Amy H. Herlihy

Natural History of Brain Lesions in Extremely Preterm Infants Studied With Serial Magnetic Resonance Imaging From Birth and Neurodevelopmental Assessment

OBJECTIVES. The aim was to survey the range of cerebral injury and abnormalities of cerebral development in infants born between 23 and 30 weeks’ gestation using serial MRI scans of the brain from birth, and to correlate those findings with neurodevelopmental outcome after 18 months corrected age. METHODS. Between January 1997 and November 2000, consecutive infants born at <30 weeks’ gestational age underwent serial MRI brain scans from birth until term-equivalent age. Infants were monitored after 18 months of age, corrected for prematurity, with the Griffiths Mental Development Scales and neurologic assessment. RESULTS. A total of 327 MRI scans were obtained from 119 surviving infants born at 23 to 30 weeks of gestation. Four infants had major destructive brain lesions, and tissue loss was seen at term for the 2 survivors. Fifty-one infants had early hemorrhage; 50% of infants with term scans after intraventricular hemorrhage had ventricular dilation. Twenty-six infants had punctate white matter lesions on early scans; these persisted for 33% of infants assessed at term. Early scans showed cerebellar hemorrhagic lesions for 8 infants and basal ganglia abnormalities for 17. At term, 53% of infants without previous hemorrhage had ventricular dilation and 80% of infants had diffuse excessive high signal intensity within the white matter on T2-weighted scans. Complete follow-up data were available for 66% of infants. Adverse outcomes were associated with major destructive lesions, diffuse excessive high signal intensity within the white matter, cerebellar hemorrhage, and ventricular dilation after intraventricular hemorrhage but not with punctate white matter lesions, hemorrhage, or ventricular dilation without intraventricular hemorrhage. CONCLUSIONS. Diffuse white matter abnormalities and post–hemorrhagic ventricular dilation are common at term and seem to correlate with reduced developmental quotients. Early lesions, except for cerebellar hemorrhage and major destructive lesions, do not show clear relationships with outcomes.

Use of multicoil arrays for separation of signal from multiple slices simultaneously excited

Increased acquisition efficiency has been achieved by exciting several slices simultaneously. The mixed data were unfolded to produce separate slices using the spatial encoding information inherent in a multicoil receiver system. Each coil yields a linear combination of signals from all excited slices weighted by the sensitivity of each coil. A matrix inversion provides a solution to unfold these images. J. Magn. Reson. Imaging 2001;13:313–317.

Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI)

We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.

In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride.

To measure regional T1 and T2 values for normal C57Bl/6 mouse brain and changes in T1 after systemic administration of manganese chloride (MnCl2) at 9.4 T.

Adiposity induced by adenovirus 5 inoculation

OBJECTIVE:To investigate the effect of viral inoculation by adenovirus 5 (Ad5) on body composition in a mouse model.DESIGN:Longitudinal monitoring before and after a single injection of virus or saline.SUBJECTS:Two groups of CD1 mice, one group given a single intraperitoneal dose of Ad5 and the control group, saline.MEASUREMENTS:Bodyweights and food intake were recorded before and up to 21 weeks after inoculation. At the end of the study, whole-body 1H magnetic resonance spectroscopy (MRS) and localised in vivo 1H MRS spectroscopy of the liver was performed to assess whole-body adiposity and intrahepatic lipid content, respectively.RESULTS:Ad5-treated animals gained significantly more weight over a period of 21 weeks after inoculation than the controls, 21.8 g (18.8–25.0) and 18.8 g (17.3–19.8) respectively, (P<0.05). The gain in bodyweight in the former animals arises from increased deposition of adipose tissue as measured by whole-body 1H MRS. Adiposity was 6.7% (3.10–11.20%), and 2.40% (0.85–5.65%) for the Ad5-treated and control animals, respectively (P<0.05). No significant difference in intrahepatic lipid content or food intake was observed between the two groups.CONCLUSION:The significantly higher percentage of adipose tissue in the Ad5-treated mice suggest viral infection may play a contributory role to a predisposition to obesity, although its contribution relative to other factors remains to be determined.

Diffusion-weighted imaging of the spine using radial k-space trajectories.

IntroductionDiffusion-weighted MR imaging (DWI) of the spine requires robust imaging methods, that are insensitive to susceptibility effects caused by the transition from bone to soft tissue and motion artifacts due to breathing, swallowing, and cardiac motion. The purpose of this study was to develop a robust imaging method suitable for DWI of the spine.Methods and subjectsA radialk-space spin echo sequence has been implemented, which is sell-navigating because each acquisition line passes through the origin ofk-space. Influence of cardiac motion and associated flow of cerebrospinal fluid is minimized by cardiac gating with a finger photoplethysmograph. The sequence has been tested on a 1.5T system. Diffusion-weighted images of six normal volunteers were acquired in the sagittal plane with 4b values between 50 and 500 s mm−2. Because of the symmetries of the cord, diffusion measurements in the head-foot (HF) or left-right (LR) directions were sufficient to measure the dominant effects of anisotropy.ResultsThe apparent diffusion coefficients (ADCs) measured, respectively, in the LR and HF directions were (0.699 ± 0.050) × 10−3 and (1.805 ± 0.086) × 10−3 mm2 s−1 in the spinal cord. (1.588 ± 0.082) × 10−3 and (1.528 ± 0.052) × 10−3 mm2 s−1 in the intervertebral disks, and (0.346 ± 0.047) × 10−3 and (0.306 ± 0.035) × 10−3 mm2 s−1 in the vertebrae of the cervicothoraeic spine.ConclusionDiffusion-weighted spin echo sequences with radial trajectories ink-space provide a means of achieving robust, high quality diffusion-weighted imaging and measuring ADCs in the spine. The application of the diffusion-weighting gradients in different directions allows diffusion anisotropy to be measured.

Physiological stability of preterm infants during magnetic resonance imaging.

AIM This study looked for evidence of physiological disturbance in preterm infants undergoing magnetic resonance imaging (MRI). METHODS Intensive care was continued, as appropriate, throughout scanning in each infant. The heart rate, oxygen saturation (SaO2), temperature and mean arterial blood pressure (BP) was monitored during MRI in preterm infants, median gestational age at birth 27 (range 23-32) weeks and median postnatal age at initial MRI, 3 days (range 1-42). The acoustic noise level during imaging was also measured. RESULTS 2087 min of data were obtained from 39 examinations in 23 infants. The median heart rate was 159 and no bradycardia < 100 or tachycardia > 200 bpm occurred. Although 42 episodes of desaturation < 90% were detected only three were < 80, and these occurred in one infant due to endotracheal tube blockage. The median axillary temperature was 36.9 degrees C (range 35.7-37.8) and median BP (n = 6) was 37 mmHg (24-48). The ambient noise level in the MR system during scanning was 67-72 dBA. CONCLUSION In preterm infants who required intensive care during scanning, MRI could be performed without major physiological instability.

MAGfect: a novel liposome formulation for MRI labelling and visualization of cells

Cellular entry of imaging probes, such as contrast agents for magnetic resonance imaging (MRI), is a key requirement for many molecular imaging studies, particularly imaging intracellular events and cell tracking. Here, we describe the successful development and in vitro analysis of MAGfect, a novel liposome formulation containing a lipidic gadolinium contrast agent for MRI, Gd-DOTA-Chol , designed to enter and label cells. Liposome formulation and cell incubation time were optimised for maximum cellular uptake of the imaging probe in a variety of cell lines. MRI analysis of cells incubated with MAGfect showed them to be highly MRI active. This formulation was examined further for cytotoxicity, cell viability and mechanism of cell labelling. One of the key advantages of using MAGfect as a labelling vehicle arises from its potential for additional functions, such as concomitant drug or gene delivery and fluorescent labelling. The gadolinium liposome was found to be an effective vehicle for transport of plasmid DNA (pDNA) into cells and expression levels were comparable to the commercial transfection agent Trojene.

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Alcohol-dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) β1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN × C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.

The temporal sequence of gut Peptide-CNS interactions tracked in vivo by magnetic resonance Imaging

Hormonal satiety signals secreted by the gut play a pivotal role in the physiological control of appetite. However, therapeutic exploitation of the gut–brain axis requires greater insight into the interaction of gut hormones with CNS circuits of appetite control. Using the manganese ion (Mn2+) as an activity-dependent magnetic resonance imaging (MRI) contrast agent, we showed an increase in signal intensity (SI) in key appetite-regulatory regions of the hypothalamus, including the arcuate, paraventricular, and ventromedial nuclei, after peripheral injection of the orexigenic peptide ghrelin. Conversely, administration of the anorexigenic hormone peptide YY3–36 caused a reduction in SI. In both cases, the changes in SI recorded in the hypothalamic arcuate nucleus preceded the effect of these peptides on food intake. Intravenous Mn2+ itself did not significantly alter ghrelin-mediated expression of the immediate early gene product c-Fos, nor did it cause abnormalities of behavior or metabolic parameters. We conclude that manganese-enhanced MRI constitutes a powerful tool for the future investigation of the effects of drugs, hormones, and environmental influences on neuronal activity.