Peripheral Blood Pressure Changes Induced by Dobutamine Do Not Alter BOLD Signals in The Human Brain

In extending the use of functional MRI to neuropharmacology, a primary area of concern is that peripheral blood pressure changes induced by pharmacological agents could independently produce a change in the blood oxygenation level-dependent (BOLD) signal, resulting in difficulties distinguishing or interpreting drug-induced neural activations. In the present study, we utilized intravenous dobutamine, a beta-adrenergic receptor agonist, to increase the mean arterial blood pressure (MABP), while examining the effects of MABP changes on the BOLD signal in cocaine-dependent participants. Dobutamine infusion significantly increased the MABP from 93 ± 8 mm Hg to 106 ± 12 mm Hg (P \u3c 0.0005), but did not produce a significant global BOLD signal. Yet, a few voxels in the anterior cingulate showed BOLD signal changes that paralleled the changes in blood pressure (BP). Our observations support the conclusion that following the infusion of psychoactive agents, brain BOLD signals accurately reflect neuronal activity, even in the face of relatively large peripheral cardiovascular effects that transiently increase systemic BP

Expectation Modulates Human Brain Responses to Acute Cocaine: A Functional Magnetic Resonance Imaging Study

Background Human expectation of psychoactive drugs significantly alters drug effects and behavioral responses. However, their neurophysiological mechanisms are not clear. This study investigates how cocaine expectation modulates human brain responses to acute cocaine administration. Methods Twenty-six right-handed non–treatment-seeking regular cocaine abusers participated in this study. Changes in blood oxygenation level-dependent (BOLD) signals were measured, and online behavioral ratings during cocaine expectation and acute cocaine administration were recorded. Results Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus (Brodmann area [BA] 11), frontal pole (BA 10), and anterior cingulate gyrus regions. Active engagement in the amygdala and the lateral orbitofrontal cortex (OFC; BA 47) by unexpected but not expected cocaine infusion was discovered. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus. Conclusions These results suggest that cocaine expectation modulates neural-sensitivity adaptation between the expected events and the actual outcomes but did not modulate the pharmacological characteristics of cocaine. In addition, the amygdala–lateral OFC circuitry plays an important role in mediating stimulus-outcome relations and contextual factors of drug abuse

Oxygenation-sensitive cardiovascular magnetic resonance imaging (OS-CMR) : potential confounding factors in use of OS-CMR

La résonance magnétique cardiovasculaire sensible à l'oxygénation (OS-CMR) est devenue une modalité d'imagerie diagnostique pour la surveillance de changements dans l'oxygénation du myocarde. Cette technique offre un grand potentiel en tant qu'outil diagnostic primaire pour les maladies cardiovasculaires, en particulier la détection non-invasive d'ischémie. Par contre, il existe plusieurs facteurs potentiellement confondants de cette technique, quelques-uns d'ordre méthodologique comme les paramètres de séquençage et d'autres de nature physiologiques qui sont peut compris. En raison des effets causés par le contenu tissulaire d'eau, l'état d'hydratation peut avoir un impact sur l'intensité du signal. Ceci est un des aspects physiologiques en particulier dont nous voulions quantifier l'effet confondant par la manipulation de l'état d'hydratation chez des humains et l'observation des changements de l'intensité du signal dans des images OS-CMR. Méthodes: In vitro: Du sang artériel et veineux de huit porcs a été utilisé pour évaluer la dilution en série du sang et son effet correspondant sur l'intensité du signal de la séquence OS. In vivo: Vingt-deux volontaires en santé ont subi OS-CMR. Les concentrations d'hémoglobine (Hb) ont été mesurées au niveau de base et immédiatement après une l'infusion cristalloïde rapide de 1000 mL de solution Lactate Ringer's (LRS). Les images OS-CMR ont été prises dans une vue mid-ventriculaire court axe. L'intensité du signal myocardique a été mesurée durant une rétention respiratoire volontaire maximale, suite à une période d'hyperventilation de 60 secondes. Les changements dans l'intensité du signal entre le début et la fin de la rétention de la respiration ont été exprimés relativement au niveau de base (% de changement). Résultats: L'infusion a résulté en une diminution significative de l'Hb mesurée (142.5±3.3 vs. 128.8±3.3 g/L; p<0.001), alors que l'IS a augmenté de 3.2±1.2% entre les images du niveau de base en normo- et hypervolémie (p<0.05). L'IS d'hyperventilation ainsi que les changements d'IS induits par l'apnée ont été attenués après hémodilution (p<0.05). L'évaluation quantitative T2* a démontré une corrélation négative entre le temps de T2* et la concentration d'hémoglobine (r=-0.46, p<0.005). Conclusions: Il existe plusieurs éléments confondants de la technique OS-CMR qui requièrent de l'attention et de l'optimisation pour une future implémentation clinique à grande échelle. Le statut d'hydratation en particulier pourrait être un élément confondant dans l'imagerie OS-CMR. L'hypervolémie mène à une augmentation en IS au niveau de base et atténue la réponse IS durant des manoeuvres de respiration vasoactives. Cette atténuation de l'intensité du signal devrait être tenue en compte et corrigée dans l'évaluation clinique d'images OS-CMR.Background: Oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) has become a feasible diagnostic imaging modality for monitoring changes of myocardial oxygenation. This technique has great potential for use as a primary diagnostic tool for cardiovascular disease, particularly non-invasive detection of ischemia. Yet, there are several potential confounding factors of this technique, some methodological, such as sequence parameters and others are physiological and not well understood. Due to T2 effects caused by tissue water content, the hydration status may impact signal intensity. This is one physiological aspect in particular that we aimed at quantifying the confounding effect by manipulating hydration status in humans and observing signal intensity (SI) changes in OS-CMR images. Methods: In vitro: Arterial and venous blood from eight swine were used to assess serial dilution of blood and it corresponding effect on OS sequence signal intensity. In vivo: Twenty-two healthy volunteers underwent OS-CMR. Hemoglobin (Hb) concentrations were measured at baseline and immediately following rapid crystalloid infusion of 1,000ml of Lactated Ringer’s solution (LRS). OS-CMR images were acquired in a mid-ventricular short axis view. Myocardial SI was measured during a maximal voluntary breath-hold, after a 60-second period of hyperventilation. SI changes were expressed relative to baseline (% change). Results: The infusion resulted in a significant decrease in measured Hb (142.5±3.3 vs. 128.8±3.3 g/L; p<0.001), while SI increased by 3.2±1.2% between baseline images at normo- and hypervolemia (p<0.05). Both hyperventilation SI and the SI changes induced by apnea were attenuated after hemodilution (p<0.05). Quantitative assessment showed a negative correlation between T2* and hemoglobin concentration (r=-0.46, p<0.005). Conclusions: There are several confounders to the OS-CMR technique that require attention and optimization for future larger scale clinical implementation. The hydration status in particular may be a confounder in OS-CMR imaging. Hypervolemia leads to an increase in SI at baseline and attenuates the SI response during vasoactive breathing maneuvers. This attenuation in signal intensity would need to be accounted for and corrected in clinical assessment of OS-CMR images

Non-Invasive Venous Thrombus Composition and Therapeutic Response by Multiparametric MRI

Deep vein thrombosis (DVT), or a blood clot in a deep vein (commonly the legs), is known as the silent killer—there may be few or no symptoms, yet a section of the thrombus could break free and travel to the lungs causing a potentially fatal pulmonary embolism. DVT and its complications affect 900,000 people in the U.S. each year, with one third of cases resulting in fatality. Anticoagulants (the standard treatment) pose serious bleeding risks and rely on the patient’s fibrinolytic system to break up the thrombus, which is often incapable of doing so thus leading to post thrombotic syndrome (PTS) in almost 50% of patients. Removing the DVT completely via thrombolytic treatments may improve quality of life by reducing PTS. However, thrombolysis is only effective on acute thrombi. Impaired success with thrombolytic treatment is due to heterogeneity in the thrombus (old clot, which is unable to be broken up, intermixed with fresh clot, which can easily be broken up). This problem is largely overlooked based on an inability to determine thrombus composition. Currently, the only method for determining disease stage is the patient’s recollection of when their symptoms began, which is inherently unreliable and could put the patient at risk. Further, thrombi of the same chronological age may organize at different rates in different people. Magnetic resonance imaging (MRI) has the potential to provide information about thrombus composition (clot age), and thus inform patient-specific treatment planning. Since there are several limitations to studying DVT in humans, animal models are key tools for understanding the disease. Mouse models are the most commonly used, providing a unique biological environment to study disease progression and treatment. Any model requires rigorous characterization and standardization to ensure reproducibility between studies. Our first objective was to quantify structural and functional changes in the healthy venous system of young and aged mice of both sexes, at rest and under conditions which simulate exercise. Second, we assessed the endogenous response to two models of DVT mimicking the two possible clinical scenarios: total or partial occlusion. Following the necessary model characterization, we developed a multiparametric MRI approach to probe thrombus composition without the need for contrast agents. Our results show imaging correlation with known composition by histology. This method provides a novel approach to study thrombus composition, and could eventually be used clinically to provide patient-specific treatment planning for DVT. Additionally, we investigated the impact of exercise, an emerging therapeutic option, on thrombus composition. Using an in-cage running wheel, our results show that spontaneous exercise – both alone and in combination with standard treatment – reduces initial thrombus size and contributes to thrombus resolution. We found that exercise increases acute fibrin content, attenuates local inflammation, and decreases sub-chronic collagen content in pharmacologically treated mice. This work provides 1) the first in vivo characterization of the murine venous system in health and disease, 2) a foundational methodology to determine thrombus composition by MRI, and 3) insights on the impact of exercise on DVT. This research can help DVT investigators from the animal model perspective, and provides a step forward in characterizing thrombus composition for patient-specific DVT treatment planning.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149918/1/opalmer_1.pd

Characterising haemodialysis-associated cardiomyopathy using deformation imaging by cardiovascular magnetic resonance tagging and speckle-tracking echocardiography

Haemodialysis patients represent an extreme phenotype of cardiovascular risk with a pattern of disease distinct from that in the general population. Non-traditional risk factors, specific to chronic kidney disease such as hypervolaemia, arterial stiffness and advanced glycation end-product deposition are increasingly recognised. A previously demonstrated non-traditional risk factor associated with worse outcomes is the presence of uraemic cardiomyopathy. This pattern of cardiac morphology and function has previously been defined as the presence of left ventricular abnormalities, including left ventricular hypertrophy, dilatation and left ventricular systolic dysfunction. For the first time the work in this thesis studies an incident haemodialysis population using multi-parametric strain-based imaging. This uses the accuracy of cardiovascular magnetic resonance imaging of resting cardiac and aortic morphology and function augmented with strain by tagging to longitudinal strain changes during haemodialysis by speckle-tracking echocardiography. The general aim of this thesis was to characterise the relationship of left ventricular function to haemodialysis using strain-based imaging. This might allow characterisation of haemodialysis-associated cardiomyopathy which may be distinct from the traditional definition of uraemic cardiomyopathy and may better define those patients who would benefit from modifications to the process of haemodialysis

Magnetic resonance imaging of the right ventricle in human pulmonary hypertension

Pulmonary Hypertension (PH) is a rare but devastating illness which results in progressive right ventricular (RV) failure and early death. RV function determines survival in all patients with PH but it is difficult to measure accurately using existing clinical techniques. The choice and design of the experiments in this thesis was driven by a desire to improve our understanding of the reasons for right, and left,ventricular dysfunction in this context. Cardiovascular magnetic resonance (CMR)imaging was utilized throughout as it allows the non-invasive, direct and accurate study of both ventricles; at rest and during stress. In Chapter 3, CMR imaging was used to identify an NT-proBNP threshold (1685 ng/l, sensitivity 100%, specificity 94%) for the non-invasive detection of RV systolic dysfunction in patients with PH. In Chapter 4, contrast-enhanced-CMR was utilized for the first time in PH patients and revealed previously unidentified areas of myocardial fibrosis within the RV insertion points and interventricular septum. The extent of these areas correlated inversely with RV ejection fraction (r = -0.762, p < 0.001). Septal contrast enhancement was particularly associated with bowing of the interventricular septum. Finally, in Chapter 5, dobutamine stress-CMR was used to determine the individual reasons for right and left ventricular stroke volume impairment during exercise in PH patients. ∆ RV stroke volume appeared limited by diminished contractile reserve as ∆ RVEF was lower in PH patients (27%) compared to controls (38%) and ∆ RVEF correlated with ∆ RV stroke volume (r = 0.94, p < 0.001). ∆ LV stroke volume appeared limited by impaired filling, probably due to reduced LV preload as RV stroke volume and LV end-diastolic volume remained closely related at rest (r = 0.821, p < 0.001) and stress (r = 0.693, p = 0.003)

Mean systemic filling pressure : from Guyton to the ICU

Mean systemic filling pressure (Pmsf)is defined as the pressure in the blood vessels during cardiac arrest. Pmsf is an important determinant for venous return to the heart and thus for cardiac output. This thesis describes a method to measure Pmsf at the bedside in intensive care patients and describes the clinical significance of Pmsf in the intensive careUBL - phd migration 201

Human brain mechanisms of pain perception and regulation in health and disease

Context The perception of pain due to an acute injury or in clinical pain states undergoes substantial processing at supraspinal levels. Supraspinal, brain mechanisms are increasingly recognized as playing a major role in the representation and modulation of pain experience. These neural mechanisms may then contribute to interindividual variations and disabilities associated with chronic pain conditions. Objective To systematically review the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts. Data Sources MEDLINE and PRE‐MEDLINE searches were performed to identify all English‐language articles that examine human brain activity during pain, using hemodynamic (PET, fMRI), neuroelectrical (EEG, MEG) and neurochemical methods (MRS, receptor binding and neurotransmitter modulation), from January 1, 1988 to March 1, 2003. Additional studies were identified through bibliographies. Study Selection Studies were selected based on consensus across all four authors. The criteria included well‐designed experimental procedures, as well as landmark studies that have significantly advanced the field. Data Synthesis Sixty‐eight hemodynamic studies of experimental pain in normal subjects, 30 in clinical pain conditions, and 30 using neuroelectrical methods met selection criteria and were used in a meta‐analysis. Another 24 articles were identified where brain neurochemistry of pain was examined. Technical issues that may explain differences between studies across laboratories are expounded. The evidence for and the respective incidences of brain areas constituting the brain network for acute pain are presented. The main components of this network are: primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus (Th). Evidence for somatotopic organization, based on 10 studies, and psychological modulation, based on 20 studies, is discussed, as well as the temporal sequence of the afferent volley to the cortex, based on neuroelectrical studies. A meta‐analysis highlights important methodological differences in identifying the brain network underlying acute pain perception. It also shows that the brain network for acute pain perception in normal subjects is at least partially distinct from that seen in chronic clinical pain conditions and that chronic pain engages brain regions critical for cognitive/emotional assessments, implying that this component of pain may be a distinctive feature between chronic and acute pain. The neurochemical studies highlight the role of opiate and catecholamine transmitters and receptors in pain states, and in the modulation of pain with environmental and genetic influences. Conclusions The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90300/1/j.ejpain.2004.11.001.pd