Oxygen Level-dependent Magnetic Resonance Research Articles

Cyclosporin a induces renal episodic hypoxia

Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hif-mediated responses and the impact of interventional Hif upregulation. Mice received CsA or its solvent cremophore for up to 6weeks. Low salt diet (Na+ ↓) was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen level-dependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O2 tensions below 10mmHg), Hif-α proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rtTA-based knockout of von Hippel-Lindau protein (Vhl-KO), which is crucial for Hif-α degradation. Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2h, but decreased at 24h after CsA treatment. Na+ ↓/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif-α proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na+ ↓/CsA/Vhl-KO aggravated morpho-functional outcome of chronic renal CsA toxicity. Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl-KO worsens the outcome of chronic CsA-induced renal toxicity.

Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging.

Determinations of renal oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in chronic kidney disease (CKD) patients have given heterogeneous results, possibly due to the lack of a reproducible method to analyse BOLD-MRI. It therefore remains uncertain whether patients with CKD have a reduced renal tissue oxygenation. We developed a new method to analyse BOLD-MRI signals and applied it to CKD patients and controls. MRI was performed under standardized conditions before and 15 min after IV furosemide in 104 CKD patients, 61 hypertensives and 42 controls. MR images were analysed with the new twelve-layer concentric objects method (TLCO) that divides renal parenchyma in 12 layers of equal thickness. The mean R2* value of each layer was reported, along with the change in R2* between successive layers, as measured by the slope steepness of the relevant curve. Inter-observer variability was 2.3 ± 0.9%, 1.9 ± 0.8% and 3.0 ± 2.3% in, respectively, controls, moderate and severe CKD. The mean R2* of the outer (more cortical) layers was significantly higher in CKD, suggesting lower cortical oxygenation as compared with controls. In CKD patients, the response to furosemide was blunted in the inner (more medullary) layers, and the R2* slope was flatter. In multivariable regression analysis, the R2* slope correlated positively with estimated glomerular filtration rate (eGFR) in patients with an eGFR <90 mL/min/1.73 m2 (P < 0.001). Using the new TLCO method, we confirm the hypothesis that renal cortical oxygenation is reduced in CKD in humans, and that the level of cortical oxygenation correlates with CKD severity.

Modulation of renal oxygenation and perfusion in rat kidney monitored by quantitative diffusion and blood oxygen level dependent magnetic resonance imaging on a clinical 1.5T platform.

BackgroundTo investigate the combined use of intravoxel incoherent motion (IVIM) diffusion-weighted (DW) and blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) to assess rat renal function using a 1.5T clinical platform.MethodsMultiple b-value DW and BOLD MR images were acquired from adult rats using a parallel clinical coil arrangement, enabling quantitation of the apparent diffusion coefficient (ADC), IVIM-derived diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f), and the transverse relaxation time T2*, for whole kidney, renal cortex, and medulla. Following the acquisition of two baseline datasets to assess measurement repeatability, images were acquired following i.v. administration of hydralazine, furosemide, or angiotensin II for up to 40 min.ResultsExcellent repeatability (CoV <10 %) was observed for ADC, D, f and T2* measured over the whole kidney. Hydralazine induced a marked and significant (p < 0.05) reduction in whole kidney ADC, D, and T2*, and a significant (p < 0.05) increase in D* and f. Furosemide significantly (p < 0.05) increased whole kidney ADC, D, and T2*. A more variable response to angiotensin II was determined, with a significant (p < 0.05) increase in medulla D* and significant (p < 0.05) reduction in whole kidney T2* established.ConclusionsMultiparametric MRI, incorporating quantitation of IVIM DWI and BOLD biomarkers and performed on a clinical platform, can be used to monitor the acute effects of vascular and tubular modulating drugs on rat kidney function in vivo. Clinical adoption of such functional imaging biomarkers can potentially inform on treatment effects in patients with renal dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0356-x) contains supplementary material, which is available to authorized users.

Blood oxygenation level dependent signal and neuronal adaptation to optogenetic and sensory stimulation in somatosensory cortex in awake animals.

The adaptation of neuronal responses to stimulation, in which a peak transient response is followed by a sustained plateau, has been well-studied. The blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal has also been shown to exhibit adaptation on a longer time scale. However, some regions such as the visual and auditory cortices exhibit significant BOLD adaptation, whereas other such as the whisker barrel cortex may not adapt. In the sensory cortex a combination of thalamic inputs and intracortical activity drives hemodynamic changes, although the relative contributions of these components are not entirely understood. The aim of this study is to assess the role of thalamic inputs vs. intracortical processing in shaping BOLD adaptation during stimulation in the somatosensory cortex. Using simultaneous fMRI and electrophysiology in awake rabbits, we measured BOLD, local field potentials (LFPs), single- and multi-unit activity in the cortex during whisker and optogenetic stimulation. This design allowed us to compare BOLD and haemodynamic responses during activation of the normal thalamocortical sensory pathway (i.e., both inputs and intracortical activity) vs. the direct optical activation of intracortical circuitry alone. Our findings show that whereas LFP and multi-unit (MUA) responses adapted, neither optogenetic nor sensory stimulation produced significant BOLD adaptation. We observed for both paradigms a variety of excitatory and inhibitory single unit responses. We conclude that sensory feed-forward thalamic inputs are not primarily responsible for shaping BOLD adaptation to stimuli; but the single-unit results point to a role in this behaviour for specific excitatory and inhibitory neuronal sub-populations, which may not correlate with aggregate neuronal activity.

Simultaneous multi-slice (SMS) acquisition enhances the sensitivity of hemodynamic mapping using gas challenges.

Hemodynamic mapping using gas inhalation has received increasing interest in recent years. Cerebrovascular reactivity (CVR), which reflects the ability of the brain vasculature to dilate in response to a vasoactive stimulus, can be measured by CO2 inhalation with continuous acquisition of blood oxygen level-dependent (BOLD) magnetic resonance images. Cerebral blood volume (CBV) can be measured by O2 inhalation. These hemodynamic mapping methods are appealing because of their absence of gadolinium contrast agent, their ability to assess both baseline perfusion and vascular reserve, and their utility in calibrating the functional magnetic resonance imaging (fMRI) signal. However, like other functional and physiological indices, a major drawback of these measurements is their poor sensitivity and reliability. Simultaneous multi-slice echo planar imaging (SMS EPI) is a fast imaging technology that allows the excitation and acquisition of multiple two-dimensional slices simultaneously, and has been shown to enhance the sensitivity of several MRI applications. To our knowledge, the benefit of SMS in gas inhalation imaging has not been investigated. In this work, we compared the sensitivity of CO2 and O2 inhalation data collected using SMS factor 2 (SMS2) and SMS factor 3 (SMS3) with those collected using conventional EPI (SMS1). We showed that the sensitivity of SMS scans was significantly (p=0.01) higher than that of conventional EPI, although no difference was found between SMS2 and SMS3 (p=0.3). On a voxel-wise level, approximately 20-30% of voxels in the brain showed a significant enhancement in sensitivity when using SMS compared with conventional EPI, with other voxels showing an increase, but not reaching statistical significance. When using SMS, the scan duration can be reduced by half, whilst maintaining the sensitivity of conventional EPI. The availability of a sensitive acquisition technique can further enhance the potential of gas inhalation MRI in clinical applications.

Foreword

To evaluate the feasibility and repeatability of applying blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in the feet to quantify regional dynamic changes in tissue oxygenation during proximal cuff occlusion and reactive hyperemia.Ten healthy male subjects underwent BOLD and T1-weighted imaging of the feet on two separate occasions, using a 3-T scanner. Dynamic changes in BOLD signal intensity were assessed before and during proximal cuff occlusion of the thigh and during reactive hyperemia, and BOLD time course data were evaluated for the time-to-half ischemic minimum, minimum ischemic value, peak hyperemic value, time-to-peak hyperemia, time-to-half peak hyperemia, and end value. T1-weighted images were used for segmentation of volumes of interest (VOI) in anatomical regions of the foot (heel, toes, dorsal foot, medial and lateral plantar foot). Repeatability of vascular responses was assessed for each foot VOI using semiautomated image registration and quantification of serial BOLD images.The heel VOI demonstrated a significantly higher peak hyperemic response, expressed as percent change from baseline BOLD signal intensity, compared with all other VOIs of the foot (heel, 7.4 ± 1.2%; toes, 5.6 ± 0.8%; dorsal foot, 5.7 ± 1.6%; medial plantar, 5.6 ± 1.7%; lateral plantar, 5.6 ± 1.5% [p < .05]). Additionally, the lateral plantar VOI had a significantly lower terminal signal intensity value (i.e., end value) when compared with all foot VOIs (p < .05). BOLD MRI was repeatable between visits in all foot VOIs, with no significant differences between study visits for any of the evaluated functional indices.BOLD MRI offers a repeatable technique for volumetric assessment of regional foot tissue oxygenation. Future application of BOLD imaging in the feet of patients with peripheral vascular disease may permit serial evaluation of regional tissue oxygenation and allow for improved assessment of therapeutic interventions targeting specific sites of the foot.

Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity.

White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH. We examined 45 subjects (age range = 50-91 years; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood oxygen level-dependent magnetic resonance imaging signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and 1-year follow-up, with automated coregistration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the 1-year period. CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (p < 0.001). T2 and MD were higher by 8.7% (7.9%) and 17.0% (8.5%), respectively, compared to the contralateral homologous NAWM (p < 0.001). Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.

Prognostic Significance of Transverse Relaxation Rate (R2*) in Blood Oxygenation Level-Dependent Magnetic Resonance Imaging in Patients with Invasive Breast Cancer

ObjectiveTo examine the relationship between magnetic resonance transverse relaxation rate (R2*) and prognostic factors.Materials and MethodsA total of 159 women with invasive ductal carcinomas (IDCs) underwent breast magnetic resonance imaging (MRI) including blood oxygenation level-dependent (BOLD) sequence at 3 T. The distribution of the measured R2* values were analyzed, and the correlation between R2* and various prognostic factors (age, tumor size, histologic grade, lymphovascular invasion, and axillary lymph node status, as well as expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, p53, and Ki-67) were retrospectively assessed using patient medical records.ResultsThe baseline R2* values of the IDCs were very heterogeneous with wide range among the patients. The mean R2* value was (32.8 ± 14.0) Hz with a median of 29.3 Hz (range 13.5–109.4 Hz). In multivariate analysis, older age was associated with decreased R2* value (P = 0.011) and IDCs with p53-overexpression showed higher R2* values than those without p53-overexpression group (P = 0.031). Other prognostic factors were not significantly correlated with R2* value.ConclusionIn this study, R2* values were significantly correlated with age and expression of p53. Further studies are necessary to determine the prognostic value of BOLD-MRI.

Blood oxygenation level-dependent magnetic resonance imaging during carbogen breathing: differentiation between prostate cancer and benign prostate hyperplasia and correlation with vessel maturity.

ObjectiveThe aim of this study was to investigate whether the blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) can evaluate tumor maturity and preoperatively differentiate prostate cancer (PCa) from benign prostate hyperplasia (BPH).Patients and methodsBOLD MRI based on transverse relaxation time*-weighted echo planar imaging was performed to assess PCa (19) and BPH (22) responses to carbogen (95% O2 and 5% CO2). The average signal values of PCa and BPH before and after carbogen breathing and the relative increased signal values were computed, respectively. The endothelial-cell marker, CD31, and the pericyte marker, α-smooth muscle actin (mature vessels), were detected with immunofluorescence, and were assessed by microvessel density (MVD) and microvessel pericyte density (MPD). The microvessel pericyte coverage index (MPI) was used to evaluate the degree of vascular maturity. The changed signal from BOLD MRI was correlated with MVD, MPD, and MPI.ResultsAfter inhaling carbogen, both PCa and BPH showed an increased signal, but a lower slope was found in PCa than that in BPH (P<0.05). PCa had a higher MPD and MVD but a lower MPI than BPH. The increased signal intensity was positively correlated with MPI in PCa and that in BPH (r=0.616, P=0.011; r=0.658, P=0.002); however, there was no correlation between the increased signal intensity and MPD or MVD in PCa than that in BPH (P>0.05).ConclusionOur results confirmed that the increased signal values induced by BOLD MRI well differentiated PCa from BPH and had a positive correlation with vessel maturity in both of them. BOLD MRI can be utilized as a surrogate marker for the noninvasive assessment of the degree of vessel maturity.

Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients.

Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level-dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.

Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades.

The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20–29 to 70–79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging.

WE-FG-BRA-03: Oxygen Interplay in Hypofractionated Radiotherapy: A Hidden Opportunity

Purpose: Local oxygen during a radiotherapy fraction has been shown to change over a full range of the oxygen enhancement ratio (OER) during the same time scale as the treatment fraction. Interplay with local oxygen is then likely a concern, especially for hypofractionation. Our experiments that show a strong role for metabolic dynamics suggesting one could manipulate this interplay for more efficacious treatments. Methods: Two published experiments are presented with the same human head and neck cancer cell line (UM-SCC-22B). One is a cell-specific in vitro prompt response to a 10 Gy dose of orthovotage radiation using fluorescence lifetime imaging (FLIM), benchmarked with a Seahorse assay. The other in vivo study uses autocorrelation analysis with blood oxygen level dependent magnetic resonance imaging (MRI-BOLD) on xenografts. In vivo results are verified with diffuse optics using spectra fitting and photoacoustic measurements. All these measurements are at high time resolution: sampling is one per minute. Results: Interplay happens when the radiosensitivity modulates at the same time scale as the radiation. These results show dynamics at these time scales. 1. The dominant time scale of the acute hypoxia in cell line xenografts is shown to be on the order of minutes to tens of minutes: similar to a metabolic oscillation known as the ‘glycolytic oscillator.’ 2. The radiation dose itself alters metabolism within minutes to tens of minutes also. Conclusion: These results vary with cell type. There is a possibility that special timing and dose levels could be used for radiation. Gating could be used for maximal oxygen during treatment. There is an analogy to the interplay discussions with tumor motion, except that an oxygen interplay could more likely be patient-specific at a more fundamental level.

Indices of adrenal deficiency involved in brain plasticity and functional control reorganization in hemodialysis patients with polysulfone membrane: BOLD-fMRI study.

This work purpose was to estimate the implication of suspected adrenal function deficiencies, which was influenced by oxidative stress (OS) that are generating brain plasticity, and reorganization of the functional control. This phenomenon was revealed in two-hemodialysis patients described in this paper. Blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI) revealed a significant activation of the motor cortex. Hemodialysis seems to originate an inflammatory state of the cerebral tissue reflected by increased OS, while expected to decrease since hemodialysis eliminates free radicals responsible for OS. Considering adrenal function deficiencies, sensitivity to OS and assessed hyponatremia and hypercalcemia, adrenal function deficiencies is strongly suspected in both patients. This probably contributes to amplify brain plasticity and a reorganization of functional control after hemodialysis that is compared to earlier reported studies. Brain plasticity and functional control reorganization was revealed by BOLD-fMRI with a remarkable sensitivity. Brain plastic changes are originated by elevated OS associating indices of adrenal function deficiencies. These results raise important issues about adrenal functional deficiencies impact on brain plasticity in chronic hemodialysis-patients. This motivates more global studies of plasticity induced factors in this category of patients including adrenal functional deficiencies and OS.

Nox2 and Cyclosporine-Induced Renal Hypoxia.

We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.

Th17/Treg Imbalance Induced by Dietary Salt Variation Indicates Inflammation of Target Organs in Humans.

The functions of T helper 17 (Th17) and regulatory T (Treg) cells are tightly orchestrated through independent differentiation pathways that are involved in the secretion of pro- and anti-inflammatory cytokines induced by high-salt dietary. However, the role of imbalanced Th17/Treg ratio implicated in inflammation and target organ damage remains elusive. Here, by flow cytometry analysis, we demonstrated that switching to a high-salt diet resulted in decreased Th17 cells and reciprocally increased Treg cells, leading to a decreased Th17/Treg ratio. Meanwhile, Th17-related pathway was down-regulated after one day of high salt loading, with the increase in high salt loading as shown by microarray and RT-PCR. Subsequently, blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) observed hypoxia in the renal medulla (increased R2* signal) during high-salt loading, which was regressed to its baseline level in a step-down fashion during low-salt feeding. The flow-mediated vasodilatation (FMD) of the branchial artery was significantly higher on the first day of high salt loading. Collectively, these observations indicate that a short-term increase in dietary salt intake could induce reciprocal switches in Th17/Treg ratio and related cytokines, which might be the underlying cellular mechanism of high-salt dietary induced end organ inflammation and potential atherosclerotic risk.

First Steps in Using Multi-Voxel Pattern Analysis to Disentangle Neural Processes Underlying Generalization of Spider Fear.

A core symptom of anxiety disorders is the tendency to interpret ambiguous information as threatening. Using electroencephalography and blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI), several studies have begun to elucidate brain processes involved in fear-related perceptual biases, but thus far mainly found evidence for general hypervigilance in high fearful individuals. Recently, multi-voxel pattern analysis (MVPA) has become popular for decoding cognitive states from distributed patterns of neural activation. Here, we used this technique to assess whether biased fear generalization, characteristic of clinical fear, is already present during the initial perception and categorization of a stimulus, or emerges during the subsequent interpretation of a stimulus. Individuals with low spider fear (n = 20) and high spider fear (n = 18) underwent functional MRI scanning while viewing series of schematic flowers morphing to spiders. In line with previous studies, individuals with high fear of spiders were behaviorally more likely to classify ambiguous morphs as spiders than individuals with low fear of spiders. Univariate analyses of BOLD-MRI data revealed stronger activation toward spider pictures in high fearful individuals compared to low fearful individuals in numerous areas. Yet, neither average activation, nor support vector machine classification (i.e., a form of MVPA) matched the behavioral results – i.e., a biased response toward ambiguous stimuli – in any of the regions of interest. This may point to limitations of the current design, and to challenges associated with classifying emotional and neutral stimuli in groups that differ in their judgment of emotionality. Improvements for future research are suggested.

Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance.

Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the β3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 ± 1 mm(3) versus 65 ± 3 mm(3) ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 ± 4% versus 6 ± 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright © 2016 John Wiley & Sons, Ltd.

Global Functional Connectivity Differences between Sleep-Like States in Urethane Anesthetized Rats Measured by fMRI

Sleep is essential for nervous system functioning and sleep disorders are associated with several neurodegenerative diseases. However, the macroscale connectivity changes in brain networking during different sleep states are poorly understood. One of the hindering factors is the difficulty to combine functional connectivity investigation methods with spontaneously sleeping animals, which prevents the use of numerous preclinical animal models. Recent studies, however, have implicated that urethane anesthesia can uniquely induce different sleep-like brain states, resembling rapid eye movement (REM) and non-REM (NREM) sleep, in rodents. Therefore, the aim of this study was to assess changes in global connectivity and topology between sleep-like states in urethane anesthetized rats, using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging. We detected significant changes in corticocortical (increased in NREM-like state) and corticothalamic connectivity (increased in REM-like state). Additionally, in graph analysis the modularity, the measure of functional integration in the brain, was higher in NREM-like state than in REM-like state, indicating a decrease in arousal level, as in normal sleep. The fMRI findings were supported by the supplementary electrophysiological measurements. Taken together, our results show that macroscale functional connectivity changes between sleep states can be detected robustly with resting-state fMRI in urethane anesthetized rats. Our findings pave the way for studies in animal models of neurodegenerative diseases where sleep abnormalities are often one of the first markers for the disorder development.

Visual, Auditory, and Cross Modal Sensory Processing in Adults with Autism: An EEG Power and BOLD fMRI Investigation.

Electroencephalography (EEG) and blood oxygen level dependent functional magnetic resonance imagining (BOLD fMRI) assessed the neurocorrelates of sensory processing of visual and auditory stimuli in 11 adults with autism (ASD) and 10 neurotypical (NT) controls between the ages of 20–28. We hypothesized that ASD performance on combined audiovisual trials would be less accurate with observable decreased EEG power across frontal, temporal, and occipital channels and decreased BOLD fMRI activity in these same regions; reflecting deficits in key sensory processing areas. Analysis focused on EEG power, BOLD fMRI, and accuracy. Lower EEG beta power and lower left auditory cortex fMRI activity were seen in ASD compared to NT when they were presented with auditory stimuli as demonstrated by contrasting the activity from the second presentation of an auditory stimulus in an all auditory block vs. the second presentation of a visual stimulus in an all visual block (AA2-VV2).We conclude that in ASD, combined audiovisual processing is more similar than unimodal processing to NTs.

Robust preprocessing for stimulus-based functional MRI of the moving fetus.

Fetal motion manifests as signal degradation and image artifact in the acquired time series of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. We present a robust preprocessing pipeline to specifically address fetal and placental motion-induced artifacts in stimulus-based fMRI with slowly cycled block design in the living fetus. In the proposed pipeline, motion correction is optimized to the experimental paradigm, and it is performed separately in each phase as well as in each region of interest (ROI), recognizing that each phase and organ experiences different types of motion. To obtain the averaged BOLD signals for each ROI, both misaligned volumes and noisy voxels are automatically detected and excluded, and the missing data are then imputed by statistical estimation based on local polynomial smoothing. Our experimental results demonstrate that the proposed pipeline was effective in mitigating the motion-induced artifacts in stimulus-based fMRI data of the fetal brain and placenta.