Detailing the relation between renal T(2)* and renal tissue pO2 using an integrated approach of parametric magnetic resonance imaging and invasive physiological measurements

OBJECTIVES: This study was designed to detail the relation between renal T2* and renal tissue pO2 using an integrated approach that combines parametric magnetic resonance imaging (MRI) and quantitative physiological measurements (MR-PHYSIOL. MATERIALS AND METHODS: Experiments were performed in 21 male Wistar rats. In vivo modulation of renal hemodynamics and oxygenation was achieved by brief periods of aortic occlusion, hypoxia, and hyperoxia. Renal perfusion pressure (RPP), renal blood flow (RBF), local cortical and medullary tissue pO2, and blood flux were simultaneously recorded together with T2*, T2 mapping, and magnetic resonance-based kidney size measurements (MR-PHYSIOL). Magnetic resonance imaging was carried out on a 9.4-T small-animal magnetic resonance system. Relative changes in the invasive quantitative parameters were correlated with relative changes in the parameters derived from MRI using Spearman analysis and Pearson analysis. RESULTS: Changes in T2* qualitatively reflected tissue pO2 changes induced by the interventions. T2* versus pO2 Spearman rank correlations were significant for all interventions, yet quantitative translation of T2*/pO2 correlations obtained for one intervention to another intervention proved not appropriate. The closest T2*/pO2 correlation was found for hypoxia and recovery. The interlayer comparison revealed closest T2*/pO2 correlations for the outer medulla and showed that extrapolation of results obtained for one renal layer to other renal layers must be made with due caution. For T2* to RBF relation, significant Spearman correlations were deduced for all renal layers and for all interventions. T2*/RBF correlations for the cortex and outer medulla were even superior to those between T2* and tissue pO2. The closest T2*/RBF correlation occurred during hypoxia and recovery. Close correlations were observed between T2* and kidney size during hypoxia and recovery and for occlusion and recovery. In both cases, kidney size correlated well with renal vascular conductance, as did renal vascular conductance with T2*. Our findings indicate that changes in T2* qualitatively mirror changes in renal tissue pO2 but are also associated with confounding factors including vascular volume fraction and tubular volume fraction. CONCLUSIONS: Our results demonstrate that MR-PHYSIOL is instrumental to detail the link between renal tissue pO2 and T2* in vivo. Unravelling the link between regional renal T2* and tissue pO2, including the role of the T2* confounding parameters vascular and tubular volume fraction and oxy-hemoglobin dissociation curve, requires further research. These explorations are essential before the quantitative capabilities of parametric MRI can be translated from experimental research to improved clinical understanding of hemodynamics/oxygenation in kidney disorders

Probing renal blood volume with magnetic resonance imaging

Damage to the kidney substantially reduces life expectancy. Renal tissue hypoperfusion and hypoxia are key elements in the pathophysiology of acute kidney injury and its progression to chronic kidney disease. In vivo assessment of renal haemodynamics and tissue oxygenation remains a challenge. Blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) is sensitive to changes in the effective transversal relaxation time (T(2)*) in vivo, is non-invasive and indicative of renal tissue oxygenation. However, the renal T(2)* to tissue pO(2) relationship is not governed exclusively by renal blood oxygenation, but is affected by physiological confounders with alterations in renal blood volume fraction (BVf) being of particular relevance. To decipher this interference probing renal BVf is essential for the pursuit of renal MR oximetry. Superparamagnetic iron oxide nanoparticle (USPIO) preparations can be used as MRI visible blood pool markers for detailing alterations in BVf. This review promotes the opportunities of MRI based assessment of renal BVf. Following an outline on the specifics of renal oxygenation and perfusion, changes in renal BVf upon interventions and their potential impact on renal T(2)* are discussed. We also describe the basic principles of renal BVf assessment using ferumoxytol enhanced MRI in the equilibrium concentration regime. We demonstrate that ferumoxytol does not alter control of renal haemodynamics and oxygenation. Preclinical applications of ferumoxytol enhanced renal MRI as well as considerations for its clinical implementation for examining renal BVf changes are provided alongside practical considerations. Finally, we explore the future directions of MRI based assessment of renal BVf

How bold is blood oxygenation level dependent (BOLD) magnetic resonance imaging of the kidney? Opportunities, challenges and future directions

Renal tissue hypoperfusion and hypoxia are key elements in the pathophysiology of acute kidney injury and its progression to chronic kidney disease. Yet, in vivo assessment of renal haemodynamics and tissue oxygenation remains a challenge. Many of the established approaches are invasive, hence not applicable in humans. Blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) offers an alternative. BOLD-MRI is non-invasive and indicative of renal tissue oxygenation. Nonetheless recent (pre-)clinical studies revived the question as to how bold renal BOLD-MRI really is. This review aims to deliver some answers. It is designed to inspire the renal physiology, nephrology, and imaging communities to foster explorations into the assessment of renal oxygenation and haemodynamics by exploiting the powers of MRI. For this purpose the specifics of renal oxygenation and perfusion are outlined. The fundamentals of BOLD-MRI are summarized. The link between tissue oxygenation and the oxygenation sensitive MR biomarker T2 * is outlined. The merits and limitations of renal BOLD-MRI in animal and human studies are surveyed together with their clinical implications. Explorations into detailing the relation between renal T2 * and renal tissue partial pressure of oxygen (pO2 ) are discussed with a focus on factors confounding the T2 * versus tissue pO2 relation. Multi-modality in vivo approaches suitable for detailing the role of the confounding factors that govern T2 * are considered. A schematic approach describing the link between renal perfusion, oxygenation, tissue compartments and renal T2 * is proposed. Future directions of MRI assessment of renal oxygenation and perfusion are explored

The morphology of the intraparietal sulcus in children prenatally exposed to alcohol in a sample of children from the Western Cape, South Africa and its potential relationship with number processing

The intraparietal sulcus (IPS) is a prominent feature in the parietal lobe and extends posteriorly from the postcentral sulcus through the parietal lobe to end in the occipital. It is involved in visuospatial functions and is known to play a critical role in number processing. Fetal alcohol spectrum disorders (FASD) result from prenatal exposure to alcohol and are particularly prevalent in the Western Cape region of South Africa. Arithmetic is a domain of cognitive function that is particularly sensitive to prenatal alcohol exposure, and effects on arithmetic remain significant after controlling for lower IQ. Magnetic resonance imaging (MRI) was used to investigate the morphology of the IPS and whether this morphology had a relation to the number processing abilities of children prenatally exposed to alcohol in a Western Cape community. Participants were 9 to 14-year-old children from the same community in Cape Town, South Africa, who formed part of a study aimed at investigating the effects of prenatal alcohol exposure (PAE) on brain structure and function particularly during number processing. Mothers were interviewed regarding alcohol consumption during pregnancy using a timeline follow-back approach. The first analysis included designing a protocol for manually parcellating the IPS into two regions of interest (ROI): the medial wall (MIPS) and the lateral wall (LIPS) respectively. The neuroimaging program MultiTracer was used for the manual tracing and to calculate the volume of the cortex of both the MIPS and LIPS. The purpose of this first analysis was to examine the effects of PAE on IPS volume and asymmetry using manual tracing, the relation between IPS volume and number processing performance, and potential moderation by PAE of the relation between IPS volume and number processing performance. Results indicated that when comparing the FAS/PFAS (Fetal Alcohol Syndrome/Partial FAS) children to the controls, PAE had an effect on the left LIPS and higher arithmetic scores were associated with larger bilateral MIPS volumes suggesting that the effect of PAE on math may not be moderated by IPS volume. The left LIPS was significantly smaller in FAS/PFAS individuals when compared by FASD diagnosis, and this remained a trend after controlling for potential confounders. In the second analysis, the automated neuroimaging software program FreeSurfer was used to parcellate the IPS. These volumes were then compared with our previously manually traced volumes. Intra-rater reliability testing was statistically significant for consistency and absolute agreement indicating good retraceability of the designed protocol for manual tracing. Both left and right IPS volumes were significantly larger with the manually traced method compared to automated tracing. The manually traced left IPS yielded stronger results when comparing volumes by diagnostic groups, conversely the automated volumes showed stronger associations with alcohol measures. A possible explanation is that FreeSurfer parcellated the IPS differently to our protocol and does not take into account the extensive variability of the morphology of the sulcus. BrainVoyager QX, another neuroimaging software program was used in the third analysis when looking at the BOLD fMRI data of the participants. For this analysis, the manually traced MIPS and LIPS were subdivided into five ROI's for the left and right hemispheres respectively: (1) the superior MIPS, (2) the medial branch of the MIPS, (3) the inferior MIPS, (4) the superior LIPS, and (5) the inferior LIPS. The percent signal change were calculated for each participant for the proximity judgement (PJ) tasks they performed inside the scanner. Associations of the percent signal change of the ROI's of the PAE children with absolute alcohol per occasion (oz) were all significant even after controlling for IQ except the left inferior LIPS, supporting what is found in the literature. The current findings, in agreement with previous studies, demonstrate that PAE is associated with both structural and functional changes in the brain. While the morphology of the IPS may not moderate the effects of PAE on arithmetic function, some cortical volumes within the IPS were sensitive to PAE. Moreover, altered activation of the IPS in the performance of magnitude comparison tasks was strongly associated with PAE. The IPS is an extremely variable structure whose anatomy is often misunderstood, which emphasises the importance of anatomical knowledge for imaging studies. Future research will refine the protocol for manual tracing of the IPS, which may lead to greater understanding of the functions of the different areas. It is to be hoped that these findings will give more insight into understanding the functioning of children and adults with FASDs and contribute to more effective therapeutic interventions for these individuals

Understanding Neural Networks in Awake Rat by Resting-State Functional MRI: A Dissertation

Resting-state functional magnetic resonance imaging (rs-fMRI) is a non-invasive neuroimaging technique that utilizes spontaneous low-frequency fluctuations of blood-oxygenation-level dependent (BOLD) signals to examine resting-state functional connectivity in the brain. In the past two decades, this technique has been increasingly utilized to investigate properties of large-scale functional neural networks as well as their alterations in various cognitive and disease states. However, much less is known about large-scale functional neural networks of the rodent brain, particularly in the awake state. Therefore, we attempted to unveil local and global functional connectivity in awake rat through a combination of seed-based analysis, independent component analysis and graph-theory analysis. In the current studies, we revealed elementary local networks and their global organization in the awake rat brain. We further systematically compared the functional neural networks in awake and anesthetized states, revealing that the rat brain was locally reorganized while maintaining global topological properties from awake to anesthetized states. Furthermore, specific neural circuitries of the rat brain were examined using resting-state fMRI. First anticorrelated functional connectivity between infralimbic cortex and amygdala were found to be evident with different preprocessing methods (global signal regression, regression of ventricular and white matter signal and no signal regression). Secondly the thalamocortical connectivity was mapped for individual thalamic groups, revealing group-specific functional cortical connections that were generally consistent with known anatomical connections in rat. In conclusion, large-scale neural networks can be robustly and reliably studied using rs-fMRI in awake rat, and with this technique we established a baseline of local and global neural networks in the awake rat brain as well as their alterations in the anesthetized condition

Conectividade efectiva em epilepsia

A epilepsia é uma das mais comuns patologias que afectam o cérebro humano e caracteriza-se por uma actividade cerebral oscilatória desordenada e excessiva que prejudica gravemente a qualidade de vida do doente. Com o objectivo de detectar o percurso da actividade cerebral anormal a ressonância magnética, em conjunto com a técnica de electroencefalografia (EEG) têm evoluído no sentido de tornar a identificação do foco epiléptico e respectivas vias de propagação mais clara e fácil para o neurocirurgião. Esta detecção pode recorrer ao efeito BOLD (do inglês “Blood Oxygenation Level Dependent”) para, de forma indirecta, obter um mapa de activação neuronal da zona em estudo contribuindo para uma possível intervenção cirúrgica à área epiléptica. No entanto, para chegar a uma conclusão definitiva sobre este mapa neuronal é necessário ter em conta que diferentes regiões podem apresentar HRFs (do inglês “Hemodynamic Response Functions”) diferentes, influenciando o resultado de qualquer análise se este facto não for tido em conta. Na presente dissertação foi aplicado um método de cálculo de influência causal entre regiões do cérebro humano a dados de epilepsia obtidos através da técnica EEG+fMRI. Foram utilizadas técnicas de conectividade efectiva (causalidade de Granger) usando um pacote de software (PyHRF) para estimar com precisão a HRF da região em estudo e permitir a desconvolução do sinal antes do cálculo de conectividade. Foi demonstrada a utilidade desta contribuição metodológica para a caracterização topográfica e dinâmica de uma crise epiléptica

Oculomotor Biomarkers in Trait and State Model : Systems of Psychosis

Antipsychotic drugs are highly effective in reducing positive symptoms of psychosis. However, despite major efforts, negative and cognitive symptoms are still not sufficiently treatable. Importantly, these symptoms have been found to be strongly related to psychosocial functioning, thus emphasizing the urgent requirement of new treatments. Model systems are one approach to investigate underlying mechanisms of psychosis and aid the development of new treatments. In this thesis, I investigated the validity of schizotypy, a multidimensional attribute that in-cludes positive, negative, and disorganized traits, and of sleep deprivation as model systems of psychosis. Furthermore, I combined the two models to evaluate potential interactions between them. In order to validate cognitive performance alterations in schizotypy and after sleep deprivation, I applied widely studied oculomotor biomarkers of psychosis (i.e. smooth pursuit eye movements and antisaccades). To evaluate the usefulness of oculomotor bi-omarkers as time stable cognitive patterns, I additionally conducted a study on the trait-like nature of saccadic tasks. The first part of the thesis deals with the research background of psychotic disorders, the foundation of schizotypy and sleep deprivation as valuable model systems, and an introduction to widely studied oculomotor biomarkers of psychosis. The following chapter is a description with introductory information about the methods that I have deployed in the empirical studies. These methods include the recording and analysis of eye movements, latent state-trait modeling, and functional magnetic resonance imaging. Following the presentation of the main findings of the empirical studies, the thesis closes with an integration of the results in the present research literature and with indications to limitations of the studies and ideas for future research

Functional and structural substrates of increased dosage of Grik4 gene elucidated using multi-modal MRI

Grik4 is the gene responsible for encoding the high-affinity GluK4 subunit of the kainate receptors. Increased dosage of this subunit in the forebrain was linked to an increased level of anxiety, lack of social communication, and depression. On the synaptic level, abnormal synaptic transmission was also reported. The manifestations of this abnormal expression have not been investigated at the circuit level, nor the correlations between those circuits and the abnormal patterns of the behavior previously reported. In this line of work, we aspired to use different non-invasive magnetic resonance imaging (MRI) modalities to elucidate any disturbance that might stem from the increased dosage of Grik4 and how those changes might explain the abnormal behaviors. MRI offers a noninvasive way to look into the intact brain in vivo. Resting-state functional MRI casts light on how the brain function at rest on the network level and has the capability to detect any anomalies that might occur within or between those networks. On the microstructural level, the diffusion MRI is concerned with the underlying features of the tissues, using the diffusion of water molecules as a proxy for that end. Moving more macroscopically, using structural scans, voxel-based morphometry can detect subtle differences in the morphology of the different brain structures. We recorded videos of our animals performing two tasks that have long been linked to anxiety, the open field and the plus-maze tests before acquiring structural and functional scans. Lastly, we recorded blood-oxygenationlevel dependent (BOLD) signals in a different set of animals during electrical stimulation of specific white matter tracts in order to investigate how neuronal activity propagates. Our analysis showed a vast spectrum of changes in the transgenic group relative to the animals in the control group. On the resting-state networks level, we observed an increase in the within-network strength spanning different structures such as the hippocampus, some regions of the cortex, and the hypothalamus. The increased internal coherence or strength in the networks contrasted with a significant reduction in between-networks connectivity for some regions such as parts of the cortex and the hypothalamus, suggesting long-range network decorrelation. Supporting this idea, major white matter (WM) tracts, such as the corpus callosum and the hippocampal commissure, suffered from substantial changes compatible with an important reduction in myelination and/or a decrease in the mean axonal diameter. Macrostructurally speaking, the overexpression of GluK4 subunit had a bimodal effect, with expansion in some cortical areas in the transgenic animals accompanied by a shrinkage in the subcortical regions. Upon stimulating the brain with an electrical current, we noticed a difference in activity propagation between the two hemispheres. In transgenic animals, the evoked activity remained more confined to the stimulated hemisphere, again consistent with an impaired long-range connectivity. The structural changes both, at the micro and macro level, were in tight correlation with different aspects of the behavior including markers of anxiety such as the time spent in the open arms vs the closed arms in the plus-maze test and the time spent in the center vs the corners in the open field test. Our findings reveal how the disruption of kainate receptors, or more globally the glutamate receptors, and the abnormal synaptic transmission can translate into brain-wide changes in connectivity and alter the functional equilibrium between macro-and mesoscopic networks. The postsynaptic enhancement previously reported in the transgenic animals was here reflected in the BOLD signal and measured as an increase in the within-network strength. Importantly, the correlations between the structural changes and the behavior help to put the developmental changes and their behavioral ramifications into context. RESUMEN Grik4 es el gen responsable de codificar la subunidad GluK4 de alta afinidad de los receptores de kainato. El aumento de la dosis de esta subunidad en el prosencéfalo se relacionó con un mayor nivel de ansiedad, falta de comunicación social y depresión. A nivel sináptico, también se informó una transmisión sináptica anormal. Las manifestaciones de esta expresión anormal no se han investigado a nivel de circuito, ni las correlaciones entre esos circuitos y los patrones anormales de la conducta previamente informada. En esta línea de trabajo, aspiramos a utilizar diferentes modalidades de imágenes por resonancia magnética (MRI) no invasivas para dilucidar cualquier alteración que pudiera derivarse del aumento de la dosis de Grik4 y cómo esos cambios podrían explicar los comportamientos anormales. La resonancia magnética ofrece una forma no invasiva de observar el cerebro intacto in vivo. La resonancia magnética funcional en estado de reposo arroja luz sobre cómo funciona el cerebro en reposo en el nivel de la red y tiene la capacidad de detectar cualquier anomalía que pueda ocurrir dentro o entre esas redes. En el nivel microestructural, la resonancia magnética de difusión se ocupa de las características subyacentes de los tejidos utilizando la difusión de moléculas de agua como un proxy para ese fin. Moviéndose más macroscópicamente, utilizando escaneos estructurales, la morfometría basada en vóxeles puede detectar diferencias sutiles en la morfología de las diferentes estructuras cerebrales. Grabamos videos de nuestros animales realizando dos tareas que durante mucho tiempo se han relacionado con la ansiedad, el campo abierto y las pruebas de laberinto positivo antes de adquirir escaneos estructurales y funcionales. Por último, registramos señales dependientes del nivel de oxigenación de la sangre (BOLD) en un grupo diferente de animales durante la estimulación eléctrica de tractos específicos de materia blanca para investigar cómo se propaga la actividad neuronal. Nuestro análisis mostró un amplio espectro de cambios en el grupo transgénico en relación con los animales en el grupo de control. En el nivel de las redes de estado de reposo, observamos un aumento en la fuerza dentro de la red que abarca diferentes estructuras como el hipocampo, algunas regiones de la corteza y el hipotálamo. La mayor coherencia interna o fuerza en las redes contrastó con una reducción significativa en la conectividad entre redes para algunas regiones como partes de la corteza y el hipotálamo, lo que sugiere una descorrelación de redes de largo alcance. Apoyando esta idea, los grandes tractos de materia blanca (WM), como el cuerpo calloso y la comisura del hipocampo, sufrieron cambios sustanciales compatibles con una importante reducción de la mielinización y / o una disminución del diámetro axonal medio. Macroestructuralmente hablando, la sobreexpresión de la subunidad GluK4 tuvo un efecto bimodal, con expansión en algunas áreas corticales en los animales transgénicos acompañada de una contracción en las regiones subcorticales. Al estimular el cerebro con una corriente eléctrica, notamos una diferencia en la propagación de la actividad entre las dos hemiesferas. En los animales transgénicos, la actividad evocada permaneció más confinada al hemisferio estimulado, de nuevo consistente con una conectividad de largo alcance deteriorada. Los cambios estructurales, tanto a nivel micro como macro, estaban en estrecha correlación con diferentes aspectos de la conducta, incluidos marcadores de ansiedad como el tiempo pasado con los brazos abiertos frente a los brazos cerrados en la prueba del laberinto positivo y el tiempo pasado en el centro vs las esquinas en la prueba de campo abierto. Nuestros hallazgos revelan cómo la interrupción de los receptores de kainato, o más globalmente los receptores de glutamato, y la transmisión sináptica anormal pueden traducirse en cambios de conectividad en todo el cerebro y alterar el equilibrio funcional entre las redes macro y mesoscópicas. La mejora postsináptica informada anteriormente en los animales transgénicos se reflejó aquí en la señal BOLD y se midió como un aumento en la fuerza dentro de la red. Es importante destacar que las correlaciones entre los cambios estructurales y elcomportamiento ayudan a contextualizar los cambios en el desarrollo y sus ramificaciones conductuales