182 research outputs found

    Mapping Transient Hyperventilation Induced Alterations with Estimates of the Multi-Scale Dynamics of BOLD Signal

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    Temporal blood oxygen level dependent (BOLD) contrast signals in functional MRI during rest may be characterized by power spectral distribution (PSD) trends of the form 1/fα. Trends with 1/f characteristics comprise fractal properties with repeating oscillation patterns in multiple time scales. Estimates of the fractal properties enable the quantification of phenomena that may otherwise be difficult to measure, such as transient, non-linear changes. In this study it was hypothesized that the fractal metrics of 1/f BOLD signal trends can map changes related to dynamic, multi-scale alterations in cerebral blood flow (CBF) after a transient hyperventilation challenge. Twenty-three normal adults were imaged in a resting-state before and after hyperventilation. Different variables (1/f trend constant α, fractal dimension Df, and, Hurst exponent H) characterizing the trends were measured from BOLD signals. The results show that fractal metrics of the BOLD signal follow the fractional Gaussian noise model, even during the dynamic CBF change that follows hyperventilation. The most dominant effect on the fractal metrics was detected in grey matter, in line with previous hyperventilation vaso-reactivity studies. The α was able to differentiate also blood vessels from grey matter changes. Df was most sensitive to grey matter. H correlated with default mode network areas before hyperventilation but this pattern vanished after hyperventilation due to a global increase in H. In the future, resting-state fMRI combined with fractal metrics of the BOLD signal may be used for analyzing multi-scale alterations of cerebral blood flow

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

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    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 SkƂodowska-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]

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

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    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 Ƃ 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)

    The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

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    Funder: Amsterdam NeuroscienceAbstract: Accurate identification of brain function is necessary to understand neurocognitive aging, and thereby promote health and well‐being. Many studies of neurocognitive aging have investigated brain function with the blood‐oxygen level‐dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is, therefore, essential to distinguish the age effects on vascular versus neural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable, and robust means to calibrate vascular responsivity, as an alternative to breath‐holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age‐related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health (CVH) and cerebrovascular function, are insufficient when used alone to fully explain age‐related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population‐based, lifespan Cam‐CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age differences in RSFA, after controlling for CVH. The results were consistent between voxel‐level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterize neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging

    Pitfalls in fMRI

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    Several different techniques allow a functional assessment of neuronal activations by magnetic resonance imaging (fMRI). The by far most influential fMRI technique is based on a local T2*-sensitive hemodynamic response to neuronal activation, also known as the blood oxygenation level dependent or BOLD effect. Consequently, the term ‘fMRI' is often used synonymously with BOLD imaging. Because interpretations of fMRI brain activation maps often appear intuitive and compelling, the reader might be tempted not to critically question the fundamental processes and assumptions. We review some essential processes and assumptions of BOLD fMRI and discuss related confounds and pitfalls in fMRI - from the underlying physiological effect, to data acquisition, data analysis and the interpretation of the results including clinical fMRI. A background framework is provided for the systematic and critical interpretation of fMRI result

    Development of Pharmacological Magnetic Resonance Imaging Methods and their Application to the Investigation of Antipsychotic Drugs: a Dissertation

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    Pharmacological magnetic resonance imaging (phMRI) is the use of functional MRI techniques to elucidate the effects that psychotropic drugs have on neural activity within the brain; it is an emerging field of research that holds great potential for the investigation of drugs that act on the central nervous system by revealing the changes in neural activity that mediate observable changes in behavior, cognition, and perception. However, the realization of this potential is hampered by several unanswered questions: Are the MRI measurements reliable surrogates of changing neural activity in the presence of pharmacological agents? Is it relevant to investigate psychiatric phenomena such as reward or anxiolysis in anesthetized, rather than conscious animals? What are the methods that yield reproducible and meaningful results from phMRI experiments, and are they consistent in the investigations of different drugs? The research presented herein addresses many of these questions with the specific aims of 1) Developing pharmacological MRI methodologies that can be used in the conscious animal, 2) Validating these methodologies with the investigation of a non-stimulant, psychoactive compound, and 3) Applying these methodologies to the investigation of typical and atypical antipsychotic drugs, classes of compounds with unknown mechanisms of therapeutic action Building on recent developments in the field of functional MRI research, we developed new techniques that enable the investigator to measure localized changes in metabolism commensurate with changing neural activity. We tested the hypothesis that metabolic changes are a more reliable surrogate of changes in neural activity in response to a cocaine challenge, than changes observed in the blood-oxygen-level-dependent (BOLD) signal alone. We developed a system capable of multi-modal imaging in the conscious rat, and we tested the hypothesis that the conscious brain exhibits a markedly different response to systemic morphine challenge than the anesthetized brain. We identified and elucidated several fundamental limitations of the imaging and analysis protocols used in phMRI investigations, and developed new tools that enable the investigator to avoid common pitfalls. Finally, we applied these phMRI techniques to the investigation of neuroleptic compounds by asking the question: does treatment with typical or atypical antipsychotic drugs modulate the systems in the brain which are direct or indirect (i.e. downstream) substrates for a dopaminergic agonist? The execution of this research has generated several new tools for the neuroscience and drug discovery communities that can be used in neuropsychiatric investigations into the action of psychotropic drugs, while the results of this research provide evidence that supports several answers to the questions that currently limit the utility of phMRI investigations. Specifically, we observed that metabolic change can be measured to resolve discrepancies between anomalous BOLD signal changes and underlying changes in neural activity in the case of systemically administered cocaine. We found clear differences in the response to systemically administered morphine between conscious and anesthetized rats, and observed that only conscious animals exhibit a phMRI response that can be explained by the pharmacodynamics of morphine and corroborated by behavioral observations. We identified fundamental and drug-dependent limitations in the protocols used to perform phMRI investigations, and designed tools and alternate methods to facilitate protocol development. By applying these techniques to the investigation of neuroleptic compounds, we have gained a new perspective of the alterations in dopaminergic signaling induced by treatment with antipsychotic medications, and have found effects in many nuclei outside of the pathways that act as direct substrates for dopamine. A clearer picture of how neuroleptics alter the intercommunication of brain nuclei would be an invaluable resource for the classification of investigational antipsychotic drugs, and would provide the basis for future studies that examine the neuroplastic changes that confer therapeutic efficacy following chronic treatment with antipsychotic medications

    Quantitative functional MRI of the Cerebrovascular Reactivity to CO2

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    Le dioxyde de carbone (CO2) est un rĂ©sidu naturel du mĂ©tabolisme cellulaire, la troisiĂšme substance la plus abondante du sang, et un important agent vasoactif. À la moindre variation de la teneur en CO2 du sang, la rĂ©sistance du systĂšme vasculaire cĂ©rĂ©bral et la perfusion tissulaire cĂ©rĂ©brale subissent des changements globaux. Bien que les mĂ©canismes exacts qui sous-tendent cet effet restent Ă  ĂȘtre Ă©lucidĂ©s, le phĂ©nomĂšne a Ă©tĂ© largement exploitĂ© dans les Ă©tudes de rĂ©activitĂ© vasculaire cĂ©rĂ©brale (RVC). Une voie prometteuse pour l’évaluation de la fonction vasculaire cĂ©rĂ©brale est la cartographie de la RVC de maniĂšre non-invasive grĂące Ă  l’utilisation de l’Imagerie par RĂ©sonance MagnĂ©tique fonctionnelle (IRMf). Des mesures quantitatives et non-invasives de de la RVC peuvent ĂȘtre obtenus avec l’utilisation de diffĂ©rentes techniques telles que la manipu- lation du contenu artĂ©riel en CO2 (PaCO2) combinĂ©e Ă  la technique de marquage de spin artĂ©riel (Arterial Spin Labeling, ASL), qui permet de mesurer les changements de la perfusion cĂ©rĂ©brale provoquĂ©s par les stimuli vasculaires. Toutefois, les prĂ©occupations liĂ©es Ă  la sensibilitĂ© et la fiabilitĂ© des mesures de la RVC limitent de nos jours l’adoption plus large de ces mĂ©thodes modernes de IRMf. J’ai considĂ©rĂ© qu’une analyse approfondie ainsi que l’amĂ©lioration des mĂ©thodes disponibles pourraient apporter une contribution prĂ©cieuse dans le domaine du gĂ©nie biomĂ©dical, de mĂȘme qu’aider Ă  faire progresser le dĂ©veloppement de nouveaux outils d’imagerie de diagnostique. Dans cette thĂšse je prĂ©sente une sĂ©rie d’études oĂč j’examine l’impact des mĂ©thodes alternatives de stimulation/imagerie vasculaire sur les mesures de la RVC et les moyens d’amĂ©liorer la sensibilitĂ© et la fiabilitĂ© de telles mĂ©thodes. J’ai aussi inclus dans cette thĂšse un manuscrit thĂ©orique oĂč j’examine la possible contribution d’un facteur mĂ©connu dans le phĂ©nomĂšne de la RVC : les variations de la pression osmotique du sang induites par les produits de la dissolution du CO2. Outre l’introduction gĂ©nĂ©rale (Chapitre 1) et les conclusions (Chapitre 6), cette thĂšse comporte 4 autres chapitres, au long des quels cinq diffĂ©rentes Ă©tudes sont prĂ©sentĂ©es sous forme d’articles scientifiques qui ont Ă©tĂ© acceptĂ©s Ă  des fins de publication dans diffĂ©rentes revues scientifiques. Chaque chapitre dĂ©bute par sa propre introduction, qui consiste en une description plus dĂ©taillĂ©e du contexte motivant le(s) manuscrit(s) associĂ©(s) et un bref rĂ©sumĂ© des rĂ©sultats transmis. Un compte rendu dĂ©taillĂ© des mĂ©thodes et des rĂ©sultats peut ĂȘtre trouvĂ© dans le(s) dit(s) manuscrit(s). Dans l’étude qui compose le Chapitre 2, je compare la sensibilitĂ© des deux techniques ASL de pointe et je dĂ©montre que la derniĂšre implĂ©mentation de l’ASL continue, la pCASL, offre des mesures plus robustes de la RVC en comparaison Ă  d’autres mĂ©thodes pulsĂ©s plus ĂągĂ©es. Dans le Chapitre 3, je compare les mesures de la RVC obtenues par pCASL avec l’utilisation de quatre mĂ©thodes respiratoires diffĂ©rentes pour manipuler le CO2 artĂ©rielle (PaCO2) et je dĂ©montre que les rĂ©sultats peuvent varier de maniĂšre significative lorsque les manipulations ne sont pas conçues pour fonctionner dans l’intervalle linĂ©aire de la courbe dose-rĂ©ponse du CO2. Le Chapitre 4 comprend deux Ă©tudes complĂ©mentaires visant Ă  dĂ©terminer le niveau de reproductibilitĂ© qui peut ĂȘtre obtenu en utilisant des mĂ©thodes plus rĂ©centes pour la mesure de la RVC. La premiĂšre Ă©tude a abouti Ă  la mise au point technique d’un appareil qui permet des manipulations respiratoires du CO2 de maniĂšre simple, sĂ©curitaire et robuste. La mĂ©thode respiratoire amĂ©liorĂ©e a Ă©tĂ© utilisĂ©e dans la seconde Ă©tude – de neuro-imagerie – oĂč la sensibilitĂ© et la reproductibilitĂ© de la RVC, mesurĂ©e par pCASL, ont Ă©tĂ© examinĂ©es. La technique d’imagerie pCASL a pu dĂ©tecter des rĂ©ponses de perfusion induites par la variation du CO2 dans environ 90% du cortex cĂ©rĂ©bral humain et la reproductibilitĂ© de ces mesures Ă©tait comparable Ă  celle d’autres mesures hĂ©modynamiques dĂ©jĂ  adoptĂ©es dans la pratique clinique. Enfin, dans le Chapitre 5, je prĂ©sente un modĂšle mathĂ©matique qui dĂ©crit la RVC en termes de changements du PaCO2 liĂ©s Ă  l’osmolaritĂ© du sang. Les rĂ©ponses prĂ©dites par ce modĂšle correspondent Ă©troitement aux changements hĂ©modynamiques mesurĂ©s avec pCASL ; suggĂ©rant une contribution supplĂ©mentaire Ă  la rĂ©activitĂ© du systĂšme vasculaire cĂ©rĂ©bral en lien avec le CO2.Carbon dioxide (CO2) is a natural byproduct of cellular metabolism, the third most abundant substance of blood, and a potent vasoactive agent. The resistance of cerebral vasculature and perfusion of the brain tissue respond to the slightest change in blood CO2 content. The physiology of such an effect remains elusive, yet the phenomenon has been widely exploited in studies of the cerebral vascular function. A promising avenue for the assessment of brain’s vascular function is to measure the cerebrovascular reactivity to CO2 (CVR) non-invasively using functional MRI. Quantitative and non-invasive mapping of CVR can be obtained using respiratory manipulations in arterial CO2 and Arterial Spin Labeling (ASL) to measure the perfusion changes associated with the vascular stimulus. However, concerns related to the sensitivity and reliability of CVR mea- sures by ASL still limit their broader adoption. I considered that a thorough analysis and amelioration of available methods could bring a valuable contribution in the domain of biomedical engineering, helping to advance new diagnostic imaging tools. In this thesis I present a series of studies where I exam the impact of alternative manipulation/ASL methods on CVR measures, and ways to improve the sensitivity and reliability of these measures. I have also included in this thesis a theoretical paper, where I exam the possible contribution of an unappreciated factor in the CVR phenomenon: the changes in blood osmotic pressure induced by the products of CO2 dissolution. Apart from a general introduction (Chapter 1) and conclusion (Chapter 6), this thesis comprises 4 other chapters, in which five different research studies are presented in the form of articles accepted for publication in scientific journals. Each of these chapters begins with its own specific introduction, which consists of a description of the background motivating the study and a brief summary of conveyed findings. A detailed account of methods and results can be found in the accompanying manuscript(s). The study composing Chapter 2 compares the sensitivity of two state-of-the-art ASL techniques and show that a recent implementation of continuous ASL, pCASL, affords more robust measures of CVR than older pulsed methods. The study described in Chapter 3 compares pCASL CVR measures obtained using 4 different respiratory methods to manipulate arterial CO2 (PaCO2) and shows that results can differ significantly when manipulations are not designed to operate at the linear range of the CO2 dose-response curve. Chapter 4 encompasses two complementary studies seeking to determine the degree of reproducibility that can be attained measuring CVR using the most recent methods. The first study resulted in the technical development of a breathing apparatus allowing simple, safe and robust respiratory CO2 manipulations. The improved respiratory method was used in the second – neuroimaging – study, in which I and co-authors investigate the sensitivity and reproducibility of pCASL measuring CVR. The pCASL imaging technique was able to detect CO2-induced perfusion responses in about 90% of the human brain cortex and the reproducibility of its measures was comparable to other hemodynamic measures already adopted in the clinical practice. Finally, in Chapter 5 I present a mathematical model that describes CVR in terms of PaCO2-related changes in blood osmolarity. The responses predicted by this model correspond closely to the hemodynamic changes measured with pCASL, suggesting an additional contribution to the reactivity of cerebral vasculature to CO2

    Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

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    Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology
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