data. Finally, we observe a small further improvement with low-pass filtering at 0.20 Hz and milder variants of WM denoising, but not with scrubbing