Wireless peripheral nerve stimulation increases pain threshold in two neuropathic rat models

Neurostimulation approaches including spinal cord and peripheral nerve stimulation are typically used to treat intractable chronic pain in individuals who are refractory to pain medications. Our earlier studies have shown that a voltage controlled capacitive discharge (VCCD) method of stimulation of nerve activation is able to selectively recruit activity in large myelinated nerve fibers. In this study, we were able to wirelessly activate the sciatic nerve using the VCCD waveform. The purpose of this study was to determine whether this waveform can effectively improve two of the most troublesome pain symptoms experienced by patients with chronic neuropathic pain mechanical and cold hyperalgesia. Neuropathic mechanical hyperalgesia was reproduced using the Spinal Nerve Ligation (SNL) rat model whereas cold allodynia was reproduced using the Chronic Constriction Injury (CCI) model in male rats. Von Frey and cold plate tests were used to evaluate paw withdrawal threshold and latency to withdrawal before and after stimulation in experimental and control rats. Paw withdrawal threshold increased significantly compared to post-lesion baseline after VCCD stimulation in SNL rats. We also observed a significant improvement in cold allodynia in the active implant CCI rats after stimulation. These results suggest that the VCCD stimulation using a wireless microstimulator may be effective in the treatment of neuropathic pain.     

Effects of change in dietary folic acid content on pentylenetetrazol seizure threshold in rat

Pentylenetetrazol (PT) eeg thresholds were measured in rats on a folic acid (FA) deficient diet, normal diet, and a diet supplemented with large amounts of folic acid. The intraperitoneal dose per kilogram body weight of PT is significantly higher in the FA deficient group and significantly lower in the FA supplemented group than in rats on a normal diet. This indicates an effect of FA metabolism on PT epilepsy. The Lactobacillus casei minus Streptococcus faecalis activity of the brain is decreased in the FA deficient and increased in the FA supplemented group. The relation between brain folate metabolism and epilepsy is discussed.     

Antiepileptic efficacy of topiramate: assessment in two in vitro seizure models

The antiepileptic efficacy of topiramate (TPM) has been demonstrated in both whole animal seizure models and clinical trials; however, there is no consensus concerning its mechanism of action. We determined first whether the antiepileptic effect of TPM generalized to in vitro seizure models. Epileptiform discharges, recorded extracellularly, were evoked by repeated tetanic stimulation of Schaffer collaterals and layer III association fibers in entorhinal cortex/hippocampus and piriform cortex slices, respectively. TPM was applied at concentrations of 20 or 100 microM. Whole cell recordings were made from CA1 pyramidal neurons and the effect of TPM was assessed on a variety of intrinsic membrane properties including resting membrane potential, input resistance and postspike potentials. TPM (20 microM) was without effect in entorhinal cortex/hippocampus (N=6); however, 100 microM TPM decreased significantly the Coastline Burst Index from 358.3+/-65.8 to 225. 5+/-77.1 (N=4), the frequency of spontaneous epileptiform discharges to 44.6+/-21.8 (N=5) and the duration of primary afterdischarge (PAD) to 65.9+/-10.1 (N=10) percent of control. In contrast, phenytoin (50 microM, N=7; 100 microM, N=8) reduced PAD to 96.9+/-14. 8 and 86.5+/-17.3 percent of control, respectively. TPM (100 microM) did not reduce significantly the frequency of spontaneous discharges in piriform cortex (85.4+/-12.3 percent of control; N=5). TPM (100 microM) was without significant effect on intrinsic membrane properties in CA1 pyramidal neurons. Likely candidate mechanisms underlying the antiepileptic effect produced by TPM include enhancement of chloride-mediated GABA(A) currents and reduction of kainate and L-type calcium currents.     

Postnatal caffeine treatment affects differently two pentylenetetrazol seizure models in rats

Effects of repeated postnatal administration of caffeine (10 and 20 mg/kg s.c. daily from P7 to P11) were studied in two models of epileptic seizures characterized by spike-and-wave EEG rhythm in 18- and 25-day-old rats. Rhythmic metrazol activity (RMA, model of human absences) was induced by low dose of pentylenetetrazol (PTZ, 20 mg/kg or 40 mg/kg, i.p.) and minimal clonic seizures (model of human myoclonic seizures) by two successive doses of PTZ (20 and 40 mg/kg i.p.). Early postnatal caffeine treatment resulted in significant changes of RMA only in 18-day-old rats. Anticonvulsant effects were observed in RMA episodes elicited by the 20-mg/kg dose of PTZ in both caffeine groups whereas latency of RMA episodes induced by the 40-mg/kg dose was shortened and their duration was prolonged. No changes were found in 25-day-old animals. Incidence, EEG and motor pattern of minimal clonic seizures were not changed. Some animals in both control age groups exhibited transition to generalized tonic–clonic seizures. This type of seizures never appeared in caffeine-treated 25-day-old animals. Mixed effects of postnatal caffeine exposure were demonstrated; these predominantly anticonvulsant effects are age- and model-specific.     

Studies of dosage, seizure threshold, and seizure duration in ECT

Seizure threshold, defined as the minimal electrical dosage necessary to elicit adequate generalized seizure, was determined throughout the course of electroconvulsive therapy (ECT) in depressed patients randomly assigned to bilateral and right unilateral treatment, with brief pulse, constant current stimulation. In Study 1, it was found that seizure threshold may be more accurately measured using the unit of charge compared to the traditional unit of watt-second. In Study 2, it was found that seizure threshold was associated with seizure duration. Patients with high thresholds had shorter seizure durations. This indicated that the seizure threshold measure assesses in part functional neural activity. In Study 3, it was found that failure for seizure threshold to increase substantially over the course of ECT was associated with poor clinical outcome. In Study 4, it was found that electrical dosage at threshold was not related to magnitude of acute cognitive impairments. This suggested that the degree to which dosage exceeds threshold may be more strongly tied to adverse effects than the absolute dosage administered to patients. Implications of the data are discussed, particularly in relation to a hypothesized link between the anticonvulsant properties of ECT and its mechanism of therapeutic action.     

Change in seizure threshold during electroconvulsive therapy

The seizure threshold (ST) is a measure of the minimum electrical energy necessary to induce a grand mal seizure. Dose titration of the ST has been suggested to optimize stimulus dosing in electroconvulsive therapy (ECT). The change in ST with remission is examined in a large sample of unipolar depressed patients. METHODS: In a study of continuation treatments after successful ECT, the ST was determined at the first treatment and again 1 week after remission using a conventional ST measurement protocol. Patients were treated with bilateral electrode placement at 150% above the measured ST. RESULTS: In 80 subjects, the ST measured the same in 70%, increased in 21%, and decreased in 9% at remission. CONCLUSIONS: In a study of bilateral ECT, the ST did not rise conclusively with remission.     

Mouse strain variation in maximal electroshock seizure threshold

Maximal electroshock seizure threshold (MEST) is a classical measure of seizure sensitivity with a wide range of experimental applications. We determined MEST in nine inbred mouse strains and one congenic strain using a procedure in which mice are given one shock per day with an incremental (1 mA) current increase in each successive trial until a maximal seizure (tonic hindlimb extension) is elicited. C57BL/6J and DBA/2J mice exhibited the highest and lowest MEST, respectively, with the values of other strains falling between these two extremes. The relative rank order of MEST values by inbred strain (highest to lowest) is as follows: C57BL/6J > CBA/J = C3H/HeJ > A/J > Balb/cJ = 129/SvIMJ = 129/SvJ > AKR/J > DBA/2J. Results of experiments involving a single electroconvulsive shock given to separate groups of mice at different current intensities suggest that determination of MEST by the method used is not affected by repeated sub-maximal seizures. Overall, results document a distinctive mouse strain distribution pattern for MEST. Additionally, low within strain variability suggests that environmental factors which affect quantification of MEST are readily controlled under the conditions of this study. We conclude that MEST represents a useful tool for dissecting the multifactorial nature of seizure sensitivity in mice.     

Determinants of seizure threshold of electroconvulsive therapy in Chinese

OBJECTIVES: Debates continue whether dose-titration, formula-based or fixed-dosage method should be used during ECT. Regardless of the dosing method used, the range and the determinants of seizure threshold in different ethnic groups are useful clinical information. METHOD: Seizure threshold was quantified at the first ECT session using standardized dose titration and anesthetic protocols in 165 Chinese patients. One-hundred and five patients were treated with bilateral ECT and 60 with unilateral ECT. RESULTS: The mean seizure threshold was 95.9 mC (range = 32-403 mC). The mean and range of seizure threshold for bilateral ECT were 115.1 mC and 48-403 mC, for unilateral ECT, the mean and range were 62.1 mC and 32-192 mC. Stepwise regression analysis showed that electrode placement and age were the two most important predictors of seizure threshold and accounted for 32 and 20% of its variance respectively. Of lesser significance greater body mass index and concurrent use of antiepileptic were associated with higher seizure threshold. Unlike previous Western studies, we showed that gender had no significant relationship with seizure threshold for the total sample and unilateral ECT while for bilateral ECT interpretation is limited by the higher starting dose in men. CONCLUSION: Our finding added to the database on ECT in different ethnic groups and would be useful for the clinical practice of ECT in Chinese.     

Long-term metabolic alterations in a febrile seizure model

Objective: Febrile seizures (FS) are the most common neurological disease in infancy and early childhood, it can lead to metabolic changes and have long-term health implications. Aim of this study was to investigate the long-term effects of FS on metabolism. Methods: We measured certain metabolic parameters in hyperthermia-prone (HP) rats, which were developed using a selective breeding process and showed a lower seizure threshold than wild-type (WT) rats. Body weight, body length, abdominal circumference and the levels of fasting blood glucose, serum triglyceride, and total cholesterol concentrations were analyzed. The mRNA expression of genes involved in glucose and lipid metabolism was determined by qPCR and the histone methylation level in the liver was determined by western blot. Results: We found that the body weight of the HP rats was significantly lower than that of the WT rats. Similarly, the fasting blood glucose and serum triglyceride levels were lower in the HP group compared with the WT group. These changes were accompanied by increased mRNA expression of genes such as phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyl transferase-1 (CPT-1), but not peroxisome proliferator-activated receptor α (PPARα). We also found tri-methylation of histone 3 at Lys9 and Lys27 was decreased in the HP group. Conclusions: These data may suggest an underlying mechanism by which FS have a long-term effect on energy metabolism via histone methylation.     

Serum sodium does not correlate with seizure length or seizure threshold in electroconvulsive therapy

Disorders of sodium balance can result in seizures. In electroconvulsive therapy (ECT) practice, it is customary to obtain electrolytes, including sodium, before treatment. A question that arises is whether the patient with mild disturbances of sodium can safely be treated with ECT or whether normalization of serum sodium is needed first. In this series, 207 patients were treated with ECT and had a serum sodium performed within a week before the first treatment. A few patients were mildly hypernatremic or hyponatremic. We found no correlation between baseline sodium and seizure threshold or seizure duration at the first treatment session. We conclude that although it is ideal to have normal sodium values before ECT, mild abnormalities do not necessarily presage prolonged seizures or lower seizure thresholds in ECT.     

Age-related differences in seizure susceptibility to flurothyl

The purpose of the present study was to determine whether the susceptibility to seizures induced by inhalation of flurothyl ether (FE) varies with age. Adult rats and 16-day-old rat pups were tested in different sized chambers to also determine whether the size of the FE-test chamber influences seizure thresholds. Results indicate that pups developed age-specific seizure patterns; their seizure latency thresholds were shorter than those of adult animals. For both age-groups, seizure thresholds varied as a function of chamber size; the smaller the chamber the faster seizures occurred.     

Sex differences in seizure types and symptoms

BackgroundDespite the increasing interest in sex differences in disease manifestations and responses to treatment, very few data are available on sex differences in seizure types and semiology. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative study that aims to create a comprehensive repository of detailed clinical information and DNA samples from a large cohort of people with epilepsy. We used this well-characterized cohort to explore differences in seizure types as well as focal seizure symptoms between males and females.MethodsWe reviewed the EPGP database and identified individuals with generalized epilepsy of unknown etiology (GE) (n = 760; female: 446, male: 314), nonacquired focal epilepsy (NAFE) (n = 476; female: 245, male: 231), or both (n = 64; female: 33, male: 31). Demographic data along with characterization of seizure type and focal seizure semiologies were examined.ResultsIn GE, males reported atonic seizures more frequently than females (6.5% vs. 1.7%; p < 0.001). No differences were observed in other generalized seizure types. In NAFE, no sex differences were seen for seizure types with or without alteration of consciousness or progression to secondary generalization. Autonomic (16.4% vs. 26.6%; p = 0.005), psychic (26.7% vs. 40.3%; p = 0.001), and visual (10.3% vs. 19.9%; p = 0.002) symptoms were more frequently reported in females than males. Specifically, of psychic symptoms, more females than males endorsed déjà vu (p = 0.001) but not forced thoughts, derealization/depersonalization, jamais vu, or fear. With corrections for multiple comparisons, there were no significant differences in aphasic, motor, somatosensory, gustatory, olfactory, auditory, vertiginous, or ictal headache symptoms between sexes.ConclusionsSignificant differences between the sexes were observed in the reporting of atonic seizures, which were more common in males with GE, and for autonomic, visual, and psychic symptoms associated with NAFE, which were more common in females.     

Triheptanoin in acute mouse seizure models

Triheptanoin, the triglyceride of heptanoate, is used to treat certain hereditary metabolic diseases in USA because of its anaplerotic potential. In two chronic mouse seizure models this clear tasteless oil was found to be reproducibly anticonvulsant. Here we investigated the effects of triheptanoin feeding in C3H and CD1 mice using standard acute seizure models. Feeding 30-40% triheptanoin (caloric intake) consistently elevated blood propionyl-carnitines, but inconsistent anticonvulsant effects were observed in the fluorothyl, pentylenetetrazole and 6Hz seizure models. A 2mA consistent increase in the maximal electroshock threshold was found after 3 weeks of 35% triheptanoin feeding (p=0.018). In summary, triheptanoin shows a unique anticonvulsant profile in seizure models, compared to other treatments that are in the clinic. Therefore, despite small and/or inconsistent effects of triheptanoin in acute seizure models, triheptanoin remains of interest as a potential add-on treatment for patients with medically refractory epilepsy.     

EEG and seizure threshold in normal and lissencephalic ferrets

Changes in EEG and susceptability to electrically induced seizures were examined in the ferret with lissencephaly produced by exposure to a single injection of methylazoxymethanol acetate (MAM Ac) given to the pregnant jill on gestation day 32. Ten lissencephalic and 11 normal ferrets were chronically implanted with 14 cortical stainless steel electrodes. EEG records were sampled from various stages of the sleep/awake cycle. Six of each group were subjected to electrical stimulation for seizure threshold. Although the number of stimulations and the current intensity required to produce epileptiform afterdischarges (AD) and seizures were not different between the two groups, the lissencephalic ferrets had significantly longer AD and seizures, and a greater number of generalized seizures, indicating an enhanced seizure susceptibility. The EEG of the lissencephalic ferrets was characterized by increased slow wave activity within the low theta band range, extreme spindle activity, focal or multifocal slow and sharp waves, spikes, or spike and slow wave complexes. The differences in the EEG were more pronounced during drowsiness and sleep stages. The brains of all of the treated animals were lissencephalic and hydrocephalic, and weighed significantly less than those of the normals. The cerebral cortex was thin and flattened, with the parieto-occipital region most severely affected. Heterotopic foci were found in the cerebellum as well as in the cerebral cortex. Abnormalities in the configuration of the cerebellar folia were also seen. Comparison between the electrophysiological and neuropathological data suggests that the extent of the extreme spindle activity, and longer AD and seizure duration depended on the degree of cerebellar dysplasia, whereas the EEG focal abnormalities were related to lesions in the cerebral hemispheres.     

Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice

Epilepsy is characterized by spontaneous recurrent seizures and represents one of the most frequent neurological diseases, affecting about 60 million people worldwide. The cellular and neurocircuit bases of epilepsy are poorly understood. Constipation is a common gastrointestinal disorder characterized by symptoms such as straining, hard stool, and infrequent defecation. Population-based studies have shown that the prevalence of constipation is up to 30% of the population in developed countries. The causal link between seizure and constipation is a common belief among patients and physicians, but there are no scientific data to support this association. The current investigation evaluated the effects of constipation induced by loperamide (a peripheral μ-opioid receptor agonist without effect on central nervous system receptors) and clidinium (a quaternary amine antimuscarinic agent with reduced central nervous system effects) on two different seizure models of mice: (1) myoclonic, clonic, and generalized tonic seizures and death induced by intraperitoneal administration of pentylenetetrazole and (2) clonic seizure threshold induced by intravenous infusion of pentylenetetrazole. We demonstrated that the measured intestinal transit (%intestinal transit) decreased after loperamide or clidinium treatment for 3 days. Constipation in mice which was induced by loperamide or clonidine caused a decrease in threshold to clonic seizure in the intravenous pentylenetetrazole seizure model. Moreover loperamide- or clidinium-induced constipation decreased latencies to, clonic, and tonic seizures and death in the intraperitoneal pentylenetetrazole model of mice. Serum ammonia levels were slightly elevated in both loperamide- and clidinium-treated mice. In conclusion, loperamide- or clidinium-induced constipated mice are more prone to seizure which might confirm the belief of patients and physicians about constipation as a trigger of seizure.     

Initial seizure threshold of bilateral electroconvulsive therapy in Chinese.

INTRODUCTION: This preliminary study examined the initial seizure threshold for bilateral electroconvulsive therapy (ECT) in Chinese and the correlates of this seizure threshold. METHOD: Fifty-four patients underwent stimulus dose titration in a standardized protocol. RESULTS: The mean initial seizure threshold was 117 mC (range 48-403 mC). Stepwise regression analysis showed that age, body mass index, and gender were independently related to seizure threshold and accounted for 36, 7, and 6% of its variance, respectively. Determination of a relationship between gender and seizure threshold was limited by the higher starting electrical dosage in men. DISCUSSION: This preliminary study suggests that the seizure threshold for bilateral ECT in Chinese is comparable with that in the Western population. Our finding that body mass index is related to seizure threshold has not been reported previously. We also propose several differences between bilateral and unilateral ECT in the determinants of seizure threshold.     

Vagus nerve stimulation elevates seizure threshold in the kindling model

Purpose: Vagus nerve stimulation (VNS) provides partial relief of medically refractory partial seizures in a subset of patients. The optimal pattern of stimulation and the mechanism of the antiseizure effects are uncertain. Establishing the efficacy of VNS in an animal model of epilepsy would provide an experimental preparation with which to address these questions. We sought to determine whether VNS exerted antiseizure effects in the kindling model of epilepsy. Methods: We implanted adult rats with bipolar stimulating electrodes in the right amygdala and VNS devices around the left vagus nerve. Following induction of kindling, electrographic seizure threshold (EST) was determined by quantifying the amygdala electrode current required to evoke a seizure. Once stable ESTs were established, VNS devices were programmed to deliver U.S. Food and Drug Administration (FDA)–approved, clinically used (standard) or an experimental (microburst) pattern of stimulation of variable intensity. VNS devices were programmed identically in control animals except that no current was delivered. EST was examined at 60 min and 1 week in the control and vagus nerve stimulated groups. Key Findings: Significant reductions of EST values were detected in control animals when tested both 60 min and 1 week following device programming. Both clinically used and experimental patterns of VNS prevented the reduction of EST evident in control animals when tested either 60 min or 1 week after device programming. Significance: These findings establish an experimental preparation with which to elucidate the antiseizure mechanisms of VNS and to determine patterns of VNS most effective at elevating seizure threshold.     

Bemegride lengthens seizure duration during electric convulsive therapy in a schizophrenic patient with increased seizure threshold

A 48-year-old man who had a history of schizophrenia for 30 years was treated with electroconvulsive therapies. Because of poor seizure even at maximum electrical dosage, aminophylline was administered just before initiating electroconvulsive therapy. Although aminophylline augmentation lengthened the seizure duration, tachycardia and hypertension were observed. Therefore, we switched to bemegride, an antagonist to barbiturate, and seizure length was improved without any side effects. The present case suggested that bemegride is one of the alternative measures in patients with poor seizure quality.     

Increased seizure threshold in mice lacking aquaporin-4 water channels

Mice deficient in the glial water channel aquaporin-4 (AQP4) show decreased cerebral edema and improved neurological outcome following water intoxication or ischemic challenge. In this report, we tested seizure susceptibility in AQP4 mice. AQP4 mice and wild-type controls were given the chemoconvulsant pentylenetetrazol (PTZ) and monitored for seizure activity. At 40 mg/kg PTZ, all wild-type mice exhibited seizure activity, whereas six of seven AQP4 mice did not exhibit seizure activity. At 50 mg/kg PTZ, both groups exhibited seizure activity; however, the latency to generalized (tonic-clonic) seizures was significantly lower in wild-type than AQP4 mice. These results suggest that glial water channels may modulate brain excitability and the initiation and generalization of seizure activity.