Bruce J. Gluckman

In Vivo Modulation of Hippocampal Epileptiform Activity with Radial Electric Fields

Summary:  Purpose: Electric field stimulation can interact with brain activity in a subthreshold manner. Electric fields have been previously adaptively applied to control seizures in vitro. We report the first results from establishing suitable electrode geometries and trajectories, as well as stimulation and recording electronics, to apply this technology in vivo.

Toward rational design of electrical stimulation strategies for epilepsy control

Electrical stimulation is emerging as a viable alternative for patients with epilepsy whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy, namely, seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy.

A Model of the Effects of Applied Electric Fields on Neuronal Synchronization

We examine the effects of applied electric fields on neuronal synchronization. Two-compartment model neurons were synaptically coupled and embedded within a resistive array, thus allowing the neurons to interact both chemically and electrically. In addition, an external electric field was imposed on the array. The effects of this field were found to be nontrivial, giving rise to domains of synchrony and asynchrony as a function of the heterogeneity among the neurons. A simple phase oscillator reduction was successful in qualitatively reproducing these domains. The findings form several readily testable experimental predictions, and the model can be extended to a larger scale in which the effects of electric fields on seizure activity may be simulated.

Control and synchronization of chaos in high dimensional systems: Review of some recent results

Controlling chaos and synchronization of chaos have evolved for a number of years as essentially two separate areas of research. Only recently it has been realized that both subjects share a common root in control theory. In addition, as limitations of low dimensional chaotic systems in modeling real world phenomena become increasingly apparent, investigations into the control and synchronization of high dimensional chaotic systems are beginning to attract more interest. We review some recent advances in control and synchronization of chaos in high dimensional systems. Efforts will be made to stress the common origins of the two subjects. (c) 1997 American Institute of Physics.

Rapid Eye Movement Sleep and Hippocampal Theta Oscillations Precede Seizure Onset in the Tetanus Toxin Model of Temporal Lobe Epilepsy

Improved understanding of the interaction between state of vigilance (SOV) and seizure onset has therapeutic potential. Six rats received injections of tetanus toxin (TeTX) in the ventral hippocampus that resulted in chronic spontaneous seizures. The distribution of SOV before 486 seizures was analyzed for a total of 19 d of recording. Rapid eye movement sleep (REM) and exploratory wake, both of which express prominent hippocampal theta rhythm, preceded 47 and 34%, for a total of 81%, of all seizures. Nonrapid eye movement sleep (NREM) and nonexploratory wake, neither of which expresses prominent theta, preceded 6.8 and 13% of seizures. We demonstrate that identification of SOV yields significant differentiation of seizure susceptibilities, with the instantaneous seizure rate during REM nearly 10 times higher than baseline and the rate for NREM less than half of baseline. Survival analysis indicated a shorter duration of preseizure REM bouts, with a maximum transition to seizure at ∼90 s after the onset of REM. This study provides the first analysis of a correlation between SOV and seizure onset in the TeTX model of temporal lobe epilepsy, as well as the first demonstration that hippocampal theta rhythms associated with natural behavioral states can serve a seizure-promoting role. Our findings are in contrast with previous studies suggesting that the correlations between SOV and seizures are primarily governed by circadian oscillations and the notion that hippocampal theta rhythms inhibit seizures. The documentation of significant SOV-dependent seizure susceptibilities indicates the potential utility of SOV and its time course in seizure prediction and control.

Improved sleep-wake and behavior discrimination using MEMS accelerometers.

State of vigilance is determined by behavioral observations and electrophysiological activity. Here, we improve automatic state of vigilance discrimination by combining head acceleration with EEG measures. We incorporated biaxial dc-sensitive microelectromechanical system (MEMS) accelerometers into head-mounted preamplifiers in rodents. Epochs (15s) of behavioral video and EEG data formed training sets for the following states: Slow Wave Sleep, Rapid Eye Movement Sleep, Quiet Wakefulness, Feeding or Grooming, and Exploration. Multivariate linear discriminant analysis of EEG features with and without accelerometer features was used to classify behavioral state. A broad selection of EEG feature sets based on recent literature on state discrimination in rodents was tested. In all cases, inclusion of head acceleration significantly improved the discriminative capability. Our approach offers a novel methodology for determining the behavioral context of EEG in real time, and has potential application in automatic sleep-wake staging and in neural prosthetic applications for movement disorders and epileptic seizures.

Seizure entrainment with polarizing low-frequency electric fields in a chronic animal epilepsy model

Neural activity can be modulated by applying a polarizing low-frequency (<<100 Hz) electric field (PLEF). Unlike conventional pulsed stimulation, PLEF stimulation has a graded, modulatory effect on neuronal excitability, and permits the simultaneous recording of neuronal activity during stimulation suitable for continuous feedback control. We tested a prototype system that allows for simultaneous PLEF stimulation with minimal recording artifact in a chronic tetanus toxin animal model (rat) of hippocampal epilepsy with spontaneous seizures. Depth electrode local field potentials recorded during seizures revealed a characteristic pattern of field postsynaptic potentials (fPSPs). Sinusoidal voltage-controlled PLEF stimulation (0.5-25 Hz) was applied in open-loop cycles radially across the CA3 of ventral hippocampus. For stimulated seizures, fPSPs were transiently entrained with the PLEF waveform. Statistical significance of entrainment was assessed with Thomsons harmonic F-test, with 45/132 stimulated seizures in four animals individually demonstrating significant entrainment (p < 0.04). Significant entrainment for multiple presentations at the same frequency (p < 0.01) was observed in three of four animals in 42/64 stimulated seizures. This is the first demonstration in chronically implanted freely behaving animals of PLEF modulation of neural activity with simultaneous recording.

Adaptive electric field control of epileptic seizures

We describe a novel method of adaptively controlling epileptic seizure-like events in hippocampal brain slices using electric fields. Extracellular neuronal activity is continuously recorded during field application through differential extracellular recording techniques, and the applied electric field strength is continuously updated using a computer-controlled proportional feedback algorithm. This approach appears capable of sustained amelioration of seizure events in this preparation when used with negative feedback. Seizures can be induced or enhanced by using fields of opposite polarity through positive feedback. In negative feedback mode, such findings may offer a novel technology for seizure control. In positive feedback mode, adaptively applied electric fields may offer a more physiological means of neural modulation for prosthetic purposes than previously possible.

Electric field modulation of synchronization in neuronal networks

Abstract Motivated by the observation that applied electric fields modulate hippocampal seizures, and that seizures may be asynchronous, we modeled synaptically coupled two-compartment hippocampal pyramidal neurons embedded within an electrically resistive lattice in order to examine network synchronization properties under the influence of externally applied electric fields. Excitatory electric fields were shown to synchronize or desynchronize the network depending on the natural frequency mismatch between the neurons. Such frequency mismatch was found to decrease as a function of increasing electric field amplitude. These findings provide testable hypotheses for future seizure control experiments.

Stochastic resonance in mammalian neuronal networks

We present stochastic resonance observed in the dynamics of neuronal networks from mammalian brain. Both sinusoidal signals and random noise were superimposed into an applied electric field. As the amplitude of the noise component was increased, an optimization (increase then decrease) in the signal-to-noise ratio of the network response to the sinusoidal signal was observed. The relationship between the measures used to characterize the dynamics is discussed. Finally, a computational model of these neuronal networks that includes the neuronal interactions with the electric field is presented to illustrate the physics behind the essential features of the experiment. (c) 1998 American Institute of Physics.