Richard A. Komoroski

Regional proton magnetic resonance spectroscopy in schizophrenia and exploration of drug effect

Schizophrenia is a disorder with an unclear pathophysiology, despite numerous attempts to elucidate its etiology. We have employed proton magnetic resonance spectroscopy in vivo to explore the neurochemistry of several brain regions (left frontal and temporal cortices, left basal ganglia, and left and right thalamus) in patients with schizophrenia and in normal control subjects. We have also examined patients in different medication states. A trend toward a decreased level of inositol/creatine was found in the left temporal lobe of patients with schizophrenia, as was a trend toward a reduced level of N-acetylaspartate/creatine in the left thalamus of patients. In schizophrenic patients treated with atypical antipsychotics, decreased levels of choline were found in the left basal ganglia, while increased levels of N-acetylaspartate were found in the left frontal cortex. These results suggest altered metabolism in patients with schizophrenia, and imply that further study is needed to clarify the effects of the more recently available antipsychotics.

An in vitro 1H nuclear magnetic resonance study of the temporoparietal cortex of Alzheimer brains

The concentrations of selected metabolites in the posterior temporoparietal cortex of 13 Alzheimers diseased (AD) and four nondemented postmortem brains (of individuals between the ages of 63 and 95) were determined using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy. The estimates for glutamate and inositol for AD brains did not show any statistically significant difference (P>0.05) from those for the nondemented brains. The putative neuronal marker N-acetyl aspartate (NAA), creatine, and GABA were decreased in AD brains compared with the nondemented brains. The estimates for creatine, glutamate, and GABA showed significant linear correlations with those of NAA. Creatine, glutamate, GABA, and NAA appeared to be negatively correlated with the neurofibrillary tangles. Our results support a neuronal loss in the posterior temporoparietal cortices of AD brains.

Effects of gender and region on proton MRS of normal human brain

Localized, in vivo 1H magnetic resonance spectroscopy has been performed in a number of brain regions of neuropsychiatric interest in male and female control subjects to determine if gender and region affect the measured metabolite ratios. In contrast to some previous reports, no significant differences were seen in any region for any metabolite ratio between males and females. As expected, significant variations with brain region were seen for metabolite ratios for the total group of subjects.

Analysis of phospholipid molecular species in brain by 31P NMR spectroscopy

Techniques are described for the 31P NMR analysis of glycerophospholipid (PL) headgroup and molecular species in brain. The 31P NMR spectrum of PLs from human temporal cortex, solubilized in aqueous Na cholate, typically showed 3 major resonances, assigned to phosphatidylcholine (PC) molecular species containing 0, 1, or 2 fully saturated acyl chains. Less species resolution was obtained for the other PL headgroups under these conditions. Alkylacyl‐ and alkenylacyl‐PC were readily discerned using the CHCl3‐CH3OH‐H2O solvent method. The chain‐length, temperature, and species dependences of the 31P NMR chemical shifts were explored in model PLs. Assignments of signals from phosphatidylethanolamine (PE) subclasses were confirmed in the sodium‐cholate system by lipase‐mediated selective hydrolysis of bovine‐brain PE. The utility of 31P NMR to monitor enzymatic PL oxidation was further demonstrated. Possible changes in PL composition with postmortem interval (PMI) in rat brain were examined. No significant changes were seen in PL headgroup or PC species composition with PMI at up to 18 hours. Where comparable, the Na‐cholate‐solubilization and solvent methods gave similar quantitative results for headgroup analysis on the same samples. The present work demonstrates the feasibility and utility of the dual system for analysis of PLs in brain. Magn Reson Med 44:215–223, 2000.

Evidence of resilience: Neuroimaging in former prisoners of war

In this study, single voxel proton magnetic resonance spectroscopic imaging ((1)H-MRS) and volumetric analysis of hippocampal magnetic resonance imaging (MRI) images were used to determine if any differences in hippocampal biochemistry or volume were present between former prisoners of war (POWs) with and without posttraumatic stress disorder (PTSD) and control subjects matched for age and education. This study did not find lower hippocampal concentrations of N-acetylaspartate (NAA), smaller hippocampal volumes, or more impaired memory function in older veterans with PTSD compared with a group matched for traumatic experience or a nontraumatized control group.

Fluoxetine and trifluoperazine in human brain: A 19F-nuclear magnetic resonance spectroscopy study

Fluorine-19 (19F) is a nonradioactive isotope that is well-suited to nuclear magnetic resonance spectroscopy (NMRS) and is a constituent of several medications used to treat psychiatric illnesses. Fluoxetine, a trifluorinated agent, generated a signal from brain that was readily measured by 19F-NMRS. Estimated brain concentrations ranged from 1.3-5.7 micrograms/ml in six subjects at a steady state dose of 40 mg/day. Enhanced sensitivity of 19F has been obtained by conforming the surface coil to the shape of the forehead. Hence, at the current state of development, 19F-NMRS can be applied to clinical questions relevant to concentrations of fluoxetine in brain. We also report observation of NMRS signals from fluorinated neuroleptics in a number of patients at steady state. These signals continue to be difficult to obtain, although a correlation between dose and estimated brain concentrations is suggested.

High field carbon-13 NMR spectroscopy. Conformational mobility in gramicidin S and frequency dependence of 13C spin-lattice relaxation times

Summary The use of superconducting solenoids in 13C NMR can result in a substantial increase in spectral resolution over that obtained at commonly employed magnetic fields. Results are presented here for the cyclic decapeptide gramicidin S in both CD3OD and DMSO-d6 solutions. It was possible to monitor the complete motional behavior of the side chains of gramicidin S in CD3OD using 13C spin lattice relaxation times. Preliminary data are reported which confirm the frequency dependence of spin-lattice relaxation times for carbons in molecules not satisfying the extreme narrowing condition.

Effects of antipsychotic drugs on metabolite ratios in rat brain in vivo

Localized in vivo proton magnetic resonance spectroscopy at 4.7 T was used to examine the brains of rats that were given the antipsychotic drugs haloperidol, clozapine, or olanzapine for 1 week. Spectra were collected before and during treatment. The ratios of N‐acetylaspartate (NAA) to creatine (Cr) and choline to Cr were determined from the spectra. No significant differences in these ratios were seen among the rats given the various antipsychotic medications or between the control rats and the treated rats. No significant time‐dependent changes were seen in most cases, except for a small reduction of NAA/Cr after 7 days of olanzapine administration. These results suggest that differences in brain metabolite ratios in vivo in schizophrenics relative to controls, at least for short‐term treatment, arise from the disease, and not as a metabolic effect of the medication. Magn Reson Med 43:355–358, 2000.

In vivo 7Li nuclear magnetic resonance study of lithium pharmacokinetics and chemical shift imaging in psychiatric patients

New data are presented on the application of 7Li in vivo nuclear magnetic resonance (NMR) spectroscopy to human studies. The technique was used to monitor the between-dose pharmacokinetics of lithium (Li) in brain for three patients on Li therapy. Brain Li concentrations were at their highest from 0 to 2 hours after the peak occurred in serum concentration. Elimination from brain tissue took longer than elimination from muscle, and no signal could be detected from brain at 10 days after termination of therapy. A birdcage radiofrequency coil for 7Li was constructed and used to measure the 7Li spin-lattice relaxation time of 4.6 seconds in vivo in human head, and to acquire preliminary spectroscopic images of a phantom and human brain.

Applications of 7Li NMR in biomedicine

The applications of (7)Li NMR spectroscopy and imaging in biology and experimental medicine have been progressing steadily. The interest derives primarily from the clinical use of Li salts to treat mania and manic-depressive illness. One area of investigation is ionic transport across the cellular membrane and compartmentation, so as to elucidate the mechanism(s) of therapeutic action and toxicity in clinical practice. The second is the development of a noninvasive, in vivo analytical tool to measure brain Li concentrations in humans, both as an adjunct to treatment and as a mechanistic probe. Here we review progress to date in this area.