A novel method of combining blood oxygenation and blood flow sensitive magnetic resonance imaging techniques to measure the cerebral blood flow and oxygen metabolism responses to an unknown neural stimulus.

Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimation, we could significantly improve the precision of our estimates of the hemodynamic response to a visual stimulus and, under the conditions of a calibrated BOLD experiment, accurately determine the ratio of the oxygen metabolic response to the hemodynamic response. Importantly we were able to accomplish this without utilizing a priori knowledge of the temporal nature of the neural stimulus, suggesting that BOLD Constrained Perfusion estimation may make it feasible to quantitatively study the cerebral metabolic and hemodynamic responses to more natural stimuli that cannot be easily repeated or averaged

Lag-Optimized Blood Oxygenation Level Dependent Cerebrovascular Reactivity Estimates Derived From Breathing Task Data Have a Stronger Relationship With Baseline Cerebral Blood Flow

Published: 15 June 2022Cerebrovascular reactivity (CVR), an important indicator of cerebrovascular health, is commonly studied with the Blood Oxygenation Level Dependent functional MRI (BOLD-fMRI) response to a vasoactive stimulus. Theoretical and empirical evidence suggests that baseline cerebral blood flow (CBF) modulates BOLD signal amplitude and may influence BOLD-CVR estimates. We address how acquisition and modeling choices affect the relationship between baseline cerebral blood flow (bCBF) and BOLD-CVR: whether BOLD-CVR is modeled with the inclusion of a breathing task, and whether BOLD-CVR amplitudes are optimized for hemodynamic lag effects. We assessed between-subject correlations of average GM values and within-subject spatial correlations across cortical regions. Our results suggest that a breathing task addition to a resting-state acquisition, alongside lag-optimization within BOLD-CVR modeling, can improve BOLD-CVR correlations with bCBF, both between- and within-subjects, likely because these CVR estimates are more physiologically accurate. We report positive correlations between bCBF and BOLD-CVR, both between- and within-subjects. The physiological explanation of this positive correlation is unclear; research with larger samples and tightly controlled vasoactive stimuli is needed. Insights into what drives variability in BOLD-CVR measurements and related measurements of cerebrovascular function are particularly relevant when interpreting results in populations with altered vascular and/or metabolic baselines or impaired cerebrovascular reserve.This work was supported by the Center for Translational Imaging at Northwestern University. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [K12HD073945]. KZ was supported by an NIH-funded training program [T32EB025766]. SM was supported by the European Union’s Horizon 2020 research and innovation program [Marie Skłodowska-Curie grant agreement No. 713673] and a fellowship from La Caixa Foundation [ID 100010434, fellowship code LCF/BQ/IN17/11620063]. CC-G was supported by the Spanish Ministry of Economy and Competitiveness [Ramon y Cajal Fellowship, RYC2017-21845], the Basque Government [BERC 2018-2021 and PIBA_2019_104], and the Spanish Ministry of Science, Innovation and Universities [MICINN; PID2019- 105520GB-100]

DETECTING BRAIN-WIDE INTRINSIC CONNECTIVITY NETWORKS USING fMRI IN MICE

Functional neuroimaging methods in mice are essential for unraveling complex neuronal networks that underlie maladaptive behavior in neurological disorder models. By using fMRI to detect intrinsic connectivity networks in mice, we can examine large scale alteration in brain activity and functional connectivity to establish causal associations in brain network changes. The work presented in this dissertation is organized into five chapters. Chapter 1 provides the necessary background required to understand how functional neuroimaging tools such as fMRI detect signal changes attributed to spontaneous neuronal activity of intrinsic connectivity networks in mice. Chapter 2 describes the development of our isotropic fMRI acquisition sequence in mice and semi-automated pipeline for mouse fMRI data. Naïve mouse fMRI scans were used to validated the pipeline by reliably and reproducibly extracting intrinsic connectivity networks. Chapter 3 establishes the development and validation of a novel superparamagenetic iron-oxide nanoparticle to enhance fMRI signal sensitivity. Chapter 4 studies the effects norepinephrine released by locus coeruleus neurons on the default mode network in mice. Norepinephrine release selectively enhanced neuronal activity and connectivity in the Frontal module of the default mode network by suppressing information flow from the Retrosplenial-Hippocampal to the Association modules. Chapter 5 addresses the implications of our findings and addresses the limitations and future studies that can be conducted to expand on this research.Doctor of Philosoph

Analysis of Transcranial Doppler Ultrasound Waveform Morphology for the Assessment of Cerebrovascular Hemodynamics

The use of transcranial Doppler (TCD) ultrasound for the assessment of cerebral blood flow velocity (CBFV) provides an indication of cerebral blood flow assuming the diameter of the insonated vessel remains constant. Studies using TCD have traditionally described cerebrovascular hemodynamics with respect to CBFV and cerebrovascular resistance (CVRi); however, a more complete assessment of the cerebral circulation can be gleaned from the analysis of within beat characteristic of the TCD velocity waveform for the determination of cerebrovascular tone. Therefore, the general purpose of the presented studies was to assess CBFV responses and within beat characteristic for the description of cerebrovascular hemodynamics after long duration spaceflight, with sustained orthostasis, in response to changes in the partial pressure of end tidal carbon dioxide (PETCO2), and with NG stimulation. After long duration spaceflight, cerebrovascular autoregulation was found to be impaired along with a reduction in cerebrovascular CO2 reactivity (Study 1). Additionally, critical closing pressure (CrCP) was found to be increased suggesting potential remodelling of the cerebrovasculature contributing to an increase in cerebrovascular tone (Study 2). With sustained orthostasis, CBFV was found to progressively decrease and to be related to reductions in PETCO2 and increases in CrCP suggesting the contribution of changes in cerebrovascular tone leading to the development of syncope (Study 4). The CBFV reduction with the progression towards syncope was also associated with changes in waveform morphology such that the dicrotic notch point was less than the end diastolic value (Study 3). Mathematical modelling (RCKL) was used to further assess changes in cerebrovascular hemodynamics for physiological interpretation of changes in CBFV waveform morphology and found that the amplitude of the dicrotic notch and the calculation of the augmentation index were both significantly related to vascular compliance before and after stimulation with NG (Study 5). The use of quantitative assessments of common carotid artery (CCA) blood flow as an indicator of cerebral blood flow suggested the dilation of the middle cerebral artery (MCA) with NG (Study 5 and 6) and changes in MCA diameter with acute alterations in PETCO2 (Study 6). CCA and MCA velocity wave morphology were assessed showing that with changes in PETCO2, changes in CBFV velocity wave were not reflected in the CCA trace (Study 7). In addition, further assessment of the CBFV velocity trace and the calculation of CrCP and the augmentation index suggested that with changes in PETCO2 cerebrovascular compliance and cerebrovascular tension, both thought to be components of cerebrovascular tone, change independently (Study 7). Combined, the results of the presented studies suggest that changes in cerebrovascular hemodynamics can be determined from alterations in the CBFV velocity waveform morphology. However, further work is required to determine how these variations relate to specific components of cerebrovascular tone, including alterations in cerebrovascular compliance and vascular tension, and how these variables change with acute and chronic alterations in cerebrovascular hemodynamics

The influence of sex hormones on cerebrovascular function

The disproportionate rise in cerebrovascular disease risk for females in the first 10 years post-menopause indicates a role for ovarian sex hormones (i.e., oestrogen and progesterone) in healthy cerebrovascular function and regulation. However, the exact influence of changing sex hormones across the lifespan on the cerebrovasculature is yet to be elucidated. The primary aim of this thesis was to determine the influence of sex hormones on cerebrovascular function. A systematic review and meta-analysis established that hormone replacement therapy in post-menopausal females has the potential to improve cerebrovascular function, as reflected by a significant reduction in pulsatility index. Further, the effects of changing sex hormones in other hormone groups (e.g., menstrual cycle, menopause) remains unclear due to the substantial heterogeneity and limited evidence in the literature. Subsequently, three experimental studies examined measures of cerebrovascular function across the menstrual cycle, between males and females, and between pre- and post-menopausal females. Firstly, cerebrovascular responsiveness (indexed via measures of middle/posterior cerebral blood flow velocity (MCAv/PCAv) responses to altered arterial partial pressure of carbon dioxide (CO2)) across the menstrual cycle revealed a greater MCAv-CO2 responsiveness to hypocapnia during ovulation (O) when compared to the early follicular (EF) phase. Assessment of sex differences showed cerebrovascular-CO2 responsiveness to hypo- and hypo-to-hypercapnia was greater in females during EF in the PCA, and females during O in the MCA, when compared to males. Use of passive heat stress as an additional perturbation did not change cerebrovascular-CO2 responsiveness across the menstrual cycle, while a diminished PCA responsiveness to hypercapnia during heat stress was only evident in males. Finally, pre-menopausal females were shown to have an improved MCAv-CO2 responsiveness to hypercapnia compared to post-menopausal females, irrespective of menstrual phase. Preliminary data indicates possible differences between pre- and post-menopausal females in internal carotid artery (ICA) responsiveness to hypercapnia, and in cerebral autoregulation (indexed via MCAv responses to repeated squat-to-stand-induced changes in blood pressure). Collectively, these findings indicate that 1) acute fluctuations in oestrogen across the menstrual cycle can alter the vasoconstrictive capacity of the MCA, while progesterone appears to counteract the effects of oestrogen. 2) Sex differences in cerebrovascular-CO2 responsiveness are dependent on menstrual phase and the insonated vessel, and differences are present even when females are early follicular phase of the menstrual cycle. Further, cerebrovascular responses to passive heating are sex specific. Finally, 3) post-menopausal females have a blunted MCAv responsiveness to hypercapnia compared to pre-menopausal females. Overall, the findings that pre-menopausal females exhibit improved intracranial cerebrovascular-CO2 responsiveness compared to both young males and post-menopausal females supports the premise that sex hormones play a protective role in cerebrovascular function

Decreased Default Mode Network connectivity correlates with age-associated structural and cognitive changes

Ageing entails cognitive and motor decline as well as brain changes such as loss of gray (GM) and white matter (WM) integrity, neurovascular and functional connectivity alterations. Regarding connectivity, reduced resting-state fMRI connectivity between anterior and posterior nodes of the Default Mode Network (DMN) relates to cognitive function and has been postulated to be a hallmark of ageing. However, the relationship between age-related connectivity changes and other neuroimaging-based measures in ageing is fragmentarily investigated. In a sample of 116 healthy elders we aimed to study the relationship between antero-posterior DMN connectivity and measures of WM integrity, GM integrity and cerebral blood flow (CBF), assessed with an arterial spin labeling sequence. First, we replicated previous findings demonstrating DMN connectivity decreases in ageing and an association between antero-posterior DMN connectivity and memory scores. The results showed that the functional connectivity between posterior midline structures and the medial prefrontal cortex was related to measures of WM and GM integrity but not to CBF. Gray and WM correlates of anterio-posterior DMN connectivity included, but were not limited to, DMN areas and cingulum bundle. These results resembled patterns of age-related vulnerability which was studied by comparing the correlates of antero-posterior DMN with age-effect maps. These age-effect maps were obtained after performing an independent analysis with a second sample including both young and old subjects. We argue that antero-posterior connectivity might be a sensitive measure of brain ageing over the brain. By using a comprehensive approach, the results provide valuable knowledge that may shed further light on DMN connectivity dysfunctions in ageing

Statistical approaches for resting state fMRI data analysis

This doctoral dissertation investigates the methodology to explore brain dynamics from resting state fMRI data. A standard resting state fMRI study gives rise to massive amounts of noisy data with a complicated spatio-temporal correlation structure. There are two main objectives in the analysis of these noisy data: establishing the link between neural activity and the measured signal, and determining distributed brain networks that correspond to brain function. These measures can then be used as indicators of psychological, cognitive or pathological states. Two main issues will be addressed: retrieving and interpreting the hemodynamic response function (HRF) at rest, and dealing with the redundancy inherent to fMRI data. Novel approaches are introduced, discussed and validated on simulated data and on real datasets, in health and disease, in order to track modulation of brain dynamics and HRF across different pathophysiological conditions

Why Blood Pressure and Body Mass Should be Controlled for in Resting-State Functional Magnetic Resonance Imaging Studies

Masteroppgave i psykologiMAPSYK360INTL-PSYKINTL-HFINTL-JUSINTL-MEDINTL-KMDMAPS-PSYKINTL-SVINTL-M