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ABSTRACT: Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 overexpression results in the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture.
Developmental cell 04/2013; · 13.36 Impact Factor
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Stephane Jamain,
Konstantin Radyushkin,
Kurt Hammerschmidt,
Sylvie Granon,
Susann Boretius,
Frederique Varoqueaux,
Nelina Ramanantsoa,
Jorge Gallego,
Anja Ronnenberg,
Dorina Winter, Jens Frahm,
Julia Fischer,
Thomas Bourgeron,
Hannelore Ehrenreich,
Nils Brose
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ABSTRACT: Real-time magnetic resonance imaging (MRI) methods generally shorten the
measuring time by acquiring less data than needed according to the sampling
theorem. In order to obtain a proper image from such undersampled data, the
reconstruction is commonly defined as the solution of an inverse problem, which
is regularized by a priori assumptions about the object. While practical
realizations have hitherto been surprisingly successful, strong assumptions
about the continuity of image features may affect the temporal fidelity of the
estimated images. Here we propose a novel approach for the reconstruction of
serial real-time MRI data which integrates the deformations between nearby
frames into the data consistency term. The method is not required to be affine
or rigid and does not need additional measurements. Moreover, it handles
multi-channel MRI data by simultaneously determining the image and its coil
sensitivity profiles in a nonlinear formulation which also adapts to
non-Cartesian (e.g., radial) sampling schemes. Experimental results of a motion
phantom with controlled speed and in vivo measurements of rapid tongue
movements demonstrate image improvements in preserving temporal fidelity and
removing residual artifacts.
04/2013;
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ABSTRACT: PURPOSE: To correct gradient-induced phase errors in radial MRI. METHODS: Gradient-induced eddy currents affect the MRI data acquisition by gradient delays and phase errors that may lead to severe image artifacts for non-Cartesian imaging scenarios such as radial trajectories. While gradient delays are dealt with by respective shifts of the acquisition window during radial image acquisition, this work introduces a simple method for quantifying and correcting phase errors from the actual data prior to image reconstruction. For a given gradient system, the approach yields a specific phase error per gradient that can be used for correcting the raw data. RESULTS: Phantom studies at 9.4 T demonstrated marked improvements in radial image quality. It could be shown that the phase correction is not compromised by data undersampling. Moreover, the selective correction of gradient-induced phase errors retained the phase information caused by different concentrations of a paramagnetic contrast agent. CONCLUSION: The proposed method does not require additional reference measurements and separately corrects for phase errors induced by eddy currents, while retaining the residual phase of the object which may carry physiologic information. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 02/2013; · 2.96 Impact Factor
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ABSTRACT: Halogenated volatile anesthetics (HVA) are widely used in medicine and research but their effects on brain metabolism in intact organisms are still largely unknown. Here, localized proton magnetic resonance spectroscopy (MRS) of anesthetized mice was applied to evaluate HVA effects on cerebral metabolites in vivo. Experimental protocols combined different concentrations of isoflurane, halothane, sevoflurane, and desflurane with known modulators of adrenergic, GABAergic, and glutamatergic neurotransmission. As a most striking finding, brain lactate increased in individual mice from 1.0±0.6mM (awake state) to 6.2±1.5mM (1.75% isoflurane). In addition, relative to total creatine, there were significant isoflurane-induced increases of alanine by 82%, creatine by 4%, GABA by 17%, choline-containing compounds by 17%, and myo-inositol by 9% which were accompanied by significant decreases of glucose by 51% and phosphocreatine by 10%. The elevation of lactate was most pronounced in the striatum. The HVA effects correlated with the respective minimal alveolar concentrations and were mostly reversible within minutes. The observed alterations are best explained by an HVA-induced stimulation of adrenergic pathways in conjunction with an inhibition of the respiratory chain. Apart from casting new light on cerebral energy metabolism, the present results challenge brain studies of HVA-anesthetized animals.
NeuroImage 12/2012; · 5.89 Impact Factor
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ABSTRACT: This work compares magnetization transfer (MT) MRI of living mice with contrast-enhanced MT MRI using intraventricular administration of gadopentetate dimeglumine (Gd-DTPA), systemic administration of MnCl(2), and both. In MT MRI at 9.4T, the contrast-to-noise ratio (CNR) between white matter (WM) and gray matter (GM) increased by 85% after Gd-DTPA injection into the lateral ventricle. When applied in conjunction with manganese-enhanced MT MRI (117μm isotropic resolution, 6min measuring time), Gd-DTPA boosted the CNR increase from +56% to +117%. Additional T(1) measurements at 2.35T revealed that intraventricular Gd-DTPA shortens the T(1) of GM much more than that of WM, which corresponds to estimated extracellular spaces of 26% in GM and only 15% in WM. These results explain the additional MT contrast enhancement by Gd-DTPA and demonstrate that the T(1) shortening by intracellular Mn(2+) is well complemented by extracellular Gd-DTPA. The data suggest a high myelin and low water content to hinder access of hydrophilic paramagnetic agents, so that the resulting differential accumulation effectively reduces the MT saturation in water-rich tissues and thereby facilitates the mapping of myelin-rich tissues. Finally, a 156% CNR increase between GM and WM for contrast-enhanced MT MRI at 9.4T using both Gd-DTPA and manganese allowed for 60μm isotropic resolution (102min measuring time), which delineated myelinated fibers and layers even within GM areas such as the thalamus and cerebellar cortex. Improved MT contrasts were also seen in the cervical spinal cord.
NeuroImage 07/2012; 63(2):812-7. · 5.89 Impact Factor
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Ursula Fünfschilling,
Lotti M Supplie,
Don Mahad,
Susann Boretius,
Aiman S Saab,
Julia Edgar,
Bastian G Brinkmann,
Celia M Kassmann,
Iva D Tzvetanova,
Wiebke Möbius,
Francisca Diaz,
Dies Meijer,
Ueli Suter,
Bernd Hamprecht,
Michael W Sereda,
Carlos T Moraes, Jens Frahm,
Sandra Goebbels,
Klaus-Armin Nave
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ABSTRACT: Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
Nature 05/2012; 485(7399):517-21. · 36.28 Impact Factor
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ABSTRACT: Dynamic MRI studies of the upper airway during speaking, singing or swallowing are complicated by the need for high temporal resolution and the presence of air-tissue interfaces that may give rise to image artifacts such as signal void and geometric distortions. This work exploits a recently developed real-time MRI technique to address these challenges for monitoring speech production at 3 T. The method combines a short-echo time radial FLASH MRI sequence (pulse repetition time/echo time = 2.22/1.44 ms; flip angle 5°) with pronounced undersampling (15 radial spokes per image) and image reconstruction by regularized nonlinear inversion. The resulting serial images at 1.5 mm in-plane resolution and 33.3 ms acquisition time are free of motion or susceptibility artifacts. This application focuses on a dynamic visualization of the main articulators during natural speech production (Standard Modern German). Respective real-time MRI movies at 30 frames per second clearly demonstrate the spatiotemporal coordination of lips, tongue, velum, and larynx for generating vowels, consonants, and coarticulations. The quantitative results for individual phonetic events are in agreement with previous non-MRI findings. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 04/2012; · 2.96 Impact Factor
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Nora Hagemeyer,
Sandra Goebbels,
Sergi Papiol,
Anne Kästner,
Sabine Hofer,
Martin Begemann,
Ulrike C Gerwig,
Susann Boretius,
Georg L Wieser,
Anja Ronnenberg,
Artem Gurvich,
Stephan H Heckers, Jens Frahm,
Klaus-Armin Nave,
Hannelore Ehrenreich
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ABSTRACT: Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase) is among the oligodendrocyte/myelin-associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional 'pro-inflammatory hit'. This phenotype is strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species with their partial CNP 'loss-of-function' genotype are best described as 'catatonia-depression' syndrome. As a consequence of perturbed CNP expression, mice show secondary low-grade inflammation/neurodegeneration. Analogously, in man, diffusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases.
EMBO Molecular Medicine 04/2012; 4(6):528-39. · 10.33 Impact Factor
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ABSTRACT: Erythropoietin (EPO) reduces symptoms of experimental autoimmune encephalomyelitis in rodents and shows neuroregenerative effects in chronic progressive multiple sclerosis. The mechanisms of action of EPO in these conditions with shared immunological etiology are still unclear. Therefore, we used a model of toxic demyelination allowing exclusion of T cell-mediated inflammation. In a double-blind (for food/injections), placebo-controlled, longitudinal four-arm design, 8-wk-old C57BL/6 mice (n = 26/group) were assigned to cuprizone-containing (0.2%) or regular food (ground chow) for 6 wks. After 3 wks, mice were injected every other day with placebo or EPO (5,000 IU/kg intraperitoneally) until the end of cuprizone feeding. Half of the mice were exposed to behavioral testing, magnetic resonance imaging (MRI) and histology immediately after treatment cessation, whereas the other half were allowed a 3-wk treatment-free recovery. Immediately after termination of cuprizone feeding, all toxin-exposed mice were compromised regarding vestibulomotor function/coordination, with EPO-treated animals performing better than placebo. Likewise, ventricular enlargement after cuprizone, as documented by MRI, was less pronounced upon EPO. After a 3-wk recovery, remarkable spontaneous improvement was observed in all mice with no measurable further benefit in the EPO group ("ceiling effect"). Histological analysis of the corpus callosum revealed attenuation by EPO of the cuprizone-induced increase in microglial numbers and amyloid precursor protein accumulations as a readout of inflammation and axonal degeneration. To conclude, EPO ameliorates neurological symptoms in the cuprizone model of demyelination, possibly by reduction of inflammation-associated axonal degeneration in white matter tracts. These findings underscore the value of future therapeutic strategies for multiple sclerosis based on EPO or EPO variants.
Molecular Medicine 02/2012; 18(1):628-35. · 3.76 Impact Factor
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ABSTRACT: To evaluate the use of a novel real-time magnetic resonance imaging (MRI) technique for the assessment of normal swallowing dynamics.
In a cohort of 10 healthy subjects, real-time MRI movies at 24.3 frames per second were obtained in sagittal, coronal, and axial orientation during self-controlled swallows of 5 mL pineapple juice as oral contrast bolus. All studies were performed with the use of a commercial MRI system at 3 T combining two sets of radiofrequency receiver coils. Real-time movies relied on a fast low-angle shot (FLASH) MRI sequence with radial undersampling and image reconstruction by nonlinear inversion yielding 41.23 msec acquisition time for an in-plane resolution of 1.5 mm. Evaluations focused on clinical image quality as well as visualization and temporal quantification of distinct swallowing functions.
Throughout the entire process, the swallowing dynamics were well depicted and characterized with almost no visible image artifacts in all subjects. The mid-sagittal plane turned out to be most valuable. The movies allowed for a quantitative determination of the temporal pattern of all swallowing events.
The proposed real-time MRI technique yields noninvasive, robust, and quantitative access to the physiology of normal swallowing in healthy subjects at high temporal resolution and image quality.
Journal of Magnetic Resonance Imaging 01/2012; 35(6):1372-9. · 2.70 Impact Factor
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ABSTRACT: Velocity-encoded phase-contrast MRI of cardiovascular blood flow commonly relies on electrocardiogram-synchronized cine acquisitions of multiple heartbeats to quantitatively determine the flow of an averaged cardiac cycle. Here, we present a new method for real-time phase-contrast MRI that combines flow-encoding gradients with highly undersampled radial fast low-angle shot acquisitions and phase-sensitive image reconstructions by regularized nonlinear inversion. Apart from calibration studies using steady and pulsatile flow, preliminary in vivo applications focused on through-plane flow in the ascending aorta of healthy subjects. With bipolar velocity-encoding gradients of alternating polarity that overlap the slice-refocusing gradient, the method yields flow-encoded images with an in-plane resolution of 1.8 mm, section thickness of 6 mm and measuring time at 3 T of 24 ms (TR/TE = 3.44/2.76 ms; flip angle, 10º; seven radial spokes per image). Accordingly, phase-contrast maps and corresponding velocity profiles achieve a temporal resolution of 48 ms. The evaluated peak velocities, stroke volumes, flow rates and respective variances over at least 20 consecutive heartbeats are in general agreement with literature data.
NMR in Biomedicine 12/2011; 25(7):917-24. · 3.21 Impact Factor
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ABSTRACT: Magnetic resonance imaging (MRI) is the gold standard for the detection of multiple sclerosis (MS) lesions. However, current MRI techniques provide little information about the structural features of a brain lesion with inflammatory cell infiltration, demyelination, gliosis, acute axonal damage and axonal loss. To identify methods for a differentiation of demyelination, inflammation, and axonal damage we developed a novel mouse model combining cuprizone-induced demyelination and experimental autoimmune encephalomyelitis. MS-like brain lesions were assessed by T1-weighted, T2-weighted, and magnetization transfer MRI as well as by diffusion tensor imaging (DTI). T2-weighted MRI differentiated control and diseased mice, while T1-weighted MRI better reflected the extent of inflammation and axonal damage. In DTI, axonal damage and cellular infiltration led to a reduction of the axial diffusivity, whereas primary demyelination after cuprizone treatment was reflected by changes in radial but not axial diffusivity. Importantly, alterations in radial diffusivity were less pronounced in mice with demyelination, inflammation, and acute axonal damage, indicating that radial diffusivity may underestimate demyelination in acute MS lesions. In conclusion, the combined information from different DTI parameters allows for a more precise identification of solely demyelinated lesions versus demyelinated and acutely inflamed lesions. These findings are of relevance for offering individualized, stage-adapted therapies for MS patients.
NeuroImage 09/2011; 59(3):2678-88. · 5.89 Impact Factor
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ABSTRACT: This work demonstrates that the principles underlying phase-contrast MRI may be used to encode spatial rather than flow information along a perpendicular dimension, if this dimension contains an MRI-visible object at only one spatial location. In particular, the situation applies to 3D mapping of curved 2D structures which requires only two projection images with different spatial phase-encoding gradients. These phase-contrast gradients define the field of view and mean spin-density positions of the object in the perpendicular dimension by respective phase differences. When combined with highly undersampled radial fast low angle shot (FLASH) and image reconstruction by regularized nonlinear inversion, spatial phase-contrast MRI allows for dynamic 3D mapping of 2D structures in real time. First examples include 3D MRI movies of the acting human hand at a temporal resolution of 50 ms. With an even simpler technique, 3D maps of curved 1D structures may be obtained from only three acquisitions of a frequency-encoded MRI signal with two perpendicular phase encodings. Here, 3D MRI movies of a rapidly rotating banana were obtained at 5 ms resolution or 200 frames per second. In conclusion, spatial phase-contrast 3D MRI of 2D or 1D structures is respective two or four orders of magnitude faster than conventional 3D MRI.
Magnetic Resonance in Medicine 08/2011; 66(4):950-6. · 2.96 Impact Factor
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ABSTRACT: To develop a model-based reconstruction technique for T2 mapping based on multi-echo spin-echo MRI sequences with highly undersampled Cartesian data encoding.
The proposed technique relies on a nonlinear inverse reconstruction algorithm which directly estimates a T2 and spin-density map from a train of undersampled spin echoes. The method is applicable to acquisitions with single receiver coils but benefits from multi-element coil arrays. The algorithm is validated for trains of 16 spin echoes with a spacing of 10 to 12 ms using numerical simulations as well as human brain MRI at 3 Tesla (T).
When compared with a standard T2 fitting procedure using fully sampled T2-weighted images, and depending on the available signal-to-noise ratio and number of coil elements, model-based nonlinear inverse reconstructions for both simulated and in vivo MRI data yield accurate T2 estimates for undersampling factors of 5 to 10.
This work describes a promising strategy for T2-weighted MRI that simultaneously offers accurate T2 relaxation times and properly T2-weighted images at arbitrary echo times. For a standard spin-echo MRI sequence with Cartesian encoding, the method allows for a much higher degree of undersampling than obtainable by conventional parallel imaging.
Journal of Magnetic Resonance Imaging 08/2011; 34(2):420-8. · 2.70 Impact Factor
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ABSTRACT: Current thresholding strategies for the analysis of functional MRI (fMRI) datasets may suffer from specific limitations (e.g. with respect to the required smoothness) or lead to reduced performance for a low signal-to-noise ratio (SNR). Although a previously proposed two-threshold (TT) method offers a promising solution to these problems, the use of preset settings limits its performance. This work presents an optimised TT approach that estimates the required parameters in an iterative manner.
The iterative TT (iTT) method is compared with the original TT method, as well as other established voxel-based and cluster-based thresholding approaches and spatial mixture modelling (SMM) for both simulated data and fMRI of a hometown walking task at different experimental settings (spatial resolution, filtering and SNR).
In general, the iTT method presents with remarkable sensitivity and good specificity that outperforms all conventional approaches tested except for SMM in a few cases. This also holds true for challenging conditions such as high spatial resolution, the absence of filtering, high noise level, or a low number of task repetitions.
Thus, iTT emerges as a good candidate for both scientific fMRI studies at high spatial resolution and more routine applications for clinical purposes.
European Radiology 06/2011; 21(11):2369-87. · 3.22 Impact Factor
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ABSTRACT: This study explored the question of intra-digit somatotopy of sensory representations in the little and index finger of 10 subjects using tactile stimulation of the fingertip (p1) and base (p4) and functional magnetic resonance imaging (fMRI) at 1.5mm isotropic spatial resolution. The Euclidian distances between p1 and p4 peak representations in Brodmann area 3b resulted in 5.0±0.7mm for the little finger and 6.7±0.5mm for the index finger. These non-collocated representations were found to be consistently ordered across subjects for the little but not the index finger. When using separate distances for medial-lateral, anterior-posterior, and inferior-superior orientations, p4 was 1.9±0.7mm medial to p1 for the little finger in agreement with findings in macaque monkeys, whereas no consistent intra-digit somatotopy across subjects was found for the index finger. This discrepancy could point to differences in the map-forming processes based on sensory input. On the behavioral level it may be attributed to our everyday use of the hand, for which p4 of the index finger plays a much less important role than p4 of the little finger, which is located at the outer border of the hand.
NeuroImage 03/2011; 56(4):2138-43. · 5.89 Impact Factor
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ABSTRACT: This study evaluated the use of a novel real-time MRI technique based on fast low angle shot (FLASH) MRI with radial encoding, gridding reconstruction, and sliding window for the assessment of temporomandibular joint (TMJ) dynamics in a cohort of 30 young volunteers without prior diagnosis of TMJ pathology. High-resolution images (0.75 0.75 mm 2 , 5 mm section thickness) were obtained at 3 frames per second for active jaw movements without adjunctive devices. Real-time movies were evaluated with respect to image artefacts, anatomical visibility, diagnostic confidence, and TMJ function. During the entire opening and closing of the mouth, the relative positions of the mandibular condyle and articular disc were well depicted. Mean scores were 1.01 ± 0.65 for motion artefacts (scale: 0 = no to 3 = severe artefacts) and 2.03 ± 0.71 for anatomical detectability (scale: 1 = excellent to 5 = not visible). High inter-observer agreements were found for assessments of mandibular condyle movements (= 0.83) and articular disc displacements (= 0.91). In latter cases, the point of disc reduction could precisely be identified. In conclusion, the proposed real-time MRI method offers robust access to TMJ dynamics with good image quality.
The Open Medical Imaging Journal 01/2011; 511(1):1-7.
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ABSTRACT: Manganese-enhanced magnetic resonance imaging (MEMRI) relies on contrasts that are due to the shortening of the T (1) relaxation time of tissue water protons that become exposed to paramagnetic manganese ions. In experimental animals, the technique combines the high spatial resolution achievable by MRI with the biological information gathered by tissue-specific or functionally induced accumulations of manganese. After in vivo administration, manganese ions may enter cells via voltage-gated calcium channels. In the nervous system, manganese ions are actively transported along the axon. Based on these properties, MEMRI is increasingly used to delineate neuroanatomical structures, assess differences in functional brain activity, and unravel neuronal connectivities in both healthy animals and models of neurological disorders. Because of the cellular toxicity of manganese, a major challenge for a successful MEMRI study is to achieve the lowest possible dose for a particular biological question. Moreover, the interpretation of MEMRI findings requires a profound knowledge of the behavior of manganese in complex organ systems under physiological and pathological conditions. Starting with an overview of manganese pharmacokinetics and mechanisms of toxicity, this chapter covers experimental methods and protocols for applications in neuroscience.
Methods in molecular biology (Clifton, N.J.) 01/2011; 771:531-68.
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ABSTRACT: One of the characteristics of the blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) response to functional challenges of the brain is the poststimulation undershoot, which has been suggested to originate from a delayed recovery of either cerebral blood volume (CBV) or cerebral metabolic rate of oxygen to baseline. Using bolus-tracking MRI in humans, we recently showed that relative CBV rapidly normalizes after the end of stimulation. As this observation contradicts at least part of the blood-pool contrast agent studies performed in animals, we reinvestigated the CBV contribution by dynamic T1-weighted three-dimensional MRI (8 seconds temporal resolution) and Vasovist at 3 T (12 subjects). Initially, we determined the time constants of individual BOLD responses. After injection of Vasovist, CBV-related T1-weighted signal changes revealed a signal increase during visual stimulation (1.7% ± 0.4%), but no change relative to baseline in the poststimulation phase (0.2% ± 0.3%). This finding renders the specific nature of the contrast agent unlikely to be responsible for the discrepancy between human and animal studies. With the assumption of normalized cerebral blood flow after stimulus cessation, a normalized CBV lends support to the idea that the BOLD MRI undershoot reflects a prolonged elevation of oxidative metabolism.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2011; 31(1):82-9. · 5.46 Impact Factor
