Christoph Segebarth

fMRI of emotional responses to odors: influence of hedonic valence and judgment, handedness, and gender.

Previous positron emission tomography studies of right-handed individuals show that the left orbitofrontal cortex is dominant during emotional processing of odors. We collected functional magnetic resonance imaging data from 28 subjects to study this network as a function of odor hedonic valence (pleasant vs. unpleasant), active hedonic judgments versus passive sensation of hedonically charged odors, handedness, and gender. Two functional runs were performed, with pleasant and unpleasant odors presented in different epochs. In the first run, subjects passively smelled odorants, whereas in the second run they rated degree of odor pleasantness or unpleasantness by using a finger-span technique that simulated a visual rating scale. Electrodermal and plethysmography responses were simultaneously recorded to control for covert, physiological manifestations of the emotional response. The piriform-amygdala area and ventral insula were activated more for unpleasant than pleasant odors. More extreme ratings were also associated with higher electrodermal amplitude, suggesting that activation stemmed more from emotional or hedonic intensity than valence, and that unpleasant odors induced more arousal than pleasant odors. Unpleasant odors activated the left ventral insula in right-handers and the right ventral insula in left-handers, suggesting lateralized processing of emotional odors as a function of handedness. Active decisions about odor pleasantness induced specific left orbitofrontal cortex activation, implicating the role of this area in the conscious assessment of the emotional quality of odors. Finally, left orbitofrontal cortex was more active in women than men, potentially in relation to womens well-documented advantage in odor identification.

Assessment of blood volume, vessel size, and the expression of angiogenic factors in two rat glioma models: a longitudinal in vivo and ex vivo study

Assessment of angiogenesis may help to determine tumor grade and therapy follow‐up. In vivo imaging methods for non‐invasively monitoring microvasculature evolution are therefore of major interest for tumor management. MRI evaluation of blood volume fraction (BVf) and vessel size index (VSI) was applied to assess the evolution of tumor microvasculature in two rat models of glioma (C6 and RG2). The results show that repeated MRI of BVf and VSI – which involves repeated injection of an iron‐based MR contrast agent – does not affect either the physiological status of the animals or the accuracy of the MR estimates of the microvascular parameters. The MR measurements were found to correlate well with those obtained from histology. They indicate that microvascular evolution differs significantly between the two glioma models, in good agreement with expression of angiogenic factors (vascular endothelial growth factor, angiopoietin‐2) and with activities of matrix metalloproteinases, also assessed in this study. These MRI methods thus provide considerable potential for assessing the response of gliomas to anti‐angiogenic and anti‐vascular agents, in preclinical studies as well as in the clinic. Furthermore, as differences between the fate of tumor microvasculature may underlie differences in therapeutic response, there is a need for preclinical study of several tumor models. Copyright

Characterization of tumor angiogenesis in rat brain using iron-based vessel size index MRI in combination with gadolinium-based dynamic contrast-enhanced MRI

This study aimed at combining an iron-based, steady-state, vessel size index magnetic resonance imaging (VSI MRI) approach, and a gadolinium (Gd)-based, dynamic contrast-enhanced MRI approach (DCE MRI) to characterize tumoral microvasculature. Rats bearing an orthotopic glioma (C6, n=14 and RG2, n=6) underwent DCE MRI and combined VSI and DCE MRI 4 h later, at 2.35 T. Gd-DOTA (200 μmol of Gd per kg) and ultrasmall superparamagnetic iron oxide (USPIO) (200 μmol of iron per kg) were used for DCE and VSI MRI, respectively. C6 and RG2 gliomas were equally permeable to Gd-DOTA but presented different blood volume fractions and VSI, in good agreement with histologic data. The presence of USPIO yielded reduced Ktrans values. The Ktrans values obtained with Gd-DOTA in the absence and in the presence of USPIO were well correlated for the C6 glioma but not for the RG2 glioma. It was also observed that, within the time frame of DCE MRI, USPIO remained intravascular in the C6 glioma whereas it extravasated in the RG2 glioma. In conclusion, VSI and DCE MRI can be combined provided that USPIO does not extravasate with the time frame of the DCE MRI experiment. The mechanisms at the origin of USPIO extravasation remain to be elucidated.

Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy.

Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mices heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT.

Evaluation of a quantitative blood oxygenation level-dependent (qBOLD) approach to map local blood oxygen saturation.

Blood oxygen saturation (SO2) is a promising parameter for the assessment of brain tissue viability in numerous pathologies. Quantitative blood oxygenation level‐dependent (qBOLD)‐like approaches allow the estimation of SO2 by modelling the contribution of deoxyhaemoglobin to the MR signal decay. These methods require a high signal‐to‐noise ratio to obtain accurate maps through fitting procedures. In this article, we present a version of the qBOLD method at long TE taking into account separate estimates of T2, total blood volume fraction (BVf) and magnetic field inhomogeneities. Our approach was applied to the brains of 13 healthy rats under normoxia, hyperoxia and hypoxia. MR estimates of local SO2 (MR_LSO2) were compared with measurements obtained from blood gas analysis. A very good correlation (R2u2009=u20090.89) was found between brain MR_LSO2 and sagittal sinus SO2. Copyright

Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects

Early imaging or blood biomarkers of tumor response is needed to customize anti‐tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U‐87 MG) and randomized into three groups: one group received an anti‐angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3‐bis(2‐chloroethyl)‐1‐nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment‐dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti‐tumor drugs and the optimization of combined therapies. Copyright

fMRI assessment of hemispheric language dominance using a simple inner speech paradigm.

Hemispheric language dominance (HLD) has been determined by means of functional MRI (fMRI) using a simple, inner speech, word fluency paradigm. During the task periods, subjects perform mental imagery of visual scenes and generate silently the nouns of all objects visualized. During the control periods, subjects attend to the scanner noise. Activated areas have been identified by means of cross‐correlation analysis. HLD indices have been determined by comparing the number of activated pixels detected in both hemispheres within predefined cortical areas (Brodmann areas 6, 9, 10, 39, 40 and 44–47). The paradigm has been assessed on 10 healthy, right‐handed volunteers. A volume 35u2005mm thick, centered on the inferior frontal gyrus, was imaged. A conventional GRE MR sequence was used on a 1.5u2005T clinical MR scanner. HLD indices were compared with those determined for overt speech. Robust fMRI reponses were obtained. HLD indices indicated left hemispheric language dominance for all subjects examined. They correlated well with those obtained for overt speech (R2u2005u2005=u2005u20050.93, regression coefficientu2005u2005=u2005u20050.998, with pu2005<u200510−4). Thus, an inner speech paradigm based on visual imagery is well adapted for assessment of HLD by means of fMRI. Copyright

Vessel size index measurements in a rat model of glioma: comparison of the dynamic (Gd) and steady-state (iron-oxide) susceptibility contrast MRI approaches

Vessel size index (VSI), a parameter related to the distribution of vessel diameters, may be estimated using two MRI approaches: (i) dynamic susceptibility contrast (DSC) MRI following the injection of a bolus of Gd‐chelate. This technique is routinely applied in the clinic to assess intracranial tissue perfusion in patients; (ii) steady‐state susceptibility contrast with USPIO contrast agents, which is considered here as the standard method. Such agents are not available for human yet and the steady‐state approach is currently limited to animal studies. The aim is to compare VSI estimates obtained with these two approaches on rats bearing C6 glioma (nu2009=u20097). In a first session, VSI was estimated from two consecutive injections of Gd‐Chelate (Gd1 and Gd2). In a second session (4u2009hours later), VSI was estimated using USPIO. Our findings indicate that both approaches yield comparable VSI estimates both in contralateral (VSI{USPIO}u2009=u20097.5u2009±u20092.0u2009µm, VSI{Gd1}u2009=u20096.5u2009±u20090.7u2009µm) and in brain tumour tissues (VSI{USPIO}u2009=u200919.4u2009±u20097.1u2009µm, VSI{Gd1}u2009=u200916.6u2009±u20094.5u2009µm). We also observed that, in the presence of BBB leakage (as it occurs typically in brain tumours), applying a preload of Gd‐chelate improves the VSI estimate with the DSC approach both in contralateral (VSI{Gd2}u2009=u20097.1u2009±u20090.4u2009µm) and in brain tumour tissues (VSI{Gd2}u2009=u200918.5u2009±u20094.3u2009µm) but is not mandatory. VSI estimates do not appear to be sensitive to T1 changes related to Gd extravasation. These results suggest that robust VSI estimates may be obtained in patients at 3u2009T or higher magnetic fields with the DSC approach. Copyright

The Ammonium-Induced Increase in Rat Brain Lactate Concentration is Rapid and Reversible and is Compatible with Trafficking and Signaling Roles for Ammonium:

The glutamate—glutamine shuttle requires a flux of fixed N from neurons to astrocytes. The suggestion that some or all of this N is ammonium has received support from reports that ammonium (as NH+4) rapidly enters astrocytes. Ammonium might also help control astrocyte energy metabolism by increasing lactate production. If ammonium has these functions, then its effect on brain metabolism must be rapid and reversible. To make a minimal test of this requirement, we have followed the time courses of the changes induced by a 4 min venous infusion of 1 mol/L NH4Cl, 2.5 mmol/kg body weight, in rat. Extracellular [NH+4] in cortex, monitored with ion-selective microelectrodes, reached a peak of approximately 0.7 mmol/L 1.65 mins after the end of the infusion, then recovered. Brain metabolites were monitored non-invasively every 4 mins by 1H magnetic resonance spectroscopy. Lactate peak area during the 3.2 min acquisition starting at the end of the infusion was 1.84 ± 0.24 times baseline (± s.e.m., P = 0.009, n = 9). Lactate increased until 13.2 ± 2.1 mins after the end of the infusion and recovered halfway to baseline by 31.2 mins. Glutamate decreased by at least 7.1% (P = 0.0026). Infusion of NaCl caused no change in lactate signal. Cerebral blood flow, measured by arterial magnetization labeling, more than doubled, suggesting that the lactate increase was not caused by hypoxia. At least three consecutive ammonium-induced increases in lactate signal could be evoked. The results are compatible with an intercellular trafficking/signaling function for ammonium.

Retrospective intra-scan motion correction

This paper analyzes the effects of intra-scan motion and demonstrates the possibility of correcting them directly in k-space with a new automatic retrospective method. The method is presented for series of 2D acquisitions with Cartesian sampling. Using a reference k-space acquisition (corrected for translations) within the series, intra-scan motion parameters are accurately estimated for each trajectory in k-space of each data set in the series resulting in pseudo-random sample positions. The images are reconstructed with a Bayesian estimator that can handle sparse arbitrary sampling in k-space and reduces intra-scan rotation artefacts to the noise level. The method has been assessed by means of a Monte Carlo study on axial brain images for different signal-to-noise ratios. The accuracy of motion estimates is better than 0.1 degrees for rotation, and 0.1 and 0.05 pixel, respectively, for translation along the read and phase directions for signal-to-noise ratios higher than 6 of the signals on each trajectory. An example of reconstruction from experimental data corrupted by head motion is also given.