Biomedical subjects

Hoby P Hetherington

Publications and source records attributed to Hoby P Hetherington.

15 recordsLinked to original sources

PubMed2006

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus.

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

Animals↗

PubMed2006

Imaging beta-galactosidase activity using 19F chemical shift imaging of LacZ gene-reporter molecule 2-fluoro-4-nitrophenol-beta-D-galactopyranoside.

2-Fluoro-4-nitrophenol-beta-D-galactopyranoside (OFPNPG) belongs to a novel class of NMR active molecules (fluoroaryl-beta-D-galactopyranosides), which are highly responsive to the action of beta-galactosidase (beta-gal). OFPNPG has a single 19F peak (-55 ppm relative to aqueous sodium trifluoroacetate). Upon cleavage by beta-gal, the pH sensitive aglycone 2-fluoro-4-nitrophenol (OFPNP) is observed at a chemical shift of -59 to -61 ppm. The chemical shift response is sufficient to observe beta-gal activity using chemical shift imaging (CSI). 19F CSI studies of enzyme activity and lacZ gene expression in 9L-glioma and MCF7 breast cancer cells are presented, providing further evidence for the utility of OFPNPG as a gene-reporter molecule for future in vivo studies.

Breast Neoplasms↗

PubMed2006

Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice.

Hepatocyte transplantation (HT) is being explored as a substitute for liver transplantation for the treatment of liver diseases. For the clinical application of HT, a preparative regimen that allows preferential proliferation of transplanted cells in the host liver and a noninvasive method to monitor donor cell engraftment, proliferation, and immune rejection would be useful. We describe an imaging method that employs the creatine kinase (CK) gene as a marker of donor hepatocytes. Creatine kinase is unique among marker genes, because it is normally expressed in brain and muscle tissues and is therefore not immunogenic. Preferential proliferation of transplanted CK-expressing hepatocytes was induced by preparative hepatic irradiation and expression of hepatocyte growth factor using a recombinant adenoviral vector. CK is normally not expressed in mouse liver and its expression by the donor cells led to the production of phosphocreatine in the host liver, permitting (31)P magnetic resonance spectroscopic imaging of liver repopulation by engrafted hepatocytes. In conclusion, this study combined a noninvasive imaging technique to assess donor hepatocyte proliferation with a preparative regimen of partial liver irradiation that allowed regional repopulation of the host liver. Our results provide groundwork for future development of clinical protocols for HT.

Animals↗

PubMed2006

1H NMR spectroscopic imaging of the mouse brain at 9.4 T.

PURPOSE: To assess the feasibility of 1H spectroscopic imaging (SI) in the mouse brain at 9.4 T, and investigate regional variations in brain metabolites. MATERIALS AND METHODS: A total of 21 SI studies were performed in CD-1 mice to evaluate the basal ganglia (N=5), hippocampus and thalamus (N=11), and cerebellum (N=5). We adjusted the B0 homogeneity for each slice using a fully automated shim calculation method based on the B0 map, which we measured using a multislice gradient-echo sequence with multiple phase evolution delays. The SI employed a modified localization by adiabatic selective refocusing (LASER) sequence with TE/TR of 50/2000 msec, 24x24 encodes over a field of view (FOV) of 24 mmx24 mm, 1 microL voxel resolution, and two averages, for a total acquisition time of 38 minutes. RESULTS: Sufficient shimming was achieved and high-quality spectra were consistently obtained in each slice. N-acetyl aspartate (NAA)/creatine (Cr) ratios in the basal ganglia and thalamus (0.86+/-0.07, and 0.87+/-0.07, respectively) were significantly higher than those in the hippocampus and cerebellum (0.76+/-0.03 and 0.67+/-0.07), which were also significantly different from each other. CONCLUSION: 1H SI of the mouse brain is highly reproducible and allows differences in regional metabolite ratios to be easily visualized.

Analysis of Variance↗

PubMed2006

SENSE imaging with a quadrature half-volume transverse electromagnetic (TEM) coil at 4T.

PURPOSE: To demonstrate the feasibility of high-field SENSE imaging of large objects, such as the human head, using a semicircular (half-volume) coil for both transmission and multi-channel reception. MATERIALS AND METHODS: As a proof of concept, we present experimental data obtained using a seven-element half-volume (180 degrees of arc) transmit/receive quadrature transverse electromagnetic (TEM) coil. SENSE images of the human brain were acquired with a reduction factor of R=2, using two degenerate linear modes of the same coil as independent receive channels at 4T. Since the need for additional hardware (i.e., a separate set of receive coils) is eliminated, the design can be substantially simplified. RESULTS: The experimental data demonstrate that linear modes of the half-volume TEM coil have essentially no noise correlation, and their sensitivity profiles satisfy the requirement for small g-factors. Also, this type of coil provides efficient transmission with a relatively large uniform region and a reception profile that is more uniform than that of the surface coils. CONCLUSION: We demonstrate the feasibility of SENSE imaging using a half-volume coil. Half-volume coils allow reduced total power deposition compared to full-volume coils, and may replace the latter in body imaging applications in which the target region of interest (ROI) is smaller than the entire torso.

Brain Mapping↗

PubMed2006

Fully automated shim mapping method for spectroscopic imaging of the mouse brain at 9.4 T.

For spectroscopic imaging studies of the mouse brain, it is critical to obtain optimal B(0) homogeneity over a large region of interest (ROI). In this paper, a fully automated shimming method for mouse brain at 9.4 T, based on B(0) mapping, is described. B(0) maps were obtained using a multislice gradient echo sequence with multiple phase evolution time delays with a novel unwrapping scheme. The unwrapping method allows phase maps with large bandwidths (+/-1 kHz) but with high resolution (0.3 Hz/ degrees ) to be acquired in a single acquisition, thereby minimizing the number of iterations required. The SD of the B(0) over the ROI (8 x 5 x 1 mm) was less than 10 Hz after shimming. Application of this method to the in vivo mouse brain allowed reproducible, high-quality spectroscopic data to be collected with 1-microl voxels.

Animals↗

PubMed2006

Fast spectroscopic imaging using online optimal sparse k-space acquisition and projections onto convex sets reconstruction.

Long acquisition times, low resolution, and voxel contamination are major difficulties in the application of magnetic resonance spectroscopic imaging (MRSI). To overcome these difficulties, an online-optimized acquisition of k-space, termed sequential forward array selection (SFAS), was developed to reduce acquisition time without sacrificing spatial resolution. A 2D proton MRSI region of interest (ROI) was defined from a scout image and used to create a region of support (ROS) image. The ROS was then used to optimize and obtain a subset of k-space (i.e., a subset of nonuniform phase encodings) and hence reduce the acquisition time for MRSI. Reconstruction and processing software was developed in-house to process and reconstruct MRSI using the projections onto convex sets method. Phantom and in vivo studies showed that good-quality MRS images are obtainable with an approximately 80% reduction of data acquisition time. The reduction of the acquisition time depends on the area ratio of ROS to FOV (i.e., the smaller the ratio, the greater the time reduction). It is also possible to obtain higher-resolution MRS images within a reasonable time using this approach. MRSI with a resolution of 64 x 64 is possible with the acquisition time of the same as 24 x 24 using the traditional full k-space method.

Algorithms↗

PubMed2006

Robust fully automated shimming of the human brain for high-field 1H spectroscopic imaging.

Although a variety of methods have been proposed to provide automated adjustment of shim homogeneity, these methods typically fail or require large numbers of iterations in vivo when applied to regions with poor homogeneity, such as the temporal lobe. These limitations are largely due to 1) the limited accuracy of single evolution time measurements when full B0 mapping studies are used, and 2) inaccuracies arising from projection-based methods when the projections pass through regions where the inhomogeneity exceeds the order of the fitted parameters. To overcome these limitations we developed a novel B0 mapping method using multiple evolution times with a novel unwrapping scheme in combination with a user-defined ROI selection tool. We used these methods at 4T on 10 control subjects to obtain high-resolution spectroscopic images of glutamate from the bilateral hippocampi.

Automation↗

PubMed2006

Endothelin in a murine model of cerebral malaria.

Cerebral malaria (CM) remains a deadly complication of Plasmodium falciparum infection, and children are at high risk of developing encephalopathy as a result of CM. This is probably a consequence of the activation of many of the inflammatory cytokines as well as the glial cells and the vascular endothelium in the brain. We have previously demonstrated that there is a striking reduction in cerebral blood flow by magnetic resonance imaging when mice are infected with Plasmodium berghei ANKA (PbA), and we now demonstrate a possible role for endothelin (ET-1) in the pathogenesis of CM. The brains of female C57BL/6 mice with PbA infection were examined at Day 5 for the expression of ET-1, endothelin converting enzyme (ECE), and the endothelin receptors A and B (ET(A) and ET(B)) by both reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time PCR. ET-1 and ECE mRNA expression was markedly increased by RT-PCR in PbA-infected mice. Real-time quantitative PCR demonstrated a 3-fold increase in ET-1 (P < 0.05) and a significant increase in ET(A) and ET(B) expression (P < 0.05) in PbA-infected mice. Histopathology bof PbA-infected mice demonstrated a transformation in the morphology of microglial cells and clustering of these cells consistent with activation. Though the full impact of ET-1 on CM remains to be elucidated, these findings demonstrate that in the murine model, there is a significant increase in ET-1 and its components, which is associated with the vasculopathy and immunopathology of CM.

Animals↗

PubMed2004

4 T actively detunable transmit/receive transverse electromagnetic coil and 4-channel receive-only phased array for (1)H human brain studies.

The design and construction of a 4 T transverse electromagnetic (TEM) transmit/receive head coil and a four-channel phased array receive-only RF system are described. To enable both high-resolution imaging of the entire brain and high-resolution spectroscopic imaging, active PIN diode decoupling was used in both the TEM resonator and each surface coil in the array. This configuration allows for both transmission and reception from the volume coil as well as reception from the phased array. The surface coils were decoupled by overlapping the coils and using preamplifier decoupling. Since at high frequencies construction of a lumped element matching quarter wavelength transformer, an important component of the preamplifier decoupling, becomes difficult, a transmission line approach was used. The system was tested and compared to a TEM volume transmit/receive head coil. A four- to sixfold improvement in signal-to-noise ratio from the sensitive volume of the array was achieved.

Brain Mapping↗

PubMed2004

1H and 31P spectroscopic imaging of epilepsy: spectroscopic and histologic correlations.

Although MRS measurements are useful in assessing the biochemical alterations underlying human epilepsy, to date their use has been limited primarily by three factors: (a) the lack of widespread methods and appropriate hardware for acquiring high-resolution spectroscopic imaging data, (b) difficulties in spectral interpretation associated with metabolic heterogeneity, and (c) difficulties in biological interpretation due to a lack of correlative histologic studies. In this work, we (a) describe approaches to overcome these hurdles, and (b) discuss the biological interpretation of the spectroscopic findings in TLE.

Adult↗

PubMed2003

Modified perturbation method for transverse electromagnetic (TEM) coil tuning and evaluation.

A modified perturbation method for tuning and testing volume head coils was developed. The common perturbation method, utilizing the change in resonance frequency of a resonator in response to the presence of a small dielectric or magnetic probe, was modified to modulate the frequency shift due to rotation of a probe. This modification enabled the RF magnetic and electric fields as well as the angular distribution of current in the longitudinal elements of the coil to be mapped. The latter serves as a quick test of magnetic field homogeneity by comparing the measured distribution with the sinusoidal function required for the field to be homogenous. The method was experimentally applied to tune and test a transverse electromagnetic (TEM) head coil.

Algorithms↗

PubMed2002

1H and 31P spectroscopy and bioenergetics in the lateralization of seizures in temporal lobe epilepsy.

Over the past decade, (1)H and (31)P spectroscopy measurements have demonstrated that significant metabolic alterations occur in temporal lobe epilepsy. However, to most accurately interpret these changes, metabolic heterogeneity and differences between gray and white matter must be accounted for. These alterations, decreased NAA and the ratio of phosphocreatine/inorganic phosphate, can be reversed with successful treatment of seizures. The reversibility of these two measures is consistent with the localization of NAA synthesis to neuronal mitochondria and the important role for bioenergetics in the pathophysiology of temporal lobe epilepsy.

Brain↗

PubMed2002

[2,4-13 C2 ]-beta-Hydroxybutyrate metabolism in human brain.

Infusions of [2,4-13C2]-beta-hydroxybutyrate and 1H-13C polarization transfer spectroscopy were used in normal human subjects to detect the entry and metabolism of beta-hydroxybutyrate in the brain. During the 2-hour infusion study, 13C label was detectable in the beta-hydroxybutyrate resonance positions and in the amino acid pools of glutamate, glutamine, and aspartate. With a plasma concentration of 2.25 +/- 0.24 mmol/L (four volunteers), the apparent tissue beta-hydroxybutyrate concentration reached 0.18 +/- 0.06 mmol/L during the last 20 minutes of the study. The relative fractional enrichment of 13C-4-glutamate labeling was 6.78 +/- 1.71%, whereas 13C-4-glutamine was 5.68 +/- 1.84%. Steady-state modeling of the 13C label distribution in glutamate and glutamine suggests that, under these conditions, the consumption of the beta-hydroxybutyrate is predominantly neuronal, used at a rate of 0.032 +/- 0.009 mmol. kg-1. min-1, and accounts for 6.4 +/- 1.6% of total acetyl coenzyme A oxidation. These results are consistent with minimal accumulation of cerebral ketones with rapid utilization, implying blood-brain barrier control of ketone oxidation in the nonfasted adult human brain.

3-Hydroxybutyric Acid↗

PubMed2002

Regional cerebral blood flow and magnetic resonance spectroscopic imaging findings in diaschisis from stroke.

BACKGROUND AND PURPOSE: This study evaluated blood flow and metabolite changes in cerebral diaschisis from internal capsule region infarction using regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) and 1H magnetic resonance spectroscopic imaging (MRSI). We hypothesized that complementary measures of diaschisis effects in white matter (characterized by 1H MRSI) and gray matter (characterized by changes in rCBF) can be measured and exhibit parallel changes. METHODS: Five stroke patients and 16 normal controls underwent Tc-99m hexamethylpropyleneamine-oxime brain SPECT and 1H MRSI at 4.1 T. The metabolites N-acetyl aspartate (NAA) and creatine (Cr) were measured using 1H MRSI. The tissue content was expressed as the percent of gray or white matter in each MRSI voxel to allow comparison of the differential effects of diaschisis in gray and white matter tissue types. The blood flow and metabolite changes were evaluated at superior cerebral regions distant from the stroke to allow a measure of diaschisis relatively unconfounded by their expected changes in the infarction region. RESULTS: The rCBF SPECT data in stroke patients showed a perfusion defect, with size ranging from 1.23 cc to 10.23 cc, in the region of cortical diaschisis. 1H MRSI showed increased Cr/NAA ratios in regions of white matter diaschisis. There was a tendency for larger rCBF defect size to be associated with greater increases in Cr/NAA values in the same diaschitic cerebral hemisphere, ipsilateral to the infarction. CONCLUSION: Diaschisis ipsilateral to stroke in white matter can be characterized by 1H MRSI, and diaschisis ipsilateral to stroke in cortical gray matter regions can be characterized by changes in rCBF. The tendency for greater reductions in cortical rCBF values to be associated with increased Cr/NAA values in the same diaschitic cerebral hemisphere implies that a relationship exists between rCBF reductions in gray matter and abnormal changes in white matter subservient to it.

Adult↗