Evaluation of Quantitative Imaging Biomarkers in the DSS Colitis Model.

PURPOSE: In humans, colonoscopy is the gold standard for the diagnosis of inflammatory changes of the colon wall. Aim of this study was the identification of less invasive imaging biomarkers in the dextran sodium sulfate (DSS) colitis model to provide additional information on transmural changes of the colon wall. PROCEDURES: Colitis was induced in C57BL/6 mice by administration of 2, 3, and 4 % DSS over a period of 5 days. Colon wall thickness was measured using magnetic resonance imaging (MRI), ultrasound (US), and x-ray computed tomography (CT), gut inflammation by positron emission tomography/CT, and mucosal changes of the colon wall by colonoscopy. Colon samples were examined histologically. RESULTS: MRI, CT, US, and histological data revealed increased colon wall thickness in DSS-treated mice compared to healthy controls. Elevated 2-deoxy-2[(18)F]fluoro-D-glucose uptake and colonoscopy confirmed high inflammatory load in the guts of colitis mice. CONCLUSIONS: The established quantitative imaging readouts offer promising perspectives to develop new compounds and to translate these methods into the clinical setting.

MRI allows for longitudinal quantitative analysis of body fat composition in rats: an analysis of sibutramine-associated changes at the group level.

PURPOSE: Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant. MATERIALS AND METHODS: Twenty rats on a high caloric diet were investigated by the identical MRI protocol at baseline and after seven weeks. Ten rats received a treatment with sibutramine, 10 rats served as vehicle control group. To longitudinally assess body fat components, MRI analysis was used with two approaches: 2D slicewise graphic analysis (SGA) was compared with an automated 3D analysis algorithm (3DA). RESULTS: At the group level, fat volume differences showed a longitudinal increase of subcutaneous and visceral fat volumes for the control group, whereas the sibutramine group showed stable subcutaneous fat volumes and decrease in visceral fat volumes. SGA and 3DA volume determination showed significant correlations for subcutaneous fat volume (C=0.85, p<0.001), visceral fat volume (C=0.87, p<0.001), and total fat volume (C=0.90, p<0.001). CONCLUSION: It could be demonstrated that computer-based analysis of T1w MRI could be used to longitudinally assess changes in body fat compartments in rats at the group level. In detail, it was possible to investigate the effect of sibutramine separate on the fat compartments in rats.

A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.

Inductively coupled Helmholtz coil on a dedicated imaging platform for the in vivo 1H-MRS measurement of intramyocellular lipids in the hind leg of rats.

Skeletal muscle triglycerides are markers for insulin resistance in type 2 diabetes. Recently, MR spectroscopy was adapted for in vivo measurement of triglycerides in animal models and for the characterization of new therapeutic approaches. Because of small MR spectroscopy voxel sizes used in skeletal muscles, surface coils are used for signal reception. Furthermore, to obtain well-resolved and undistorted lipid spectra, muscle fibers must be aligned parallel to the magnetic field. Consequently, to achieve a high signal-to-noise ratio and spectral quality, a coil setup must combine high sensitivity with a reliable and reproducible positioning of muscle and voxel. These demands are difficult to match using surface coils. Here, a coil platform is described, which uses inductively coupled Helmholtz coil setup combined with a leg retainer system for rats. The new system allows for measurement of intramyocellular lipids with high signal-to-noise ratio and for significantly improved animal handling, positioning, and throughput.

Long-range diffusion of hyperpolarized 3He in rats.

Based on a stimulated-echo technique, a method to construct an apparent diffusion coefficient (ADC) map of hyperpolarized (3)He in a long-range diffusion scale is presented with a phase-cycle alternative to remove all unwanted echoes. The approach was successfully applied to determine in vivo diffusion constants in rat lungs. The ADC values in healthy rats show a good agreement with reported values for diffusion times of approximately. These long diffusivity measurements may be sensitive to detect emphysema progression or tissue remodeling and thus have enormous potential for the diagnosis and tracking of disease progression and for drug evaluation.

Vacuolization correlates with spin-spin relaxation time in motor brainstem nuclei and behavioural tests in the transgenic G93A-SOD1 mouse model of ALS.

In recent years, magnetic resonance imaging (MRI) has emerged as a preferred tool for the diagnosis of amyotrophic lateral sclerosis (ALS) in humans. A widely used animal model for human ALS is the G93A-superoxide dismutase 1 (G93A-SOD1) transgenic mouse model. However, the mechanisms for the selective degeneration of motor neurons in the brainstem and spinal cord are still uncertain. In our study, we applied MRI at 4.7 Tesla to non-invasively evaluate pathological alterations in the brainstem of this animal model and to follow the progression of the disease. Extending previous investigation, we used the relaxation parameter T(2) as a suitable measure for the progression of ALS, and evaluated the potential agreement with histological evaluation and behavioural data of open-field tests. In the brainstem of G93A-SOD1 mice, T(2) values were significantly increased in the motor nuclei Nc. V, Nc. VII and Nc. XII, as early as Day 80, i.e. before the average disease onset at about Day 90. Moreover, this increase is associated with a progressive development of vacuoles in the brainstem motor nuclei and a significantly decreased performance in behavioural tests. Overall, MRI is a very sensitive tool to obtain correlates for neuronal degeneration in vivo. Furthermore, MRI enables us to investigate a follow up at different time points of the disease. These advantages are especially useful for therapeutic studies with respect to survival rates of motor neurons using mouse models. Finally, our data suggest that MRI does not only resemble the findings of behavioural tests, but is potentially superior to behavioural studies.

Working memory specific activity in auditory cortex: potential correlates of sequential processing and maintenance.

Working memory (WM) tasks involve several interrelated processes during which past information must be transiently maintained, recalled, and compared with test items according to previously instructed rules. It is not clear whether the rule-specific comparisons of perceptual with memorized items are only performed in previously identified frontal and parietal WM areas or whether these areas orchestrate such comparisons by feedback to sensory cortex. We tested the latter hypothesis by focusing on auditory cortex (AC) areas with low-noise functional magnetic resonance imaging in a 2-back WM task involving frequency-modulated (FM) tones. The control condition was a 0-back task on the same stimuli. Analysis of the group data identified an area on right planum temporale equally activated by both tasks and an area on the left planum temporale specifically involved in the 2-back task. A region of interest analysis in each individual revealed that activation on the left planum temporale in the 2-back task positively correlated with the task performance of the subjects. This strongly suggests a prominent role of the AC in 2-back WM tasks. In conjunction with previous findings on FM processing, the left lateralized effect presumably reflects the complex sequential processing demand of the 2-back matching to sample task.

Orbitofrontal cortical dysfunction in akinetic catatonia: a functional magnetic resonance imaging study during negative emotional stimulation.

Catatonia is a psychomotor syndrome characterized by concurrent emotional, behavioral, and motor anomalies. Pathophysiological mechanisms of psychomotor disturbances may be related to abnormal emotional-motor processing in prefrontal cortical networks. We therefore investigated prefrontal cortical activation and connectivity patterns during emotional-motor stimulation using functional magnetic resonance imaging (FMRI). We investigated 10 akinetic catatonic patients in a postacute state and compared them with 10 noncatatonic postacute psychiatric controls (age-, sex-, diagnosis-, and medication-matched) and 10 healthy controls. Positive and negative pictures from the International Affective Picture System were used for emotional stimulation. FMRI measurements covered the whole frontal lobe, activation signals in various frontal cortical regions were obtained, and functional connectivity between the different prefrontal cortical regions was investigated using structural equation modeling. Catatonic patients showed alterations in the orbitofrontal cortical activation pattern and in functional connectivity to the premotor cortex in negative and positive emotions compared to psychiatric and healthy controls. Catatonic behavioral and affective symptoms correlated significantly with orbitofrontal activity, whereas catatonic motor symptoms were rather related to medial prefrontal activity. It is concluded that catatonic symptoms may be closely related to dysfunction in the orbitofrontal cortex and consequent alteration in the prefrontal cortical network during emotional processing. Because we investigated postacute patients, orbitofrontal cortical alterations may be interpreted as a trait marker predisposing for development of catatonic syndrome in schizophrenic or affective psychosis.

Noncontact mapping of ventricular tachycardia in a closed-chest animal model of chronic myocardial infarction.

Treatment of ventricular tachyarrhythmias in the setting of chronic myocardial infarction requires accurate characterization of the arrhythmia substrate. New mapping technologies have been developed that facilitate identification and ablation of critical areas even in rapid, hemodynamically unstable ventricular tachycardia. A noncontact mapping system was used to analyze induced ventricular tachycardia in a closed-chest sheep model of chronic myocardial infarction. Twelve sheep were studied 96 +/- 10 days after experimental myocardial infarction. During programmed stimulation, 15 different ventricular tachycardias were induced in nine animals. Induced ventricular tachycardia had a mean cycle length of 190 +/- 30 ms. In 12 ventricular tachycardias, earliest endocardial activity was recorded from virtual electrodes, preceding the surface QRS onset by 30 +/- 7 ms. Noncontact mapping identified diastolic activity in ten ventricular tachycardias. Diastolic potentials were recorded over a variable zone, spanning more than 30 mm. Timing of diastolic potentials varied from early to late diastole and could be traced back to the endocardial exit site. Entrainment with overdrive pacing was attempted in nine ventricular tachycardias, with concealed entrainment observed in seven. Abnormal endocardium in the area of chronic myocardial infarction identified by unipolar peak voltage mapping was confirmed by magnetic resonance imaging. These data suggest that induced ventricular tachycardia in the late phase of myocardial infarction in the sheep model is due to macroreentry involving the infarct borderzone. The combination of this animal model with noncontact mapping technology will allow testing of new strategies to cure and prevent ventricular tachycardia in the setting of chronic myocardial infarction.

The growth of cat cerebral cortex in postnatal life: a magnetic resonance imaging study.

To follow up the development of an individual brain over time and to measure its growth we have analysed the brains of individual cats from postnatal day 12 to adulthood using magnetic resonance imaging. From the anatomical images, four parameters were calculated: anteroposterior extent of the telencephalon, brain volume, neocortical surface area and neocortical volume. The development of the anteroposterior extent was similar in all cats. It increased between the 3rd and 6th postnatal week from 33 to 37.5 mm ending up approximately 40 mm in adulthood. The brain volume showed greater variability. On average, the volume increased from 11.5 to 16.5 cm3 in the same period. Adult values were approximately 19 cm3. Considerable interindividual variability was observed in neocortical surface area. In one cat, it expanded from 12.5 to 26 cm2 between days 14 and 41. In another cat, this area expanded from 16 to 24.5 cm2 between days 12 and 40. On average, the surface area expanded by 34% between the 3rd and 6th week. Adult values ranged from 27 to 30 cm2. Neocortical volume increased from 2.9 to 4.1 cm3 between the 3rd and 6th postnatal week and to 4.5-5.2 cm3 in adulthood. The asymmetry between the hemispheres in both neocortical surface area and volume was < 3% in all animals for most of the observation period. Comparison of the neocortical surface measurements with data on postnatal growth of cat primary visual cortex obtained by 2-deoxyglucose autoradiography indicates that the primary visual cortex grows at the same speed and amounts to approximately 15% of the entire neocortical surface area throughout development.

GABA-ergic modulation of prefrontal spatio-temporal activation pattern during emotional processing: a combined fMRI/MEG study with placebo and lorazepam.

Various prefrontal cortical regions have been shown to be activated during emotional stimulation, whereas neurochemical mechanisms underlying emotional processing in the prefrontal cortex remain unclear. We therefore investigated the influence of the GABA-A potentiator lorazepam on prefrontal cortical emotional-motor spatio-temporal activation pattern in a combined functional magnetic resonance imaging/magnetoencephalography study. Lorazepam led to the reversal in orbito-frontal activation pattern, a shift of the early magnetic field dipole from the orbito-frontal to medial prefrontal cortex, and alterations in premotor/motor cortical function during negative and positive emotional stimulation. It is concluded that negative emotional processing in the orbito-frontal cortex may be modulated either directly or indirectly by GABA-A receptors. Such a modulation of orbito-frontal cortical emotional function by lorazepam has to be distinguished from its effects on cortical motor function as being independent from the kind of processing either emotional or nonemotional.