Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2 , and pO2.

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2 ) resulting in blood hyperoxygenation, the basis of BOLD fMRI contrast. Explanations for the high CBF vs. CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintainenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2 ). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2 , and pO2 as a function of baseline OEF (OEF0 ), CBF, CMRO2 , and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0 . We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

The early days of ex vivo 1 H, 13 C, and 31 P nuclear magnetic resonance in the laboratory of Dr. Robert G. Shulman from 1975 to 1995.

This paper provides a brief description of the early use of ex vivo nuclear magnetic resonance (NMR) studies of tissue and tissue extracts performed in the laboratory of Dr. Robert G. Shulman from 1975 through 1995 at Bell Laboratories, then later at Yale University. During that period, ex vivo NMR provided critical information in support of resonance assignments and the quantitation of concentrations for magnetic resonance spectroscopy studies. The period covered saw rapid advances in magnet technology, starting with studies of microorganisms in vertical bore high-resolution NMR studies, then by 1981 studies of small mammals in a horizontal bore magnet, and then studies of humans in 1984. Ex vivo NMR played a critical role in all these studies. A general strategy developed in the lab for using ex vivo NMR to support in vivo studies is presented, as well as illustrative examples.

Deep Versus Lobar Intraparenchymal Hemorrhage: Seizures, Hyperexcitable Patterns, and Clinical Outcomes.

OBJECTIVES: To compare electrographic seizures, hyperexcitable patterns, and clinical outcomes in lobar and deep intraparenchymal hemorrhage. Additionally, to characterize electrographic seizure and hyperexcitable pattern predictors in each group and determine seizure risk with thalamic involvement. DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. PATIENTS: Consecutive adult patients with nontraumatic intraparenchymal hemorrhage undergoing continuous electroencephalography at our center between January 2013 and December 2016. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Based on head CT closest to the initial continuous electroencephalography session, we classified intraparenchymal hemorrhage as isolated deep (no insular, subarachnoid, subdural extension) or lobar. Hyperexcitable patterns included the following: periodic discharges, spike-wave complexes, any rhythmic delta other than generalized. We used Fisher exact test for categorical and Mann-Whitney U test for continuous variables. Multivariable regression identified predictors of electrographic seizures, hyperexcitable patterns, and poor outcomes (score of 1-2 on Glasgow Outcome Scale) in lobar intraparenchymal hemorrhage. The cohort comprised of 128 patients, 88 lobar, and 40 deep intraparenchymal hemorrhage. Electrographic seizures occurred in 17% of lobar and 5% of deep intraparenchymal hemorrhage (p = 0.09). Hyperexcitable patterns were more frequent in the lobar group (44.3% vs 17.5%; p = 0.005). In multivariable analyses in the lobar group, lateralized rhythmic delta activity predicted electrographic seizures (odds ratio, 6.24; CI, 1.49-26.08; p = 0.012); insular involvement predicted hyperexcitable patterns (odds ratio, 4.88; CI, 1.36-17.57; p = 0.015); coma, temporal lobe involvement, intraparenchymal hemorrhage volume, and electrographic seizures predicted poor outcome. Thalamic involvement did not affect electrographic seizures or hyperexcitable patterns in either group. CONCLUSIONS: Electrographic seizures are frequent in lobar intraparenchymal hemorrhage, occurring in one in six monitored patients, as opposed to only 5% in isolated deep intraparenchymal hemorrhage not extending to cortex/insula, subarachnoid, or subdural spaces. Patients with lobar intraparenchymal hemorrhage and lateralized rhythmic delta activity were six times as likely to have electrographic seizures, which were associated with 5.47 higher odds of a poor outcome. Coma, temporal lobe involvement, hematoma volume, and electrographic seizures predicted poor outcome in lobar intraparenchymal hemorrhage.

Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T.

Typical magnetic resonance spectroscopy J-editing methods designed to quantify GABA suffer from contamination of both overlapping macromolecules and homocarnosine signal, introducing potential confounds. The aim of this study was to develop a novel method to assess accurately both the relative concentrations of homocarnosine as well as GABA free from overlapping creatine, homocarnosine and macromolecule signal. A novel method which utilized the combination of echo time STEAM and MEGA-sLASER magnetic resonance spectroscopy experiments at 7T were used to quantify the concentration of GABA and homocarnsoine independently, which are typically quantified in tandem. The metabolites GABA and homocarnosine were measured in brain of 6 healthy control subjects, and in a single subject medicated with isoniazid. It was found that (16.6±10.2)% of the supposed GABA signal in the brain originated from homocarnosine, and that isoniazid caused significantly elevated concentration of GABA and homocarnosine in a single subject compared to controls.

Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices.

The primary goal of this study was to establish whether inhibition of GABA synthesis was sufficient to induce network hyperexcitability in a rat hippocampal slice model comparable to that seen with GABA receptor blockade. We used field and intracellular recordings from the CA1 region of rat hippocampal slices to determine the physiological effects of blocking GABA synthesis with the convulsant, 3-mercaptoproprionic acid (MPA). We measured the rate of synthesis of GABA and glutamate in slices using 2-13C-glucose as a label source and liquid chromatography-tandem mass spectrometry. There was little effect of 3.5mM MPA on evoked events under control recording conditions. Tissue excitability was enhanced following a series of stimulus trains; this effect was enhanced when GABA transport was blocked. Evoked inhibitory potentials (IPSPs) failed following repetitive stimulation and MPA. Spontaneous epileptiform activity was seen reliably with elevated extracellular potassium (5mM). GABA synthesis decreased by 49% with MPA alone and 45% with the combination of MPA and excess potassium; GABA content was not substantially altered. Our data indicate: (1) GABAergic inhibition cannot be significantly compromised by MPA without network activation; (2) GABAergic synaptic inhibition is mediated by newly synthesized GABA; (3) there is a depletable pool of GABA that can sustain GABAergic inhibition when synthesis is impaired under basal, but not activated conditions; (4) overt hyperexcitability is only seen when newly synthesized GABA levels are low.

Cyclic seizures in critically ill patients: Clinical correlates, DC recordings and outcomes.

OBJECTIVE: To describe EEG and clinical correlates, DC recordings and prognostic significance of cyclic seizures (CS). METHODS: We reviewed our prospective continuous EEG database to identify patients with CS, controls with non-cyclic status epilepticus (SE) and controls without seizure matched for age and etiology. EEG was reviewed with DC settings. RESULTS: 39/260 (15%) patients with electrographic seizures presented with CS. These patients were older (62 vs. 54years; p=0.04) and more often had acute or progressive brain injury (77% vs. 52%; p=0.03) than patients with non-cyclic SE and had a lower level of consciousness, were more severely ill, than matched controls. CS almost always had focal onset, often from posterior regions. Patients with CS trended towards worse prognosis. When available (12 patients), DC recordings showed an infraslow cyclic oscillation of EEG baseline synchronized to the seizures in all cases. CONCLUSIONS: CS occur mostly in older patients with acute or progressive brain injury, are more likely to be associated with poor outcome than patients with other forms of nonconvulsive SE, and are accompanied by synchronous oscillations of the EEG baseline on DC recordings. SIGNIFICANCE: CS are a common form of non-convulsive status epilepticus in critically ill patients and provide further insights into the relationship between infraslow activity and seizures; further study on this relationship may shed light on the mechanisms of seizure initiation and termination.

The use and yield of continuous EEG in critically ill patients: A comparative study of three centers.

OBJECTIVE: Continuous EEG (cEEG) monitoring of critically ill patients has gained widespread use, but there is substantial reported variability in its use. We analyzed cEEG and antiseizure drug (ASD) usage at three high volume centers. METHODS: We utilized a multicenter cEEG database used daily as a clinical reporting tool in three tertiary care sites (Emory Hospital, Brigham and Women's Hospital and Yale - New Haven Hospital). We compared the cEEG usage patterns, seizure frequency, detection of rhythmic/periodic patterns (RPP), and ASD use between the sites. RESULTS: 5792 cEEG sessions were analyzed. Indication for cEEG monitoring and recording duration were similar between the sites. Seizures detection rate was nearly identical between the three sites, ranging between 12.3% and 13.6%. Median time to first seizure and detection rate of RPPs were similar. There were significant differences in doses of levetiracetam, valproic acid, and lacosamide used between the three sites. CONCLUSIONS: There was remarkable uniformity in seizure detection rates within three high volume centers. In contrast, dose of ASD used frequently differed between the three sites. SIGNIFICANCE: These large volume data are in line with recent guidelines regarding cEEG use. Difference in ASD use suggests discrepancies in how cEEG results influence patient management.

A comparison of the power spectral density of scalp EEG and subjacent electrocorticograms.

OBJECTIVE: Our study investigated the effects of the intact skull on background EEG rhythms recorded simultaneously by subdural electrocorticography (ECoG) and scalp EEG. METHODS: We performed a retrospective analysis of twenty patients undergoing intracranial EEG monitoring. EEG and ECoG were recorded simultaneously from the central and occipital scalp and subjacent subdural electrodes removed (median 46 mm, interquartile 27-65) from the craniotomy. The power spectral density (PSD) of artifact-free EEG and ECoG segments and ratio of the scalp EEG to subjacent ECoG PSD was calculated. RESULTS: Overall both ECoG and scalp EEG power decreased by over three orders of magnitude from delta to gamma frequency band with an empirical inverse power relationship. The ratio of scalp EEG to ECoG PSD decreased across the delta and theta frequency bands, remained the same across the alpha, beta and low gamma bands, but increased at the higher frequency bands. CONCLUSIONS: EEG PSD mirrored changes in ECoG PSD across the frequency bands. As ECoG power continued to decrease above 42 Hz, extracranial voltage sources contributed to a greater fraction of scalp EEG power. SIGNIFICANCE: Monitoring the gamma frequency band using scalp EEG was limited by low power on ECoG and masking by extracranial voltage sources.

Clinical Correlates and Prognostic Significance of Lateralized Periodic Discharges in Patients Without Acute or Progressive Brain Injury: A Case-Control Study.

PURPOSE: Lateralized periodic discharges (LPDs, also known as periodic lateralized epileptiform discharges) in conjunction with acute brain injuries are known to be associated with worse prognosis but little is known about their importance in absence of such acute injuries. We studied the clinical correlates and outcome of patients with LPDs in the absence of acute or progressive brain injury. METHODS: This is a case-control study of 74 patients with no acute brain injury undergoing continuous EEG monitoring, half with LPDs and half without, matched for age and etiology of remote brain injury, if any, or history of epilepsy. RESULTS: Lateralized periodic discharges were found in 145/1785 (8.1%) of subjects; 37/145 (26%) had no radiologic evidence of acute or progressive brain injury. Those with LPDs were more likely to have abnormal consciousness (86% vs. 57%; P = 0.005), seizures (70% vs. 24%; P = 0.0002), and functional decline (62% vs. 27%; P = 0.005), and were less likely to be discharged home (24% vs. 62%; P = 0.002). On multivariate analysis, LPDs and status epilepticus were associated with abnormal consciousness (P = 0.009; odds ratio = 5.2, 95% CI = 1.60-20.00 and P = 0.017; odds ratio = 5.0, 95% CI = 1.4-21.4); and LPDs were independently associated with functional decline (P = 0.001; odds ratio = 4.8, 95% CI = 1.6-15.4) and lower likelihood of being discharged home (P = 0.009; odds ratio = 0.2, 95% CI = 0.04-0.6). CONCLUSIONS: Despite absence of acute or progressive brain injury, LPDs were independently associated with abnormal consciousness and worse outcome at hospital discharge.

GABA and glutamate in the human brain.

Cortical excitability reflects a balance between excitation and inhibition. Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex. Changes in glutamate and GABA metabolism may play important roles in the control of cortical excitability. Glutamate is the metabolic precursor of GABA, which can be recycled through the tricarboxylic acid cycle to synthesize glutamate. GABA synthesis is unique among neurotransmitters, having two separate isoforms of the rate-controlling enzyme, glutamic acid decarboxylase. The need for two separate genes on two chromosomes to control GABA synthesis is unexplained. Two metabolites of GABA are present in uniquely high concentrations in the human brain. Homocarnosine and pyrrolidinone have a major impact on GABA metabolism in the human brain. Both of these GABA metabolites have anticonvulsant properties and can have a major impact on cortical excitability.

Gabapentin and vigabatrin increase GABA in the human neocortical slice.

The effects of antiepileptic drugs, gabapentin and vigabatrin, on gamma-aminobutyric acid (GABA) concentrations were studied in human (n=14) and rat (n=6) neocortical slice preparations. In this study, neocortical slices were incubated with gabapentin, vigabatrin or no drugs for 3 h in an oxygenated environment. Proton magnetic resonance spectroscopy (MRS) of perchloric acid (PCA) extracts was used to measure GABA concentrations. Vigabatrin increased cellular GABA concentrations in both human and rat neocortical slices by 62% (P<0.001) and 88% (P<0.03), respectively. Gabapentin significantly increased GABA concentrations by 13% (P<0.02) in human neocortical slices made from tissue resected during epilepsy surgery. However, in the rat neocortical slice exposed to the same conditions as the human tissue, gabapentin did not increase GABA significantly. These results confirm our MRS studies in vivo that gabapentin increases GABA levels in epileptic patients, but has minimal or no effect in a healthy rodent model. Caution must be used in extrapolating negative results obtained in rodent models to the human condition.

Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations.

The effects of antiepileptic drugs, gabapentin, pregabalin and vigabatrin, on brain gamma-aminobutyric acid (GABA), glutamate and glutamine concentrations were studied in Long Evans rats using proton magnetic resonance spectroscopy (MRS) of perchloric acid extracts. Cellular glutamate concentrations significantly decreased by 7% (P<0.05) 2 hours after intraperitoneal injection of 100mg/kg gabapentin and 4% (P<0.05) with 1000 mg/kg. No differences were observed in cellular GABA and cellular glutamine concentrations in rats treated with gabapentin. Pregabalin, an analogue of gabapentin, significantly decreased cellular glutamate concentrations by 4% (P<0.05), while no effect was observed on cellular GABA or glutamine concentrations in the healthy rat forebrain. Vigabatrin, used as a positive control to increase GABA levels, produced a 50% increase in cellular GABA compared to saline treated rats (P<0.003). Although, gabapentin and pregabalin are anticonvulsants designed to mimic GABA, these drugs do not raise cellular GABA levels acutely but modestly decreased cellular glutamate levels in our healthy rat forebrain model.

Brief potentially ictal rhythmic discharges in critically ill adults.

IMPORTANCE: Brief potentially ictal rhythmic discharges, termed B(I)RDs, have been described mainly in neonates, and their significance in adults remains unclear. OBJECTIVE: To describe the incidence of B(I)RDs in critically ill patients and investigate their association with seizures and outcome. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the records of prospectively identified patients with B(I)RDs and patients serving as controls matched for age (±5 years) and primary diagnosis. MAIN OUTCOMES AND MEASURES: The prevalence of seizures during continuous electroencephalography and functional outcome, as measured by the Glasgow Outcome Scale, were determined. RESULTS: We identified B(I)RDs in 20 patients (2%). The pattern most often consisted of very brief (1-3 seconds) runs of sharply contoured theta activity without obvious evolution. All patients with B(I)RDs had cerebral injury, and in cases with a single focal lesion (11 [55%]), B(I)RDs were localized in the same region in all but 2 cases (18%). Patients with B(I)RDs were more likely to have seizures during continuous electroencephalography than were patients without B(I)RDs (15 of 20 [75%] vs 10 of 40 [25%]; P < .001), and 9 patients with B(I)RDs (60%) had only subclinical seizures. Brief potentially ictal rhythmic discharges were identified before seizures in all but 1 case (93%) and ceased in all 12 cases (80%) in which seizures were controlled. Patients with B(I)RDs tended to have a worse outcome than controls (16 [80%] vs 25 [63%]); however, this finding was not statistically significant. CONCLUSIONS AND RELEVANCE: Brief potentially ictal rhythmic discharges in critically ill patients are associated with a high prevalence (75%) of electrographic seizures and might serve as an early predictor of seizures during subsequent monitoring. A larger prospective study is needed to better understand their clinical and prognostic significance.

Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients.

IMPORTANCE: The increasing use of continuous electroencephalography (EEG) monitoring in the intensive care unit has led to recognition of new EEG patterns that are of unclear or unknown significance. OBJECTIVE: To describe an EEG pattern, lateralized rhythmic delta activity (LRDA), encountered in critically ill subjects and determine its clinical significance in this setting. DESIGN, SETTING, AND PARTICIPANTS Retrospective review at an academic medical center of EEG recordings, medical records, and imaging studies of critically ill patients with LRDA and comparison with subjects with lateralized periodic discharges (also known as periodic lateralized epileptiform discharges), subjects with focal nonrhythmic slowing, and controls. INTERVENTION: Electroencephalography or continuous electroencephalography. MAIN OUTCOMES AND MEASURES: Cross-sectional prevalence of lateralized rhythmic delta activity; EEG characteristics; etiology, clinical, and radiological correlates; and risk of early seizures. RESULTS: We identified LRDA in 4.7%of acutely ill subjects undergoing EEG or continuous EEG monitoring. It was often associated with other focal EEG abnormalities, including lateralized periodic discharges in 44%of cases. The most common conditions associated with LRDA were intracranial hemorrhage and subarachnoid hemorrhage. Lateralized rhythmic delta activity was an independent predictor of acute seizures, with 63%of subjects having seizures during their acute illness, a proportion similar to subjects with lateralized periodic discharges (57%) and significantly higher than associated with focal nonrhythmic slowing (20%) or in control subjects (16%). Most patients (80%-90%) in the LRDA and lateralized periodic discharges groups who had seizures while undergoing continuous EEG monitoring had only nonconvulsive seizures, whereas this was the case for only 17%of patients in the other groups. Lateralized rhythmic delta activity and lateralized periodic discharges were both associated with lesions involving the cortex or juxtacortical white matter. CONCLUSIONS AND RELEVANCE: Lateralized rhythmic delta activity in critically ill patients has a similar clinical significance as lateralized periodic discharges. It reflects the presence of a focal lesion and is associated with a high risk of acute seizures, especially nonconvulsive.

Glutamate and astrocytes--key players in human mesial temporal lobe epilepsy?

Approximately one-third of all patients with epilepsy continue to suffer from seizures even after appropriate treatment with antiepileptic drugs. Medically refractory epilepsies are associated with considerable morbidity and mortality, and more efficacious therapies against these disorders are clearly needed. However, the discovery of better therapies has been lagging due to an incomplete understanding of the mechanisms underlying the development of epilepsy (epileptogensis) and seizures (ictogenesis) in humans. An increasing number of studies have suggested that an abnormal amplification of glutamatergic activity--often referred to as the "glutamate hypothesis"--is involved in the pathophysiology of seizures and certain types of medically refractory epilepsies. For example, elevated levels of extracellular glutamate in hyperexcitable areas of the brain, up-regulation of glutamate receptors, and loss of the glutamate-metabolizing enzyme, glutamine synthetase (GS), have all been reported in patients with mesial temporal lobe epilepsy (MTLE). Moreover, it appears that glial cells, particularly the astrocyte, may play a key role in the glutamate overflow in MTLE. Proliferation of astrocytes is a hallmark of the epileptogenic focus in MTLE, and the proliferated cells are characterized by several unique features that are permissive for the excessive accumulation and release of astrocytic glutamate. Here, we assess recent data regarding the glutamate excess in epilepsy, review the role of glutamine synthetase, and discuss the implications of astrocytes in the pathophysiology of MTLE.

Neurometabolism in human epilepsy.

PURPOSE: Because of the large and continuous energetic requirements of brain function, neurometabolic dysfunction is a key pathophysiologic aspect of the epileptic brain. Additionally, neurometabolic dysfunction has many self-propagating features that are typical of epileptogenic processes, that is, where each occurrence makes the likelihood of further mitochondrial and energetic injury more probable. Thus abnormal neurometabolism may be not only a chronic accompaniment of the epileptic brain, but also a direct contributor to epileptogenesis. METHODS: We examine the evidence for neurometabolic dysfunction in epilepsy, integrating human studies of metabolic imaging, electrophysiology, microdialysis, as well as intracranial EEG and neuropathology. RESULTS: As an approach of noninvasive functional imaging, quantitative magnetic resonance spectroscopic imaging (MRSI) measured abnormalities of mitochondrial and energetic dysfunction (via 1H or 31P spectroscopy) are related to several pathophysiologic indices of epileptic dysfunction. With patients undergoing hippocampal resection, intraoperative 13C-glucose turnover studies show a profound decrease in neurotransmitter (glutamate-glutamine) cycling relative to oxidation in the sclerotic hippocampus. Increased extracellular glutamate (which has long been associated with increased seizure likelihood) is significantly linked with declining energetics as measured by 31P MR, as well as with increased EEG measures of Teager energy, further arguing for a direct role of glutamate with hyperexcitability. DISCUSSION: Given the important contribution that metabolic performance makes toward excitability in brain, it is not surprising that numerous aspects of mitochondrial and energetic state link significantly with electrophysiologic and microdialysis measures in human epilepsy. This may be of particular relevance with the self-propagating nature of mitochondrial injury, but may also help define the conditions for which interventions may be developed.

Brain homocarnosine and seizure control of patients taking gabapentin or topiramate.

PURPOSE: To assess the relation between seizure control and brain homocarnosine and gamma-aminobutyric acid (GABA) levels of patients with complex partial seizures taking gabapentin (GBP) or topiramate (TPM) as adjunctive therapy. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using (1)H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Poor seizure control was defined as more recent seizures than the median for the two groups of patients studied. RESULTS: Homocarnosine levels were higher in patients with better seizure control than in those with poor control. No differences were found in the intracellular GABA levels between the patients who responded to GBP or TPM compared with those who did not. CONCLUSIONS: In the visual neocortex, which is remote from the presumed seizure-onset zone, higher homocarnosine levels were associated with better seizure control in the patients taking GBP or TPM as adjunctive therapy; elevated intracellular GABA levels appeared to offer no additional protection.

N-acetyl-aspartate, total creatine, and myo-inositol in the epileptogenic human hippocampus.

BACKGROUND: Mesial temporal lobe epilepsy (mTLE) is characterized by hippocampal atrophy, decreased N-acetyl-aspartate, and a low N-acetyl-aspartate/total creatine ratio, often attributed to neuron loss and gliosis. Qualitative studies reported that N-acetyl-aspartate content was significantly lower in hippocampal sclerosis. OBJECTIVE: It was proposed to measure the effects of neuron loss and gliosis on the hippocampal content of N-acetyl-aspartate, total creatine, and myo-inositol in mTLE. METHODS: Twenty hippocampal specimens were obtained during temporal lobectomy and frozen quickly. Perchloric acid extracts of the small metabolites were prepared and analyzed by proton MRS at 11.75 T. Adjacent samples were used for cell counts. RESULTS: There were no significant associations between hippocampal neuron loss and the cellular content of N-acetyl-aspartate, total creatine, or myo-inositol, despite more than a threefold difference in neuron loss and a twofold increase in glial density. Metabolite concentrations varied two- to fourfold. Variation in the cellular content of total creatine accounted for more than three-quarters of the rank-order variance of the N-acetyl-aspartate concentrations. There were no associations between myo-inositol and N-acetyl-aspartate or total creatine. Overall, mean N-acetyl-aspartate levels were below those reported by in vivo MRS studies of control subjects. CONCLUSIONS: These data suggest that decreased N-acetyl-aspartate in mesial temporal lobe epilepsy reflects altered mitochondrial metabolism, not merely neuron loss or gliosis. It is hypothesized that the altered N-acetyl-aspartate and creatine metabolism could reflect mitochondrial dysfunction or proliferation of immature glial cells that could contribute to the epileptogenic state.

Neuronal and glial metabolite content of the epileptogenic human hippocampus.

Mesial temporal lobe epilepsy is characterized by hippocampal atrophy, hypometabolism, and decreased N-acetylaspartate, often attributed to neuron loss and gliosis. Twenty hippocampal specimens were obtained during temporal lobectomy and frozen quickly. Perchloric acid extracts of the small metabolites were analyzed by proton magnetic resonance spectroscopy. There were no significant associations between hippocampal neuron loss and the cellular content of N-acetylaspartate, glutamate, GABA, glutamine, or aspartate. The mean metabolite content of hippocampi with less than 30% of neurons remaining was the same as those with greater than 65% of neurons surviving. Mean N-acetylaspartate levels were below those reported by in vivo studies of control subjects. The highest and the lowest glutamate concentrations were seen in specimens with the worst neuron loss. A highly significant association between hippocampal N-acetylaspartate and glutamate content was seen with weak associations between N-acetylaspartate and aspartate and glutamate and aspartate. The hippocampal content of N-acetylaspartate, glutamate, GABA, glutamine, and aspartate is altered minimally by severe neuron loss in mesial temporal lobe epilepsy. The epileptic human hippocampus has increased intracellular glutamate content that may contribute to the epileptogenic nature of hippocampal sclerosis.