Glutamate levels in the medial prefrontal cortex of healthy pregnant women compared to non-pregnant controls.

Very little is known about maternal cerebral changes during pregnancy. Since there is an increased risk for major depression during pregnancy and postpartum, it is important to understand the structural and neurochemical changes that occur in the brain during pregnancy. Using proton magnetic resonance spectroscopy (1H-MRS) (3 T field strength), glutamate (Glu) levels were measured in the medial prefrontal cortex (MPFC) of 21 healthy gravid subjects 2-3 weeks before their due date (6.74 ± 1.39), and in 14 non-pregnant healthy controls during their follicular phase (8.53 ± 1.55). Water quantified MPFC Glu levels were decreased in pregnant women (p < 0.01). We also observed a 13.9% decrease in percentage grey matter (%GM) (p < 0.01) in our MPFC voxel. As Glu is mostly found in GM, we repeated the statistical analysis after adjustment for %GM and found that the difference in Glu levels was no longer statistically significant when adjusted for %GM (p = 0.10). This investigation is the only systematic direct investigation of brain tissue composition and Glu levels in pregnant women. The main finding of this investigation is the decreased %GM in healthy pregnant women compared to non-pregnant women. These findings of decreased %GM in pregnancy may be responsible for the frequent complaints by pregnant women of cognitive difficulties also described as pregnesia.

Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS.

BACKGROUND: The clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis. METHODS: Magnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle. RESULTS: Subjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects. CONCLUSIONS: The present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain.

Chronic lithium does not alter human myo-inositol or phosphomonoester concentrations as measured by 1H and 31P MRS.

Lithium may act by decreasing intracellular concentrations of myo-inositol. The present study measured the effects of chronic lithium on myo-inositol concentrations in volunteers. Eleven subjects received either lithium (n = 7) or placebo (n = 4) for 7 days in a double-blind study. Myo-inositol concentrations at baseline and day 8 were measured in vivo using 1H magnetic resonance spectroscopy (MRS). The results showed that lithium did not alter brain myo-inositol concentrations compared to placebo. In 5 other subjects we used 1H MRS and 31P MRS to measure changes in both myo-inositol and phosphomonoester concentrations. This second study showed that lithium did not alter myo-inositol or phosphomonoester concentrations. Thus, the present studies do not support the hypothesis that lithium significantly affects the brain concentrations of myo-inositol or phosphomonoesters; however, it is possible these findings represent an inability to detect the changes in myo-inositol and phosphomonoester concentrations that may have occurred following lithium administration.

In vivo assessment of focal brain lactate alterations with NMR proton spectroscopy.

Spectral editing techniques and localization of 1H signals were applied to monitor lactate accumulation in a circumscribed region of brain damage. The experiments were performed at 2.35 T (100 MHz) in a 40-cm bore magnet. Following unilateral craniectomy in anesthetized adult cats, a two-turn surface coil was positioned over the dural surface. Proton spectra were obtained before and 1-5 h after production of a cortical cold lesion from three curved shells of brain tissue, each approximately 3 mm thick. The localized spectrum was obtained from each region with and without spectral difference editing for the lactate CH3 protons, but always with the maximum excitation produced by the semiselective binomial pulse centered on the lactate CH3 resonance. Region 1 represented the damaged area, Region 2 was located immediately below Region 1, and Region 3 was immediately below Region 2. Spin-echo magnetic resonance imaging was used to confirm the relationship between the location of the lesion and the regions from which the spectra were obtained. Spectra obtained without lactate editing showed, in addition to the N-acetylaspartate peak, a large lactate peak in Region 1 after production of the cold lesion. In Regions 2 and 3, changes in lactate were more difficult to assess owing to the presence of a lipid peak at a similar frequency that results from incomplete suppression by the spin-echo pulse sequence alone. Spectra acquired using lactate editing did not contain the lipid peak and clearly showed relatively small lactate accumulations in Regions 2 and 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of brainstem neuronal loss in amyotrophic lateral sclerosis with in vivo proton magnetic resonance spectroscopy.

In vivo proton magnetic resonance spectroscopy (MRS) may be used to quantify brainstem neuronal degeneration in ALS because of the neuronal localization of N-acetylaspartate and N-acetylaspartylglutamate, together termed NA, which are estimated with this technique. We measured the ratio of NA to creatine/phosphocreatine (NA/Cr) with proton MRS at 3.0 tesla (T) in a 4.3-cm3 volume in the pons and upper medulla of 12 ALS patients and 17 age-matched control subjects. Brainstem NA/Cr was reduced in ALS versus control subjects (mean +/- SD: 1.57 +/- 0.20 versus 1.95 +/- 0.14; p < 0.0001). Patients with severe spasticity or prominent bulbar weakness had the lowest NA/Cr ratios; those with predominantly lower motor neuron limb weakness had near-normal ratios. We conclude that proton MRS may quantify region-specific neuronal dysfunction in ALS.

Skeletal muscle metabolism during short-term, high-intensity exercise in prepubertal and pubertal girls.

To test the hypothesis that glycolytic metabolism in muscle is attenuated in prepubertal children, (31)P-magnetic resonance spectroscopy was used to determine calf muscle intracellular pH (pH(i)) in nine prepubertal (Pre) and nine pubertal female swimmers (Pub). Maximal plantar flexion work capacity (100% MWC) was established by using a graded exercise test. Between 5 and 10 days later, calf muscle images (magnetic resonance imaging) and phosphorus spectra were acquired at rest, during 2 min of light exercise (40% MWC), and during 2 min of supramaximal exercise (140% MWC) in a 3.0-T NMR system. End-exercise pH(i) was 6.66 +/- 0.11 and 6.76 +/- 0.17 for Pub and Pre, respectively. No significant differences in the mean values for pH(i) or the P(i)-to-phosphocreatine ratio were observed between groups during the protocol; however, an interaction effect was found for the P(i)-to-phosphocreatine ratio during the supramaximal exercise challenge. Cross-sectional area of gastrocnemius was 15.12 +/- 0.46 and 9.37 +/- 0.37 cm(2) for Pub and Pre, respectively (P < 0.05). Differences in muscle size must be considered when interpreting the unlocalized magnetic resonance spectroscopy data. These results suggest that glycolytic metabolism in physically active children is not maturity dependent.

Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.

Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI-cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myo-inositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myo-inositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myo-inositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI-cycle.

Posterior cingulate metabolic changes occur in Parkinson's disease patients without dementia.

The basis for cognitive deficits in Parkinson's disease (PD) is unknown. Hippocampal atrophy has been shown in Alzheimer's disease (AD) and PD. N-Acetyl aspartate (NAA)/creatine (Cr) ratio in the posterior cingulate gyrus (PCG) is decreased in AD, but unknown in PD. Volumetric magnetic resonance (MR) imaging (at 1.5 T) determined corrected HC volume and MR spectroscopy (MRS) PCG metabolites in 12 non-demented mild to moderately affected PD patients (six male, six female) and ten controls (five male, five female). Age (PD=60.6 years, control=62.2; P=0.62), education (PD=14.1 years, controls=13.8; P=0.89) and global cognition (Mini-Mental State Exam score: PD=28.7, controls=29.6; P=0.14) did not differ. Only recall (CVLT-II, P=0.046) and NAA/Cr (PD=1.53, controls=1.78; P=0.03) were decreased in PD. Memory correlated with NAA/Cr (r=0.65, P=0.02) in PD. In conclusion, cingulate metabolic changes occur in PD.

Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myoinositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high-resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myoinositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myoinositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI cycle.

Effects of chronic lithium and sodium valproate on concentrations of brain amino acids.

The present study was designed to determine if the mood stabilizers, lithium and valproate, have common effects on concentrations of amino acid neurotransmitters which may be related to their mechanisms of action. Two separate groups of rats were administered therapeutic doses of lithium, sodium valproate, or saline for 2 weeks. Whole brain extracts were then examined using either high-field 1H NMR spectroscopy or HPLC. Both drugs decreased whole brain concentrations of aspartate, glutamate, and taurine while brain concentrations of gamma-aminobutyric acid (GABA) and alanine decreased following chronic sodium valproate administration but not following chronic lithium administration. These findings indicate that lithium and sodium valproate share common effects on the concentrations of certain amino acid neurotransmitters in whole brain which may be related to their mechanisms of action in bipolar disorder.

High field 1H-NMR analysis of the 1:1 intercalation complex of the antitumor agent mitoxantrone and the DNA duplex [d(CpGpCpG)].

Complete 1H-nmr assignment has been achieved of the stoichiometric 1:1 complex of the antitumor agent mitoxantrone with the duplex oligomer [d(CpGpCpG)]2. The techniques used included 2D-COSY, 1D-NOE and 2D-HH-INADEQUATE. Comparisons of 1H and 13C chemical shift changes upon addition of drug suggest symmetrical intercalative binding to the center of the tetramer. NOE difference measurements and 31P studies suggest binding of the terminal OH groups of the side chains to the central phosphate groups such that the methylene groups are proximate to C(3)6, C(3)6 and G(4)8 base protons all in the major groove. The data suggest that the side chains bind to the neighboring base pairs from the intercalation site. This is in accord with independent evidence of G,C base preference for binding from spectroscopic and electron microscopy studies.

Complete 1H assignments of the non-exchangeable protons of the non self-complementary heptadeoxyribonucleotide d[(GTCGTCA).(TGACGAC)] and its component strands by high field NMR.

The non self complementary heptadeoxyribonucleotides d(GTCGTCA) and d(TGACGAC) were synthesized by the phosphotriester method. While complete 1H-NMR assignments of the former were obtained by a combination of one and two-dimensional techniques at room temperature, extensive stacking of the latter under these conditions dictated analysis at 50 degrees C when the lines were sharply resolved. The duplex form of the annealed strands under the conditions of the 1H-NMR experiment was established independently of the NMR evidence by 32P end labeling with T4 polynucleotide kinase followed by butt end joining using the absolute specificity of T4 ligase for double strand DNA. Analysis of the resulting ladder of polymers was performed using gel electrophoresis and autoradiography. Complete 1H-NMR assignments of the non-exchangeable protons in the self complementary heptamer was achieved. The assignments were confirmed using NOE differences, and two-dimensional COSY, and HH-INADEQUATE experiments at 400 and 500 MHz. The assignments are in accord with a conformation for the heptamer belonging to the B family of structures.

1H-NMR assignments of the non-exchangeable protons of the consensus donor exon:intron junction d(CpApGpGpTpApApGpT).

The consensus donor exon:intron junction d(CpApGpGpTpApApGpT) has been synthesized by a modified phosphotriester method. The non-self-complementary nonamer has, in principle, only two G,C or four A,T points of self-recognition. The inference that it exists in the single strand form at 20 degrees C was confirmed by temperature variable 1H-NMR and NOE measurements. The proton assignments were secured using two-dimensional COSY which provided intra-nucleotide correlations, then NOE difference measurements as well as inversion recovery T1 experiments. Systematic procedures were developed for the assignment of the individual bases and their component protons based on the effects of molecular environment on chemical shifts. These latter procedures should be useful for the assignment of other random-coil single strand oligodeoxyribonucleotides.

Structure and conformation of saframycin R determined by high field 1H and 13C NMR and its interactions with DNA in solution.

The chemical structure and conformation of the new antitumor antibiotic saframycin R have been determined by high field 1H and 13C NMR as well as FAB mass spectrometry. Unlike other members of the saframycin family, saframycin R contains a reduced quinone ring bearing a glycolic ester moiety. Saframycin R exhibits acid promoted equilibrium and reversible covalent binding to DNA templates and, in the presence of a reducing agent, oxygen dependent single strand scission of supercoiled DNA. The extent of DNA scission is enhanced by in situ porcine carboxyl esterase or base catalyzed cleavage of the glycolic ester function plausibly by the release of the more reactive reduced saframycin A. This suggests that saframycin R may be regarded as a less toxic pro-drug for the active forms of saframycins A or S.

Measurement of ethanol in the human brain using NMR spectroscopy.

Ethanol in the human brain is readily observable by noninvasive 1H NMR spectroscopy. We have made such observations in a human subject with a time resolution per measurement of 6.5 min and volume resolution of 16 cc. The ethanol methyl proton signal is well separated from signals of other metabolites in 1H spectra from human brain and it is one of the most intense signals in such spectra when blood ethanol concentration is 0.1% (21.7 mM)--the legal definition of alcoholic intoxication in many jurisdictions. These properties, plus the fact that the ethanol signal can be further isolated from other resonances by spectral editing, open several possibilities for further investigation.

The application of depth-pulse localized 31P NMR spectroscopy to monitor tumor metabolism and response to chemotherapy in the rat kidney.

To illustrate the spatial variations in metabolism within tumors, 31P spectral data are presented from a predefined, depth-pulse localized region of a rat kidney impregnated with Walker sarcoma cells. These data display the changes in energy metabolism during infiltration of the kidney by the tumor and during treatment of the tumor with cyclophosphamide.

The modification of the RF field distribution of surface coils by weakly conducting saline samples.

The modification of the RF field distribution of a surface coil, which is brought about by both loading and skin effect conditions arising from the proximity of weakly conducting saline samples, is demonstrated. A procedure for the calibration of the depth of the spectral acquisition region in depth-pulse localized in vivo spectroscopy is shown to be acceptable.

Lithium does not alter the choline/creatine ratio in the temporal lobe of human volunteers as measured by proton magnetic resonance spectroscopy.

OBJECTIVE: To study the effect of lithium administration on brain choline/creatine (Cho/Cr) ratios in healthy volunteers. DESIGN: Double-blind, placebo-controlled, prospective study. SETTING: The Nuclear Magnetic Resonance Research Unit at the University of Alberta. PARTICIPANTS: Sixteen healthy volunteers, recruited through advertisements. Subjects were excluded if they had a physical illness, or a personal or family history of psychiatric illness. The study period was from Feb. 6, 1996, to Mar. 21, 1996. INTERVENTIONS: Subjects received a baseline proton magnetic resonance spectroscopy (1H MRS) scan, and then were instructed to take either lithium (1,200 mg) or placebo at night for 7 days. On Day 8, the subjects returned for a second 1H MRS scan. Study participants were seen by a physician at the beginning and at the end of the experiment, and had access to the physician throughout the study period. OUTCOME MEASURES: Ratios of Cho/Cr measured in the temporal lobes by 1H MRS. RESULTS: There were no significant differences in the Cho/Cr ratios between the 2 groups on the test day (placebo 0.748 [standard deviation 0.29] versus lithium 0.811 [SD 0.25]; F = 0.147, p = 0.72), and there was no significant change from baseline in either group (0.003 above baseline for placebo; 0.056 above baseline for lithium; F = 1.21, p = 0.32). CONCLUSIONS: Lithium administration to healthy volunteers does not alter the Cho/Cr ratio in temporal lobe as measured by 1H MRS. The result concurs with reports that differences in Cho/Cr ratios observed in patients with bipolar disorder are likely specific to the illness, and are not the result of lithium therapy. Hence, alterations in choline function are not involved in the clinical effectiveness of lithium.

Proton magnetic resonance spectroscopy (1H-MRS) of the cerebellum in men with schizophrenia.

OBJECTIVE: To investigate whether there are cerebellar vermis abnormalities in schizophrenia. DESIGN: Prospective imaging study with proton magnetic resonance spectroscopy (1H-MRS). SETTING: Schizophrenia clinic at a large urban hospital. PATIENTS AND CONTROLS: Twelve right-handed male patients with schizophrenia, and 12 control subjects with no psychiatric history. INTERVENTIONS: MRS data were acquired from a 2.0 x 2.0 x 2.0 cm volume of interest that included the entire cerebellar vermis. OUTCOME MEASURES: Spectral peak arising from N-acetylaspartate (NAA), phosphocreatine/creatine (Cr) and choline (Cho). RESULTS: There were no significant differences between the patients with schizophrenia and the controls in cerebellar vermis ratios of NAA to Cr (p = 0.71) or Cho to Cr (p = 0.50). CONCLUSIONS: This study does not support earlier structural studies that found abnormalities of the cerebellar vermis in schizophrenia, although it does support reported neurochemical studies. It does not rule out cerebellar involvement in schizophrenia through mechanisms such as aberrant circuitry. Larger in vivo structural/neurochemical and functional imaging studies in other parts of the cerebellum are needed.