Biomedical subjects

Michael A King

Publications and source records attributed to Michael A King.

At least 19 recordsLinked to original sources

PubMed2006

Fully 4D motion-compensated reconstruction of cardiac SPECT images.

In this paper, we investigate the benefits of a spatiotemporal approach for reconstruction of image sequences. In the proposed approach, we introduce a temporal prior in the form of motion compensation to account for the statistical correlations among the frames in a sequence, and reconstruct all the frames collectively as a single function of space and time. The reconstruction algorithm is derived based on the maximum a posteriori estimate, for which the one-step late expectation-maximization algorithm is used. We demonstrated the method in our experiments using simulated single photon emission computed tomography (SPECT) cardiac perfusion images. The four-dimensional (4D) gated mathematical cardiac-torso phantom was used for simulation of gated SPECT perfusion imaging with Tc-99m-sestamibi. In addition to bias-variance analysis and time activity curves, we also used a channelized Hotelling observer to evaluate the detectability of perfusion defects in the reconstructed images. Our experimental results demonstrated that the incorporation of temporal regularization into image reconstruction could significantly improve the accuracy of cardiac images without causing any significant cross-frame blurring that may arise from the cardiac motion. This could lead to not only improved detection of perfusion defects, but also improved reconstruction of the heart wall which is important for functional assessment of the myocardium.

Algorithms↗

PubMed2006

Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus.

The hippocampus is a critical structure for learning and memory formation injured by diverse neuropathologies such as epilepsy or Alzheimer's disease. Recently, clinical investigations have attempted to use diffusion tensor MRI as a more specific surrogate marker for hippocampal damage. To first better understand the tissue architecture of healthy hippocampal regions, this study characterized 10 rat hippocampi with diffusion tensor imaging (DTI) at 50-microm in-plane image resolution using a 14.1-T magnet. Chemical fixation of the dissected and straightened rat hippocampus provided a simple, effective way to reduce partial volume effects when segmenting hippocampal regions and improved mean signal-to-noise per unit time (e.g. 50.6+/-4.4 at b=1250 s/mm2 in 27 min). Contrary to previous reports that water diffusion is homogeneous throughout the nervous system, statistically different mean diffusivities were observed (e.g. 0.238+/-0.054 and 0.318+/-0.084 microm2/ms for the molecular and granule cell layers respectively) (ANOVA, P<0.05). Different hippocampal subregions had lower fractional anisotropy than uniformly fibrous structures like corpus callosum because of their complex architecture. DTI-derived color fiber orientation maps and tractography demonstrated most components of the trisynaptic intrahippocampal pathway (e.g. orientations in stratum lacunosum-moleculare were dominated by perforant and Schaffer fibers) and also permitted some assessment of connectivity in the rat hippocampus.

Animals↗

PubMed2006

Memory-related deficits following selective hippocampal expression of Swedish mutation amyloid precursor protein in the rat.

The gene encoding for the Swedish double mutation (K595N/M596L) of amyloid precursor protein (APP695Swe) was expressed bilaterally in adult rat hippocampus to determine its long-term effects on memory-related behavior as well as amyloid deposition. Recombinant adeno-associated viral serotype 2 (rAAV2) vectors were injected that contained either non-expressing DNA or cDNA encoding for APP695Swe under control of a chicken beta actin/cytomegalovirus promoter/enhancer. Immunolabeling human APP with the antibody 6E10 was observed throughout the cytoplasm of aspiny and, to a lesser extent, spine-bearing hippocampal neurons 6 and 12 months post-injection of the APP695Swe but not control vector. Abeta1-42 immunolabeling was identified in unusual immunoreactive objects within the hilus of the dentate gyrus and in the granule cell layer, proximal to the injection site. At 12 months post-transduction, rats that received the APP695Swe gene also demonstrated significant deficits in the acquisition and probe components of the spatial-memory-related Morris water task compared to control animals. These behavioral deficits occurred in the absence of any amyloid plaques, gliosis, or FluoroJade labeling of dying neurons. In conclusion, prolonged and localized APP695Swe expression in hippocampal neurons is sufficient to produce memory deficits without plaque formation or neuronal loss.

Alzheimer Disease↗

PubMed2006

Reduced excitatory drive in interneurons in an animal model of cortical dysplasia.

Cortical dysplasia (CD) is strongly associated with epilepsy. Enhanced excitability in dysplastic neuronal networks is believed to contribute to epileptogenesis, but the underlying mechanisms for the hyperexcitability are poorly understood. Cortical GABAergic interneurons provide the principal inhibition in the neuronal networks by forming inhibitory synapses on excitatory neurons. The aim of the present study was to determine if the function of interneurons in CD is compromised. In a rat model of CD, in utero irradiation, we studied spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) in cortical interneurons using whole cell recording techniques. Two types of interneurons, type I and type II, were identified based on their distinctive spike patterns and short-term synaptic plasticity. We found that the frequencies of sEPSCs and mEPSCs were significantly decreased in both types of interneurons in CD. However, the amplitude and kinetics of sEPSCs and mEPSCs were not different. Five-pulse, 20-Hz stimulation produced short-term depression in type I interneurons in both CD and control tissue. Type II interneurons showed a robust short-term facilitation in both CD and control tissue. Morphological analysis of biocytin-filled neurons revealed that dendritic trees of both types of interneurons were not altered in CD. Our results demonstrate that the excitatory drive, namely sEPSCs and mEPSCs, in two main types of interneuron is largely attenuated in CD, probably due to a reduction in the number of excitatory synapses on both types of interneurons in CD.

Animals↗

PubMed2006

Polycystin-1 can interact with homer 1/Vesl-1 in postnatal hippocampal neurons.

Polycystin-1 (PC-1) has been identified as critical to development of the nervous system, but the significance of PC-1 expression in neurons remains undefined, and little is known of its roles outside the kidney, where mutation results in autosomal dominant polycystic kidney disease (ADPKD). In kidney, PC-1 interacts with cadherins, catenins, and its cognate calcium channel polycystin-2 (PC-2), which in turn interacts with a number of actin-regulatory proteins. Because some of the proteins that interact with PC-1 in kidney also participate in synaptic remodeling and plasticity in the hippocampus, we decided to test PC-1's potential to interact with a recently discovered type of plasticity-associated protein (homer 1a/Vesl-1S) in postnatal mouse hippocampus. Homer 1a/Vesl-1S is an activity-induced protein believed to participate in synaptic remodeling/plasticity responses to temporal lobe seizure and learning. Here we report the following. 1) PC-1 contains a homer-binding motif (PPxxF), which lies within its purported cytoplasmic domain. 2) Immunoreactivity for PC-1 (PC-1-ir) is highly colocalized with homer 1a immunoreactivity (H1a-ir) in primary cultured hippocampal neurons. 3) PC-1-ir and H1a-ir are present and appear to be colocalized in mouse hippocampus but not cortex on postnatal day 2 (P2), when higher frequencies of spontaneous activity are normal for hippocampus compared with cortex. 4) An endogenous PC-1-ir band with the correct size for the reported C-terminal G-protein-sensitive domain cleavage product of PC-1 (approximately 150 kDa) coimmunoprecipitates with endogenous homer 1/Vesl-1 proteins from mouse brain, suggesting that PC-1 can interact with homer 1/Vesl-1 proteins in postnatal hippocampal neurons.

Animals↗

PubMed2006

Comparing cardiac ejection fraction estimation algorithms without a gold standard.

RATIONALE AND OBJECTIVES: Imaging and estimation of left ventricular function have major diagnostic and prognostic importance in patients with coronary artery disease. It is vital that the method used to estimate cardiac ejection fraction (EF) allows the observer to best perform this task. To measure task-based performance, one must clearly define the task in question, the observer performing the task, and the patient population being imaged. In this report, the task is to accurately and precisely measure cardiac EF, and the observers are human-assisted computer algorithms that analyze the images and estimate cardiac EF. It is very difficult to measure the performance of an observer by using clinical data because estimation tasks typically lack a gold standard. A solution to this "no-gold-standard" problem recently was proposed, called regression without truth (RWT). MATERIALS AND METHODS: Results of three different software packages used to analyze gated, cardiac, and nuclear medicine images, each of which uses a different algorithm to estimate a patient's cardiac EF, are compared. The three methods are the Emory method, Quantitative Gated Single-Photon Emission Computed Tomographic method, and the Wackers-Liu Circumferential Quantification method. The same set of images is used as input to each of the three algorithms. Data were analyzed from the three different algorithms by using RWT to determine which produces the best estimates of cardiac EF in terms of accuracy and precision. RESULTS AND DISCUSSION: In performing this study, three different consistency checks were developed to ensure that the RWT method is working properly. The Emory method of estimating EF slightly outperformed the other two methods. In addition, the RWT method passed all three consistency checks, garnering confidence in the method and its application to clinical data.

Algorithms↗

PubMed2006

Acute pressor effect of central angiotensin II is mediated by NAD(P)H-oxidase-dependent production of superoxide in the hypothalamic cardiovascular regulatory nuclei.

BACKGROUND: Centrally applied angiotensin II (Ang II) increases sympathetic nervous activity and mean arterial blood pressure (MAP), but the mediation of these effects is not fully understood. OBJECTIVE: To test the hypothesis that central effects of Ang II are mediated by reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H]-oxidase-dependent production of superoxide in the hypothalamus. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats were given an intracerebroventricular infusion of either artificial cerebrospinal fluid or apocynin (4 microg/kg per min), a selective inhibitor for NAD(P)H oxidase, for 30 min, followed by Ang II (20 ng) or carbachol (200 ng), while MAP and heart rate were measured at the femoral artery. At the end of the experiments, hydroethidine, a superoxide-sensitive fluorescent dye, was infused intravenously for 10 min, and superoxide production was assessed in the vasoregulatory hypothalamic nuclei using confocal microscopy. RESULTS: Ang II elicited a rapid 11 +/- 2-mmHg increase in MAP and a 16 +/- 2-beats/min decrease in heart rate. Apocynin abolished these effects of Ang II in a specific manner, as carbachol-induced increases in MAP were unaffected by the inhibition of NAD(P)H oxidase (MAP increased by 9 +/- 2 and 8 +/- 1 mmHg in the absence and presence of apocynin, respectively). In response to Ang II, apocynin-sensitive production of superoxide increased significantly in the nuclei of the anterior hypothalamus, in the subfornical organ, and in the paraventricular nucleus of the hypothalamus. CONCLUSION: These findings demonstrate that acute pressor responses of central Ang II are mediated by NAD(P)H-oxidase-dependent production of superoxide in the hypothalamus.

Acetophenones↗

PubMed2006

Use of three-dimensional Gaussian interpolation in the projector/backprojector pair of iterative reconstruction for compensation of known rigid-body motion in SPECT.

Due to the extended imaging times employed in single photon emission computed tomography (SPECT) and positron emission tomography (PET), patient motion during imaging is a common clinical occurrence. The fast and accurate correction of the three-dimensional (3-D) translational and rotational patient motion in iterative reconstruction is thus necessary to address this important cause of artifacts. We propose a method of incorporating 3-D Gaussian interpolation in the projector/backprojector pair to facilitate compensation for rigid-body motion in addition to attenuation and distance-dependent blurring. The method works as the interpolation step for moving the current emission voxel estimates and attenuation maps in the global coordinate system to the new patient location in the rotating coordinate system when calculating the expected projection. It also is employed for moving back the backprojection of the ratio of the measured projection to the expected projection and backprojection of the unit value (sensitivity factor) to the original location. MCAT simulations with known six-degree-of-freedom (6DOF) motion were employed to evaluate the accuracy of our method of motion compensation. We also tested the method with acquisitions of the data spectrum anthropomorphic phantom where motion during SPECT acquisition was measured using the Polaris IR motion tracking system. No motion artifacts were seen on the reconstructions with the motion compensation.

Algorithms↗

PubMed2006

Incorporation of system resolution compensation (RC) in the ordered-subset transmission (OSTR) algorithm for transmission imaging in SPECT.

In order to reconstruct attenuation maps with improved spatial resolution and quantitative accuracy, we developed an approximate method of incorporating system resolution compensation (RC) in the ordered-subset transmission (OSTR) algorithm for transmission reconstruction. Our method approximately models the blur caused by the finite intrinsic detector resolution, the nonideal source collimation and detector collimation. We derived the formulation using the optimization transfer principle as in the derivation of the OSTR algorithm. The formulation includes one forward-blur step and one back-blur step, which do not severely slow down reconstruction. The formulation could be applicable to various transmission geometries, such as point-source, line-source, and sheet-source systems. Through computer simulations of the MCAT phantom and transmission measurements of the air-filled Data Spectrum Deluxe single photo emission computed tomography (SPECT) Phantom on a system which employed a cone-beam geometry and a system which employed a scanning-line-source geometry, we showed that incorporation of RC increased spatial resolution and improved the quantitative accuracy of reconstruction. In simulation studies, attenuation maps reconstructed with RC correction improved the quantitative accuracy of emission reconstruction.

Algorithms↗

PubMed2006

Reconstruction of dynamic gated cardiac SPECT.

In this paper we propose an image reconstruction procedure which aims to unify gated single photon emission computed tomography (SPECT) and dynamic SPECT into a single method. We divide the cardiac cycle into a number of gate intervals as in gated SPECT, but treat the tracer distribution for each gate as a time-varying signal. By using both dynamic and motion-compensated temporal regularization, our reconstruction procedure will produce an image sequence that shows both cardiac motion and time-varying tracer distribution simultaneously. To demonstrate the proposed reconstruction method, we simulated gated cardiac perfusion imaging using the gated mathematical cardiac-torso (gMCAT) phantom with Tc99m-Teboroxime as the imaging agent. Our results show that the proposed method can produce more accurate reconstruction of gated dynamic images than independent reconstruction of individual gate frames with spatial smoothness alone. In particular, our results show that the former could improve the contrast to noise ratio of a simulated perfusion defect by as much as 100% when compared to the latter.

Algorithms↗

PubMed2005

Medial septal/diagonal band cells express multiple functional nicotinic receptor subtypes that are correlated with firing frequency.

The medial septum-diagonal band (MS/DB) contains primarily cholinergic and GABAergic neurons that project to the hippocampus, and are important for learning and memory. Whole-cell patch clamp methods with brain slices from p11--p20 rats were used to measure MS/DB cell responses to focal somatic application of 1mM acetylcholine (ACh) and a series of current pulses was applied in order to assess firing frequencies and the presence of hyperpolarization-activated currents (Ih). We identified three types of cells: (1) cells with fast inward currents blocked by methyllycaconitine (MLA) with slow firing rates (3--12 Hz), accommodating action potentials, and no Ih (n=20); (2) cells with currents that had both fast (MLA-sensitive) and slow components that were blocked with mecamylamine (MEC) that showed fast firing (up to 60 Hz) and slow firing (up to 3 Hz), with accommodating and non-accommodating action potentials (n=46), 33% of which had Ih; and (3) cells not responsive to ACh with moderate firing rates (10--42 Hz), some with accommodating action potentials and some without (n=19), of which 92% had Ih. These results are among the first to demonstrate functional nicotinic receptors in the MS/DB. The data suggest that these receptors include alpha 7 and non-alpha 7 subtypes and that the expression of each is correlated with firing frequency and the presence of Ih. Responses to ACh were not affected by tetrodotoxin (TTX) and CdC l(2) but were blocked by MLA or MLA and MEC, suggesting that these currents involve direct activation of nicotinic receptors.

Action Potentials↗

PubMed2005

MR microscopy of rat hippocampal slice cultures: a novel model for studying cellular processes and chronic perturbations to tissue microstructure.

Brain slices provide a useful nervous tissue model to investigate the relationships between magnetic resonance imaging (MRI) contrast mechanisms and tissue microstructure; yet, these acutely isolated tissues remain viable for only 10-12 h. To study slower biological processes, this work describes the first MRI microscopy characterization of organotypic rat hippocampal slice cultures that can be maintained for several weeks. Diffusion-weighted images of slice cultures acquired with a 14.1-T magnet demonstrated the laminar anatomy of the hippocampus with relatively high signal-to-noise ratios. Diffusion data analyzed using a two-compartment model with exchange indicated that cultured slices had a comparable microstructure to acute brain slices and to in vivo brain. Immunohistochemistry indicated that slice cultures tolerated the conditions required for MRI study well. MRI of cultured tissue slices is highly amenable to correlative microscopy techniques and offers great promise for future MRI investigations of pathological tissue reorganization, molecular imaging and stem cell therapies.

Animals↗

PubMed2005

AAV2/5-mediated NGF gene delivery protects septal cholinergic neurons following axotomy.

Nerve growth factor (NGF) therapy has been proposed to treat cognitive impairments in aged patients including those with Alzheimer's disease. Various viral vectors, including adeno-associated virus serotype 2 (AAV2), have been investigated for their ability to deliver NGF in brain. In this study, hybrid vectors (AAV2/5) consisting of the genome of recombinant AAV2 and the capsid of AAV serotype 5 were evaluated for their ability to deliver NGF and green fluorescent protein (GFP) genes into brain. Compared to AAV2, AAV2/5 consistently led to more septal neurons being transduced with GFP over a wider range of distribution. However, both types of vector provided similar levels of long-term (17 weeks) protection of septal cholinergic neurons from axotomy and led to similar levels of NGF accumulation in this region. These results demonstrate that rAAV-mediated NGF gene delivery is neuroprotective for an extended period of time, but that factors other than transduction efficiency appear to determine transgenic NGF expression in septum.

Animals↗

PubMed2005

Testosterone reverses ethanol-induced deficit in spatial reference memory in castrated rats.

The present study was designed to evaluate the effects of ethanol, testosterone and combination of ethanol and testosterone, on spatial reference memory and beta-endorphin (beta-EN) levels in castrated rats. Male Sprague-Dawley rats (120-150 g) were used in this study, Animals were castrated and ethanol, testosterone or combination of the drugs were administered to rats at 09:00 h. The drugs were administered after a training period of 5 days and spatial reference memory was evaluated for 7 days using the Morris water maze. One hour after the last injection, animals were sacrificed, their brains removed and dissected into cortex, hypothalamus, hippocampus and midbrain. The beta-EN levels in these brain regions were determined by radioimmunoassay. The time to find the platform (latency period) was significantly increased in ethanol-treated rats, indicating that ethanol induces deficit in spatial reference memory. On the other hand, testosterone administration improved spatial reference memory by significantly decreasing the latency period. In addition, there was a significant decrease in latency period in the animals treated with combination of ethanol and testosterone. Results also indicate that administration of ethanol resulted in a significant increase in beta-EN levels in the hippocampus and in the cortex while concurrent administration with testosterone abolished this increase. These findings clearly indicate that administration of testosterone did not only improve memory but also abolished the spatial memory deficit induced by ethanol in castrated rats.

Animals↗

PubMed2005

Endothelin-1 modulates anterograde fast axonal transport in the central nervous system.

Anterograde fast axonal transport (FAxT) maintains synaptic function and provides materials necessary for neuronal survival. Localized changes in FAxT are associated with a variety of central nervous system (CNS) neuropathies, where they may contribute to inappropriate remodeling, a process more appropriately involved in synaptic plasticity and development. In some cases, developmental remodeling is regulated by localized secretion of endothelins (ETs), neuroinflammatory peptides that are also pathologically elevated in cases of neurologic disease, CNS injury, or ischemia. To investigate the potential role of ETs in these processes, we decided to test whether locally elevated endothelin-1 (ET-1) modulates FAxT in adult CNS tissues. We used the established in vivo rat optic nerve model and a novel ex vivo rat hippocampal slice model to test this hypothesis. In vivo, exogenously elevated vitreal ET-1 significantly affected protein composition of FAxT-cargos as well as the abundance and peak delivery times for metabolically-labeled proteins that were transported into the optic nerve. Proteins with molecular weights of 139, 118, 89, 80, 64, 59, 51, 45, 42, 37, and 25 kDa were evaluated at injection-sacrifice intervals (ISIs) of 24, 28, 32, and 36 hr. In acute hippocampal slices maintained on nonvascular supplies of glucose and oxygen, ET-1 significantly decreased the distance traveled along the Schaffer collateral tract by nonmetabolically-labeled lipid rafts at 5 and 10 min after pulse-labeling. In both models, ET-1 significantly affected transport or targeted delivery of FaxT-cargos, suggesting that ET-1 has the potential to modulate FAxT in adult CNS tissues.

Animals↗

PubMed2005

Septal innervation regulates the function of alpha7 nicotinic receptors in CA1 hippocampal interneurons.

The hippocampus receives substantial input from the medial septum/diagonal band of broca (MS/DB) via the fibria-fornix (FF). Projections from the MS/DB innervate hippocampal interneurons that express alpha7 nicotinic receptors and regulate excitation in principal cell populations. In the present report we used stereotaxic surgery, whole-cell patch clamping, and immunohistochemical techniques to evaluate the effects of FF and MS/DB lesions on alpha7 nicotinic receptors in stratum radiatum interneurons. Focal somatic application of ACh (1 mM) evoked methyllycaconitine (MLA)-sensitive currents that were markedly reduced following aspirative lesions of the FF. Reductions in current amplitudes were prevented or restored to levels not significantly different from controls following in vivo treatment with the alpha7-selective agonist GTS-21, and GTS-21 treatment did not change current amplitudes measured in tissue from unlesioned animals. MS/DB injections of the selective cholinergic neurotoxin 192 IgG-saporin did not affect alpha7 receptor currents, although MS/DB ChAT and hippocampal AChE immunolabeling were significantly reduced. In contrast, kainic acid lesions of the MS/DB, potentially more selective for GABAergic projection neurons, produced significant reductions in current amplitudes. These findings are the first to show functional changes in alpha7 receptors following hippocampal denervation and suggest that MS/DB hippocampal innervation regulates functional aspects of hippocampal alpha7 receptors. The results confirm hippocampal alpha7 nicotinic receptors as viable therapeutic targets in diseases that involve degradation of the septohippocampal pathway and may indicate that GABAergic MS/DB hippocampal input plays a more substantial role in the regulation of alpha7 nicotinic receptor function than MS/DB hippocampal cholinergic input.

Acetyl-CoA C-Acetyltransferase↗

PubMed2005

Counting moles automatically from back images.

Density of moles is a strong predictor of malignant melanoma, therefore, enumeration of moles is often an integral part of many studies that look at malignant melanoma. An automatic method of segmenting and counting moles would help standardize studies, compared with manual counting. We have developed an unsupervised algorithm for segmenting and counting moles from two-dimensional color images of the back torso region, as part of a study to evaluate the effectiveness of sunscreen. The method consists of a new variant of mean shift filtering that forms clusters in the image and removes noise, a region growing procedure to select candidates, and a rule-based classifier to identify moles. When this algorithm was compared to an assessment by an expert dermatologist, the algorithm showed a sensitivity rate of 91% and diagnostic accuracy of 90% on the test set, for moles larger than 1.5 mm in diameter.

Algorithms↗

PubMed2005

A comparison of human and model observers in multislice LROC studies.

Model and human observers have been compared in a series of localization receiver operating characteristic (LROC) studies involving single-slice and multislice image displays. The task was detection of Ga-avid lymphomas within single photon emission computed tomography (SPECT)-reconstructed transverse slices of a mathematical phantom, and the studies involved four reconstruction strategies: the filtered-backprojection (FBP) and ordered-subset expectation-maximization (OSEM) algorithms with two- and three-dimensional postreconstruction filtering. The human-observer data was drawn from studies performed by Wells et al. (2000), while multiclass versions of the nonprewhitening (NPW), channelized nonprewhitening (CNPW), and channelized Hotelling (CH) model observers, each capable of performing the tumor search task, were applied. The channelized observers were evaluated with multiple square-channel models and both with and without internal noise. For the multislice studies, two different capacities for integrating the slice information were also tested. The CH observer gave good quantitative agreement with the human data from both image-display studies when the internal-noise model was used. The CNPW observer performed similarly with the iterative strategies. Wells et al. had shown that human observers are imperfect integrators of multislice information, and this is characterized as increased internal noise with the model observers.

Algorithms↗