An implantable RF solenoid for magnetic resonance microscopy and microspectroscopy.

Miniature solenoids routinely enhance small volume nuclear magnetic resonance imaging and spectroscopy; however, no such techniques exist for patients. We present an implantable microcoil for diverse clinical applications, with a microliter coil volume. The design is loosely based on implantable depth electrodes, in which a flexible tube serves as the substrate, and a metal stylet is inserted into the tube during implantation. The goal is to provide enhanced signal-to-noise ratio (SNR) of structures that are not easily accessed by surface coils. The first-generation prototype was designed for implantation up to 2 cm, and provided initial proof-of-concept for microscopy. Subsequently, we optimized the design to minimize the influence of lead inductances, and to thereby double the length of the implantable depth (4 cm). The second-generation design represents an estimated SNR improvement of over 30% as compared to the original design when extended to 4 cm. Impedance measurements indicate that the device is stable for up to 24 h in body temperature saline. We evaluated the SNR and MR-related heating of the device at 3T. The implantable microcoil can differentiate fat and water peaks, and resolve submillimeter features.

Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis. Effect on arterial blood gases, lactate concentrations, hemodynamic variables, and myocardial intracellular pH.

The effects of Carbicarb, sodium bicarbonate, and sodium chloride on arterial blood gases, lactate concentrations, hemodynamics, and myocardial intracellular pH were compared in hypoxic lactic acidosis with controlled carbon dioxide elimination. Twenty-one young mongrel dogs were anesthetized, mechanically ventilated, and randomly allocated into one of three treatment groups. After hypoxic lactic acidosis was induced and maintained, 2.5 mEq/kg of one of the agents was infused over 30 min. Arterial blood gases, pH, lactate concentrations, and hemodynamic variables were measured immediately prior to the infusion of the agent and 30 min after the infusion was completed. With sodium bicarbonate administration, there was a significant increase in arterial PCO2 as compared to both Carbicarb or sodium chloride administration. With Carbicarb administration, there was a significant increase in arterial pH, base excess, and cardiac index, without a significant increase in arterial lactate concentration as compared to sodium bicarbonate or sodium chloride administration. Stroke volume index was also increased significantly with decreased heart rate. The data suggest that Carbicarb administration in hypoxic lactic acidosis improved hemodynamics compared with sodium bicarbonate or sodium chloride administration. The increased stroke volume and cardiac contractility appear to be due to improved myocardial intracellular pH.

Advances in human in vivo magnetic resonance spectroscopy.

Magnetic resonance spectroscopy holds promise as another tool for functional and metabolic assessment in diagnosis and in monitoring therapy. Although the maturation and acceptance of MR spectroscopy as a clinical tool lags significantly behind that of MR imaging, important technical and methodologic advances continue at a rapid pace. Some of the advances that have occurred recently are described in this review.

Tissue oxygenation: a novel determination using 19F surface coil NMR spectroscopy of sequestered perfluorocarbon emulsion.

This work examines the variation with oxygen tension (pO2) of the individual spin-lattice relaxation times (T1) of the 19F resonances of the perfluorocarbon emulsion Oxypherol-ET (FC-43). A linear relationship between 1/T1 and pO2 has been confirmed for all four resonances at any specific temperature. Using a saturation recovery sequence, T1 has been successfully measured using surface coil NMR spectroscopy. This has facilitated measurement of T1 in vivo in a subcutaneous murine tumor. Mice were predosed with Oxypherol-ET emulsion: following complete vascular clearance of the perfluorocarbon, 19F signal was observed specifically from material sequestered in tissue, thus avoiding flow artifacts. Comparison of the pO2 estimated from each of the 19F resonances provided an internal consistency check. A pO2 = 0.1 +/- 2.2% was determined in a Meth-A murine tumor. When the mouse breathed carbogen (95% O2, 5% CO2) no significant change in tumor pO2 was detected, whereas the pO2 in the liver showed a distinct increase.

Abnormal high-energy phosphate metabolism in human muscle phosphofructokinase deficiency.

We studied the pattern of high-energy phosphate metabolism in five patients with phosphofructokinase deficiency (PFKD) and five healthy subjects (HS) during graded rhythmic handgrip performed for 5 min at 17, 33, 50, and 100% of maximal voluntary contraction (MVC). The range of MVC was similar in both groups. Force production was recorded, and intracellular concentrations of phosphorus compounds and pH were measured in the flexor digitorum profundus of the active forearm. At exercise intensities greater than or equal to 50% MVC, changes in concentrations of high-energy phosphate metabolites were abnormal in PFKD. During maximal effort, [ADP], calculated from the creatine kinase reaction, was 64.3 +/- 13.5 (SE) mumol/kg in PFKD vs. 25.7 +/- 4.0 in HS (P less than 0.05). Ammonia (NH3), a product of AMP deamination and an index of muscle [AMP], increased approximately twofold more in venous effluent during maximal forearm exercise in PFKD than in HS (P less than 0.05). Phosphocreatine concentration was 9.4 +/- 1.3 (SE) mmol/kg in HS and 13.0 +/- 1.7 in PFKD (P less than 0.05). Inorganic phosphate concentration was 15.8 +/- 1.4 mmol/kg in HS and 7.4 +/- 0.5 in PFKD (P less than 0.05). During strenuous exercise, PFKD patients exhibit an impairment in the rephosphorylation of ADP related to a subnormal oxidative capacity, an absence of glycolysis, and an attenuated breakdown of phosphocreatine.

New directions in medical imaging of cancer. Magnetic resonance methods and single photon emission computed tomography.

Magnetic resonance methods and single photon emission computed tomography (SPECT) are developing technologies that provide both functional and anatomic information. Their role in the diagnosis and monitoring of cancer is the subject of current clinical research. Magnetic resonance imaging (MRI) delineates organs and tissue heterogeneities using differences in the relaxation parameters of water and fat protons; both protons and other nuclei can be imaged or studied by magnetic resonance spectroscopy (MRS) to provide information on the state of naturally occurring or infused molecules. SPECT quantifies the distribution of radiolabeled agents in tissues and organs; labeled monoclonal antibodies provide highly specific imaging of tumors. Spatial resolution is the limiting technologic factor. Proton MRI provides the highest current resolution, better than 1 mm in vivo in deep tissues, whereas the resolution of MRS and SPECT is limited to several cubic centimeters. Recent advances in these technologies have significantly increased their specificity and ability to detect small, deep lesions.

Improved MR imaging in extremely inhomogeneous radio-frequency fields.

An improvement to the method for imaging with extremely inhomogeneous radio-frequency fields is presented which uses a pseudo-noise-modulated selective (PNMS) excitation prepulse to randomize the signal from outside the selected slice. This prepulse reduces the problems that arise from imperfect subtraction involved with the one-dimensional ISIS-type slice selection procedures. The results demonstrate two to three times improvement in the signal-to-noise ratio and reduction in the image artifacts when this prepulse is used.

Multinuclear NMR investigations of probe construction materials at 4.7 T.

Since background signal from NMR probes can overwhelm the signal from a sample, the NMR analysis of plastics or machinable ceramics is a prerequisite to their use in probe implementations. The contributions from a variety of materials to proton, fluorine, and carbon NMR spectra are presented.

Effect of plasma glucose concentration on cerebral metabolism during partial ischemia in neonatal piglets.

We used neonatal piglets to determine the influence of plasma glucose concentration on cerebral energy metabolism during and immediately after partial ischemia. We assessed cerebral metabolism using in vivo phosphorus-31 magnetic resonance spectroscopy. Arterial plasma glucose concentration was increased in four piglets by systemic infusions of dextrose in water for comparison with infusions of saline in four controls or decreased in eight piglets by fasting for 24-48 hours for comparison with four fed piglets. Plasma glucose concentration showed a significant linear correlation with intracellular pH (r = -0.7, p less than 0.05). Piglets that developed hypoglycemia during partial ischemia had a smaller reduction in intracellular pH and a larger increase in inorganic phosphate content than piglets that were normoglycemic or hyperglycemic during ischemia. Similar differences persisted during the first 5 minutes of postischemic reperfusion. Subsequently, the cerebral concentrations of phosphorylated compounds returned to normal in all piglets. Our results demonstrate that 1) arterial plasma glucose concentration influences cerebral energy metabolism and intracellular pH during ischemia, 2) neonatal piglets can develop profound brain acidosis, and 3) brain acidosis during ischemia does not influence the restoration of cerebral phosphorylated compounds to control levels during the first 90 minutes after ischemia.

A novel editing technique for 19F MRI: molecule-specific imaging.

A novel technique is proposed to facilitate the selective imaging of specific molecules from a mixture. The application of the technique presented here demonstrates the ability to selectively produce 19F MR images of either trifluoroacetic acid or the perfluorocarbon emulsion Oxypherol-ET (perfluorotributylamine), when both molecules are present simultaneously. Selective detection is based on the presence of homonuclear J-modulation in one molecule and differential spin-spin relaxation time (T2). Perfluorotributylamine, an A3B2 system, is subject to homonuclear J-modulation, which produces a null signal from the antiphase components of the triplet (A3) when an echo time (TE) = 1/2J is used in a spin-echo image. At this echo time the second molecule, in this example trifluoroacetic acid, a non-coupled spin system, is selectively imaged. At longer echo times, e.g., TE = 1/J there is substantial recovery of the J-modulated signal, which may be solely observed due to T2 decay of the trifluoroacetic acid signal. The method is demonstrated both using phantoms and in vivo.

Applications of magnetic resonance techniques to deep tumor hyperthermia.

Magnetic resonance imaging and spectroscopy have the potential for supporting clinical hyperthermia advances in the treatment of deep tumors. Current spectroscopic techniques can monitor treatment delivery and effectiveness through changes in metabolism and blood flow. Spectra can be obtained in vivo, repetitively and noninvasively; furthermore, current techniques have been implemented to give spatially resolved information. Further advances in MRI/MRS techniques may make it possible to obtained the information necessary for individualized treatment planning, for qualitative monitoring and assessment of treatment results, and for the measurement of thermal fields in vivo.

1989 ARRS Executive Council Award. Exercise-enhanced MR imaging of variations in forearm muscle anatomy and use: importance in MR spectroscopy.

31P MR spectroscopic studies of forearm exercise frequently assume that the volume sampled is appropriate for the muscle of interest and that individual variations in muscle anatomy and use are not important. Postexercise MR imaging was used to assess variations in the size, location, and use of forearm flexors and the accuracy of palpation as a method for locating the muscle of interest. By using the information obtained with MR, the effects of errors in surface-coil position relative to the muscle of interest on 31P MR spectroscopy were examined. In the midforearm of seven men, the greatest diameter of the flexor carpi ulnaris was 29 +/- 4 mm, and that of the flexor digitorum superficialis was 28 +/- 6 mm. However, in the proximal forearm, 58 +/- 10% of the diameter was covered by the palmaris longus, when present (79% of subjects). An unexpected finding was that a focal portion of the superficial finger flexor was used primarily as a wrist flexor in 26% of subjects. Palpation incorrectly identified flexor muscle margins by more than 15 mm in 50% of attempts. When a surface coil was positioned over wrist flexors during handgrip, attenuation of exercise-induced changes in 31P spectra resulted. Exercise-enhanced MR imaging reveals variations in forearm muscle anatomy and use that are common and difficult to appreciate by palpation. It therefore allows improved localization of the sensitive volume for MR spectroscopic studies of muscle physiology.

Perfluorocarbon imaging in vivo: a 19F MRI study in tumor-bearing mice.

Multiresonance perfluorocarbon emulsions (Oxypherol and Fluosol-DA) were imaged in tumor-bearing mice using 19F spin-echo magnetic resonance imaging in vivo. Multiple thin-slice fluorine images free of chemical shift artifacts were obtained in 13 minutes and these were correlated with proton images obtained during the same experiment to delineate the anatomic distribution of perfluorocarbons. Sequential images were used to determine the time course of the distribution and the retention of the compounds in tumors and organs. 19F MR spectroscopy was used ex vivo to determine with high sensitivity the relative concentration of perfluorocarbons in different tissues and organs and to confirm the results obtained from imaging experiments. The fluorine images visually demonstrated the preferential localization of the perfluorocarbons in the liver and spleen; shortly after injection, the images also revealed the highly vascularized tumor-chest wall interface. Imaging and spectroscopy together showed that the perfluorocarbons were removed from the blood pool within hours and remained sequestered in tissues at later times; the highest concentrations were found in the spleen and liver, where the agents were retained without spectral changes for the duration of these studies. The perfluorocarbons accumulated within tumors at dose-dependent concentrations, one to two orders of magnitude smaller than those observed in the spleen and liver.

Effect of ischemia on NMR detection of phosphorylated metabolites in the intact rat heart.

Phosphorus NMR spectroscopy is an important technique for the investigation of metabolism in tissues and intact organisms (including man). However, quantitation of the signals from an NMR experiment is difficult because it is not known from which regions of a cell metabolites are detected. It is generally believed that only metabolites free in the cytosol are observed. In this study a comparison of concentration measurements obtained by NMR and after freeze extraction was made in the normoxic and ischemic rat heart. The influence of ischemia was examined because of its potential effect on the level of phosphate metabolites in various compartments. The same fraction of ATP always appears visible to NMR, whereas inorganic phosphate is largely NMR invisible until after a period of ischemia and the phosphomonoesters are only partially observed early in ischemia.

Use of 31P magnetic resonance spectroscopy to characterize evolving brain damage after perinatal asphyxia.

We investigated postasphyxial brain damage with 31P magnetic resonance spectroscopy (MRS) and correlated it with neurologic assessment and standard laboratory evaluation during the first 10 months of life in 1 infant, baby G. We compared these observations to 31P MRS data from 7 healthy term newborns, 1 normal infant examined serially over the first 8.5 months of life, and 5 other term infants following perinatal asphyxia. MRS noninvasively provides biochemical correlates of the evolution of brain damage following perinatal asphyxia and suggests that pH derived from the inorganic phosphate peak may serve as a marker for brain injury.

Hypotonia of rickets: a sequential study by P-31 magnetic resonance spectroscopy.

To address the role of high-energy phosphorus compounds in the hypotonia of vitamin D-dependent rickets, nuclear magnetic resonance spectra were obtained sequentially from resting gastrocnemius muscle of a 10-month-old infant with rachitic hypotonia during supplementation with vitamin D, calcium, and phosphorus. During the initial weeks of treatment, the hypotonia resolved before evidence of epiphyseal mineralization. Over the early treatment period, the muscle phosphocreatine/beta-adenosine triphosphate [PCr/beta-ATP] ratio increased from 2.7-2.8 [wk 1-2] to 3.9-4.5 [wk 7-9]. The PCr/beta-ATP ratio for 6-month-old normal infant gastrocnemius and adult forearm were 4.0 and 5.7, respectively. Muscle strength appeared to recover concomitantly with an increase in retained muscle phosphorus and high-energy phosphate compounds, and with relative increase in the muscle phosphocreatine to ATP ratio. The synchrony of clinical recovery may relate to the recovery kinetics of these metabolic changes.

Intracellular pH, lactate, and energy metabolism in neonatal brain during partial ischemia measured in vivo by 31P and 1H nuclear magnetic resonance spectroscopy.

Sequential 31P and 1H nuclear magnetic resonance spectra were measured for neonatal piglets (n = 7) to determine the relationship between brain intracellular pH (pHi), lactate, and phosphorylated energy metabolites during partial ischemia. Simultaneous determinations of arterial and cerebral venous blood gases, pH, O2 content, and plasma concentrations of glucose and lactate were also made. Ischemia, induced by bilateral carotid artery ligation plus hemorrhagic hypotension for 35 min, resulted in variable reductions in ATP, phosphocreatine, and increases in Pi, H+, and lactate relative to control levels. In four piglets, whose arterial blood glucose rose above control, brain lactate exceeded 20 mumol g-1 with corresponding decreases in pHi of greater than 0.7 units compared to control levels. The extents of brain acidosis and lactosis showed a strong linear correlation with each other (r = 0.94). Maximal changes in brain lactate, pHi, and ATP at the end of ischemia showed significant positive linear correlations with the control levels of arterial blood glucose, but did not correlate with arterial glucose or arterial cerebral-venous glucose difference values during ischemia. The relationship between pHi and buffer base deficit was comparable to results reported for adult animals up to 20 mumol ml-1. However, in contrast to models proposed for adult brain, the continued linear relationship between pH and higher buffer base levels is most consistent with a theoretical model that assumes the presence of weak acid buffers with pKa values from 6.7 to 5.2.

Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans.

We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.

Effects of repeated ischemia on cerebral blood flow and brain energy metabolism.

To determine if cerebral blood flow (CBF) and cerebral metabolic alterations during partial ischemia are affected by a prior interval of ischemia, 13 neonatal piglets were studied during two successive protocols (termed A and B), each consisting of an interval before, during and after partial ischemia induced by hypotension. Piglets were studied with either microspheres (n = 6) to measure CBF and calculate cerebral uptake of O2 and glucose or 31P nuclear magnetic resonance spectroscopy (n = 6) to measure intracellular pH (pHi) and cerebral phosphorylated metabolites. One piglet was used to determine time effects. Control values of all variables were similar during protocol A and B. In each protocol hypotension was associated with similar reductions in CBF and cerebral O2 uptake but cerebral glucose uptake differed (0.10 +/- 0.05 vs 0.05 +/- 0.02 mmol.min-1.100 g-1 during hypotension of A and B, respectively, p less than 0.05). During hypotension of protocol A and B similar changes in phosphorylated metabolites and pHi occurred and were characterized by a reduction in pHi, phosphocreatine and adenosine triphosphate and an increase in inorganic phosphate. Changes in phosphate metabolites and pHi were reversible within 25 min following hypotension in both protocols. Thus, changes in CBF, cerebral O2 uptake, pHi and cerebral energy metabolism are similar during repeated episodes of partial ischemia. However, differences in cerebral glucose uptake in protocol A and B raise the possibility that the balance between energy production and utilization is altered, or alternative substrates are metabolized or enzymatic activity in the glycolytic pathway is changed.

Alterations in cerebral blood flow and phosphorylated metabolites in piglets during and after partial ischemia.

Ventilated piglets were studied before, during (15 min), and after (90 min) hemorrhagic hypotension to correlate a 60% reduction in cerebral blood flow with cerebral energy state using radiolabeled microspheres (n = 12) and in vivo 31P nuclear magnetic resonance spectroscopy (n = 11). Cerebral blood flow (ml.min-1.100 g-1) decreased during hypotension (98 +/- 28 to 41 +/- 28, p less than 0.05), increased at 5 min postreperfusion (131 +/- 53, p less than 0.05), and returned to control values by 90 min postreperfusion. Cerebral O2 uptake was reduced during partial ischemia, remained depressed 5 min postreperfusion, and increased to within 20% of control values at 90 min postreperfusion. Relative to control, hypotension was associated with decreased (p less than 0.05) phosphocreatine (62 +/- 11%), phosphocreatine/inorganic phosphate ratio (41 +/- 10%), and nucleoside triphosphate (82 +/- 12%) while inorganic phosphate increased (155 +/- 32%, p less than 0.05). During ischemia intracellular pH dropped from 7.06 +/- 0.07 to 6.59 +/- 0.31 (p less than 0.05) and the cerebral arteriovenous difference of glucose increased. Phosphorylated metabolites returned to within 10% of control 15 min after blood reinfusion and remained constant thereafter. Based on calculations of ATP synthesis and utilization rates during control and hypotension, we speculate that the rate of energy utilization of the brain during ischemia is reduced 18-49% relative to the control utilization rate.