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Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis?

The effect of pretreatment with either tetanus toxin (in ventral hippocampus) or kainic acid (into dorsal hippocampus, with or without suppression of seizures by phenobarbital) on the subsequent development of epilepsy in rats injected with tetanus toxin (into ventral hippocampus) has been studied. Both treatments advanced the timing of the development of the subsequent epilepsy by a few days but did not affect the severity of the syndrome. The fits stopped after 3 weeks in all the rats but recurred in 6 of 20 of those given kainic acid, with or without phenobarbital, but not in those given only tetanus toxin. It is concluded that while fits make the brain more sensitive to a further epileptogenic stimulus they do not themselves increase their severity or persistence. It is the destruction of the CA3/4 area of the hippocampus which results in this advance and in the predisposition to permanent epilepsy.

Limbic encephalitis (LE) with waxing and waning neuropsychiatric manifestations including behavioral, personality, psychiatric, and memory changes can evolve over days to months. Many features of LE show remarkable overlap with the characteristics of mesial-temporal (limbic) status epilepticus (MTLSE or LSE). With LE, these prolonged impaired states are assumed not to be due to ongoing epileptic activity or MTLSE, because scalp EEGs usually show no epileptiform spike-wave activity; cycling behavioral and motor changes are attributed to LE; there may be little immediate improvement with antiepileptic drugs (AEDs); and of course, implanted electrodes are rarely used. Conversely, it is known that in pre-surgical patients with refractory limbic epilepsy, implanted electrodes have revealed limbic seizures that cannot be seen at the scalp. This paper assembles a chain of inferences to advance the proposition that refractory LE might represent LSE more often than is thought, and that implanted electrodes should be considered in some cases. We present two cases that suggest that LE was also LSE, one of which warranted implanted electrodes (case 1).

Studies of febrile seizures have been driven by two major enigmas: first, how these most common of human seizures are generated by fever has not been known. Second, epidemiological studies have linked prolonged febrile seizures with the development of temporal lobe epilepsy, yet whether long or recurrent febrile seizures cause temporal lobe epilepsy has remained unresolved. To investigate these questions, a model of prolonged (complex) febrile seizures was developed in immature rats and mice, permitting mechanistic examination of the potential causal relationships of fever and seizures, and of febrile seizures and limbic epilepsy. Although the model relied on hyperthermia, it was discovered that the hyperthermia-induced secretion of endogenous fever mediators including interleukin-1beta, which contributed to the generation of these 'febrile' seizures. In addition, prolonged experimental febrile seizures provoked epilepsy in a third of the animals. Investigations of the mechanisms of this epileptogenesis demonstrated that expression of specific ion (HCN) channels and of endocannabinoid signaling, may be involved. These may provide novel drug targets for intervention in the epileptogenic process.

We perform a systematic data analysis on high resolution (0.5–12 kHz) multiarray microelectrode recordings from an animal model of spontaneous limbic epilepsy, to investigate the role of high frequency oscillations and the occurrence of early precursors for seizures. Results of spectral analysis confirm the importance of very high frequency oscillations (even greater than 600 Hz) in normal (healthy) and abnormal (epileptic) hippocampus. Furthermore, we show that the measures of Recurrence Quantification Analysis (RQA) and Recurrence Time Statistics (RTS) are successful in indicating, rather uniquely, the onset of ictal state and the occurrence of some warnings/precursors during the pre-ictal state, in contrast to the linear measures investigated.

The susceptibility of rats with genetically inherited epilepsy to the genesis and consequences of secondary temporal lobe epilepsy is unknown. Here, we induced lithium-pilocarpine status epilepticus (SE) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) or in Wistar audiogenic sensitive (AS) rats. Wistar AS needed less pilocarpine than GAERS and Non-Epileptic Rats (NERs) to develop SE. Sixty six, 40 and 5% of Wistar AS, GAERS and NERs, respectively, died within 24 h after SE. In GAERS, SE prevented the occurrence of absence seizures for 5 days. Thereafter a limited number of absence seizures with low amplitude and short duration were recorded. Wistar AS developed limbic epilepsy within 9 days after SE while GAERS and NERs needed 36-39 days to develop spontaneous motor seizures. Neuronal loss consecutive to SE was similar in the three strains and particularly marked in limbic forebrain and parahippocampal cortices. In conclusion, the development of focal limbic epilepsy in GAERS largely impairs the expression of absence seizures. The genetic background underlying the expression of audiogenic seizures sensitizes strongly the rats to a further insult and compromises their survival.

We investigated the potential of 4-AP (50-100 microM) to induce seizure-like events (SLEs) in combined entorhinal cortex-hippocampal slices from Sprague Dawley rats which developed spontaneous limbic seizures following kainic acid induced status epilepticus. Slices from control rats (n=8) displayed SLEs in the entorhinal and perirhinal cortex upon application of 50 or 100 microM 4-AP. By contrast, 4-AP failed to induce SLEs in slices from chronic epileptic rats (n=13) except for one slice from one rat. This animal displayed only minor cell loss in layer III of the entorhinal cortex, in contrast to the other epileptic rats for which layer III neuronal loss was extensive. In all slices from epileptic rats, 4-AP induced recurrent epileptiform discharges similar to the interictal activity observed in control rats. Combined application of 4-AP (100 microM) and bicuculline methiodide (30 microM) induced frequent and prolonged recurrent epileptiform discharges in both control and chronic epileptic rats. 4-AP at 50-100 microM likely affects potassium channels containing Kv1.4, Kv1.5, Kv3.1 or Kv3.2 subunits. Real-time PCR revealed no significant downregulation of Kv1.4, Kv1.5, Kv3.1 or Kv3.2 in the subiculum, entorhinal and perirhinal cortex from chronic epileptic rats compared to controls. However, the expression of Kv3.4, responding to 4-AP in mM range, was significantly reduced. Using sub-unit-specific antibodies, the real-time PCR findings were confirmed by immunocytochemistry. We suggest that after chronic epilepsy, reorganization in the entorhinal cortex is accompanied by adaptations in homeostatic plasticity with anticonvulsant consequences.

Understanding neural network behavior is essential to shed light on epileptogenesis and seizure propagation. The interconnectivity and plasticity of the limbic and cortical regions of the mammalian brain provide the substrate for the hypersynchrony and hyperexcitability associated with epilepsy and seizure activity. Recurrent unprovoked seizures are the hallmark of epilepsy, and limbic epilepsy is the most common type of medically-intractable focal epilepsy in adolescents and adults that necessitates surgical evaluation. In this review, we describe the role and relationships among the piriform (PIRC), perirhinal (PRC), and entorhinal cortex (ERC) in seizure-generation and epilepsy. The inherent function, anatomy, and histological composition of these cortical regions are discussed. In addition, the neurotransmitters, intrinsic and extrinsic connections, and the interaction of these regions are described. Furthermore, we provide evidence based on clinical research and animal models that suggest that these cortical regions may act as key seizure-trigger zones and, even, epileptogenesis.

Deep brain stimulation (DBS) is a potentially potent means for disrupting the aberrant rhythms that arise during a seizure. However, current DBS strategies typically employed are formulated a priori and do not reflect dynamics within the brain during ictogenesis which may severely limit stimulation efficacy. This study investigated how DBS could be improved using endogenous dynamics to inform stimulation protocols. Multi-site brain dynamics within the circuit of Papez was calculated in a chronic rat limbic epilepsy model. Stimulation/recording electrodes were placed in the CA3 region of both hippocampi and in the anteromedial nucleus of the thalamus. Deconvolution of signals using empirical mode decomposition and coherence analysis were used to identify key dynamics as seizures progressed. Synchronization of field potentials across sites occurred as both spontaneous and evoked seizures naturally terminated. The location and frequency of synchrony varied between subjects suggesting that endogenous rhythms during natural seizure termination may vary in humans as well. DBS efficacy was significantly more effective at stopping seizures when the frequency of multisite synchronized stimulation reflected endogenous synchrony dynamics observed in each subject. Thus, tailoring DBS protocols to individual endogenous rhythms that may represent how brains naturally resolve epileptic seizures could play a critical role in improving overall efficacy of this potentially important therapy.

A 10-week-old, male German shepherd dog was presented with a primary complaint of episodic ptyalism, dysphagia, vomiting, and mandibular salivary gland enlargement. An esophagram with fluoroscopy showed normal pharyngeal and esophageal function; however, upper gastrointestinal endoscopy and cervical ultrasonography revealed a focal circumferential thickening of the midcervical esophageal muscular wall, consistent with esophageal spasm. The puppy responded dramatically and completely to phenobarbital treatment. An unusual syndrome of phenobarbital-responsive hypersialosis was consistent with this dog’s clinical presentation and the finding of apparent esophageal spasm. The pathogenesis of this syndrome is unclear, but it may represent a form of limbic epilepsy or peripheral autonomic dysfunction.

Surgery for the mesial temporal lobe epilepsy syndrome is highly effective in controlling seizures in as many as 80% of the patients who undergo this procedure. However, the majority of the patients with successful operations still require medications to control their seizures. Only a small minority are able to stop medications and remain seizure free, patients who would be considered cured. Why are so few patients cured by this procedure? The answer may lie in the relation of the critical seizure circuits to the tissue that is actually resected. In this paper we will discuss two hypotheses for the functional anatomy of limbic epilepsy in light of what is known about the pathology and physiology of limbic epilepsy. Combining the clinical and scientific observations with these constructs for seizure initiation may lead us to a better understanding of this particular epilepsy syndrome as well as to more effective surgical approaches.

Limbic epilepsy refers to a condition that consists of epileptic seizures that originate in or preferentially involve the limbic system. The majority of cases are medically refractory, necessitating surgical resection when possible. However, even resection of structures thought to be responsible for seizure generation may not leave a patient seizure free. While mesial temporal lobe limbic structures are centrally involved, there is growing evidence that the epileptogenic network consists of a broader area, involving structures outside of the temporal lobe and the limbic system. Information on structural, functional, and metabolic connectivity in patients with limbic epilepsy is available from a large body of studies employing methods such as MRI, EEG, MEG, fMRI, PET, and SPECT scanning, implicating the involvement of various brain regions in the epileptogenic network. To date, there are no consistent and conclusive findings to define the exact boundaries of this network, but it is possible that in the future studies of network connectivity in the individual patient may allow more tailored treatment and prognosis in terms of surgical resection.

Chronic, limbic epilepsy was induced in male rats by a single systemic injection of lithium and pilocarpine. In two separate experiments, each 6 mo. in duration, the proportion of the population that displayed an overt motor seizure (head nodding, rearing, and forelimb clonus) within 10 min. each day after delivery of food pellets (despite food provided ad libitum) was recorded. Cumulative records for the numbers of rats in each population that displayed overt seizure for the first time during the observation period were plotted as a function of time. The occurrence of the saturated (approaching 100%) asymptote at about five months was interpreted to indicate that brief (10 min.) sampling over the 144 successive days that would compose a single 24-hr. period could serve as an estimate of the average probability of an overt seizure during an average 24-hr. period. If this assumption is correct, then these rats would have displayed about one overt seizure per day.

Summary: Purpose: To investigate the exploratory response to novelty in rats that have recovered from experimental limbic epilepsy. Methods: Epilepsy was induced in 12 male rats by injecting a minute amount of tetanus toxin into the ventral hippocampus (and buffer vehicle was injected into 12 controls). Eight weeks after the injection, when the animals appeared behaviourally normal (and previous work would indicate that their electroencephalograms also would have returned to normal), they were tested on the playground maze. In this, their exploratory response to a novel object introduced in the context of seven familiar objects is measured. Simultaneously, their locomotion and investigation of familiar objects is measured. Results: Whereas the control animals showed a significant response to the novel object on both test days, in the toxin-injected rats the novelty response was not present. There was no difference between the groups on the locomotion measure, but the toxin rats explored the familiar as well as the novel objects less. Conclusions: The exploratory response to a novel object was abolished in the previously epileptic rats.

BACKGROUND The available information about certain microanatomic features of the AChA perforators is incomplete. Precise knowledge of these vessels is necessary to understand the consequences of their occlusion and to safely operate in their region. METHODS The AChA perforators were microdissected and examined under the stereoscopic microscope in 10 vascular casts and in 20 hemispheres injected with india ink or radiopaque substance. RESULTS The perforating branches ranged in number from 2 to 9 (mean, 4.6) and in diameter between 90 μm and 600 μm (mean, 317 μm). The most proximal perforator arose 3.2 mm on average caudal to the AChA origin. The most distal (capsulothalamic) perforator varied in size from 200 μm to 610 μm (mean, 431 μm). One or more of the perforators always originated from the AChA (100%), but some of them also from the uncal (33.3%) or parahippocampal branch (10%) of the AChA, either as individual vessels only (70%) or from common trunks (30%). The perforators gave off the peduncular (20%), optic (23.3%), or uncal side branches (26.7%). CONCLUSIONS Our findings concerning the origin, position, number, size, branching, penetration site, and relationships of the AChA perforators gave the anatomic basis for safe operations in patients with AChA aneurysms or mediobasal limbic epilepsy

In three separate experiments, groups (4/group) of male rats with limbic epilepsy were exposed for 80 min every 24 hr during the midscotophase for 24 successive days to sham-field conditions or to one of four complex patterns of magnetic fields whose average intensities ranged between 20 nT to 500 nT. The numbers of episodes of boxing, biting, mounting, eating, drinking and grooming were then recorded each night during the latter 20 min. Moderately strong statistically significant interactions occurred between the presence or absence of the field and the pattern of the field explained 25% and 50% of the variance in the numbers of biting and boxing responses, respectively. Other behaviors were not affected. The results suggest that group aggression can be increased or decreased as a function of the temporal characteristics and morphology (shape) of the applied magnetic field.

Kindling has become the most widely studied animal model of limbic epilepsy. Understanding the molecular basis of kindling development may provide novel therapeutic approaches to prevention of limbic epileptogenesis. I briefly describe the kindling model and outline the basis for my thinking that kindling represents a synaptic reorganization triggered by pathologic activity in the mature nervous system. The pathologic activity is postulated to evoke a cascade of gene expression driven, at least in part, by glutamate receptor activation. Evidence in support of this hypothesis is presented, as are future challenges that permit critical tests of these ideas.

Epilepsy is a common chronic disorder of the central nervous system. Approximately 30% of epilepsy patients are resistant to the present anti-epileptic drugs (AEDs), with the majority of these pharmacoresistant patients suffering from temporal lobe epilepsy (situated in the limbic system). Thus, it is of great importance to find novel drug targets that act differently from the AEDs available. Ghrelin is a 28-amino acid peptide, known as the endogenous ligand of the ghrelin receptor (GHSR1a)1. GHSR1a is expressed in several areas of the central nervous tissue, such as the pituitary, hypothalamus, thalamus, cortex and hippocampus2. Recently, ghrelin has been implicated in epilepsy and the current animal studies indicate that ghrelin has anticonvulsant properties3,4. Human studies are more contradictory, however it is evident that plasma ghrelin levels are altered in epilepsy patients5,6. Recent evidence from our laboratory suggest that inactivation of the GHSR1a attenuates limbic seizures in acute in vivo and in vitro animal models. Our aim is to further clarify the role of the GHSR1a in a corneal kindling mouse model. In this chronic experimental epilepsy model, we will compare GHSR1a+/+ and GHSR1a-/- corneally kindled mice, and see if there is a difference in seizure stage and/or number of stimulations to reach a plateau in seizure severity. In fully kindled GHSR1a+/+ mice, we will also investigate whether ghrelin administration can be protective against epileptic seizures. Since it is known that GHSR1a is expressed on neurons in the hypothalamus7 and that the receptor plays a role in glial cell activation4, we will also characterize the cellular distribution of the GHSR1a in the mouse hippocampus (double immunofluorescence labeling with markers for neurons, glia and microglia). Finally, we will investigate whether there is a possible shift in GHSR1a cell type distribution following induction of epilepsy, using fully corneal kindled mice and immunofluorescence stainings. With these experiments we want to further characterize the role of ghrelin and the GHSR1a in limbic epilepsy. 1Kojima M. et al. (1999) Ghrelin is a growth hormone-releasing acylated peptide from the stomach. Nature. 402, 656-660. 2Zigman J.F. et al (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol. 494, 528-548. 3Obay B.D. et al (2007) Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides. 28, 1214-1219. 4Lee J. et al. (2010) Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Endorcrinol. 205, 263-70. 5Berilgen M.S. et al. (2006) Serum ghrelin levels are enhanced in patients with epilepsy. Seizure. 15, 106-111. 6Prodam F. et al (2010) Ghrelin levels are reduced in prepubertal epileptic children under treatment with carbamazepine or valproic acid. Epilepsia. 51, 312-315. 7Cowley M.A. et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 37, 649-661.

In the last two decades our understanding of MTLE and its pathophysiology has grown remarkably. Perhaps the most important recognition is that it is not a single entity with a uniform pathology. Rather, it is associated with significant variations in pathology that, in turn, are likely associated with different causes, functional anatomies, physiologies, and outcomes to treatment (medi-cal and surgical). There are numerous changes in the expression of channels and receptors that contribute to the development of epilepsy and, perhaps, drug resistance. This progress in our understanding has also been aided immeasurably by the development of animal models with many parallels to the human condition.These models have allowed us to look at changes in anatomy and physiology and to dissect the circuits in ways that have not been possible in humans. The animal models have also allowed us to create hypotheses about the pathophysiology of the disorder that we have started to exam-ine with the new imaging tools. At present, it is best to summarize our understanding of MTLE by saying there are multiple changes in multiple sites that contribute to the development of the chronic condition. For this reason alone, we should consider MTLE to be a systems disorder.

Slater's work on the schizophrenia-like psychoses of epilepsy is re-examined in the light of subsequent developments in psychiatry and neurology. Simple causal links of the sort he postulated between epilepsies and psychoses appear increasingly tenuous, despite indications that some psychotic symptoms and some localised structural changes are linked. A resumption of the study of electrophysiological similarities between schizophrenia and limbic epilepsy may offer a useful alternative programme for research.

Kindling is an experimental model for epilepsy in which repeated stimuli induce longer electrographic seizures and eventually cause behavioral convulsions. Although kindling has some features that are similar to chronic human epilepsy, it is not known whether this process plays a role in the development of chronic seizure disorders. We have recently described a rat model of chronic spontaneous limbic seizures that has a number of similarities to human limbic epilepsy. To determine whether a kindling process is involved in the ontogeny of the seizures in this animal model, we continuously monitored 16 rats with EEG and closed circuit television until they had experienced a minimum of 5 and as many as 10 seizures following the first motor seizure. All animals had at least one non-motor seizure before the first motor event (mean 5.1 ± 0.9 S.E.M. initial non-motor seizures, range 1–12). In addition the seizures significantly lengthened in duration with succeeding events (mean 90 s for the first motor seizure to mean 110 s for the tenth subsequent seizure). These data demonstrate that there is a kindling process involved in the early development of chronic limbic seizures.

Surgical techniques and postoperative results of 100 patients who underwent selective amygdala-hippocampectomy for temporal lobe epilepsy without apparent macroscopic lesions are presented.

Epilepsy was induced in female rats by the injection of tetanus toxin (5 mouse LD50) unilaterally into the ventral hippocampus under anesthesia. During the 2-4 weeks that the rats exhibited intermittent spontaneous convulsions, daily vaginal smear tests showed that their estrous cycle was interrupted. In control rats such interruption only occurred for just a few days after the operation. Investigation of mating behavior, on the first night of proestrus, which occurred after 7 weeks from the operation, showed that there were fewer mounts, intromissions or ejaculations from the males, which were caged with previously epileptic animals. These females produced slightly smaller litters than their controls and there was a marked failure of their young to thrive in comparison with those of the control females. This failure appeared to be related to relatively high "stress" levels in the general laboratory environment. The impairment of reproductive success only lasted about 3 months after the original induction of epilepsy since subsequent litters to the same animals thrived normally.

Two patients are reported, one with severe brain damage and epilepsy, and the other with limbic epilepsy, who were treated with unilateral microsurgical amygdalo-hippocampectomy for the control of rage and aggression. Both had significant improvement in their aggressiveness, and the second patient also improved in the frequency of his seizures and psychotic episodes. The significance of these observations for our understanding of the morphophysiological basis of rage and aggression is discussed.

We have previously reported preictal spatiotemporal transitions in human mesial temporal lobe epilepsy (MTLE) using short term Lyapunov exponent (STL max ) and average angular frequency (\( \Omega \) ). These results have prompted us to apply the quantitative nonlinear methods to a limbic epilepsy rat (CLE), as this model has several important features of human MTLE. The present study tests the hypothesis that preictal dynamical changes similar to those seen in human MTLE exist in the CLE model. Forty-two, 2-hr epoch data sets from 4 CLE rats (mean seizure duration 74±20 sec) are analyzed, each containing a focal onset seizure and intracranial data beginning 1 hr before the seizure onset. Three nonlinear measures, correlation integral, short-term largest Lyapunov exponent and average angular frequency are used in the current study. Data analyses show multiple transient drops in STL max values during the preictal period followed by a significant drop during the ictal period. Average angular frequency values demonstrate transient peaks during the preictal period followed by a significant peak during the ictal period. Convergence among electrode sites is also observed in both STL max and \( \Omega \) values before seizure onset. Results suggest that dynamical changes precede and accompany seizures in rat CLE. Thus, it may be possible to use the rat CLE model as a tool to refine and test real-time seizure prediction, and closed-loop intervention techniques.

Summary: Correlations were sought among neuroendocrine, psychopathologic, neuropsychological, and seizure variables in 16 male patients with limbic epilepsy. Plasma prolactin and luteinizing hormone levels were directly correlated with seizure frequency. Plasma prolactin was inversely correlated with thought disorder. Post hoc findings included a strong direct correlation between total plasma testosterone levels and aggression. These relationships may help to elucidate mechanisms related to interictal symptomatology in patients with limbic epilepsy. RESUMEN Se nan buscado las correlaciones entre variables neuroendocrinologicas, psicopatologicas. neuropsicologicas y ataques en 16 pacientes con epilepsia limbica. Los niveles plasmaticos de prolactina y de hormona luteinizante, se correlacionaron directamente con la frecuencia de los ataques. La prolactina plasmatica se correlaciono inversamente con los trastomos de pensamiento. Los hallazgos posteriores incluyeron una fuerte correlacion directa entre los niveles plasmaticos totales de testosterona y la agresion. Estos datos pueden ayudar a aclarar los mecanismos relacionados con la sintomatologia interictal en enfermos con epilepsia limbica. ZUSAMMENFASSUNG Bei 16 mannlichen Patienten mit einer limbischen Epilepsie (LE) wurde nach Korrelationen zwischen Endokrinium, Psychopathologie, neuropsychologischen Veranderungen und unter-schiedlichen Anfallstypen gesucht. Das Plasma-Prolaktin korrelierte umgekehrt mit Denkstorungen. Postiktale Befunde zeigten eine deutliche direkte Korrelation zwischen Gesamt-Plasma-Testosteron und Aggression. Diese Abhangigkeiten konnten Mechanismen aufdecken, die mit den intenktalen Symptomen bei Patienten mit limbischer Epilepsie zusammenhangen.

High Frequency Oscillations (HFO) in limbic epilepsy represent a marked difference between abnormal and normal brain activity. Faced with the difficult of visually detecting HFOs in large amounts of intracranial EEG data, it is necessary to develop an automated process. This paper presents Teager Energy as a method of finding HFOs. Teager energy is an ideal measure because unlike conventional energy it takes into account the frequency component of the signal as well as signal amplitude. This greatly aids in the dissection of HFOs out of the noise and other signals contained in the EEG. Therein, Teager energy analysis is able to detect high- frequency, low-amplitude components that conventional energy measurements would miss.

The concept of a neuromatrix as a determinant of behavior proposes that complex neuroelectromagnetic patterns supported by specific spatial configurations of neurons underlie the generation of behaviors. When the pattern of neuronal connectivity is changed, as occurs during limbic epilepsy, neuroelectromagnetic patterns change in parallel to sustain behavioral output. Thus, a testable prediction of the neuromatrix concept is that the "normal" behaviors of animals with markedly reorganized neuroelectromagnetic patterns are vulnerable to specific stimuli that are ineffective when applied to a normal population. Because rats treated with ketamine after being induced to seize with pilocarpine exhibit behaviors indistinguishable from those of control populations despite marked changes in brain structure, they represent an ideal population in which to examine this hypothesis. Ketamine-treated pilocarpine-seized rats and normal rats were exposed continuously either to a complex sequence magnetic field or to control conditions during the acquisition of a radial arm maze task for 8 consecutive days. After 14 days of subsequent exposure to a frequency-modulated field (7-500 nT), during which time there was no training, the rats that had been induced to seize and had been exposed continuously to this magnetic configuration exhibited conspicuously slower response durations per arm than rats that had been induced to seize and exposed to control conditions or normal rats that had been exposed to either magnetic fields or control conditions. Thus, the behaviors of rats who have sustained multiple, discrete injuries throughout the brain may be seriously disrupted by the appropriate pattern of exogenous weak magnetic fields. Our results represent the first empirical support for the concept of the neuromatrix.

To test the hypothesis that sudden unexplained death (SUD) in some epileptic patients is related to geomagnetic activity we exposed rats in which limbic epilepsy had been induced to experimentally produced magnetic fields designed to simulate sudden storm commencements (SSCs). Prior studies with rats had shown that sudden death in groups of rats in which epilepsy had been induced months earlier was associated with the occurrence of SSCs and increased geomagnetic activity during the previous night. Schnabel et al. [(2000) Neurology 54:903-908] found no relationship between SUD in human patients and geomagnetic activity. A total of 96 rats were exposed to either 500, 50, 10-40 nT or sham (less than 10 nT) magnetic fields for 6 min every hour between midnight and 0800 hours (local time) for three successive nights. The shape of the complex, amplitude-modulated magnetic fields simulated the shape and structure of an average SSC. The rats were then seized with lithium and pilocarpine and the mortality was monitored. Whereas 10% of the rats that had been exposed to the sham field died within 24 h, 60% of the rats that had been exposed to the experimental magnetic fields simulating natural geomagnetic activity died (P

On three separate sessions 24 male rats with histories of limbic epilepsy were exposed to 10 temporal configurations for 5 min. each of one of two patterns of magnetic fields. Their intensities averaged about 1 microTesla (μT). The numbers of Level 5 (Racine) seizures, inferred by the rat's rearing, rapid forelimb clonus, and falling, were statistically more frequent for the frequency-modulated (Thomas) pattern when its pixel duration and interstimulus presentation were 3 msec. The effectiveness of this temporal configuration was replicated in a second within-subjects experiment ( n = 9) that directly compared the numbers of seizures during exposures to each of the two patterns and to a sham-field. These results suggest that brains with sensitive limbic systems might respond to weak magnetic fields, generated from multiple overlapping fields from communication and computer systems whose temporal derivatives emerge as complex sequences with pixel durations within the millisecond range.

The course of untreated epilepsy is not well established. This study uses a model of chronic limbic epilepsy (pilocarpine model of epilepsy) to determine the pattern of occurrence of seizures in untreated animals. Following pilocarpine administration, 21 rats were monitored continuously with a video system for 135 days after the first spontaneous seizure. Animals showed a great variability in seizure numbers and were divided in two subgroups presenting either a low frequency of seizures (n = 9 animals presenting ten or less seizures in the first 15 days of observation) or a high frequency of seizures (n = 12 animals presenting more than ten seizures during this period). Animals with low number of seizures during the first 15 days of observation showed a significant increase in seizure frequency in the following period of analysis (until 105 days). On the other hand, those with initial high number of seizures showed significant changes in seizure frequency only in the first 2 months. The duration of each spontaneous seizure did not change significantly over time. These findings show that in untreated epilepsy there is a maturation process in the early stages and this accelerating process can be of predictive value for the treatment of epilepsy.