Contrasts in cortical magnesium, phospholipid and energy metabolism between migraine syndromes.

BACKGROUND: Previous single voxel (31)P MRS pilot studies of migraine patients have suggested that disordered energy metabolism or Mg(2+) deficiencies may be responsible for hyperexcitability of neuronal tissue in migraine patients. These studies were extended to include multiple brain regions and larger numbers of patients by multislice (31)P MR spectroscopic imaging. METHODS: Migraine with aura (MWA), migraine without aura (MwoA), and hemiplegic migraine patients were studied between attacks by (31)P MRS imaging using a 3-T scanner. RESULTS: Results were compared with those in healthy control subjects without headache. In MwoA, consistent increases in phosphodiester concentration [PDE] were measured in most brain regions, with a trend toward increase in [Mg(2+)] in posterior brain. In MWA, phosphocreatine concentration ([PCr]) was decreased to a minor degree in anterior brain regions and a trend toward decreased [Mg(2+)] was observed in posterior slice 1, but no consistent changes were found in phosphomonoester concentration [PME], [PDE], inorganic phosphate concentration ([Pi]), or pH. In hemiplegic migraine patients, [PCr] had a tendency to be lower, and [Mg(2+)] was significantly lower than in the posterior brain regions of control subjects. Trend analysis showed a significant decrease of brain [Mg(2+)] and [PDE] in posterior brain regions with increasing severity of neurologic symptoms. CONCLUSIONS: Overall, the results support no substantial or consistent abnormalities of energy metabolism, but it is hypothesized that disturbances in magnesium ion homeostasis may contribute to brain cortex hyperexcitability and the pathogenesis of migraine syndromes associated with neurologic symptoms. In contrast, migraine patients without a neurologic aura may exhibit compensatory changes in [Mg(2+)] and membrane phospholipids that counteract cortical excitability.

Single-voxel proton MRS of the human brain at 1.5T and 3.0T.

Single-voxel proton spectra of the human brain were recorded in five subjects at both 1.5T and 3.0T using the STEAM pulse sequence. Data acquisition parameters were closely matched between the two field strengths. Spectra were recorded in the white matter of the centrum semiovale and in phantoms. Spectra were compared in terms of resolution and signal-to-noise ratio (SNR), and transverse relaxation times (T(2)) were estimated at both field strengths. Spectra at 3T demonstrated a 20% improvement in sensitivity compared to 1.5T at short echo times (TE = 20 msec), which was lower than the theoretical 100% improvement. Spectra at long echo times (TE = 272 msec) exhibited similar SNR at both field strengths. T(2) relaxation times were almost twofold shorter at the higher field strength. Spectra in phantoms demonstrated significantly improved resolution at 3T compared to 1.5T, but resolution improvements in in vivo spectra were almost completely offset by increased linewidths at higher field.

Automated three-dimensional signature model for assessing brain injury in emergent stroke.

This presentation will focus on the value of established and newer MR methods that can be applied to the diagnosis and management of ischemic stroke with emphasis on future applications of MR to provide previously unmet needs of the treating clinician and clinical trials. Time alone is an inadequate indicator of the therapeutic window, especially when the time of stroke onset is uncertain. Thus, there is a need to predict the evolution of stroke in a way that more precisely and with greater resolution identifies the progression of cellular damage at the moment of investigation. This also would be of value for thrombolysis when knowledge of the degree and extent of tissue necrosis and the consequent potential for brain hemorrhage is of the utmost importance. To provide this, we perform postprocessing of diffusion-, T(1)- and T(2)-weighted images to produce the apparent diffusion coefficient of water, and T(1) and T(2) maps that are then further processed to provide maps and quantitation of the tissue signatures of ischemic histopathology. By these means, we can accomplish objective volumetric analysis of infarct size and of the proportions of potentially viable and salvageable tissue. We will show how this has the potential to predict long-term stroke outcome and facilitate decision-making in terms of safety of reperfusion strategies and the appropriateness of cytoprotective treatment. The value of our approach is to replace time as the therapeutic window and extend the opportunity of treatment to those patients presenting beyond the stringent time limits employed in current investigative clinical trials. Further, used as a surrogate marker of clinical outcome, this form of stroke analysis may speed proof of principle clinical trials in small numbers of stroke patients.

Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a mitochondrial defect in claudicating skeletal muscle.

OBJECTIVE: Decreased oxygen supply is generally accepted as the primary cause of muscle dysfunction in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication, although reported morphologic changes in the mitochondria of claudicating muscle suggest that impaired energy utilization may also play a role. With the measurement of the phosphate-rich compounds of muscle energy metabolism (adenosinetriphosphate [ATP], adenosinediphosphate [ADP], and phosphocreatine [PCr]) and pH, phosphorus P 31 magnetic resonance spectroscopy ((31)P MRS) provides a unique, noninvasive method to investigate this hypothesis further. METHODS: Calf muscle bioenergetics were studied in 12 men with moderate claudication (ankle-brachial index >/=0.5 and .5, Pearson moment correlation). CONCLUSIONS: Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication.

Effects of the anti-migraine drug sumatriptan on muscle energy metabolism: relationship to side-effects.

Sumatriptan succinate (Imitrex) is a 5-HT (5-hydroxytryptamine) agonist used for relief of migraine symptoms. Some individuals experience short-lived side-effects, including heaviness of the limbs, chest heaviness and muscle aches and pains. The effects of this drug on skeletal muscle energy metabolism were studied during short submaximal isometric exercises. We studied ATP flux from anaerobic glycolysis (An Gly), the creatine kinase reaction (CK) and oxidative phosphorylation (Ox Phos) using 31P nuclear magnetic resonance spectroscopy (31P MRS) kinetic data collected during exercise. It was found that side-effects induced acutely by injection of 6 mg sumatriptan succinate s.c. were associated with reduced oxygen storage in peripheral skeletal muscle 5-20 min after injection as demonstrated by a transient reduction in mitochondrial function at end-exercise. These results suggest that mild vasoconstriction in peripheral skeletal muscle is associated with the action of sumatriptan and is likely to be the source of the side-effects experienced by some users. Migraine with aura patients were more susceptible to this effect than migraine without aura patients.

31P MRS studies of exercising human muscle at high temporal resolution.

Methods for measuring mitochondrial activity from 31P magnetic resonance spectroscopy data collected during and after exercise were compared in controls, weight lifters, and peripheral vascular occlusive disease (PVOD) patients. There were trends toward increasing mitochondrial activity during exercise in order from PVOD patients, moderately active controls, highly active controls, to weight lifters. Results from PVOD patients show divergence of some measures due to 1) the non-exponential nature of phosphocreatine recovery, and 2) potential breakdown of [ADP] control of the mitochondria due to lack of oxygen (for Qmax calculation). These results demonstrate the utility of obtaining and directly analyzing high time resolution data rather than assuming monoexponential behavior of metabolite recovery.

T1 measurements of 31P metabolites in resting and exercising human gastrocnemius/soleus muscle at 1.5 Tesla.

This study has measured the apparent 31P T1 times at 1.5 T in human gastrocnemius/soleus muscle groups at rest, during exercise, and during recovery from a 90-sec submaximal plantar flexion exercise. T1 times were measured with a 10-sec time resolution in 11 normally active volunteers using a surface coil with a nine-point progressive saturation technique. A two-point short repetition time technique was also used. Both techniques showed similar trends in the apparent T11 times of all the 31P metabolites at rest, during exercise, and during recovery. For the nine-point progressive saturation technique, the apparent T1 of PCr and beta-ATP decreased approximately 20% to a steadystate value (P = 0.027 and P = 0.004, respectively). The two-point short repetition time technique demonstrated a 10% reduction in the apparent T1 of PCr and beta-ATP Both techniques demonstrated an apparent T1 increase of 58% for inorganic phosphate at the beginning of exercise (P<0.0001) and a return to resting value during the 90-sec submaximal isometric contraction. Neither technique showed any significant differences between resting and exercising T1 times of the alpha-ATP and gamma-ATP resonances (P = 0.06 and P>0.40, respectively).

Magnesium and pH imaging of the human brain at 3.0 Tesla.

Multislice, two-dimensional phosphorus 31 spectroscopic imaging (SI) of human brain was performed in 15 normal volunteers on a 3-Tesla magnetic resonance system. Images of free magnesium concentrations and pH as well as phosphoesters, inorganic phosphate, phosphocreatine, and adenosine triphosphate (ATP), were calculated from the SI data. By using the equations of Golding and Golding (Magn. Reson. Med. 1995;33: 467-474), average [Mg2+] for all brain regions studied was 0.42+/-0.05 mM, whereas average brain pH was found to be 7.07+/-0.03, with no significant regional variations. Phosphorus metabolite concentrations (relative to ATP, assumed to be 3.0 mM/kg wet weight)were 5.39+/-1.88, 1.30+/-0.39, 5.97+/-3.17, and 4.33+/-1.45 mM/kg wet weight for phosphomonoesters, inorganic phosphate, phosphodiesters, and phosphocreatine (PCr), respectively. These values are in good general agreement with those reported previously. Typical signal-to-noise ratios of 15:1 were obtained for PCr in spectra from nominal 31.5 cc voxel sizes with a 34-min scan time. Limits on spatial resolution and the likely error of the magnesium and pH values are discussed.

Non-P(i) buffer capacity and initial phosphocreatine breakdown and resynthesis kinetics of human gastrocnemius/soleus muscle groups using 0.5 s time-resolved (31)P MRS at 4.1 T.

High-time-resolution (0.5 s) (31)P MRS has been used to evaluate the initial phosphoreatine (PCr) breakdown and resynthesis kinetics, to calculate the non-P(i)(/non-bicarbonate) buffer capacity (betanon-P(i)(/non-bicarb)), and to calculate the constant relating the change in intracellular pH to the muscle's H(+) efflux rate (lambda). The slope of PCr vs time demonstrates that a slope calculated using the first 10 s of recovery underestimates initial PCr recovery rates by up to 56%. A 1-2 s time window is needed to produce a slope that is statistically equivalent to the slope measured using a 0.5 s time window (p = 0.008, one-way RM-ANOVA, Student-Newman-Keuls multiple comparison test). In addition, there was no delay or acceleration in PCr recovery after a 90 s maximum voluntary contraction (MVC) in normal subjects. This demonstrates that oxidative metabolism is occurring at the end of a 90-s MVC in normal individuals. Fitting recovery data has determined that betanon-P(i)(/non-bicarb) = 24.3 +/- 5.4 slyke (mmol/L/pH unit) and that lambda = 0.129 +/- 0.077 mM/(ph s) for human gastrocnemius/soleus muscle. betanon-P(i)(/non-bicarb) is in agreement with measurements in cat biceps, cat soleus and rat gastrocnemius muscles.

Time course of ADCw changes in ischemic stroke: beyond the human eye!

BACKGROUND AND PURPOSE: Using newly developed computerized image analysis, we studied the heterogeneity of apparent diffusion coefficient of water (ADCw) values in human ischemic stroke within 10 hours of onset. METHODS: Echo-planar trace diffusion-weighted images from 9 patients with focal cortical ischemic stroke were obtained within 10 hours of symptom onset. An Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm was implemented to segment different tissue types with a series of DW images. ADCw maps were calculated from 4 DW images on a pixel-by-pixel basis. The segmented zones within the lesion were characterized as low, pseudonormal, or high, expressed as a ratio of the mean+/-SD of ADCw of contralateral noninvolved tissue. RESULTS: The average ADCW in the ischemic stroke region within 10 hours of onset was significantly depressed compared with homologous contralateral tissue (626.6+/-76.8 versus 842.9+/-60.4x10(-6) mm2/s; P<0.0001). Nevertheless, ISODATA segmentation yielded multiple zones within the stroke region that were characterized as low, pseudonormal, and high. The mean proportion of low:pseudonormal:high was 72%:20%:8%. CONCLUSIONS: Despite low average ADCW, computer-assisted segmentation of DW MRI detected heterogeneous zones within ischemic lesions corresponding to low, pseudonormal, and high ADCw not visible to the human eye. This supports acute elevation of ADCw in human ischemic stroke and, accordingly, different temporal rates of tissue evolution toward infarction.

Preliminary clinical-radiological assessment of a MR tissue signature model in human stroke.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60

Adenosine triphosphate production rates, metabolic economy calculations, pH, phosphomonoesters, phosphodiesters, and force output during short-duration maximal isometric plantar flexion exercises and repeated maximal isometric plantar flexion exercises.

Measurements of adenosine triphosphate (ATP) production rates, metabolic economy, intracellular pH, phosphodiesters, and phosphomonoesters along with the force output were used to study 90-s maximum voluntary contractions and two new exercise protocols (20-10 and 30-16 exercises). The 20-10 exercise consisted of thirty-one 20-s maximal voluntary contractions separated by 10-s rest periods. The 30-16 exercise consisted of twenty 30-s maximal voluntary contractions separated by 16-s rest periods. There were no differences in ATP production rates, metabolic economy, intracellular pH, or force output between the 20-10 and 30-16 exercises. The 20-10 exercises accumulated more phosphomonoesters than the 30-16 exercises. These increases in phosphomonoesters may be attributed to increased accumulations of glucose-6-phosphate and/or inosine monophosphate. The increased perception of effort reported during and after the 20-10 exercises was not present during the 30-16 or 90-s exercises. This increased perception of effort may be related to increases in lactate, glucose-6-phosphate, inosine monophosphate, and/or NH3.

Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS.

Inadequate O2 supply may impair intramuscular oxidative metabolism and O2 availability may modulate ATP production within exercising muscle. Therefore, we studied ATP flux from anaerobic glycolysis, the creatine kinase reaction, and oxidative phosphorylation using 31P-magnetic resonance spectroscopy kinetic data collected during exercise. We examined six chronic obstructive pulmonary disease (COPD) patients with severe hypoxemia (group 1), seven COPD patients with mild hypoxemia (group 2), and seven healthy control subjects. Exercise (90-s isometric contraction of the gastrocnemius-soleus muscle group, 40% of max) was performed on room air for all subjects; for COPD patients, it was repeated during supplemental O2 at identical power outputs, with 60-min rest between the two sets. In group 1 (air vs. O2), oxidative phosphorylation ATP production was lower (P < 0.05), anaerobic glycolysis ATP production was higher (P < 0.05), and anaerobic glycolysis plus creatine kinase ATP production tended to be higher (P = 0.06). In group 2, no differences were observed across conditions. Assuming that mitochondrial size, density, function, and redox state were not affected by acute changes in the inspired O2 fraction, reduced O2 availability is the remaining factor that could have limited oxidative ATP production during hypoxemia. In conclusion, in severely hypoxemic COPD patients, O2 availability apparently limits intramuscular oxidative metabolism because acute hypoxemia increases anaerobic and decreases aerobic ATP production.

Factors which influence alterations of phosphates and pH in exercising human skeletal muscle: measurement error, reproducibility, and effects of fasting, carbohydrate loading, and metabolic acidosis.

Previous studies have shown considerable variability in the metabolic response of human skeletal muscle during a standardized exercise protocol. The goal of these studies was to investigate the factors responsible for the broad range of metabolic changes produced by fatiguing exercise. Experiments were performed to quantitate the measurement error of 31P nuclear magnetic resonance spectroscopy of human muscle, the reproducibility of changes within a single subject, and the effects of fasting, carbohydrate loading, and metabolic acidosis. The results show that none of these factors appear to be responsible for the wide variation between subjects. However, the effects of training and genetic factors were not investigated and are likely to be responsible for the substantial variability between subjects.

High frequency energy absorption and the measurement of limb muscle.

High frequency energy absorption (HFEA) is being developed as a portable, inexpensive, non-invasive procedure for the measurement of muscle mass within cross-sections of limbs. The instrument consists of a flexible coil 2.5 cm wide of which the length can be adjusted over a 10 cm range. A series of coils of different lengths has been constructed that are jointly suitable for limbs with circumferences ranging from 20 to 75 cm. To measure HFEA, a coil of appropriate length is attached to a 9v battery that, through an oscillator, produces a frequency varying from 15 MHz (longest coil) to 40 MHz (shortest coil). Zero readings, with the coil set at the same circumference as the limb, are obtained before and after HFEA is measured and they are used to adjust the observed values. HFEA, in theory, is related to the number of electrolytes deep to the coil and almost all these electrolytes are in muscle. Good precision has been demonstrated and the instrument has been successfully validated against saline solutions. A previous model was validated against magnetic resonance images with good results (r2 about 0.8). Further validation of the present model against magnetic resonance images is almost complete; these findings are presented.

P-31 spectroscopy study of response of superficial human tumors to therapy.

Studies were performed to characterize phosphorus-31 magnetic resonance (MR) spectra obtained from 10 superficial human tumors outside the brain and to determine whether P-31 MR spectroscopy could allow detection of a response to therapy before a change in tumor size was measured. The ratio of phosphomonoester to adenosine triphosphate peak intensities (PME/ATP) was unusually large in all tumors studied. The average PME/ATP in lymphomas (1.8 +/- 0.5) was greater than in nonlymphoma cancers (1.1 +/- 0.15). The average PME/ATP for all tumors studied (1.4 +/- 0.5) was much greater than that of underlying skeletal muscle (0.23 +/- .09). Eight of the tumors were studied before and after therapy. Responders were distinguished from nonresponders on the basis of changes in tumor size. PME/ATP decreased during therapy in three lymphomas that responded to therapy. In an adenocarcinoma and Ewing sarcoma that did not respond to therapy, PME/ATP increased. PME/ATP remained constant in two squamous cell carcinomas that responded to therapy and decreased in one squamous cell carcinoma that decreased in size by 40% but was classified as a nonresponder. Changes in PME/ATP did not always parallel changes in tumor size during therapy. In two patients, a decrease in PME/ATP preceded a decrease in tumor size. In four patients, PME/ATP increased transiently during periods when tumor size remained constant.

Constant relationships between force, phosphate concentration, and pH in muscles with differential fatigability.

We examined the relationships between muscle force and both phosphate and hydrogen ion concentrations in muscles with differential fatigability and in different types of exercise. We measured force and 31phosphorus nuclear magnetic resonance spectra from the tibialis anterior (a slow-contracting, fatigue resistant, postural leg muscle) during a sustained maximum contraction (anaerobic exercise) and during intermittent contractions (aerobic exercise). We observed similar relationships between the decline in muscle force during fatigue and changes in both phosphate and hydrogen ion concentrations during both aerobic and anaerobic exercise in tibialis anterior. Furthermore, these relationships were similar to those previously observed in the adductor pollicis. The demonstration of constant relationships between muscle contraction force and metabolism under different exercise conditions and in muscles of different function supports the view that both phosphate and hydrogen ions are important regulatory factors in the fatigue of human muscle.

Image-guided 31P magnetic resonance spectroscopy of normal and transplanted human kidneys.

Image-guided 31-phosphorus magnetic resonance spectroscopy (MRS) was used to obtain spatially localized 31P spectra of good quality from healthy normal human kidneys and from well-functioning renal allografts. A surface coil of 14 cm diameter was used for acquiring phosphorus signals solely from a volume-of-interest located within the kidney. To determine the effects of kidney transplantation on renal metabolism, patients with well functioning allografts were studied. Little or no phosphocreatine in all spectra verifies the absence of muscle contamination, and is consistent with proper volume localization. The intensity ratio of phosphomonoesters (PME) to adenosine triphosphate (ATP) resonances in transplanted kidneys (PME/ATP = 1.1 +/- 0.4) was slightly elevated (P = 0.2) compared to that of healthy normal kidneys (PME/ATP = 0.8 +/- 0.3). The inorganic phosphate (Pi) to ATP ratio was similar in the two groups (Pi/ATP = 1.1 +/- 0.1 in transplanted kidneys vs. 1.2 +/- 0.6 in normal kidneys). Acid/base status, as evidenced from the chemical shift of Pi, was the same in both normal controls and transplanted kidneys. Despite the practical problems produced by organ depth, respiratory movement, and tissue heterogeneity, these results demonstrate that image-guided 31P MR spectra can reliably be obtained from human kidneys.

Non-invasive quantitation of human liver metabolites using image-guided 31P magnetic resonance spectroscopy.

Phosphorus-containing metabolites in normal human liver have been quantitated non-invasively with 31P magnetic resonance spectroscopy using surface coils. The location of the volume of interest (VOI) was defined by 1H magnetic resonance imaging. Subsequently, a modified three-dimensional localization technique (ISIS) was used to acquire 31P magnetic resonance spectra from the VOI. To account for partial saturation produced by rapid signal averaging, the spin/lattice relaxation times (T1) of all hepatic phosphorus resonances were measured. The corrected resonance integrals were used to derive absolute molar concentrations for the following hepatic metabolites (mmol/kg wet weight): ATP, 2.0; inorganic phosphate, 2.1; phosphodiesters, 5.4; and phosphomonoesters, 0.9. These values are compared with previously reported values for humans using freeze-clamping techniques, and provide a basis for comparison with studies of hepatic disease in this laboratory.

The metabolic basis of recovery after fatiguing exercise of human muscle.

We investigated the metabolic basis of human muscular fatigue and recovery utilizing 31P magnetic resonance spectroscopy and measurements of maximum voluntary contraction (MVC). We produced fatigue by sustained MVC for 4 minutes in 2 different muscles (adductor pollicis, tibialis anterior) and obtained similar results in both muscles. During fatiguing exercise, there was a nonlinear relationship between MVC and both phosphocreatine and total inorganic phosphate. By contrast, there was a roughly linear relationship between the decline in MVC and the accumulation of both H+ and H2PO4-. However, during recovery after exercise, MVC rapidly returned to control levels while H+ recovered with a much slower time course. On the other hand, H2PO4- rapidly returned to control values with a time course similar to MVC. In addition, the relationship of H2PO4- to MVC was similar during both fatigue and recovery. Thus, during fatigue as well as during recovery, changes in MVC correlate best with H2PO4-, suggesting that this metabolite is an important factor in human muscle fatigue.