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Background The prefrontal cortex (PFC) has been implicated in the pathophysiology of social dysfunction, but the specific circuit partners mediating PFC function in health and disease are unclear. Methods The excitatory designer receptor exclusively activated by designer drugs (DREADD) hM3Dq was used to induce PFC activation during social behavior measured in the three-chamber sociability assay (rats/mice). Functional magnetic resonance imaging was combined with hM3Dq-mediated PFC activation to identify novel nodes in the “social brain” in a hypothesis-free manner. In multiplexed DREADD experiments, hM3Dq and the inhibitory KORDi were used to bidirectionally modulate PFC activity and measure social behavior and global functional magnetic resonance imaging signature. To characterize the functional role of specific nodes identified in this functional magnetic resonance imaging screen, we used anterograde and retrograde tracers, optogenetic and DREADD-assisted circuit mapping, and circuit behavioral experiments. Results PFC activation suppressed social behavior and modulated activity in a number of regions involved in emotional behavior. Bidirectional modulation of PFC activity further refined this subset of brain regions and identified the habenula as a node robustly correlated with PFC activity. Furthermore, we showed that the lateral habenula (LHb) receives direct synaptic input from the PFC and that activation of LHb neurons or the PFC inputs to the LHb suppresses social preference. Finally, we demonstrated that LHb inhibition can prevent the social deficits induced by PFC activation. Conclusions The LHb is thought to provide reward-related contextual information to the mesolimbic reward system known to be involved in social behavior. Thus, PFC projections to the LHb may represent an important part of descending PFC pathways that control social behavior.

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.

This study investigated the temporal pattern of brain response to emotional stimuli during 28 days of alprazolam treatment among patients with generalized anxiety disorder (GAD) randomized 2:1 to drug or placebo in a double-blind design. Functional magnetic resonance imaging scans obtained during an emotion face matching task (EFMT) and an affective stimulus expectancy task (STIMEX) were performed at baseline, one hour after initial drug administration and 28 days later. Alprazolam significantly reduced scores on the Hamilton Anxiety Scale and the Penn State Worry Questionnaire after one week and 28 days of treatment. Brain activation in the amygdala during the EFMT and in the insula during the STIMEX was reduced one hour after alprazolam administration but returned to baseline levels at Day 28. Exploratory analyses revealed significant treatment differences in brain activity during the STIMEX on Day 28 in frontal lobe, caudate nucleus, middle temporal gyrus, secondary visual cortex, and supramarginal gyrus. These results are consistent with the notion that the neural mechanisms supporting sustained treatment effects of benzodiazepines in GAD differ from those underlying their acute effects.

Proton magnetic resonance spectroscopy (1H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if 1H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, 1H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of 1H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, 1H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm3 volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative 1H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.

In experimental models, the use of23Na MRI is an appropriate tool for the determination of infarct size as well as extra- and intracellular23Na content. As stunned and hibernating myocardium show no increased23Na content, the method could be used for discrimination of viable from non-viable myocardium.

(23)Na MRI may allow distinction of normal and ischemically injured myocardium. The aim of this study was to optimize (23)Na MRI of the human heart by improvement of spatial resolution and ECG-triggering and to measure the signal/noise of blood and myocardium and the myocardium/blood signal ratios in a volunteer study. A spoiled gradient echo sequence was developed on a 1.5T scanner equipped with a (23)Na heart surface coil. 3D short axis ECG-triggered (23)Na MRI was performed in 10 healthy subjects. The signal/noise of myocardium and blood were 8.2 +/- 0.7 and 18.3 +/- 1.3, respectively, signal ratio myocardium/blood was 0.44 +/- 0.03. This value is in good agreement with the theoretical value of 0.45. ECG gated 3D (23)Na MRI of the human heart is feasible with sufficient spatial resolution and signal/noise ratio. Magn Reson Med 45:164-166, 2001.

23Na chemical shift imaging (CSI) in conjunction with shift reagents was used to obtain images of intracellular (Nai) and extracellular sodium (Nae) in isolated rat hearts. It was demonstrated that the increase of Nai concentration in ischemic myocardium can be detected with this technique. 3D acquisition-weighted 23Na CSI datasets with a nominal spatial resolution of 1.7 × 1.7 × 2.9 mm were acquired in 30 min in normoxic hearts and in globally or locally ischemic hearts. The shift reagent Tm(DOTP)5− was used to discriminate Nai and Nae signals. Nai maps could be generated in ischemic hearts, but not in normoxic hearts as the signal-to-noise ratio is too low. The Nai signal increased by more than 100% and the Nae signal decreased by more than 50% in myocardium of globally ischemic hearts (n = 3) compared to normoxic hearts (n = 3). In hearts with an acute occlusion of the left anterior descending coronary artery (n = 3), there was a local Nai signal increase in the anterior wall in the range of 60–110% compared to remote, normoxic tissue. Magn Reson Med 48:89–96, 2002. © 2002 Wiley-Liss, Inc.

Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders.

Functional magnetic resonance imaging (fMRI) has become an important method in clinical psychiatry research whereas there are still only few comparable preclinical investigations. Herein, we report that fMRI in rats can provide key information regarding brain areas underlying anxiety behavior. Perfusion as surrogate for neuronal activity was measured by means of arterial spin labeling-based fMRI in various brain areas of high anxiety F344 rats and control Sprague-Dawley rats. In one of these areas, the dorsomedial prefrontal cortex (dmPFC), c-Fos labeling was compared between these two strains with immunolabeling. The effects of a neurotoxic ibotenic acid lesion of the dmPFC in F344 rats were examined in a social approach-avoidance anxiety procedure and fMRI. Regional brain activity of high anxiety F344 rats was different in selective cortical and subcortical areas as compared to that of low anxiety Sprague-Dawley rats; the largest difference (i.e. hyperactivity) was measured in the dmPFC. Independently, c-Fos labeling confirmed that F344 rats show increased dmPFC activity. The functional role was confirmed by neurotoxic lesion of the dmPFC that reversed the high anxiety-like behavior and partially normalized the brain activity pattern of F344 rats. The current findings may have translational value as increased activity is reported in an equivalent cortical area in patients with social anxiety, suggesting that pharmacological or functional inhibition of activity in this brain area should be explored to alleviate social anxiety in patients.

Function and morphology of the cerebral vasculature were studied in the amyloid (Aβ) plaque-containing double-transgenic (TG) B6.PS2APP Alzheimer's disease (AD) mouse model with MRI at an age range of 10 to 17 months. Perfusion, blood volume, and average vessel geometry were assessed in the brain and compared to age-matched controls (wild-type [WT] C57Bl/6). Additionally, the MR relaxation times T1, T2, and T were measured to detect potential pathological changes that might be associated with Aβ plaque depositions. Both decreased perfusion and decreased blood volume were observed in the occipital cortex in B6.PS2APP mice as compared to controls. A significant decrease in T1 and T2 was found in the frontal cortex and in the subiculum/parasubiculum. Immunohistochemistry confirmed plaque depositions in the cortex and in the subiculum/parasubiculum. In summary, our data indicate a reduced blood supply of B6.PS2APP mice in the occipital cortex that parallels the findings in cortical regions of patients with AD. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.

The aim of this study was to validate continuous arterial spin labeling (CASL) as a quantitative imaging modality for pharmacological MRI (phMRI) based on local cerebral blood perfusion. Specifically, the capability of CASL to assess brain-activity signatures of pharmacological interventions in animal models was evaluated with respect to drug discovery in diseases of the central nervous system (CNS). Perfusion as a surrogate for neuronal activity was measured in various brain areas of the rat. The validation approach was threefold. First, perfusion was shown to reliably reflect differential effects of anesthesia on striatal activation. Different baseline levels and different temporal response profiles after amphetamine challenges under isoflurane, propofol, ketamine, and α-chloralose anesthesia were consistent with known properties of these anesthetics. Second, remarkable consistency of multi-area baseline perfusion patterns between independent groups of animals confirmed the notion that CASL is highly reproducible and thus particularly suitable for long-term longitudinal studies. Third, administration of the well-characterized psychotomimetic compounds amphetamine and phencyclidine (PCP) elicited dose-dependent activation patterns that were related to the drugs' particular interactions with the dopaminergic and glutamatergic systems, respectively. In conclusion, perfusion-based phMRI is a robust, reliable and valid quantitative technique suitable for evaluating brain-activation patterns in animal models of CNS diseases. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.

The low signal-to-noise ratio (SNR) is the single main factor limiting the spatial resolution that can be attained in nuclear magnetic resonance spectroscopy (MRS) in animals or man. This work first reviews the fundamental relationship between metabolite concentration, spatial resolution and SNR, which together define the frontier of sensitivity for MRS. It then presents SLOOP (Spectral Localization with Optimal Pointspread-function) as a recipe to identify an optimal set of experimental parameters that will provide the most accurate results, in situations where geometrical a priori information about the sample is available. SLOOP, which provides robust, quantifiable spectroscopic information, has mainly been applied to study cardiac energy metabolism in healthy volunteers and in patients, and these results are briefly summarized. The quality of localized spectroscopy may be further improved through the use of nonlinear pulsed magnetic field gradients. This technology, which has been named SLOOPN, is outlined and discussed. The text provides advice on the practical implementation of these methods with a focus on the high experimental quality required for localized MRS: even the most sophisticated postprocessing algorithm cannot fully compensate shortcomings in data acquisition. Keywords: magnetic resonance spectroscopy; localization methods; spectroscopic imaging; spatial resolution; sensitivity; spectral localization by imaging (SLIM); pointspread function; spatial response function; acquisition weighting; higher-order gradients

Purpose To show that density-weighted (DW) k-space sampling improves the quality of human cardiac sodium imaging, a novel method was implemented that combines the high signal-to-noise efficiency of three-dimensional phase-encoding with the advantageous localization performance of nonuniform sampling. A simulation demonstrates substantially reduced blood contamination in the myocardium. Materials and Methods At 2.0 T, DW cardiac “fast” sodium images with a voxel size of 844 μL in seven minutes and “high-resolution” scans in 30 minutes with a voxel size of 570 μL were acquired. For comparison, conventional gradient-echo imaging was also performed. Results In the DW images, a myocardial signal-to-noise ratio (SNR) of 16.0 in the left ventricle and 8.5 in the septum (N = 4) was measured. With longer experimental duration (about 30 minutes; N = 3), the image quality and the SNR could be further improved (voxel size: 570 μL; SNR: blood 16.1, septum 10.6). Compared to the gradient-echo images, the image quality was substantially improved. Conclusion This new method for human cardiac sodium imaging provides high image quality combined with optimal sensitivity and thus may improve the clinical applicability of 23Na cardiac MRI. J. Magn. Reson. Imaging 2005;21:78–81. © 2004 Wiley-Liss, Inc.

Acquisition-weighting improves the localization of MRI experiments. An approach to acquisition-weighting in a purely phase-encoded experiment is presented that is based on a variation of the sampling density in k-space. In contrast to conventional imaging or to accumulation-weighting, where k-space is sampled with uniform increments, density-weighting varies the distance between neighboring sampling points Δk to approximate a given radial weighting function. A fast, noniterative algorithm has been developed to calculate the sampling matrix in one, two, and three dimensions from a radial weighting function w(k), the desired number of scans NAtot and the nominal spatial resolution Δxnom. Density-weighted phase-encoding combines the improved shape of the spatial response function and the high SNR of acquisition-weighting with an extended field of view. The artifact energy that results from aliasing due to a small field of view is substantially reduced. The properties of density-weighting are compared to uniform and to accumulation-weighted phase-encoding in simulations and experiments. Density-weighted 31P 3D chemical shift imaging of the human heart is shown which demonstrates the superior performance of density-weighted metabolic imaging. Magn Reson Med 50:1266–1275, 2003. © 2003 Wiley-Liss, Inc.

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1 H -imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non–rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Objectives The purpose of the present study was to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in normal, hypertrophied, and failing human heart. Background Conflicting evidence exists on the extent of changes of high-energy phosphate metabolites in hypertrophied and failing human heart. Previous reports using phosphorus-31 magnetic resonance spectroscopy ( 31 P-MRS) have quantified metabolites in relative terms only. However, this analysis cannot detect simultaneous reductions. Methods Four groups of subjects (n = 10 each), were studied: volunteers and patients with hypertensive heart disease (HHD), aortic stenosis, and dilated cardiomyopathy (DCM). Left ventricular (LV) function and mass were measured by cine magnetic resonance imaging. Absolute and relative concentrations of PCr and ATP were determined by 31 P-MRS with spatial localization with optimum pointspread function. Results Left ventricular ejection fraction remained normal in HHD and aortic stenosis, but was severely reduced to 18% in DCM; LV mass was increased by 55%, 79%, and 68% respectively. In volunteers, PCr and ATP concentrations were 8.82 ± 1.30 mmol/kg wet weight and 5.69 ± 1.02 mmol/kg wet weight, and the PCr/ATP ratio was 1.59 ± 0.33. High-energy phosphate levels were unaltered in HHD. In aortic stenosis, PCr was decreased by 28%, whereas ATP remained constant. In DCM, PCr was reduced by 51%, ATP by 35%, and reduction of the PCr/ATP ratio by 25% was of borderline significance (p = 0.06). Significant correlations were observed among energetic and functional variables, with the closest relations for PCr. Conclusions In human heart failure due to DCM, both PCr and ATP are significantly reduced. Ratios of PCr to ATP underestimate changes of high-energy phosphate levels.

Translation of resting-state functional connectivity (FC) magnetic resonance imaging (rs-fMRI) applications from human to rodents has experienced growing interest, and bears a great potential in pre-clinical imaging as it enables assessing non-invasively the topological organization of complex FC networks (FCNs) in rodent models under normal and various pathophysiological conditions. However, to date, little is known about the organizational architecture of FCNs in rodents in a mentally healthy state, although an understanding of the same is of paramount importance before investigating networks under compromised states. In this study, we characterized the properties of resting-state FCN in an extensive number of Sprague-Dawley rats (n = 40) under medetomidine sedation by evaluating its modular organization and centrality of brain regions and tested for reproducibility. Fully-connected large-scale complex networks of positively and negatively weighted connections were constructed based on Pearson partial correlation analysis between the time courses of 36 brain regions encompassing almost the entire brain. Applying recently proposed complex network analysis measures, we show that the rat FCN exhibits a modular architecture, comprising six modules with a high between subject reproducibility. In addition, we identified network hubs with strong connections to diverse brain regions. Overall our results obtained under a straight medetomidine protocol show for the first time that the community structure of the rat brain is preserved under pharmacologically induced sedation with a network modularity contrasting from the one reported for deep anesthesia but closely resembles the organization described for the rat in conscious state.

Several pioneering studies have demonstrated that localized 31 P NMR spectroscopy of the human heart might become an important diagnostic tool in cardiology. The main limitation is due to the low sensitivity of these experiments, allowing only crude spatial resolution. We have implemented a three-dimensional version of SLOOP (“spectral localization with optimal pointspread function”) on a clinical instrument. SLOOP takes advantage of all available a priori information to match the size and the shape of the sensitive volumes to the anatomical structures in the examined subject. Thus, SLOOP reduces the contamination from adjacent organs and improves the sensitivity compared to conventional techniques such as ISIS or chemical shift imaging (CSI). Initial studies were performed on six healthy volunteers at 1.5 T. The good localization properties are demonstrated by the absence of resonances from blood in the heart spectra, and by PCr-free spectra from the liver. Compared to conventional CSI, the signal-to-noise ratio of the SLOOP heart spectra was improved by approximately 30%. Taking into account the varying excitation angle in the inhomogeneous B 1 field of the surface coil, the SLOOP model computes the local spin saturation at every point in space. Therefore, no global saturation correction is required in the quantitative evaluation of local spectra. In this study, we found a PCr/γ-ATP ratio in the left ventricular wall of 1.90 ± 0.33 (mean ± standard deviation).

Proton magnetic resonance spectroscopy ((1)H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if (1)H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, (1)H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of (1)H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, (1)H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm(3) volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative (1)H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.

A reduction of a factor of 10 in the time needed to measure highly resolved NMR spectra of multiple samples can be achieved with any NMR spectrometer by using a combination of chemical shift imaging and a compartmented detection volume consisting of a bundle of capillaries. The picture shows the cross-sectional image of a bundle of nine 1-mm capillaries after Fourier transformation along the spatial dimensions only.

Unconditioned fear plays an important yet poorly understood role in anxiety disorders, and only few neuroimaging studies have focused on evaluating the underlying neuronal mechanisms. In rodents the predator odor trimethylthiazoline (TMT), a synthetic component of fox feces, is commonly used to induce states of unconditioned fear. In this study, arterial spin labeling-based functional magnetic resonance imaging (fMRI) was applied to detect TMT-induced regional modulations of neuronal activity in Wistar rats. During TMT exposure the rats displayed increased freezing behavior and reduced exploration in the odor-associated area. Neuronal activity was selectively increased in the dorsal periaqueductal gray, superior colliculus and medial thalamus and reduced in the median raphe, locus coeruleus, nucleus accumbens shell, ventral tegmental area, ventral pallidum and entorhinal piriform cortex. This fMRI fingerprint involving distinct neuronal pathways was used to describe a schematic model of fear processing. Key brain areas known to underlie fear and anxiety-related autonomic and behavioral responses as well as centers of motivational processing were identified as being part of this functional circuitry of innate fear. Thus, preclinical fMRI studies based on unconditioned fear methods may provide a valuable translational approach to better characterize etiological and pathological processes underlying anxiety disorders.

The purpose of this study was to investigate the achievable precision of localization of boundaries between extended uniform objects in MRI and to study the effect of zero-filling on reaching it.A theoretical model of an object boundary in the presence of noise was introduced, and the error of localization was derived. The effect of zero-filling on reaching the achievable precision was assessed by computer simulations and experimentally on an extracted tooth in a signal-giving medium.With the help of the theoretical model, the achievable precision of localization of boundaries between two uniform extended objects was shown to surpass the nominal resolution by a factor equal to the contrast-to-noise ratio. In the simulations and phantom experiments, zero-filling followed by image segmentation allowed for approaching the theoretical value. As an application example, an MRI-based dental impression was performed in vivo, and a bridge was produced and permanently fixed to the volunteer's teeth.This work demonstrates that in an MRI experiment, the achievable precision of localization of object boundaries is not limited to the nominal resolution and can surpass it by an order of magnitude. Zero-filling is a simple and effective method of reaching it.

Signals from water and fat can cause artifacts in proton spectroscopic imaging in the human brain. The major problem is variation of the B0 field over a range of several ppm within the sensitive volume of the standard whole-head coil. Here, the coherence-pathway formalism is used to describe and evaluate the origin of artifacts in a double spin-echo (PRESS) sequence. The attenuation of unwanted coherences using pulsed field gradients is described for homogeneous and inhomogeneous B0 fields. The effect of the following parameters on the quality of the spectroscopic images is analyzed: (a) directional order of plane selection, (b) positioning of phase-encode gradients in the sequence, (c) postprocessing spatial windowing, and (d) motion. It is shown that, for a typical echo time of 272 ms, it is not necessary to first select a region of interest within the brain borders when sufficient phase-encode steps are used. Examples of 2D proton spectroscopic images with a nominal voxel volume of 0.85 ml are given for a healthy volunteer and a patient with a low-grade glioma.

Translational neuroimaging has the potential to create a more successful link between preclinical and clinical research, thereby improving the predictivity of animal models and the development of innovative therapeutics. In this review, the emphasis is on “back translation”: how can clinical imaging data be best utilized to enhance preclinical drug discovery programs? Examples selected in the fields of Alzheimer’s disease and Schizophrenia elucidate the great potential – as well as some pitfalls – of translational MRI in CNS drug discovery.

Function and morphology of the cerebral vasculature were studied in the amyloid (Abeta) plaque-containing double-transgenic (TG) B6.PS2APP Alzheimer's disease (AD) mouse model with MRI at an age range of 10 to 17 months. Perfusion, blood volume, and average vessel geometry were assessed in the brain and compared to age-matched controls (wild-type [WT] C57Bl/6). Additionally, the MR relaxation times T(1), T(2), and T(2)* were measured to detect potential pathological changes that might be associated with Abeta plaque depositions. Both decreased perfusion and decreased blood volume were observed in the occipital cortex in B6.PS2APP mice as compared to controls. A significant decrease in T(1) and T(2) was found in the frontal cortex and in the subiculum/parasubiculum. Immunohistochemistry confirmed plaque depositions in the cortex and in the subiculum/parasubiculum. In summary, our data indicate a reduced blood supply of B6.PS2APP mice in the occipital cortex that parallels the findings in cortical regions of patients with AD.

The aim of this study was to validate continuous arterial spin labeling (CASL) as a quantitative imaging modality for pharmacological MRI (phMRI) based on local cerebral blood perfusion. Specifically, the capability of CASL to assess brain-activity signatures of pharmacological interventions in animal models was evaluated with respect to drug discovery in diseases of the central nervous system (CNS). Perfusion as a surrogate for neuronal activity was measured in various brain areas of the rat. The validation approach was threefold. First, perfusion was shown to reliably reflect differential effects of anesthesia on striatal activation. Different baseline levels and different temporal response profiles after amphetamine challenges under isoflurane, propofol, ketamine, and alpha-chloralose anesthesia were consistent with known properties of these anesthetics. Second, remarkable consistency of multi-area baseline perfusion patterns between independent groups of animals confirmed the notion that CASL is highly reproducible and thus particularly suitable for long-term longitudinal studies. Third, administration of the well-characterized psychotomimetic compounds amphetamine and phencyclidine (PCP) elicited dose-dependent activation patterns that were related to the drugs' particular interactions with the dopaminergic and glutamatergic systems, respectively. In conclusion, perfusion-based phMRI is a robust, reliable and valid quantitative technique suitable for evaluating brain-activation patterns in animal models of CNS diseases.

Amyloid beta peptides and microtubule-associated protein Tau are misfolded and form aggregates in brains of Alzheimer's disease patients. To examine their specific roles in the pathogenesis of Alzheimer's disease and their relevance in neurodegenerative processes, we have created TauPS2APP triple transgenic mice that express human mutated Amyloid Precursor Protein, presenilin 2 and Tau. We present a cross-sectional analysis of these mice at 4, 8, 12 and 16 months of age. By comparing with single transgenic Tau mice, we demonstrate that accumulation of Abeta in TauPS2APP triple transgenic mice impacts on Tau pathology by increasing the phosphorylation of Tau at serine 422, as determined by a novel immunodetection method that is able to reliably measure phospho-Tau species in transgenic mouse brains. The TauPS2APP triple transgenic mouse model will be very useful for studying the effect of new therapeutic paradigms on amyloid deposition and downstream neurofibrillary tangle development.

Multidimensional NMR experiments have drawn much attention, particularly due to their ability to elucidate the structure of complex mo lecules. One of the ma jor drawbacks of many mu ltidimensional experiments is the long time required to record a dataset. In many cases, the m inimal experimental time is not lim ited by sensitivity, but rather by the number of repetitions needed to complete a phase-cycl ing protocol. Phase cycling may be necessary to select the desired coherence pathway ( 2 ) , to obtain absorptive l ineshapes (2-4, and to eliminate undesired signals such as axial peaks or quadrature artifacts (5). In order to reduce experimental time, efforts have been undertaken to design reduced phase-cycl ing schemes (6, 7). Spectral artifacts may also appear if the spin system is not in a constant state at the beginning of each pulse sequence, for example, in the case of a fast repetition rate. This problem may be solved by the use of a saturation-recovery sequence (8). Coherence pathways can also be selected in a single scan with the application of field gradients (9-11). Sotak et al. ( 12) have applied this principle to obtain in vivo 2D double-quantum spectra, and Hurd recently reported gradient-enhanced doublequantum-fi ltered COSY and gradient-enhanced TOCSY ( 13). In this contribution, we discuss how standard COSY spectra can be recorded without phase cycling if pulsed field gradients are available. Furthermore, it will be shown that quadrature detection in thef; doma in is attained inherently. F inally, solvent suppression is accomplished by using an alternative pulse sequence, and an improved deconvolut ion method for postprocessing. A similar approach, applied to in vivo 2D spectroscopy, has independently been reported by Z iegler et al. ( 14). F igure 1 a shows the two-pulse sequence for the basic COSY experiment (IS). Using the product-operator formalism to describe the evolution of a weakly coupled twospin system, the observable terms of the density operator after the second 90” pulse at the beginning of the detection period t2 are (16)

A simple pulse scheme is given for obtaining echoes with both chemical shift and homonuclear scalar coupling refocused. The procedure is illustrated for some biologically important nuclei, namely 31 P in ATP and 1 H in lactate. The refocusing of the scalar coupling J is perfect for AX systems, but incomplete for multiply coupled spins. However, for the latter, a gain in in-phase intensity is still obtained at relatively long echo times ( J ). Theory, in terms of the operator formalism, and experiment are presented for AX n systems and are in good agreement. Strategies to remove spectral artifacts resulting from pulse angle deviations are given.

The purpose of the present study was (i) to establish a modality for non-invasively probing bile composition in cynomolgus monkeys and (ii) to ascertain the variability in biliary metabolism by repeatedly assessing gallbladder bile in situ. Localised in vivo (1)H magnetic resonance spectroscopy (MRS) provided high-resolution spectra of gallbladder bile that allowed for the first time different species of bile acids, their taurine and glycine conjugates, and phospholipids to be identified and quantified in situ. A combined cross-sectional and longitudinal study of bile composition was conducted over 4 weeks in monkeys kept under standardised nutritional conditions. All biles were composed of the same major constituents. Bile acids contributed 267+/-47 micromol/ml whereof cholate, deoxycholate and chenodeoxycholate were the most abundant primary bile acids. Bile acid conjugation reached an extent of 100%. However, the actual quantitative contributions of different bile constituents varied distinctly. Correlation analysis revealed that intra-individual variability (r=0.77+/-0.03) was significantly (p0.01) smaller than inter-individual variability (r=0.68+/-0.01), thus purporting the notion that bile composition is a hallmark of individual metabolism. Extension of quantitative bile analysis by in vivo (1)H-MRS to pathological states will provide a rapid and non-invasive modality for monitoring an important, yet elusive compartment of cholesterol and lipid metabolism.

The aim of this study was to apply 31P magnetic resonance spectroscopy (MRS) using spatial localization with optimal point spread function (SLOOP) to investigate possible age and gender dependencies of the energy metabolite concentrations in the human heart. Thirty healthy volunteers (18 males and 12 females, 21–67 years old, mean = 40.7 years) were examined with the use of 31P-MRS on a 1.5 T scanner. Intra- and interobserver variability measures (determined in eight of the volunteers) were both 3.8% for phosphocreatine (PCr), and 4.7% and 8.3%, respectively, for adenosine triphosphate (ATP). High-energy phosphate (HEP) concentrations in mmol/kg wet weight were 9.7 ± 2.4 (age < 40 years, N = 16) and 7.7 ± 2.5 (age ≥ 40 years, N = 14) for PCr, and 5.1 ± 1.0 (age < 40 years) and 4.1 ± 0.8 (age ≥ 40 years) for ATP, respectively. Separated by gender, PCr concentrations of 9.2 ± 2.4 (men, N = 18) and 8.0 ± 2.8 (women, N = 12) and ATP concentrations of 4.9 ± 1.0 (men) and 4.2 ± 0.9 (women) were measured. A significant decrease of PCr and ATP was found for volunteers older than 40 years (P < 0.05), but the differences in metabolic concentrations between both sexes were not significant. In conclusion, age has a minor but still significant impact on cardiac energy metabolism, and no significant gender differences were detected. Magn Reson Med, 2006. © 2006 Wiley-Liss, Inc.

Traditional setups for in situ MR investigation of skeletal muscle function in animals use invasive systems for muscle stimulation and force measurement. These systems require surgical preparation and therefore exclude repetitive investigations on the same animal. This article describes a new experimental setup allowing strictly noninvasive MR investigations of muscle function in contracting rat gastrocnemius muscle using 1H-MR imaging and 31P-MR spectroscopy. The novelty of this setup is the integration of two noninvasive systems allowing muscle contraction by transcutaneous stimulation and force measurement with a dedicated ergometer. Muscle function was investigated in 20 rats (275-300 g) through a fatiguing stimulation protocol, either with this noninvasive setup (n = 10) or with a traditional MR setup (n = 10). T2-weighted images demonstrated that transcutaneous stimulation activated mainly the gastrocnemius muscle. Moreover, the changes in force development and in energy metabolism obtained with the noninvasive setup were qualitatively and quantitatively similar to those obtained with the traditional setup. This noninvasive setup is thus suitable for investigating skeletal muscle function in situ. It offers the possibility to repeat investigations in the same animal, avoiding individual variability and enabling longitudinal follow-up studies. This opens up new perspectives in various research areas including pharmaceutical research.

In schizophrenia research, most of the functional imaging studies have been performed in psychotic patients, but little is known about brain areas involved in the expression of psychotic-like symptoms in animal models. The objective of this study was to visualize and compare brain activity abnormalities in a neurodevelopmental and a pharmacological animal model of schizophrenia.Blood perfusion of specific brain areas, taken as indirect measure of brain activity, was investigated in adult rats following either neonatal ventral hippocampal lesion or acute administration of phencyclidine. Quantitative perfusion magnetic resonance imaging was performed on five frontal brain slices using the continuous arterial spin labeling technique. The mean perfusion was calculated in several brain structures, which were identified on anatomical images.Lesioned animals exhibiting deficits in prepulse inhibition of the startle reflex showed a significant blood perfusion increase in the nucleus accumbens, basolateral amygdala, ventral pallidum, entorhinal-piriform cortex, orbital prefrontal cortex, and in the bed nucleus of the stria terminalis, and a decrease of perfusion in the temporal cortex. Similar effects were seen following acute phencyclidine administration in naïve animals.Our data point out specific cortical and subcortical brain areas involved in the development of psychotic-like symptoms in two different animal models of schizophrenia. The observed brain activity abnormalities are reminiscent of classical neuroimaging findings described in schizophrenic patients.

The transgenic mouse line PS2APP (PS2N141I x APP(swe)) develops an age-related cognitive decline associated with severe amyloidosis, mimicking the pathophysiologic processes in Alzheimer disease (AD). In the quest for biomarkers to monitor, noninvasively, the progression of the disease, we used magnetic resonance imaging and 1H-spectroscopy to characterize PS2APP mice throughout their life span. Morphometric measurements revealed only small size differences to controls. The metabolic profile, however, showed clear indicators of hypometabolism with age in the PS2APP mice: both N-acetyl-aspartate and glutamate were significantly reduced in the older animals. These spectroscopic measures in vivo correlated well with the plaque load in the frontal cortex. A diagnostic test, based on these measures, reached 92% sensitivity and 82% specificity at age 20 months. These noninvasive biomarkers can be exploited in preclinical pharmaceutical research to cope with the high variability in transgenic animal models and to enhance the power of drug efficacy studies.

MRI of total sodium (Na) content may allow assessment of myocardial viability, but information on Na content in normal myocardium, necrotic/scar tissue, and stunned or hibernating myocardium is lacking. Thus, the aims of the study were to: 1) quantify the temporal changes in myocardial Na content post-myocardial infarction (MI) in a rat model (Protocol 1); 2) compare Na in normally perfused, hibernating, and stunned canine myocardium (Protocol 2); and 3) determine whether, in buffer-perfused rat hearts, infarct scar can be differentiated from intact myocardium by 23Na-MRI (Protocol 3). In Protocol 1, rats were subjected to LAD ligation. Infarct/scar tissue was excised at control and 1, 3, 7, 28, 56, and 128 days post-MI (N = 6–8 each), Na content was determined by 23Na-NMR spectroscopy (MRS) and ion chromatography. Na content was persistently increased at all time points post-MI averaging 306*–160*% of control values (*P < 0.0083 vs. control). In Protocol 2, 23Na-MRS of control (baseline), stunned and hibernating samples revealed no difference in Na. In Protocol 3, 23Na-MRI revealed a mean increase in signal intensity, to 142 ± 6% of control values, in scar tissue. A threshold of 2 standard deviations of the image intensity allowed determination of infarct size, correlating with histologically determined infarct size (r = 0.91, P < 0.0001). Magn Reson Med 45:756–764, 2001. © 2001 Wiley-Liss, Inc.

Fourier imaging modalities suffer from significant signal contamination between adjacent voxels, especially when the spatial resolution is comparable to the size of the anatomical structures. This contamination can be positive or negative, depending on the spatial response function and the geometry of the object. Such a situation arises in human cardiac 31P chemical shift imaging (CSI). Acquisition-weighted CSI reduces this contamination substantially, which is demonstrated by comparing conventional CSI to Hanning-weighted 3D 31P-CSI experiments in 13 healthy volunteers at 2 T. The nominal spatial resolution and the total number of scans were identical for both experiments. The improved spatial response function of the acquisition-weighted experiment led to a significantly (P < 0.0001) higher myocardial PCr/ATP ratio (2.05 ± 0.31, mean ± SD, N = 33, corrected for saturation and blood contribution) compared to the conventional CSI experiment (1.60 ± 0.46). This is explained by the absence of negative contamination from skeletal muscle, which also resulted in an increase of the observed SNR (from 5.4 ± 1.4 to 7.2 ± 1.4 for ATP). With acquisition-weighted CSI, metabolic images with a nominal resolution of 16 ml could be obtained in a measurement time of 30 min. After correction for the inhomogeneous B1 field of the surface coil, these images show uniform ATP distribution in the entire myocardium, including the posterior wall. Magn Reson Med 45:817–826, 2001. © 2001 Wiley-Liss, Inc.

For definitive conclusions, larger numbers of patients will have to be studied, but our preliminary results indicate that (1) ATP levels decline in heart failure but not in left ventricular hypertrophy and (2) phosphocreatine/ATP ratios underestimate the true changes in myocardial high-energy phosphate concentrations in chronically injured human myocardium.

Acquisition weighted (13)C-spectroscopic imaging with three spatial dimensions is demonstrated in the isolated, perfused rat heart. Experiments were performed at 11.75 T with a home-built double resonant (13)C-(1)H probehead. Three-dimensional chemical shift imaging was used to obtain (1)H-decoupled (13)C-spectra in 96-microl voxels in about 58 min. Acquisition weighting significantly reduced signal contamination and improved image quality, with no penalty in sensitivity. As a first application, infarcted hearts were studied during perfusion with [2-(13)C]-sodium acetate. The extent of the incorporation of the (13)C-label into glutamate allows us to distinguish intact and infarcted myocardium. Chemical shift images show a homogeneous glutamate distribution in intact tissue, but a negligible amount in the infarction scar.

The purpose of this work was to visualize the whole three-dimensional coronary artery tree of the perfused beating rat heart using three-dimensional MRI. The spatial resolution amounts to 140 microns. Also, vessels having smaller diameters could be detected. Different strategies for the visualization of the three-dimensional coronary angiograms including maximum intensity projection, data thresholding, and segmentation, were shown. The coronary artery tree was best visualized by hysteresis threshold segmentation and subsequent surface reconstruction.