Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy.

BACKGROUND: Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. METHODS: The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. RESULTS: The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. CONCLUSION: This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.

Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy.

BACKGROUND: There is preclinical evidence and indirect clinical evidence implicating gamma-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder. METHODS: Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized (1)H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia. RESULTS: Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.

Vigabatrin: effect on brain GABA levels measured by nuclear magnetic resonance spectroscopy.

Vigabatrin is undoubtedly one of the most exciting anti-epilepsy drugs in use today. Many open and controlled clinical trials have confirmed that it is particularly effective in controlling partial epileptic seizures with or without secondary generalization. Vigabatrin acts to increase GABA levels in the presynaptic nerve terminal by inhibiting the activity of GABA-transaminase. There is no direct correlation between the blood or brain concentration of vigabatrin and its clinical effect, so monitoring vigabatrin levels is not predictive of patient response. However, it is possible to relate the activity of vigabatrin to levels of GABA in the brain, measured by nuclear magnetic resonance spectroscopy (NMRS). NMRS studies show that following administration of vigabatrin, brain concentrations of GABA rise to about 2-3 times their baseline values. This 'extra' GABA is held within the nerve terminal, and is only released during synaptic transmission. Although there appears to be a clear dose-response relationship up to 3 g/day, it is not well documented if higher doses result in proportionately higher brain GABA levels. This finding seems to support the results of clinical studies suggesting that the optimal dose of vigabatrin may be 3 g/day. There is also some evidence for a correlation between the concentration of GABA in the brain and the clinical outcome. Continuing investigations using NMRS aim to confirm these preliminary findings, and to determine the time course and extent of changes in brain GABA levels after vigabatrin administration.

Cerebral lactate turnover after electroshock: in vivo measurements by 1H/13C magnetic resonance spectroscopy.

We reported earlier that brain activation by 10 s of cortical electroshock caused prolonged elevation of brain lactate without significant change in intracellular pH, brain high-energy phosphorylated metabolites, or blood gases. The metabolic state of the elevated lactate has been investigated in further experiments using combined, in vivo 1H-observed 13C-edited nuclear magnetic resonance spectroscopy (NMRS), homonuclear J-edited 1H-NMRS, and high-resolution 1H-NMRS of perchloric acid extracts to monitor concentrations and 13C-isotopic fractions of brain and blood lactate and glucose. We now report that electroshock-elevated lactate pool in rabbit brain approaches equilibrium with blood glucose within 1 h. There was nearly complete turnover of the raised lactate pool in brain; any pool of metabolically inactive lactate could not have been > 5% of the total. In the same experiments, blood lactate underwent < 50% turnover in 1 h. The new 1H-spectroscopic methods used for these experiments are readily adaptable for the study of human brain and may be useful in characterizing the metabolic state of elevated lactate pools associated with epilepsy, stroke, trauma, tumors, and other pathological conditions.

Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin.

Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and spread of seizure activity. Low occipital lobe GABA was associated with poor seizure control in patients with complex partial seizures. Vigabatrin irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid (CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy. Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF increase. Doubling the daily dose from 3 to 6 g failed to increase brain GABA further. Increased GABA concentrations appear to reduce GABA synthesis in humans as it does in animals. With traditional antiepileptic drugs, remission of the seizure disorder was associated with normal GABA levels. With vigabatrin, elevated CSF and brain GABA was associated with improved seizure control. Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release of GABA during seizures may be mediated in part by transporter reversal that may serve as an important protective mechanism. During a seizure, this mechanism may be critical in stopping the seizure or preventing its spread.

Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients.

OBJECTIVE: The aim of the study was to compare levels of neuroactive amino acids in the cerebral cortex of healthy subjects, recently detoxified alcohol-dependent patients, and patients with hepatic encephalopathy. METHOD: Metabolite levels were measured in the occipital cortex by using spatially localized 1H-MRS. Five recently detoxified alcohol-dependent and five hepatic encephalopathy patients with alcohol and non-alcohol-related disease were compared with 10 healthy subjects. RESULTS: The combined level of gamma-aminobutyric acid (GABA) plus homocarnosine was lower in the alcohol-dependent and hepatic encephalopathy patients than in the healthy subjects. CONCLUSIONS: The findings suggest that GABA-ergic systems are altered in both alcohol-dependent and hepatic encephalopathy patients.

Idiopathic granulomatous angiitis of the central nervous system. Diagnostic challenges.

OBJECTIVE: Granulomatous angiitis of the central nervous system (CNS) is a rare cause of vasculitis involving the brain and spinal cord and is included in lists of disorders causing strokes. To determine the frequency of strokes (eg, sudden onset of focal symptoms) as a presenting complication and to determine the sensitivity of angiography and other technologies in detecting vasculitis in histologically proved cases of idiopathic granulomatous angiitis of the CNS (IGANS), we reviewed the published literature. DATA SOURCES: A biopsy-proved case of IGANS in a patient presenting without strokes and with a normal angiogram is reported. Additional cases of pathologically proved IGANS where results of angiography or other neuroimaging procedures were available were found by search of MEDLINE and bibliographies of pertinent articles and books. DATA EXTRACTION: We compared our case with 39 reported cases of histologically proved granulomatous angiitis of the CNS not associated with Hodgkin's disease, herpes zoster, sarcoidosis, or other proximate cause. We included only those cases that had been evaluated with angiography or other neuroimaging techniques before death or biopsy. DATA SYNTHESIS: Analysis of these cases shows that strokes as presenting complications are rare in IGANS. Most patients present with a diffuse encephalopathy and, when focal symptoms develop, they tend to develop gradually. Including our case, 56% of 41 angiograms performed in 31 reported patients with histologically proved IGANS were abnormal, but only 27% were diagnostic for vasculitis. CONCLUSIONS: We conclude that stroke is uncommon as a presenting complaint in IGANS and angiography is insensitive as a screening test for these patients.

Proton magnetic resonance spectroscopic studies of agonal carbohydrate metabolism in rabbit brain.

1H magnetic resonance spectroscopic measurements of cerebral lactate accumulation were used to estimate maximum agonal cerebral glycolytic rate (AGR) after cardiac arrest in 10 rabbits, six of which had received cortical electroshock. In the four control rabbits, mean AGR was 3.1 mumol glucose equivalents/g wet weight/min (standard error of the mean, 0.6), a figure in close agreement with earlier studies by workers using other techniques. AGR depended much more on carbohydrate availability as expressed by terminal blood glucose than on the shock-conditioned state of the glycolytic system reflected by individual rate constants of lactate accumulation. Regardless of shock history, AGR rose with blood glucose as though it were limited only by substrate availability. The unique capability of magnetic resonance spectroscopy to obtain chemically specific time course data noninvasively made these observations possible. The method has considerable potential for further analysis of normal and deranged cerebral metabolism.

Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy.

OBJECTIVE: To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy. BACKGROUND: Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects. RESULTS: Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.

Homocarnosine and seizure control in juvenile myoclonic epilepsy and complex partial seizures.

OBJECTIVE: To assess the relationship between seizure control and gamma-aminobutyric acid (GABA), homocarnosine, and pyrrolidinone levels in the visual cortex of patients with epilepsy taking valproate or lamotrigine. Previous studies suggested that poor seizure control was associated with low GABA and homocarnosine levels. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made in a 14-cm(3) volume of the occipital cortex using (1)H spectroscopy with a 2.1-Tesla MR spectrometer and an 8-cm surface coil. Twenty-six adults (eight men) taking valproate or lamotrigine were recruited; 12 had complex partial seizures (CPS) and 14 had juvenile myoclonic epilepsy (JME). RESULTS: Median homocarnosine levels were normal for patients with JME and below normal for patients with CPS. Better seizure control was associated with higher homocarnosine levels for both groups. Median GABA was below normal for patients with JME, lower than for patients with CPS. Brain GABA was lowest in patients with JME even when seizure control was excellent. Pyrrolidinone levels were above normal in almost all patients with JME. CONCLUSIONS: Low GABA levels are associated with poor seizure control in patients with CPS, but not in JME. Higher homocarnosine levels are associated with better seizure control in both types of epilepsy.

Human brain GABA levels rise after initiation of vigabatrin therapy but fail to rise further with increasing dose.

Using 1H spectroscopy, we measured occipital lobe GABA levels serially in 18 patients enrolled in an ongoing open label trial of vigabatrin. Brain GABA levels were elevated twofold in patients taking vigabatrin (3 to 4 g/d) compared with nonepileptic subjects. Serial measurements suggested that brain GABA rose in proportion to vigabatrin dose up to 3 g/d. Doubling the dose from 3 to 6 g/d failed to increase brain GABA further. Serial measurements on three patients taking 6 g/d showed a gradual decrease in brain GABA in two patients over 1 to 2 years of treatment. These observations suggest that GABA synthesis may decrease at high GABA levels.

Human brain GABA levels rise rapidly after initiation of vigabatrin therapy.

OBJECTIVE: The purpose of this study was to measure changes in brain GABA after a single oral dose (50 mg/kg) of vigabatrin in patients with intractable epilepsy. BACKGROUND: Vigabatrin is a safe and effective antiepileptic medication designed to increase brain GABA by irreversibly inhibiting GABA-transaminase. Serial measurements showed that brain GABA levels increased from 1.0 (SEM, 0.07) to 2.4 mmol/kg (SEM, 0.09) in patients who were regularly taking vigabatrin (50 mg/kg/day divided into two doses). METHODS: In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T NMR spectrometer and an 8-cm surface coil to measure a 13.5 cm3 volume in the occipital cortex. RESULTS: Brain GABA increased by more than 40% within 2 hours of administration of a single 50 mg/kg oral dose of vigabatrin from 0.95 (SEM, 0.07; n = 7) to 1.34 mmol/kg (SEM, 0.13). By the next day, brain GABA increased further to 1.44 mmol/kg (SEM, 0.08). Levels declined gradually to 1.16 mmol/kg (SEM, 0.14) by day 5 and 1.03 mmol/kg (SEM, 0.10) at day 8. The patients reported no side effects and were calm but not drowsy. CONCLUSIONS: A single oral dose of vigabatrin rapidly increased brain GABA without side effects. Once-a-day dosing should be as effective as divided doses.

High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy.

We analyzed specimens of histologically normal human cerebrum obtained at surgery for medically refractory epilepsy using proton magnetic resonance spectroscopy. Perchloric acid extracts of anterolateral temporal lobe cortex contained greater concentrations of creatine, N-acetylaspartate, gamma-aminobutyric acid, alanine, and glutamate than the under lying white matter, which contained more acetate. Frontal and temporal lobe specimens composed of both gray and white matter failed to show statistically significant differences in the concentrations of creatine, N-acetylaspartate, alanine, aspartate gamma-aminobutyric acid, glutamate, glycine, taurine, threonine, valine, acetate, choline, beta-hydroxybutyric acid, inositols, lactate pyruvate, or succinate.

Proton magnetic resonance spectroscopy in Creutzfeldt-Jakob disease.

We studied two patients with Creutzfeldt-Jakob disease by in vivo proton magnetic resonance spectroscopy and obtained spectra from an extract of biopsy tissue from a third patient. In vivo spectra from the two patients, 3 months and less than 1 month after symptom onset, revealed only minor changes. A second study of one of the patients 10 months after symptom onset found a decrease in N-acetylaspartate and other metabolites. Spectroscopy of the biopsy extract obtained 4 months after onset of symptoms showed no reduction in metabolites measured by in vivo spectroscopy, in accord with quantitative pathology showing no overall neuronal loss. Changes in metabolites detectable by proton magnetic resonance spectroscopy are not an early feature of this disease.

Cerebral metabolism in hyper- and hypocarbia: 31P and 1H nuclear magnetic resonance studies.

Paralyzed rabbits ventilated with an oxygen, nitrous oxide, and carbon dioxide mixture were subjected to hyper- and hypocarbic stress. An Oxford Instrument TMR 32-200 spectrometer was used to record phosphorus-31 and nonwater proton nuclear magnetic resonance spectra of the in vivo brain. These spectra provide measurements of cerebral pHi, phosphocreatine, orthophosphate, ATP, and lactate. The brain exhibited twice as much acute pH-regulating ability as the arterial blood. During hypercarbia, orthophosphate rose while phosphocreatine declined in a reciprocal manner, and ATP remained constant. During hypocarbia, lactate rose gradually over a period of 1 hour, while orthophosphate, phosphocreatine, and ATP remained constant and calculated values of adenosine mono- and diphosphate rose.

Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy.

We determined cerebral intracellular pH in living rabbits and rats under physiologic conditions, using phosphorus NMR spectroscopy and new titration curves thought to be appropriate for brain. Mean values for the two species were, respectively, 7.14 +/- 0.04 (SD) and 7.13 +/- 0.03. These are toward the alkaline end of the range of values obtained by other methods, as values reported by other NMR workers also tend to be.

Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes.

Previous studies of human stroke by 1H nuclear magnetic resonance spectroscopy have shown elevation of lactate lasting 3 to 6 months. Complete metabolic turnover of the elevated lactate pool has been demonstrated 5 weeks after a stroke. Its cellular localization is among the first questions requiring clarification. Information pertinent to this question came to us from a patient with a 2-week-old stroke by 1H nuclear magnetic resonance spectroscopic imaging 1 week before his death led to neuropathologic examination of the brain. 1H spectra from voxels including the infarcts showed increased lactate and decreased N-acetylaspartate. Histopathology showed sheets of foamy macrophages in the infarct, but few neurons. Macrophage density ranged from 196 cells/mm2 near the surface of the infarct to 788 near its medial margin. Glial density was 500 to 800 cells/mm2. Lactate concentration in voxels including portions of the infarct was estimated at 7 to 14 mM. Voxels showing low N-acetylaspartate and high lactate on spectroscopic imaging were associated with histopathologic sections containing foamy macrophages. Brain macrophages--which begin to appear 3 days after infarction and gradually disappear over several months--could be a major source of elevated lactate signals that persist for months after stroke.

Quantitative analysis of rat synaptosomes and cerebrum using high-resolution 1H magnetic resonance spectroscopy.

This study explored the utility of 1H magnetic resonance spectroscopy to study a standard synaptosomally enriched preparation (P2 pellet) made from rat cerebrum. The preparation contained high concentrations of N-acetylaspartate and gamma-aminobutyric acid and low concentrations of glutamine, indicating that they were in fact rich in neuronal cytosol. Synaptosomes contained half the lactate and glutamine of cerebrum. Alanine, aspartate, glutamate, and succinate had the same concentrations in synaptosomes and cerebrum.

Novel methods for studying new antiepileptic drug pharmacology.

A number of new antiepileptic drugs act by indirect mechanisms and thus produce effects that may not best be measured by traditional blood studies of the drugs and their metabolites. Study of the indirect action of these drugs on GABA-mediated inhibition by microdialysis and nuclear MR spectroscopy has proved more relevant. These new investigative techniques may also prove valuable as compounds affecting glutamate or other excitatory neurotransmitters are developed.

Symbiosis between in vivo and in vitro NMR spectroscopy: the creatine, N-acetylaspartate, glutamate, and GABA content of the epileptic human brain.

High resolution 1H NMR spectroscopy was used to analyze temporal lobe biopsies obtained from patients with epilepsy. Heat-stabilized cerebrum, dialyzed cytosolic macromolecules, and perchloric acid extracts were studied using one- and two-dimensional spectroscopy. Anterior temporal lobe neocortex was enriched in GABA, glutamate, alanine, N-acetylaspartate, and creatine. Subjacent white matter was enriched in aspartate, glutamine, and inositol. The N-acetylaspartate/creatine mole ratio was lower in anterior temporal neocortex with mesial (0.66) than neocortical (0.80) temporal lobe epilepsy. Human brain biopsy samples were separated into crude and refined synaptosomes, neuronal cell bodies, and glia using density gradient centrifugation. Neuronal fractions were enriched in glutamate and N-acetylaspartate. Glial cell fractions were enriched in lactate, glutamine, and inositol. The creatine content was the same in biopsied epileptic cortex (8.8-8.9 mmol/kg) and normal in vivo occipital lobe (8.9 mmol/kg). Glutamate content was higher in epileptic cortex at biopsy (10.1-10.5 mmol/kg) than normal in vivo occipital lobe (8.8 mmol/kg). GABA content was higher in biopsies of epileptic cortex (2.3-2.2 mmol/kg) than in normal in vivo occipital lobe (1.2 mmol/kg). N-acetylaspartate content was lower in biopsied epileptic temporal cortex (5.8-6.8 mmol/kg) than normal in vivo occipital lobe (8.9 mmol/kg). Paired in vivo and ex vivo measurements are critical for a firm understanding of the changes seen in the 1H-spectra from patients with epilepsy.