Open half-volume quadrature transverse electromagnetic coil for high-field magnetic resonance imaging.

A half-volume quadrature head transverse electromagnetic (TEM) coil has been constructed for 4 T imaging applications. This coil produces a sufficiently large homogeneous B(1) field region for the use as a volume coil. It provides superior transmission efficiency, resulting in significantly lower power deposition, as well as greater sensitivity and improved patient comfort and accessibility compared with conventional full-volume coils. Additionally, this coil suppresses the RF penetration artifact that distorts the RF magnetic field profile and alters the intensity in high-field images recorded with linear surface and volume coils. These advantages make it possible to apply this device as an efficient transmit/receive coil for high-field imaging with a restricted field of view.

Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis.

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant- and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strain-specific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.

Quantitative functional imaging of the brain: towards mapping neuronal activity by BOLD fMRI.

Quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) measurements of energy metabolism (i.e. cerebral metabolic rate of oxygen consumption, CMR(O2)), blood circulation (i.e. cerebral blood flow, CBF, and volume, CBV), and functional MRI (fMRI) signal over a wide range of neuronal activity and pharmacological treatments are used to interpret the neurophysiologic basis of blood oxygenation level dependent (BOLD) image-contrast at 7 T in glutamatergic neurons of rat cerebral cortex. Multi-modal MRI and MRS measurements of CMR(O2), CBF, CBV and BOLD signal (both gradient-echo and spin-echo) are used to interpret the neuroenergetic basis of BOLD image-contrast. Since each parameter that can influence the BOLD image-contrast is measured quantitatively and separately, multi-modal measurements of changes in CMR(O2), CBF, CBV, BOLD fMRI signal allow calibration and validation of the BOLD image-contrast. Good agreement between changes in CMR(O2) calculated from BOLD theory and measured by (13)C MRS, reveals that BOLD fMRI signal-changes at 7 T are closely linked with alterations in neuronal glucose oxidation, both for activation and deactivation paradigms. To determine the neurochemical basis of BOLD, pharmacological treatment with lamotrigine, which is a neuronal voltage-dependent Na(+) channel blocker and neurotransmitter glutamate release inhibitor, is used in a rat forepaw stimulation model. Attenuation of the functional changes in CBF and BOLD with lamotrigine reveals that the fMRI signal is associated with release of glutamate from neurons, which is consistent with a link between neurotransmitter cycling and energy metabolism. Comparisons of CMR(O2) and CBF over a wide dynamic range of neuronal activity provide insight into the regulation of energy metabolism and oxygen delivery in the cerebral cortex. The current results reveal the energetic and physiologic components of the BOLD fMRI signal and indicate the required steps towards mapping neuronal activity quantitatively by fMRI at steady-state. Consequences of these results from rat brain for similar calibrated BOLD fMRI studies in the human brain are discussed.

Changes in rat cerebral blood volume due to modulation of the 5-HT(1A) receptor measured with susceptibility enhanced contrast MRI.

Brain blood volume changes in the rat in response to 5-HT(1A) agonist and antagonist administration were measured using susceptibility contrast enhanced magnetic resonance imaging (MRI). Administration of the 5-HT(1A) agonist 8-OH-DPAT resulted in decreases in fractional brain blood volumes. Administration of the 5-HT(1A) antagonist WAY-100635 following a dose of 8-OH-DPAT resulted in increases in fractional blood volumes greatest in hippocampus and cortex and smallest in thalamus and caudate-putamen. The magnitude of the regional increases in blood volumes paralleled the distribution of 5-HT(1A) receptors in the rat brain. Administration of WAY-100635 alone resulted in decreases in cortical blood volume and increases in cerebellar blood volume.

The relationship of problems in biomedical MRI to the study of porous media.

The NMR methods that are used to characterize inanimate porous media measure relaxation times and related phenomena and material transport, fluid displacement and flow. Biological tissues are comprised of multiple small, fluid-filled compartments, such as cells, that restrict the movement of the bulk solvent water and whose constituents influence water proton relaxation times via numerous interactions with macromolecular surfaces. Several of the methods and concepts that have been developed in one field of application are also of great value in the other, and it may be expected that technical developments that have been spurred by biomedical applications of MR imaging will be used in the continuing study of porous media. Some recent specific studies from our laboratory include the development of multiple quantum coherence methods for studies of ordered water in anisotropic macromolecular assemblies, studies of the degree of restriction of water diffusion in cellular systems, multiple selective inversion imaging to depict the ratios of proton pool sizes and rates of magnetization transfer between proton populations, and diffusion tensor imaging to depict tissue anisotropies. These illustrate how approaches to obtain structural information from biological media are also relevant to porous media. For example, the recent development of oscillating gradient spin echo techniques (OGSE), an approach that extends our ability to resolve apparent diffusion changes over different time scales in tissues, has also been used to compute surface to volume measurements in assemblies of pores. Each of the new methods can be adapted to provide spatially resolved quantitative measurements of properties of interest, and these can be efficiently acquired with good accuracy using fast imaging methods such as echo planar imaging. The community of NMR scientists focused on applications to porous media should remain in close communication with those who use MRI to study problems in biomedicine, to their mutual benefits.

The type IV fimbrial subunit gene (fimA) of Dichelobacter nodosus is essential for virulence, protease secretion, and natural competence.

Dichelobacter nodosus is the essential causative agent of footrot in sheep. The major D. nodosus-encoded virulence factors that have been implicated in the disease are type IV fimbriae and extracellular proteases. To examine the role of the fimbriae in virulence, allelic exchange was used to insertionally inactivate the fimA gene, which encodes the fimbrial subunit protein, from the virulent type G D. nodosus strain VCS1703A. Detailed analysis of two independently derived fimA mutants revealed that they no longer produced the fimbrial subunit protein or intact fimbriae and did not exhibit twitching motility. In addition, these mutants were no longer capable of undergoing natural transformation and did not secrete wild-type levels of extracellular proteases. These effects were not due to polar effects on the downstream fimB gene because insertionally inactivated fimB mutants were not defective in any of these phenotypic tests. Virulence testing of the mutants in a sheep pen trial conducted under controlled environmental conditions showed that the fimA mutants were avirulent, providing evidence that the fimA gene is an essential D. nodosus virulence gene. These studies represent the first time that molecular genetics has been used to determine the role of virulence genes in this slow growing anaerobic bacterium.

Dysprosium-bearing red cells as potential transverse relaxation agents for MRI.

The cytosol of intact human red blood cells was loaded with 28.1 +/- 3.4 mM of dysprosium DTPA-BMA using a hypoosmotic technique. When loaded cells were diluted with saline and control cells to give an average dysprosium concentration of 3.3 +/- 0.5 mM, the transverse relaxation rate constants R(*)(2) and R(2) increased. R(*)(2) increased from 7.5 +/- 0.9 sec(-1) to 356 +/- 50 sec(-1), and R(2) increased from 7.4 +/- 0.7 sec(-1) to 148 +/- 40 sec(-1). After lysing, R(*)(2) was 6.0 +/- 0.6 sec(-1) in the control and 13.4 +/- 1.5 sec(-1) in the mixture; R(2) was 6.4 +/- 1.1 sec(-1) and 9.8 +/- 2.4 sec(-1), respectively. Thus, the relaxivity effects were enhanced by sequestration of the dysprosium within intact red cells, and this effect was lost after lysis. At a circulating whole-blood concentration of 0.81 +/- 0.15 mM in rats, the liver signal intensity dropped 29.9% +/- 3.7% and kidney signal intensity dropped 19.4% +/- 8.7%. Dysprosium-loaded cells might be useful in the study of perfusion and tissue blood volume.

Intravascular susceptibility agent effects on tissue transverse relaxation rates in vivo.

Since vascular architecture differs among tissues, it was hypothesized that the change in transverse relaxation rate produced by a given tissue concentration of susceptibility contrast agent also varies by tissue. This is relevant to strategies to map regional blood volume by MRI using indicator dilution techniques. R*(2) was measured in rat organs over a range of susceptibility agent concentrations at 1.5 T. Rat red blood cells loaded with dysprosium-DTPA-BMA served as an intravascular susceptibility agent. Tissue samples were frozen in vivo and dysprosium concentrations were independently measured using inductively coupled plasma atomic emission spectroscopy. The slope (k) of R*(2) vs. tissue dysprosium concentration in sec(-1) mM(-1) for myocardium was 97.1 (95% C.I. 77. 0-117.2), liver 122.6 (108.3-136.9), spleen 22.5 (8.8-36.3), kidney 68.1 (58.6-77.6), and skeletal muscle 77.9 (4.1-151.6); k was significantly different (P < 0.05) for all pairings except those with skeletal muscle. Therefore, relative values of tissue blood volume derived from dynamic images of first pass contrast effects may be in error because k is not constant for different conditions.

A model for susceptibility artefacts from respiration in functional echo-planar magnetic resonance imaging.

Respiration causes variations in the signals acquired during magnetic resonance imaging (MRI) and therefore is a significant source of noise in functional brain imaging. A primary component of respiratory noise may arise from variations of bulk susceptibility or air volume in the chest. Here we investigate the nature of the image artefacts that can be caused by such changes. We develop a simple model which attempts to mimic the effects of variations in susceptibility and volume during respiration. Theoretical calculations, computer simulations and imaging experiments with this model show that small variations in susceptibility within the thorax from alterations in the paramagnetism of cavity gas may lead to a shift of the image on the order of 0.1 pixels as well as a shading of the intensity by +/-1%. These effects are observed to be predominant in the phase-encoding direction. They may lead to the production of spurious activations in functional MRI and are likely to be of more importance at higher field strengths.

Assessment of heating effects in skin during continuous wave near infrared spectroscopy.

Near infrared spectroscopy is an increasingly important tool for the investigation of human brain function, however, to date there have been few systematic evaluations of accompanying thermal effects due to absorption. We have measured the spatial distribution of temperature changes during near infrared irradiation (789 nm) as a function of laser power, in both excised tissue (chicken meat and skin) and in the forearm of an awake human volunteer. Light was applied using a 1 mm optical fiber which is characteristic of the topographic system. The temperature of excised chicken tissue increased linearly with power level as 0.097 and 0.042 degrees C/mW at depths of 0 and 1 mm, respectively. Human forearm studies yielded temperature changes of 0.101, 0.038, and 0.030 degrees C/mW at depths of 0.5, 1.0, and 1.5 mm, respectively. Due to direct irradiation of the thermocouple all measurements represent the maximum temperature increase from the laser. In all cases the estimated heating effects from continuous wave optical topography systems were small and well below levels which would endanger tissue cells. The close similarity between ex vivo and in vivo measurements suggests negligible contributions from blood flow in the skin which was further supported by measurements during cuff ischemia. Heating effects decreased sharply with both depth and lateral position; thus, for optode spacings greater than a few millimeters, fibers can be treated independently. Finite element analysis confirms that the experimental results are consistent with a simple heat conduction model.

Effects of hypoglycemia on functional magnetic resonance imaging response to median nerve stimulation in the rat brain.

The authors studied the effects of a standardized mild-moderate hypoglycemic stimulus (glucose clamp) on brain functional magnetic resonance imaging (fMRI) responses to median nerve stimulation in anesthetized rats. In the baseline period (plasma glucose 6.6 +/- 0.3 mmol/L), the MR signal changes induced by median nerve activation were determined within a fixed region of the somatosensory cortex from preinfusion activation maps. Subsequently, insulin and a variable glucose infusion were administered to decrease plasma glucose. The goal was to produce a stable hypoglycemic plateau (2.8 +/- 0.2 mmol/L) for 30 minutes. Thereafter, plasma glucose was restored to euglycemic levels (6.0 +/- 0.3 mmol/L). In the early phase of insulin infusion (15 to 30 minutes), before hypoglycemia was reached (4.7 +/- 0.3 mmol/L), the activation signal was unchanged. However, once the hypoglycemic plateau was achieved, the activation signal was significantly decreased to 57 +/- 6% of the preinfusion value. Control regions in the brain that were not activated showed no significant changes in MR signal intensity. Upon return to euglycemia, the activation signal change increased to within 10% of the original level. No significant activation changes were noted during euglycemic hyperinsulinemic clamp experiments. The authors concluded that fMRI can detect alterations in cerebral function because of insulin-induced hypoglycemia. The signal changes observed in fMRI activation experiments were sensitive to blood glucose levels and might reflect increases in brain metabolism that are limited by substrate deprivation during hypoglycemia.

High-resolution CMR(O2) mapping in rat cortex: a multiparametric approach to calibration of BOLD image contrast at 7 Tesla.

The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) method, which is sensitive to vascular paramagnetic deoxyhemoglobin, is dependent on regional values of cerebral metabolic rate of oxygen utilization (CMR(O2)), blood flow (CBF), and volume (CBV). Induced changes in deoxyhemoglobin function as an endogenous contrast agent, which in turn affects the transverse relaxation rates of tissue water that can be measured by gradient-echo and spin-echo sequences in BOLD fMRI. The purpose here was to define the quantitative relation between BOLD signal change and underlying physiologic parameters. To this end, magnetic resonance imaging and spectroscopy methods were used to measure CBF, CMR(O2), CBV, and relaxation rates (with gradient-echo and spin-echo sequences) at 7 Tesla in rat sensorimotor cortex, where cerebral activity was altered pharmacologically within the autoregulatory range. The changes in tissue transverse relaxation rates were negatively and linearly correlated with changes in CBF, CMR(O2), and CBV. The multiparametric measurements revealed that CBF and CMR(O2) are the dominant physiologic parameters that modulate the BOLD fMRI signal, where the ratios of (deltaCMR(O2)/CMR(O2)/(deltaCBF/ CBF) and (deltaCBV/CBV)/(deltaCBF/CBF) were 0.86 +/- 0.02 and 0.03 +/- 0.02, respectively. The calibrated BOLD signals (spatial resolution of 48 microL) from gradient-echo and spin-echo sequences were used to predict changes in CMR(O2) using measured changes in CBF, CBV, and transverse relaxation rates. The excellent agreement between measured and predicted values for changes in CMR(O2) provides experimental support of the current theory of the BOLD phenomenon. In gradient-echo sequences, BOLD contrast is affected by reversible processes such as static inhomogeneities and slow diffusion, whereas in spin-echo sequences these effects are refocused and are mainly altered by extravascular spin diffusion. This study provides steps by which multiparametric MRI measurements can be used to obtain high-spatial resolution CMR(O2) maps.

Quantitative multi-modal functional MRI with blood oxygenation level dependent exponential decays adjusted for flow attenuated inversion recovery (BOLDED AFFAIR).

A magnetic resonance imaging (MRI) method is described that allows interleaved measurements of transverse (R(2)(*) and R(2)) and longitudinal (R(1)) relaxation rates of tissue water in conjunction with spin labeling. The image-contrasts are intrinsically blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) weighted, but each contrast is made quantitative by two echo time (TE) and inversion recovery time (TIR) acquisitions with gradient echo (GE) and spin echo (SE) weighted echo-planar imaging (EPI). The EPI data were acquired at 7 Tesla with nominal spatial resolution of 430 x 430 x 1000 microm(3) in rat brain in vivo. The method is termed as blood oxygenation level dependent exponential decays adjusted for flow attenuated inversion recovery (BOLDED AFFAIR) and allows acquisition of R(2)(*), R(2), and CBF maps in an interleaved manner within approximately 12 minute. The basic theory of the method, associated experimental/systematic errors, and temporal restrictions are discussed. The method is validated by comparison of multi-modal maps obtained by BOLDED AFFAIR (i.e., two TE and TIR values with GE and SE sequences) and conventional approach (i.e., multiple TE and TIR values with GE and SE sequences) during varied levels of whole brain activity. Preliminary functional data from a rat forepaw stimulation model demonstrate the feasibility of this method for functional MRI (fMRI) studies. It is expected that with appropriate precautions this method in conjunction with contrast agent-based MRI has great potential for quantitative fMRI studies of mammalian cortex.

Dependence of oxygen delivery on blood flow in rat brain: a 7 tesla nuclear magnetic resonance study.

Magnetic resonance imaging (MRI) and spectroscopy (MRS) were used at a magnetic field strength of 7 T to measure CBF and CMRO2 in the sensorimotor cortex of mature rats at different levels of cortical activity. In rats maintained on morphine anesthesia, transitions to lower activity and higher activity states were produced by administration of pentobarbital and nicotine, respectively. Under basal conditions of morphine sulfate anesthesia, CBF was 0.75 +/- 0.09 mL x g(-1) x min(-1) and CMRO2 was 3.15 +/- 0.18 micromol x g(-1) x min(-1). Administration of sodium pentobarbital reduced CBF and CMRO2 by 66% +/- 16% and 61% +/- 6%, respectively (i.e., "deactivation"). In contrast, administration of nicotine hydrogen tartrate increased CBF and CMRO2 by 41% +/- 5% and 30% +/- 3%, respectively (i.e., "activation"). The resting values of CBF and CMRO2 for alpha-chloralose anesthetized rats were 0.40 +/- 0.09 mL x g(-1) x min(-1) and 1.51 +/- 0.06 micromol x g(-1) x min(-1), respectively. Upon forepaw stimulation, CBF and CMRO2 were focally increased by 34% +/- 10% and 26% +/- 12%, respectively, above the resting nonanesthetized values (i.e., "activation"). Incremental changes in CBF and CMRO2, when expressed as a percentage change for "deactivation" and "activation" from the respective control conditions, were linear (R2 = 0.997) over the entire range examined with the global and local perturbations. This tight correlation for cerebral oxygen delivery in vivo is supported by a recent model where the consequence of a changing effective diffusivity of the capillary bed for oxygen, D, has been hypothetically shown to be linked to alterations in CMRO2 and CBF. This assumed functional characteristic of the capillary bed can be theoretically assessed by the ratio of fractional changes in D with respect to changes in CBF, signified by omega. A value 0.81 +/- 0.23 was calculated for omega with the in vivo data presented here, which in turn corresponds to a supposition that the effective oxygen diffusivity of the capillary bed is not constant but presumably varies to meet local requirements in oxygen demand in a similar manner with both "deactivation" and "activation."

Density matrix simulations of the effects of J coupling in spin echo and fast spin echo imaging.

A computer simulation has been used to calculate the effects of J coupling on the amplitudes of echoes produced by CPMG sequences. The program computes the evolution of the density matrix for different pulse intervals and can predict the signals obtainable from spin systems of any size and complexity. Results from the simulation confirm the prediction that a decrease in the effects of J coupling is largely responsible for the bright fat signal seen in fast spin echo imaging at high pulse rates. The effects of J coupling on CPMG echotrains are examined for A3B2 and A3B2C2 spin systems over a wide range of J coupling and chemical shift values and pulse spacings. The effects of J coupling on the point spread function obtained with fast spin echo imaging are also discussed.

Quantitative imaging of magnetization transfer using multiple selective pulses.

New spectroscopic and imaging methods have been developed for quantitatively measuring magnetization transfer (MT). These methods use trains of radiofrequency (rf) pulses with pulse separations much longer than 1/k(mf) and pulse durations much shorter than 1/k(mf), where k(mf) is the rate of MT from the immobile (macromolecular) protons to the mobile (free water) protons. Signal sensitivity to MT occurs when these pulses affect the mobile and immobile proton pools to different degrees. The signal from water may be quantitatively related to the macromolecular content of the sample using theory. The method has been used to make quantitative measurements of macromolecular content in cross-linked bovine serum albumin and employed in conjunction with echoplanar imaging to produce maps of the spatial distribution of the macromolecular content.

Analysis of J coupling-induced fat suppression in DIET imaging.

The DIET (or dual interval echo train) sequence, a modification of the fast spin echo (FSE) sequence that selectively reduces signal from fat in MR images, has been investigated. The DIET sequence uses an initial echo spacing longer than that of a conventional FSE sequence, thus allowing J coupling-induced dephasing to take effect. The sequence is evaluated theoretically, and its effectiveness on a hydrocarbon (1-pentene) is demonstrated numerically using density matrix calculations. The sequence is also evaluated experimentally using in vitro solutions and in vivo imaging. The efficacy of the sequence is compared for different lipid chemical structures, field strengths, and pulse sequence parameters.

Higher-order brain function analysis by trans-cranial dynamic near-infrared spectroscopy imaging.

Near-infrared spectroscopy is discussed from the viewpoint of human higher-order brain function analysis. Pioneering work in this field is reviewed; then we describe our concept of noninvasive trans-cranial dynamic optical topography and its instrumentation. Also, the validity of its functional images is assessed from both physical and physiological viewpoints. After confirming the validity of this method, we have applied it to a wide variety of fields such as clinical medicine, cognitive science, and linguistics in collaboration with researchers at several other institutes. Further application possibilities and the future of trans-cranial dynamic optical topography are also discussed. © 1999 Society of Photo-Optical Instrumentation Engineers.

Physiological basis for BOLD MR signal changes due to neuronal stimulation: separation of blood volume and magnetic susceptibility effects.

An NMR method is applied for separating blood volume and magnetic susceptibility effects in response to neuronal stimulation in a rat model. The method uses high susceptibility contrast agents to enhance blood volume induced signal changes. In the absence of exogenous agent, the dominant source of signal change on neuronal activation is associated with the signal increase from the blood oxygen level dependent (BOLD) effect. The relative negative contribution of blood volume changes to BOLD changes is maximally estimated to be 34%. The blood volume changes associated with median nerve stimulation (7 Hz) in the motor cortex are 26+/-7% and the corresponding blood susceptibility changes are 0.021+/-0.006 ppm. These methods can be applied to enhance the sensitivity of fMRI signal response and provide accurate quantitative measures of blood volume response to stimulation.