1H NMR studies of glucose transport in the human brain.

The difference between 1H nuclear magnetic resonance (NMR) spectra obtained from the human brain during euglycemia and during hyperglycemia is depicted as well-resolved glucose peaks. The time course of these brain glucose changes during a rapid increase in plasma glucose was measured in four healthy subjects, aged 18-22 years, in five studies. Results demonstrated a significant lag in the rise of glucose with respect to plasma glucose. The fit of the integrated symmetric Michaelis-Menten model to the time course of relative glucose signals yielded an estimated plasma glucose concentration for half maximal transport, Kt, of 4.8 +/- 2.4 mM (mean +/- SD), a maximal transport rate, Tmax, of 0.80 +/- 0.45 micromol g-1 min-1, and a cerebral metabolic glucose consumption rate (CMR)glc of 0.32 +/- 0.16 micromol g-1 min-1. Assuming cerebral glucose concentration to be 1.0 micromol/g at euglycemia as measured by 13CMR, the fit of the same model to the time course of brain glucose concentrations resulted in Kt = 3.9 +/- 0.82 mM, Tmax = 1.16 +/- 0.29 micromol g-1 min-1, and CMRglc = 0.35 +/- 0.10 micromol g-1 min-1. In both cases, the resulting time course equaled that predicted from the determination of the steady-state glucose concentration by 13C NMR spectroscopy within the experimental scatter. The agreement between the two methods of determining transport kinetics suggests that glucose is distributed throughout the entire aqueous phase of the human brain, implying substantial intracellular concentration.

Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR.

13C isotopic tracer data previously obtained by 13C nuclear magnetic resonance in the human brain in vivo were analyzed using a mathematical model to determine metabolic rates in a region of the human neocortex. The tricarboxylic acid (TCA) cycle rate was 0.73 +/- 0.19 mumol min-1 g-1 (mean +/- SD; n = 4). The standard deviation reflects primarily intersubject variation, since individual uncertainties were low. The rate of alpha-ketoglutarate/glutamate exchange was 57 +/- 26 mumol min-1 g-1 (n = 3), which is much greater than the TCA cycle rate; the high rate indicates that alpha-ketoglutarate and glutamate are in rapid exchange and can be treated as a single combined kinetic pool. The rate of synthesis of glutamine from glutamate was 0.47 mumol min-1 g-1 (n = 4), with 95% confidence limits of 0.139 and 3.094 mumol min-1 g-1; individual uncertainties were biased heavily toward high synthesis rates. From the TCA cycle rate the brain oxygen consumption was estimated to be 2.14 +/- 0.48 mumol min-1 g-1 (5.07 +/- 1.14 ml 100 g-1 min-1; n = 4), and the rate of brain glucose consumption was calculated to be 0.37 +/- 0.08 mumol min-1 g-1 (n = 4). The sensitivity of the model to the assumptions made was evaluated, and the calculated values were found to be unchanged as long as the assumptions remained near reported physiological values.

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.

Differentiation of glucose transport in human brain gray and white matter.

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

Positive rolandic sharp waves in the EEG of the premature infant.

Ninety-seven EEGs from 30 premature infants found to have multifocal white matter necrosis on ultrasound (US) or autopsy were reviewed retrospectively. Twenty infants had intraparenchymal echodensities on US that developed into cystic lesions, a finding consistent with periventricular leukomalacia; 8 had intraparenchymal hemorrhages; and 2 had white matter necrosis at autopsy. Four of these infants had no intraventricular hemorrhage. Positive sharp waves in the central (rolandic) regions (PRS) were identified in 22 of these 30 infants (73%) and in 0 of 30 age-matched controls (p less than 0.001). The presence of PRS on the EEG of the premature infant has a high correlation with white matter necrosis rather than with intraventricular hemorrhage. In all cases, this EEG pattern was present prior to the development of cavitations when echodensities were present on US.

Leber's disease and dystonia: a mitochondrial disease.

We studied a kindred in which 8 members had the neuroretinopathy of Leber's disease; 14 had a progressive, generalized dystonia attributed to striatal degeneration; and 1 had both disorders. The mode of inheritance was compatible with maternal transmission. This neurologic disorder may be a mitochondrial disease.

Differential increase in cerebral cortical glucose oxidative metabolism during rat postnatal development is greater in vivo than in vitro.

The steady-state rate of glucose oxidation through the mitochondrial TCA cycle (V(TCA)) was measured in acid extracts of 10- and 30-day-old cerebral cortex of rats receiving [1-13C]glucose intravenously and in neocortical slices superfused in vitro with the same isotope. TCA cycle flux was determined for each age group based on metabolic modeling analysis of the isotopic turnover of cortical glutamate and lactate. The sensitivity of the calculated rates to assumed parameters in the model were also assessed. Between 10 and 30 postnatal days, V(TCA) increased by 4.3-fold (from 0.46 to 2.0 micromol g(-1) min(-1)) in the cortex in vivo, whereas only a 2-fold (from 0.17 to 0.34 micromol g(-1) min(-1)) increase was observed in neocortical slices. The much greater increase in glucose oxidative metabolism of the cortex measured in vivo over that measured in vitro as the cortex matures suggests that function-related energy demands increase during development, a process that is deficient in the slice as a result of deafferentiation and other mechanisms.

Brain regional development of the activity of alpha-ketoglutarate dehydrogenase complex in the rat.

This study was initiated to test the hypothesis that the development of alpha-ketoglutarate dehydrogenase complex (KGDHC) activity, like that of pyruvate dehydrogenase complex, is one of the late developers of tricarboxylic acid (TCA) cycle enzymes. The postnatal development of KGDHC in rat brain exhibits four distinct region-specific patterns. The age-dependent increases in olfactory bulb (OB) and hypothalamus (HYP) form one pattern: low in postnatal days (P) 2 and 4, KGDHC activity rose linearly to attain adult level at P30. The increases in mid-brain (MB) and striatum (ST) constitute a second pattern: being <40% of adult level at P2 and P4, KGDHC activity rose steeply between P10 and P17 and attained adult level by P30. The increases in cerebellum (CB), cerebral cortex (CC), and hippocampus (HIP) form a third pattern: being 25-30% of adult level at P2 and P4, KGDHC activity doubled between P10 and P17 and rose to adult level by P30. KGDHC activity development is unique in pons and medulla (PM): being >60% of the adult level at P2, it rose rapidly to adult level by P10. Thus, KGDHC activity develops earlier in phylogenetically older regions (PM) than in phylogenetically younger regions (CB, CC, HIP). Being lowest in activity among all TCA cycle enzymes, KGDHC activity in any region at any age will exert a limit on the maximum TCA cycle flux therein. The results may have functional and pathophysiological implications in control of brain glucose oxidative metabolism, energy metabolism, and neurotransmitter syntheses.

The role of clinical neurophysiology in the management of epilepsy.

Clinical neurophysiologic studies have an important role in the diagnosis and management of the patient with epilepsy. Epilepsy is a clinical diagnosis and the EEG is an important adjunct used to differentiate epileptic seizures from nonepileptic events, refine the diagnosis of epilepsy into specific seizure types and epileptic syndromes, and provide a measure of brain function. The value of the EEG is highly dependent on the clinical context in which it is being applied. In some epilepsies the interictal EEG may be diagnostic whereas in others an ictal recording may be necessary to obtain a specific diagnosis. Both the interictal and ictal EEG characteristics vary with specific seizure types and epilepsies and are described in detail in this review. The usefulness of the EEG in the management of epilepsy and in aiding in the decision to discontinue antiepileptic therapy is also discussed.

Overview--the role of NMR spectroscopy in epilepsy.

Nuclear magnetic resonance (NMR) spectroscopy permits noninvasive, serial measurements of several metabolites with important neurobiologic roles in localized brain regions in vivo. Over the last decade, this technique has been applied to investigations of both animals and humans with epilepsy. Several nuclei that include specific proton, phosphorus, and carbon isotopes provide NMR signals that measure specific compounds in vivo. This paper reviews the studies that have used these multinuclear NMR techniques to investigate the role of these methods in the diagnosis and pathogenesis of epilepsy.

The brain in partial trisomy 18: a case report.

This is a clinical and neuropathological report of a 27-year-old male with partial trisomy of the long arm of chromosome 18. Severe psychomotor retardation, blindness, and epilepsy were the major clinical features. Microcephaly, an unusual diverticulum of the left occipital lobe, and severe atrophy of the visual system were the major findings on neuropathological examination.

1H nuclear magnetic resonance spectroscopy study of neonatal hypoglycemia.

It has been hypothesized that the mechanism of hypoglycemic brain damage involves energy failure or excessive accumulation of excitatory neurotransmitters. To test these hypotheses, 1H nuclear magnetic resonance spectroscopy was employed to determine brain high-energy phosphates, carbohydrates, neurotransmitters, amino acids, and fatty acids during insulin-induced hypoglycemia in the neonatal dog. Reduction in brain glucose content was associated with an increase in blood/brain lactate ratio, as well as decreases in brain glutamate, aspartate, taurine, and inositol; however, no change was observed in GABA concentration or in brain energy state. In contrast to the adult experimental animal, brain tissue injury due to hypoglycemia is minimal in the neonatal animal. The mechanism of resistance to hypoglycemic brain injury may involve modulation of the rise of excitatory amino acids and decline in inhibitory neurotransmitters and high-energy phosphates.

The coincidence of neurocutaneous melanosis and encephalofacial angiomatosis.

The case of a 21-year-old woman who was affected by both encephalofacial angiomatosis (Sturge-Weber syndrome) and neurocutaneous melanosis is reported. Her signs and symptoms consisted of an interesting overlap of the characteristics of these two neurocutaneous syndromes with glaucoma, hydrocephalus, epilepsy, mental retardation and vascular and melanotic skin lesions observed throughout her course. The clinical diagnosis presented considerable difficulties. The simultaneous occurrence of these two disorders has not been previously reported and this is the first reported case where the cutaneous lesions and their histology, the neuropathology and the clinical features of both disorders is described in one individual.

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.

Local functional connectivity as a pre-surgical tool for seizure focus identification in non-lesion, focal epilepsy.

Successful resection of cortical tissue engendering seizure activity is efficacious for the treatment of refractory, focal epilepsy. The pre-operative localization of the seizure focus is therefore critical to yielding positive, post-operative outcomes. In a small proportion of focal epilepsy patients presenting with normal MRI, identification of the seizure focus is significantly more challenging. We examined the capacity of resting state functional MRI (rsfMRI) to identify the seizure focus in a group of four non-lesion, focal (NLF) epilepsy individuals. We predicted that computing patterns of local functional connectivity in and around the epileptogenic zone combined with a specific reference to the corresponding region within the contralateral hemisphere would reliably predict the location of the seizure focus. We first averaged voxel-wise regional homogeneity (ReHo) across regions of interest (ROIs) from a standardized, probabilistic atlas for each NLF subject as well as 16 age- and gender-matched controls. To examine contralateral effects, we computed a ratio of the mean pair-wise correlations of all voxels within a ROI with the corresponding contralateral region (IntraRegional Connectivity - IRC). For each subject, ROIs were ranked (from lowest to highest) on ReHo, IRC, and the mean of the two values. At the group level, we observed a significant decrease in the rank for ROI harboring the seizure focus for the ReHo rankings as well as for the mean rank. At the individual level, the seizure focus ReHo rank was within bottom 10% lowest ranked ROIs for all four NLF epilepsy patients and three out of the four for the IRC rankings. However, when the two ranks were combined (averaging across ReHo and IRC ranks and scalars), the seizure focus ROI was either the lowest or second lowest ranked ROI for three out of the four epilepsy subjects. This suggests that rsfMRI may serve as an adjunct pre-surgical tool, facilitating the identification of the seizure focus in focal epilepsy.

Tract-based spatial statistical analysis of diffusion tensor imaging in pediatric patients with mitochondrial disease: widespread reduction in fractional anisotropy of white matter tracts.

BACKGROUND AND PURPOSE: Often diagnosed at birth or in early childhood, mitochondrial disease presents with a variety of clinical symptoms, particularly in organs and tissues that require high energetic demand such as brain, heart, liver, and skeletal muscles. In a group of pediatric patients identified as having complex I or I/III deficits on muscle biopsy but with white matter tissue appearing qualitatively normal for age, we hypothesized that quantitative DTI analyses might unmask disturbance in microstructural integrity. MATERIALS AND METHODS: In a retrospective study, DTI and structural MR brain imaging data from 10 pediatric patients with confirmed mitochondrial disease and 10 clinical control subjects were matched for age, sex, scanning parameters, and date of examination. Paired TBSS was performed to evaluate differences in FA, MD, and the separate diffusion direction terms (λr and λa). RESULTS: In patients with mitochondrial disease, significant widespread reductions in FA values were shown in white matter tracts. Mean diffusivity values were significantly increased in patients, having a sparser distribution of affected regions compared with FA. Separate diffusion maps showed significant increase in λr and no significant changes in λa. CONCLUSIONS: Despite qualitatively normal-appearing white matter tissues, patients with complex I or I/III deficiency have widespread microstructural changes measurable with quantitative DTI.

Resting functional connectivity between the hemispheres in childhood absence epilepsy.

OBJECTIVE: The fundamental mechanisms by which childhood absence epilepsy (CAE) changes neural networks even between seizures remain poorly understood. During seizures, cortical and subcortical networks exhibit bihemspheric synchronous activity based on prior EEG-fMRI studies. Our aim was to investigate whether this abnormal bisynchrony may extend to the interictal period, using a blood oxygen level-dependent (BOLD) resting functional connectivity approach. METHODS: EEG-fMRI data were recorded from 16 patients with CAE and 16 age- and gender-matched controls. Three analyses were performed. 1) Using 16 pairs of seizure-related regions of interest (ROI), we compared the between-hemisphere interictal resting functional connectivity of patients and controls. 2) For regions showing significantly increased interhemispheric connectivity in CAE, we then calculated connectivity to the entire brain. 3) A paired-voxel approach was performed to calculate resting functional connectivity between hemispheres without the constraint of predefined ROIs. RESULTS: We found significantly increased resting functional connectivity between hemispheres in the lateral orbitofrontal cortex of patients with CAE compared to normal controls. Enhanced between-hemisphere connectivity localized to the lateral orbitofrontal cortex was confirmed by all 3 analysis methods. CONCLUSIONS: Our results demonstrate abnormal increased connectivity between the hemispheres in patients with CAE in seizure-related regions, even when seizures were not occurring. These findings suggest that the lateral orbitofrontal cortex may play an important role in CAE pathophysiology, warranting further investigation. In addition, resting functional connectivity analysis may provide a promising biomarker to improve our understanding of altered brain function in CAE during the interictal period.