Interictal brain energy metabolism and glutamate-glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.

Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.

1. The effects of protein kinase inhibitors on N-methyl-D-aspartate (NMDA)-receptor-mediated, voltage-dependent calcium channel (VDCC)-mediated, and 100-Hz long-term potentiation (LTP) were studied in area CA1 of rat hippocampal slices. 2. A 25-Hz tetanus induced a quickly developing potentiation that was blocked by the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV) and was not affected by the L-type VDCC inhibitor nifedipine, suggesting that it was mediated by NMDA receptors (NMDA-LTP). 3. Application of a 200-Hz tetanus in APV induced a slowly developing NMDA-receptor-independent potentiation that was blocked by nifedipine and thus named VDCC-LTP. NMDA- and VDCC-LTP reached comparable magnitudes despite their different induction parameters and developmental kinetics. 4. Bath perfusion of the broad-spectrum serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) blocked NMDA-LTP but not VDCC-LTP, whereas the tyrosine kinase inhibitors genistein and lavendustin A blocked VDCC-LTP but not NMDA-LTP. These results suggest a differential involvement of H-7-sensitive serine/threonine kinases and tyrosine kinases in the two forms of LTP. 5. Tetanization of 200 Hz in control media resulted in a compound potentiation twice as large as NMDA- or VDCC-LTP, implying that the two forms of LTP did not facilitate or reduce each other's expression. The often-used 100-Hz tetanus (1 s twice) induced a potentiation that was comparable in size with the 200-Hz compound LTP. Nifedipine, genistein, and lavendustin A reduced the 100-Hz LTP by approximately 50%, suggesting that this LTP is also a compound potentiation consisting of NMDA- and VDCC-mediated components and their corresponding signal transduction pathways.

SUMMARYPurpose: 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.