International Journal of Neural Systems

Even though recent studies have suggested that seizures do not occur suddenly and that before a seizure there is a period with an increased probability of seizure occurrence, neurophysiological mechanisms of interictal and pre-seizure states are unknown. The ability of mathematical methods to provide much more sensitive tools for the detection of subtle changes in the electrical activity of the brain gives promise that electrophysiological markers of enhanced seizure susceptibility can be found even during interictal periods when EEG of epilepsy patients often looks 'normal'. Previously, we demonstrated in animals that hippocampal and neocortical gamma-band rhythms (30–100 Hz) intensify long before seizures caused by systemic infusion of kainic acid. Other studies in recent years have also drawn attention to the fast activity (>30 Hz) as a possible marker of epileptogenic tissue. The current study quantified gamma-band activity during interictal periods and seizures in intracranial EEG (iEEG) in 5 patients implanted with subdural grids/intracranial electrodes during their pre-surgical evaluation. In all our patients, we found distinctive (abnormal) bursts of gamma activity with a 3 to 100 fold increase in power at gamma frequencies with respect to selected by clinicians, quiescent, artifact-free, 7–20 min "normal" background (interictal) iEEG epochs 1 to 14 hours prior to seizures. Increases in gamma activity were largest in those channels which later displayed the most intensive electrographic seizure discharges. Moreover, location of gamma-band bursts correlated (with high specificity, 96.4% and sensitivity, 83.8%) with seizure onset zone (SOZ) determined by clinicians. Spatial localization of interictal gamma rhythms within SOZ suggests that the persistent presence of abnormally intensified gamma rhythms in the EEG may be an important tool for focus localization and possibly a determinant of epileptogenesis.

EEG and field potential rhythms established in the cortex and thalamus may accommodate the propagation of seizures. This article describes the interaction between thalamus and cortex during pentylenetetrazol (PTZ) seizures in rats with and without prior treatment with ethosuximide (ESM), a well-known antiepileptic drug (AED) that raises the threshold for seizures, was given before PTZ. The AED was given before PTZ convulsant administration. We track this thalamo-cortical association with a novel measure we have called the cross-bicoherence gain, or BISCOH. This quantity allows us to measure the spectral coherence in a purely higher order spectralmethodology. BISCOH is able to track the formation of nonlinearities at specific frequencies in the recorded EEG. BISCOH showed a strong increase in low alpha wave harmonic generationat 10 and 12.5 Hz after ESM treatment (p < 0.02 and p < 0.007, respectively). Conventional coherence failed to show distinctive and significant changes in thalamo-cortical coupling after ESM treatment at those frequencies and instead showed changes at 5 Hz. This rise in cortical rhythms is evidence of harmonic generation or new frequency formation in the thalamo-cortical system withAED therapy. BISCOH could become a powerful tool in unraveling changes in coherence due to neuroelectric modulation resulting from drug treatment or electrical stimulation.

The theory of phase resetting can reveal important information about the dynamic behavior of a periodic system when a single brief stimulus is applied to that system at the appropriate time. Phase resetting studies have revealed the existence in some biological systems of a vulnerable stimulus window generating desynchronization and suppression of the activity. The objective of this study was to test the hypothesis that a "singular" stimulus could annihilate this activity. Perfusion with the high-K solution produced synchronous, quasi-periodic population bursts with inter-burst interval of ~0.8–1.5 seconds. A single 0.1 ms duration anodic pulse of programmable delay and magnitude was applied to the somatic layer of the CA3 pyramidal cells. Three types of phase-resetting behavior were observed: (1) Weak resetting with little or no effect on the timing of the subsequent burst, (2) Strong resetting where the applied current pulse delayed the next event by one time period, (3) Singular behavior where the applied pulse partially or completely suppressed the subsequent bursting. The singular stimulus parameter window, however, was very narrow making it difficult to generate the singular behavior reliably. Nevertheless, the results indicate that singularities exist for high potassium neural activity and that a well timed pulse applied with the right amplitude can suppress this activity. This study suggests that phase resetting of a population of neurons is possible for quasi-periodic interictal activity and similar techniques could be applied to the control of epileptic seizures.

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Anti-epileptic drugs are ineffective in 25~30% of cases. Electrical stimulation to control seizures may be an additive therapy. We applied noninvasive transcutaneous focal electrical stimulation (TFES) via concentric ring electrodes on the scalp of rats after inducing seizures with pentylenetetrazole. We found a significant increase in synchrony within the beta-gamma bands during seizures and that TFES significantly reduced the synchrony of the beta-gamma activity and increased synchrony in the delta band.

Preliminary results from animal and clinical studies demonstrate that electrical stimulation of brain structures can reduce seizure frequency in patients with refractory epilepsy. Since most researchers derive stimulation parameters by trial and error, it is unclear what stimulation frequency, amplitude and duration constitutes a set of optimal stimulation parameters for aborting seizure activity in a given patient. In this investigation, we begin to quantify the independent effects of stimulation parameters on electrographic seizures, such that they could be used to develop an efficient closed-loop prosthesis that intervenes before the clinical onset of a seizure and seizure generalization. Biphasic stimulation is manually delivered to the hippocampus in response to a visually detected electrographic seizure. Such focal, responsive stimulation allows for anti-seizure treatment delivery with improved temporal and spatial specificity over conventional open-loop stimulation paradigms, with the possibility of avoiding tissue damage stemming from excessive exposure to electrical stimulation. We retrospectively examine the effects of stimulation frequency (low, medium and high), pulse-width (low and high) and amplitude (low and high) in seizures recorded from 23 kainic acid treated rats. We also consider the effects of total charge delivered and the rate of charge delivery, and identify stimulation parameter sets that induce after-discharges or more seizures. Among the stimulation parameters evaluated, we note 2 major findings. First, stimulation frequency is a key parameter for inhibiting seizure activity; the anti-seizure effect cannot be attributed to only the charge delivered per phase. Second, an after-discharge curve shows that as the frequency and pulse-width of stimulation increases, smaller pulse amplitudes are capable of eliciting an after-discharge. It is expected that stimulation parameter optimization will lead to devices with enhanced treatment efficacies and reduced side-effect profiles, especially when used in conjunction with seizure prediction or detection algorithms in a closed-loop control application.

A closed-loop system for the automated detection and control of epileptic seizures was created and tested in three Genetic Absence Epilepsy Rats from Strasbourg (GAERS) rats. In this preliminary study, a set of four EEG features were used to detect seizures and three different electrical stimulation strategies (standard (130 Hz), very high (500 Hz) and ultra high (1000 Hz)) were delivered to terminate seizures. Seizure durations were significantly shorter with all three stimulation strategies when compared to non-stimulated (control) seizures. We used mean seizure duration of epileptiform discharges persisting beyond the end of electrical stimulation as a measure of stimulus efficacy. When compared to the duration of seizures stimulated in the standard approach (7.0 s ± 10.1), both very high and ultra high frequency stimulation strategies were more effective at shortening seizure durations (1.3 ± 2.2 s and 3.5 ± 6.4 s respectively). Further studies are warranted to further understand the mechanisms by which this therapeutic effect may be conveyed, and which of the novel aspects of the very high and ultra high frequency stimulation strategies may have contributed to the improvement in seizure abatement performance when compared to standard electrical stimulation approaches.