Neural Correlates of Spontaneous BOLD Fluctuations: A Simultaneous LFP-fMRI Investigation In The Non-human Primate

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to explore functional connectivity (FC) between brain regions across neurological and psychiatric diseases. However, the neural basis of spontaneous low frequency blood-oxygen level dependent (BOLD) fluctuations is poorly understood. Here, we acquired rs-fMRI data in macaque monkeys together with simultaneous recordings of local field potentials (LFPs) in prefrontal cortex area 9/46d. We first evaluated the correlation between LFPs (1-100 Hz) and BOLD signals and found unique frequency power correlates of positive and negative FC. Anti-correlation of high and low power envelopes indicated that ongoing cross-frequency interactions are a neural correlate of FC. On the other hand, seed-based analysis of the BOLD signal from the vicinity of electrode revealed the same spatial topology when using the power envelopes of high frequency bands of LFPs in the regression analysis. Variations of the canonical hemodynamic response function (HRF) in distinct cortical areas were also investigated to find the optimal HRF that can best fit in model analysis and estimate the BOLD response. While we found the optimal HRF that yields the highest correlation, the HRF shape was consistent within subjects and between brain regions. Our results suggest that intrinsic connectivity networks may be specifically driven by unique LFP profiles and these profiles contribute differently to BOLD FC. This study provides insight into the neural correlates of spontaneous BOLD FC at rest

Issues in the processing and analysis of functional NIRS imaging and a contrast with fMRI findings in a study of sensorimotor deactivation and connectivity

Includes abstract.~Includes bibliographical references.The first part of this thesis examines issues in the processing and analysis of continuous wave functional linear infrared spectroscopy (fNIRS) of the brain usung the DYNOT system. In the second part, the same sensorimotor experiment is carried out using functional magnetic resonance imaging (fMRI) and near infrared spectroscopy in eleven of the same subjects, to establish whether similar results can be obtained at the group level with each modality. Various techniques for motion artefact removal in fNIRS are compared. Imaging channels with negligible distance between source and detector are used to detect subject motion, and in data sets containing deliberate motion artefacts, independent component analysis and multiple-channel regression are found to improve the signal-to-noise ratio

Depth-Dependent Physiological Modulators of the BOLD Response in the Human Motor Cortex

This dissertation proposes a set of methods for improving spatial localization of cerebral metabolic changes using functional magnetic resonance imaging (fMRI). Blood oxygen level dependent (BOLD) fMRI estabilished itself as the most frequently used technique for mapping brain activity in humans. It is non-invasive and allows to obtain information about brain oxygenation changes in a few minutes. It was discovered in 1990 and, since then, it contributed enormously to the developments in neuroscientific research. Nevertheless, the BOLD contrast suffers from inherent limitations. This comes from the fact that the observed response is the result of a complex interplay between cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2) and has a strong dependency on baseline blood volume and oxygenation. Therefore, the observed response is mislocalized from the site where the metabolic activity takes place and it is subject to high variability across experiments due to normal brain physiology. Since the peak of BOLD changes can be as much as 4 mm apart from the site of metabolic changes, the problem of spatial mislocalization is particularly constraining at submillimeter resolution. Three methods are proposed in this work in order to overcome this limitation and make data more comparable. The first method involves a modification of an estabilished model for calibration of BOLD responses (the dilution model), in order to render it applicable at higher resolutions. The second method proposes a model-free scaling of the BOLD response, based on spatial normalization by a purely vascular response pattern. The third method takes into account the hypothesis that the cortical vasculature could act as a low-pass filter for BOLD fluctuations as the blood is carried downstream, and investigates differences in frequency composition of cortical laminae. All methods are described and tested on a depth-dependent scale in the human motor cortex

Understanding haemodynamic changes surrounding epileptic events in children

The interrelationship between cerebral haemodynamics and epileptic activity has been the subject of study for over 100 years. The overall goal of this PhD is to use and develop multimodal imaging to better understand this relationship in a paediatric population. This has important implications for the localisation of epileptic activity that can aid pre-surgical evaluation and seizure detection. The benefit of interictal epileptiform discharge (IED) suppression in clinical treatment is under debate, considering little is known about their impact on cognitive function. By applying EEG-fMRI, it was found that transient effects of IEDs were responsible for connectivity differences between patients and controls, showing the widespread impact of IEDs on BOLD signal and suggesting the importance of IED suppression for normal functional connectivity. Haemodynamic changes may occur prior to epileptic event onset. Therefore we evaluated the response function (HRF) to IEDs in paediatric focal epilepsy patients, as an HRF was created from simultaneous EEG-fMRI data and found to be beneficial in the delineation of epileptic foci. However, the underlying neurovascular changes seen in this altered HRF still needed to be explored. Therefore EEG-NIRS was utilised to interpret the mechanistic changes found in BOLD during IEDs. NIRS provides the added information of concentration changes of both –oxy and –deoxy haemoglobin rather than relative changes in deoxyhaemoglobin. To perform these experiments a new optode holder applicable to the clinical environment had to be made and tested for efficacy. The best design was a flexible optode grid, as it required no interference with the standard clinical protocol. Once tested in patients, EEG-NIRS found pre-ictal/pre-IED increases in oxygen saturation and oxyhaemoglobin concentrations, thereby corroborating with prior haemodynamic changes seen in EEG-fMRI. Therefore, by utilizing both EEG-fMRI and EEG-NIRS a greater understanding of the haemodynamic changes surrounding epileptic events in children can be obtained

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

Pericytes Wrap Vessels Tight and Keep Blood Flowing Right: An Updated View of the Structure and Function of Cerebral Pericytes

The cerebrovasculature modulates its resistance to flow in order to match blood supply with the high metabolic demand of the brain. While it is accepted that vascular smooth muscle cells are capable of modulating blood flow resistance through arterioles, whether pericytes can similarly regulate blood flow through capillaries has been a topic of debate for over 100 years. First we used new transgenic mice to characterize the structural spectrum of pericytes in the brain, and found a wide range of pericyte shapes that could be grouped into two main pericyte types. We then mapped where these “ensheathing pericytes” and “capillary pericytes” live along the cerebrovascular tree, and stimulated one or two of them at a time in vivo using two photon optogenetics through a cranial window. We found that both types of pericytes can constrict their underlying blood vessel in a way that decreases local blood flow. Importantly, vascular smooth muscle cells exhibited much more dramatic constriction upon stimulation, indicating that pericytes modulate blood flow in a slower and subtler way than do vascular smooth muscle cells. To investigate if pericytes use this ability to modulate blood flow under physiological conditions, we ablated one or two capillary pericytes in the living brain. We were surprised to find that 3 days after ablation we observed a dilation of capillaries left uncovered by the pericyte ablation, which corresponded with a doubling in the number of red blood cells flowing through that capillary. Critically, we did not observe any hemodynamic changes in control animals that either did not express optogenetic proteins, or did not have any pericytes ablated. The results therefore suggest that pericytes play a role in shaping capillary blood flow through the brain. This will inform the longstanding debate, and could lead to new ways of correcting blood flow abnormalities that plague numerous neurological diseases like traumatic brain injury, epilepsy, and stroke

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

Anatomo-functional magnetic resonance imaging of the spinal cord and its application to the characterization of spinal lesions in cats

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique.Spinal cord injury has a significant impact on quality of life since it can lead to motor (paralysis) and sensory deficits. These deficits evolve in time as reorganisation of the central nervous system occurs, involving physiological and neurochemical mechanisms that are still not fully understood. Given that both the severity of the deficit and the successful rehabilitation process depend on the anatomical pathways that have been altered in the spinal cord, it may be of great interest to assess white matter integrity after a spinal lesion and to evaluate quantitatively the functional state of spinal neurons. The great potential of magnetic resonance imaging (MRI) lies in its ability to investigate both anatomical and functional properties of the central nervous system non invasively. To address the problem of spinal cord injury, this project aimed to evaluate the benefits of diffusion-weighted MRI to assess the integrity of white matter axons that remain after spinal cord injury. The second objective was to evaluate to what extent functional MRI can measure the activity of neurons in the spinal cord. Although widely applied to the brain, diffusion-weighted MRI and functional MRI of the spinal cord are not straightforward. Various issues arise from the small cross-section width of the cord, the presence of cardiac and respiratory motions, and from magnetic field inhomogeneities in the spinal region. The main purpose of the present thesis was therefore to develop methodologies to circumvent these issues. This development notably focused on the optimization of acquisition parameters to image anatomical, diffusion-weighted and functional data in cats and humans at 3T using standard coils and pulse sequences. Moreover, various strategies to correct for susceptibility-induced distortions were investigated and the sensitivity and specificity in spinal cord functional MRI was studied. As a result, acquisition of high spatial and angular diffusion-weighted images and evaluation of the integrity of specific spinal pathways following spinal cord injury was achieved. Moreover, functional activations in the spinal cord of anaesthetized cats was detected. Although encouraging, these results highlight the need for further technical and methodological development in the near-future. Being able to develop a reliable neuroimaging tool for confirming clinical parameters would improve diagnostic and prognosis. It would also enable to monitor the effect of various therapeutic strategies. This would certainly bring hope to a large number of people suffering from trauma and neurodegenerative diseases such as spinal cord injury, tumours, multiple sclerosis and amyotrophic lateral sclerosis

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

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

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