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Brain Dynamics and Modeling in Epilepsy:

Prediction and Control Studies

Leonidas Iasemidis, Shivkumar Sabesan, Niranjan Chakravarthy, Awadhesh Prasad and Kostas Tsakalis

Abstract Epilepsy is a major neurological disorder characterized by intermittent paroxysmal neuronal electrical activity, that may remain localized or spread, and severely disrupt the brain’s normal operation. Epileptic seizures are typical mani- festations of such pathology. It is in the last 20 years that prediction and control of epileptic seizures has been the subject of intensive interdisciplinary research. In this communication, we investigate epilepsy from the point of view of pathology of the dynamics of the electrical activity of the brain. In this framework, we revisit two critical aspects of the dynamics of epileptic seizures – the seizure predictability and seizure resetting – that may prove to be the keys for improved seizure pre- diction and seizure control schemes. We use human EEG data and the concepts of spatial synchronization of chaos, phase and energy to first show that seizures could be predictable in the order of tens of minutes prior to their onset. We then present additional statistical evidence that the pathology of the brain dynamics prior to seizures is reset mostly upon seizures’ occurrence, a phenomenon we have called seizure resetting. Finally, using a biologically-plausible neural population mathe- matical model that can exhibit seizure-like behavior, we provide evidence for the effectiveness of a recently devised seizure control scheme we have called “feed- back decoupling”. This scheme also provides an interesting dynamical model for ictogenesis (generation of seizures).

1 Introduction

Epileptic seizures are manifestations of epilepsy, a neurological dynamical disor- der second only to stroke. Of the world’s 50 million people with epilepsy, about 1/3 has seizures that are not controlled by anti-convulsant medication. One of the most disabling aspects of epilepsy is the seemingly unpredictable nature of seizures. If seizures cannot be controlled, the patient experiences major limitations in fam- ily, social, educational, and vocational activities. These limitations have profound

L. Iasemidis (B) The Harrington Department of Bioengineering and Electrical Engineering, Arizona State University, Tempe, Arizona, USA

S.K. Dana et al. (eds.), Complex Dynamics in Physiological Systems:

From Heart to Brain, Understanding Complex Systems,

DOI 10.1007/978-1-4020-9143-8 12,

C Springer Science+Business Media B.V. 2009



L. Iasemidis et al.

effects on the patient’s quality of life, as well as on his or her family [1–3]. In addition, status epilepticus, a life-threatening condition where seizures occur con- tinuously, is treated only upon extreme intervention [4]. Until recently, the general belief in the medical community was that epileptic seizures could not be anticipated. Seizures were assumed to be abrupt transitions that occurred randomly over time. However, theories based on reports from clinical practice and scientific intuition, like the “reservoir theory” postulated by Lennox [5], existed and pointed out to the direction of seizure predictability. Various feelings of auras, that is, patients’ reports of sensations of an upcoming seizure, also exist in the medical literature. Penfield [6] was the first to note changes in the cerebral blood flow prior to seizures. Deterministically predictable occurrences of seizures (reflex seizures) in a small minority (about 3 to 5%) of epileptic patients have been reported as a result of various sensory stimuli [7, 8]. These theories and facts have implied that seizures might be predictable. The ability to predict epileptic seizures well prior to their occurrences may lead to novel diagnostic tools and treatment of epilepsy. Evaluation of anti-epileptic drugs and protocols, in terms of duration of patients’ seizure susceptibility periods and/or preictal (before a seizure) periods detected by seizure prediction algorithms, may lead to the design of new, more effective and with less side effects drugs for early disruption of the epileptic brain’s route towards a seizure. Electromagnetic stim- ulation and/or administration of anti-epileptic drugs (AEDs) at the beginning of the preictal period may disrupt the observed dynamical entrainment of normal brain sites with the epileptogenic focus (the area that first exhibits the electrographic onset of ictal activity), and lead to a significant reduction of epileptic seizures. Aside from their immediate clinical applications to epilepsy, successful seizure prediction and control algorithms could be useful for investigations into a wide variety of other complex, nonstationary and spatio-temporal biological and physical systems that undergo intermittent transitions. The 80s saw the emergence of new signal processing methodologies, based on the mathematical theory of nonlinear dynamics, for the study of spontaneous formation of organized spatial, temporal or spatiotemporal patterns in physical, chemical and biological systems [9,10,12,13]. These methodologies quantify the signal structure from the perspective of dynamical invariants (e.g. dimensionality of the attractor through correlation dimension, or divergence of trajectories through the largest Lya- punov exponent), and are a drastic departure from the signal processing techniques based on the linear model (e.g. Fourier analysis). In 1988, a small group at the University of Michigan, Ann Arbor, led by Iasemidis, Sackellares and Williams, reported the first application of nonlinear dynamics to clinical epilepsy [14]. That also led to the first NIH (National Institute of Health) supported clinical inves- tigation into the nonlinear dynamics of epileptic seizures (“Dynamical studies in temporal lobe epilepsy”, NIH-NINCDS RO1 NS31451). This group started to an- alyze continuous, multichannel, preictal (before seizure), ictal (during seizure) and postictal (after seizure) EEG from epileptic patients with temporal lobe epilepsy devising new and modifying existing measures from the theory of chaos to quan- tify the rate of divergence of trajectories (Lyapunov exponent) for the analysis of

Brain Dynamics and Modeling in Epilepsy: Prediction and Control Studies


EEG in epilepsy. The central concept was that seizures represented transitions of the epileptic brain from its “normal” less ordered (chaotic) state to an abnormal, more ordered state, and back to a “normal” state along the lines of chaos-to-order-to-chaos transitions [15–24]. The dynamical modeling hypothesis changed some long-held beliefs about seizures. Iasemidis et al. reported the first evidence that the transition to epileptic seizures may be consistent with a deterministic process [15, 20], and that ictal electroen- cephalogram (EEG) can be better modeled as an output of a nonlinear than a linear system [17]. The existence of long-term preictal periods (order of minutes) was shown using nonlinear dynamical analysis of subdural arrays [16], and raised the feasibility of seizure prediction algorithms by monitoring the temporal evolution of the short-term Lyapunov exponents (STL max ) [22–24]. The possibility of focus localization and seizure detection was also reported with the same technique in 1990 and 1994 respectively [18–21]. Since these initial results, several research groups in the world started to work in the area of seizure prediction (see [25] for

a review). Elger and Lehnertz investigated the spatio-temporal dynamics of the

epileptic focus in 1994 [26,27], while Scott and Schiff directed attention to the time

structure of inter-ictal spikes [28]. Lopes da Silva et al. who have been developing neurophysiology-driven dynamical models for EEG activity since the late 70s, quan- tified state bifurcations in epileptogenesis [29]. Iasemidis and Sackellares perfected their STL max technique with the use of optimization techniques and the critical mass hypothesis to predict seizures [30–36]. The fundamental issue that surfaced through this group’s investigations in seizure predictions was the importance to locate and use only the channels that carry information about an impending seizure. Changes in the spatio-temporal structure of the EEG can in principle also be quantified by sophisticated linear methods involving wavelet decompositions, coherence, and pat- tern recognition methods such as artificial neural networks, and fuzzy approaches. Several research groups are employing this approach towards the detection of the preictal period [37, 38]. However, no prospective results on seizure prediction (i.e. seizure prediction from long-term continuous EEG data using information only from past seizure occurrences) have been reported in the literature with any of the above measures yet, with the exception of Iasemidis et al.’s framework of analysis. The important conclusion from all these different techniques is an accumulation of ev- idence that there are measurable differences in the EEG prior to seizure onset that can be utilized for epileptic seizure prediction. Iasemidis’s group has reported a progressive preictal increase of spatiotemporal entrainment/synchronization between critical sites of the brain as the precursor of

epileptic seizures. The algorithm used was based on the convergence of short-term maximum Lyapunov exponents (STL max ) among critical electrode sites selected adaptively. This observation has been successfully implemented in the prospective prediction of epileptic seizures [39]. Global optimization techniques were applied for selecting the critical groups of electrode sites to observe preictal entrainment. Seizure anticipation times of about 71.7 min with a false prediction rate of 0.12 per

h were reported. To further relate these findings to the mechanism of epileptoge-

nesis, these investigators found that majority of seizures in patients with temporal


L. Iasemidis et al.

lobe epilepsy (TLE) irreversibly reset (disentrain) postictally the observed preic- tal dynamical entrainment [40, 41]. This supports the hypothesis that seizures do not occur as long as there is no need to reset the brain. Last, but not least, this

group of researchers have also shown through simulations that, in chaos-to-order- to-chaos transitions of general models of spatially coupled chaotic oscillators, with increase/decrease of coupling convergence/divergence of the oscillators’ STL max re- sembles the observed preictal entrainment and postictal dynamical disentrainment of the STL max of critical brain sites. In addition, the model exhibited hysteresis,

a phenomenon that is also observed in the epileptic transition into and out of

seizures [41]. This dynamical view leads to a characterization of the seizure itself as a mechanism that the brain has developed to reset the preictal entrainment when

a critical mass of sites, or a mass of specific, critical sites, is recruited. In order to provide insights into the development of feedback control strategies for suppression of seizures in the epileptic brain, and motivated by analysis and results of burst phenomena in adaptive systems [42,43], Tsakalis and Iasemidis [44] postulated the existence of an internal pathological feedback action in the epileptic brain that lacks the ability to compensate for excessive increases in the network cou-

pling. This situation eventually leads to seizure-like transitions [44–47]. A precursor

of this scenario is an abnormal increase in synchronization that cannot be regulated

quickly enough by the existing pathological internal feedback mechanism. Using a control-oriented approach, a functional model of an external feedback stimulation paradigm was developed. During periods of abnormally high synchrony, this scheme provides appropriate “desynchronizing feedback” to maintain “normal” synchro- nization levels between neural populations. This feedback control view of epileptic seizures and the developed seizure control strategies have been validated using cou- pled chaotic oscillator models as well as biologically plausible neurophysiologic models [46, 47]. In summary, from our group’s past and ongoing research, the following three central results about epileptic seizures have emerged. First, we have shown that seizures are manifestations of recruitment of brain sites in an abnormal hyper- synchronization. The onset of such recruitment occurs long before a seizure and pro- gressively culminates into a seizure. Seizures appear to be bifurcations of a neural network that involve a progressive coupling of the focus with the normal brain sites during a preictal period that may last days to tens of minutes. Thus, identification of such a preictal period may constitute the basis for predicting an impending seizure well in advance. Second, postictally, time-irreversible resetting of the observed preictal dynami- cal recruitment occurs (via a hysteretic loop). Preictal and postictal periods could be mathematically defined and detected from the EEG. Complete or partial reset- ting of the preictal entrainment of the epileptic brain after a seizure may affect the route to the subsequent seizure. This may contribute to the observed nonstationary nature of the seizure occurrences. Therefore, it is expected that estimation of the magnitude of resetting at a seizure will improve our understanding of the brain’s route to subsequent seizures, and may even lead to better seizure prediction and control.

Brain Dynamics and Modeling in Epilepsy: Prediction and Control Studies


Third, through control-oriented modeling, a feedback control view of epileptic seizures has been postulated, wherein epileptic seizures are hypothesized to be a result of the inability of the internal feedback/regulatory mechanisms of the brain to track excessive synchronization changes between the epileptogenic focus and other brain areas prior to a seizure. We herein present results on the preictal entrainment and brain resetting in EEG data recorded from epileptic patients, as well as on the generation and control of seizure-like behavior in a biologically-plausible mathematical model. Accordingly, the first goal was to identify the most reliable synchronization measures, across seizures in the same patient and across patients, that also issue the earliest warnings of upcoming seizures. Second, in order to further shed light on the mechanisms of seizures occurrence, the concept of seizure resetting is revisited. Third, a feedback control scheme for generation and suppression of epileptic seizures is shown, after we suitably modify a coupled neural population model from the literature to exhibit “seizures”. In the next Section 2, we first describe the available EEG data, and then the results of the application of the different synchronization measures to the predictability of the recorded epileptic seizures. In Section 3, we elaborate on the idea of brain reset- ting. Novel measures that detect resetting, as well as the sensitivity and specificity of resetting at seizure points, are investigated. We describe a feedback, systems-based modeling of the “preictal” dynamics via simulations on coupled neural populations in Section 4. In Section 5, we present a closed-loop seizure control strategy for the epilepsy-prone model in Section 4. We further discuss these results and present our conclusions in Section 6.

2 Predictability of Epileptic Seizures

In the present section, three of the most frequently utilized measures of dynamical synchronization/entrainment, namely classical energy (E), phase (Φ) and short-term Lyapunov exponent (STL max ), are compared on the basis of their ability to detect preictal changes. It is noteworthy that these three quantities, in the case of the com- plex exponential basis signal x(t) = Ae at e j(ωt+φ) , correspond to Ae at , ωt + φ, and respectively, where is the real part of the pole of the Laplace transform of x(t) and is equal to STL max , phase = ωt + φ is the imaginary part of the pole and it depends on , and energy E depends on A and . Due to the current interest in the field, and the proposed measures of energy and phase as alternatives to STL max for seizure prediction [38, 48, 49], it is important to comparatively evaluate each of the three measures’ seizure predictability (anticipation) capabilities. Quadratic integer programming techniques of global optimization were applied to select the optimal electrode sites per measure and seizure, that is the ones that exhibit maximum synchronization for every recorded seizure. Results from such an analysis of 43 seizures, recorded from two patients with temporal lobe epilepsy, showed that optimal sites selected on the basis of STL max 10 min before a seizure