Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures.

Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.

Assessing Susceptibility to Epilepsy in Three Rat Strains Using Brain Metabolic Profiling Based on HRMAS NMR Spectroscopy and Chemometrics.

The possibility that a metabolomic approach can inform about the pathophysiology of a given form of epilepsy was addressed. Using chemometric analyses of HRMAS NMR data, we compared several brain structures in three rat strains with different susceptibilities to absence epilepsy: Genetic Absence Epilepsy Rats from Strasbourg (GAERS), Non Epileptic Control rats (NEC), and Wistar rats. Two ages were investigated: 14 days postnatal (P14) before the onset of seizures and 5 month old adults with fully developed seizures (Adults). The relative concentrations of 19 metabolites were assessed using (1)H HRMAS NMR experiments. Univariate and multivariate analyses including multiblock models were used to identify the most discriminant metabolites. A strain-dependent evolution of glutamate, glutamine, scyllo-inositol, alanine, and glutathione was highlighted during cerebral maturation. In Adults, data from somatosensory and motor cortices allowed discrimination between GAERS and NEC rats with higher levels of scyllo-inositol, taurine, and phosphoethanolamine in NEC. This epileptic metabolic phenotype was in accordance with current pathophysiological hypothesis of absence epilepsy (i.e., seizure-generating and control networks) and putative resistance of NEC rats and was observed before seizure onset. This methodology could be very efficient in a clinical context.

Neural adaptation to responsive stimulation: a comparison of auditory and deep brain stimulation in a rat model of absence epilepsy.

BACKGROUND: Responsive deep brain stimulation (rDBS) has been recently proposed to block epileptic seizures at onset. Yet, long-term stability of brain responses to such kind of stimulation is not known. OBJECTIVE: To quantify the neural adaptation to repeated rDBS as measured by the changes of anti-epileptic efficacy of bilateral DBS of the substantia nigra pars reticulata (SNr) versus auditory stimulation, in a rat model of spontaneous recurrent absence seizures (GAERS). METHODS: Local field potentials (LFP) were recorded in freely moving animals during 1 h up to 24 h under automated responsive stimulations (SNr-DBS and auditory). Comparison of seizure features was used to characterise transient (repetition-suppression effect) and long-lasting (stability of anti-epileptic efficacy, i.e. ratio of successfully interrupted seizures) effects of responsive stimulations. RESULTS: SNr-DBS was more efficient than auditory stimulation in blocking seizures (97% vs. 52% of seizures interrupted, respectively). Sensitivity to minimal interstimulus interval was much stronger for SNr-DBS than for auditory stimulation. Anti-epileptic efficacy of SNr-DBS was remarkably stable during long-term (24 h) recordings. CONCLUSIONS: In the GAERS model, we demonstrated the superiority of SNr-DBS to suppress seizures, as compared to auditory stimulation. Importantly, we found no long-term habituation to rDBS. However, when seizure recurrence was frequent, rDBS lack anti-epileptic efficacy because responsive stimulations became too close (time interval < 40 s) suggesting the existence of a refractory period. This study thus motivates the use of automated rDBS in patients having transient seizures separated by sufficiently long intervals.

Manipulating the epileptic brain using stimulation: a review of experimental and clinical studies.

Neurostimulation represents an interesting alternative therapy for patients resistant to drug treatment or who cannot benefit from resective surgery. Theoretically, neurostimulation allows the control of seizures to be tailored to the individual patient and specific form of epilepsy. Here, we review both experimental and clinical studies that have reported the possible control of epileptic seizures by means of different approaches using electrical stimulation (vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation). The rationale for targeting specific areas that have thus far been considered (i.e., vagus nerve, cerebellum, anterior or centromedial thalamus, basal ganglia, cortex and temporal lobe) is addressed in the light of experimental data and clinical effectiveness in different models and forms of epilepsy. The type of seizures that can be considered for neurostimulation, as well as the optimal parameters such as stimulation frequency and modes of stimulation (chronic, continuous or adaptative), are discussed to determine the best candidates for such a therapeutic strategy. This review points out the need for improved knowledge of neural circuits that generate seizures and/or allow their propagation, as well as a better understanding of the mechanisms of action of neurostimulation.

Hypothalamic response to experimental allergic encephalomyelitis: role of substance P.

Adjuvant-induced arthritis (AA) is thought to be a model for experimental chronic stress that has as main features decreased adrenocorticotropin hormone (ACTH) plasma levels and a rise in median eminence content of arginine vasopressin (AVP) due to the activity of substance P. In experimental allergic encephalomyelitis (EAE), another chronic stress model, the role of substance P action is not clear. In this paper we tried to clarify the role of substance P in Lewis rats, which are susceptible to this disease. EAE was induced using myelin basic protein plus complete Freund's adjuvant injected into the hind limbs. One day later injections of an antagonist to substance P (RP 67580), saline, and substance P were administered daily for 12-14 days through a stainless steel cannula into the lateral ventricle of the brain, and then the rats were killed. The rats were divided into groups of controls, sham, diseased controls (no intracerebroventricular injections) and EAE (injected intracerebroventricularly). Plasma was used for the quantification of ACTH and corticosterone but not AVP which was assayed in hypothalamic median eminence extracts. In noninjected diseased rats the plasma levels of ACTH and corticosterone were significantly higher than in noninjected control rats, whereas the AVP concentrations in the median eminence were unchanged. The substance P antagonist did not affect the levels of these hormones in plasma or the median eminence. Substance P decreased the plasma levels of ACTH and corticosterone but did not increase the median eminence content of vasopressin. Administration of the antagonist 30 min before an equivalent dose of substance P increased the plasma levels of the two hormones, but did not change the content of AVP. Based on the lack of response to the antagonist RP 67580 we suggest that the substance P has different roles in EAE and AA at least in the later stages of EAE (after 11 days of immunization).