Mark G. Frei

Real-time automated detection and quantitative analysis of seizures and short-term prediction of clinical onset.

Summary: Purpose: We describe an algorithm for rapid realtime detection, quantitation, localization of seizures, and prediction of their clinical onset.

Automated seizure abatement in humans using electrical stimulation

The need for novel, efficacious, antiseizure therapies is widely acknowledged. This study investigates in humans the feasibility, safety, and efficacy of high‐frequency electrical stimulation (HFES; 100–500Hz) triggered by automated seizure detections. Eight patients were enrolled in this study, which consisted of a control and an experimental phase. HFES was delivered directly to the epileptogenic zone (local closed‐loop) in four patients and indirectly, through anterior thalami (remote closed‐loop), to the other four patients for every other automated seizure detection made by a validated algorithm. Interphase (control vs experimental phase) and intraphase (stimulated vs nonstimulated) comparisons of clinical seizure rate and relative severity (clinical and electrographic) were performed, and differences were assessed using effect size. Patients were deemed “responders” if seizure rate was reduced by at least 50%; the remaining patients were deemed “nonresponders.” All patients completed the study; rescue medications were not required. There were 1,491 HFESs (0.2% triggered after‐discharges). Mean change in seizure rate in the local closed‐loop group was −55.5% (−100 to +36.8%); three of four responders had a mean change of −86% (−100 to −58.8%). In the remote closed‐loop, the mean change of seizure rate was −40.8% (−72.9 to +1.4%); two of four responders had a mean change of −74.3% (−75.6 to −72.9%). Mean effect size was zero in the local closed‐loop (responders: beneficial and medium to large in magnitude) and negligible in the remote closed‐loop group (responders: beneficial and medium to large). HFES effects on epileptogenic tissue were immediate and also outlasted the stimulation period. This study demonstrates the feasibility and short‐term safety of automated HFES for seizure blockage, and also raises the possibility that it may be beneficial in pharmaco‐resistant epilepsies. Ann Neurol 2005;57:258–268

An introduction to contingent (closed-loop) brain electrical stimulation for seizure blockage, to ultra-short-term clinical trials, and to multidimensional statistical analysis of therapeutic efficacy.

Summary Automated seizure blockage is a top research priority of the American Epilepsy Society. This delivery modality (referred to herein as contingent or closed loop) requires for implementation a seizure detection algorithm for control of delivery of therapy via a suitable device. The authors address the many potential advantages of this modality over conventional alternatives (periodic or continuous), and the challenges it poses in the design and analysis of trials to assess efficacy and safety—in the particular context of direct delivery of electrical stimulation to brain tissue. The experimental designs of closed-loop therapies are currently limited by ethical, technical, medical, and practical considerations. One type of design that has been used successfully in an in-hospital “closed-loop” trial using subjects undergoing epilepsy surgery evaluation as their own controls is discussed in detail. This design performs a two-way comparison of seizure intensity, duration, and extent of spread between the control (surgery evaluation) versus the experimental phase, and, within the experimental phase, between treated versus untreated seizures. The proposed statistical analysis is based on a linear model that accounts for possible circadian effects, changes in treatment protocols, and other important factors such as change in seizure probability. The analysis is illustrated using seizure intensity as one of several possible end points from one of the subjects who participated in this trial. In-hospital ultra-short-term trials to assess safety and efficacy of closed-loop delivery of electrical stimulation for seizure blockage are both feasible and valuable.

Performance reassessment of a real-time seizure-detection algorithm on long ECoG series

Summary:  Purpose: Automated seizure detection and blockage requires highly sensitive and specific algorithms. This study reassessed the performance of an algorithm by using a more extensive database than that of a previous study and its suitability for safety/efficacy closed‐loop studies to block seizures in humans.

Intrinsic time-scale decomposition: time-frequency-energy analysis and real-time filtering of non-stationary signals

We introduce a new algorithm, the intrinsic time-scale decomposition (ITD), for efficient and precise time–frequency–energy (TFE) analysis of signals. The ITD method overcomes many of the limitations of both classical (e.g. Fourier transform or wavelet transform based) and more recent (empirical mode decomposition based) approaches to TFE analysis of signals that are nonlinear and/or non-stationary in nature. The ITD method decomposes a signal into (i) a sum of proper rotation components, for which instantaneous frequency and amplitude are well defined, and (ii) a monotonic trend. The decomposition preserves precise temporal information regarding signal critical points and riding waves, with a temporal resolution equal to the time-scale of extrema occurrence in the input signal. We also demonstrate how the ITD enables application of single-wave analysis and how this, in turn, leads to a powerful new class of real-time signal filters, which extract and utilize the inherent instantaneous amplitude and frequency/phase information in combination with other relevant morphological features.

Left Vagus Nerve Stimulation with the Neurocybernetic Prosthesis Has Complex Effects on Heart Rate and on Its Variability in Humans

Summary:  Purpose: The purpose of this study was to determine if stimulation of the left vagus nerve (LVNS) with the neurocybernetic prosthesis (NCP) in humans is, as claimed in the literature, without cardiac chronotropic actions.

Correlation dimension and integral do not predict epileptic seizures

Reports in the literature have indicated potential value of the correlation integral and dimension for prediction of epileptic seizures up to several minutes before electrographic onset. We apply these measures to over 2000 total hours of continuous electrocortiogram, taken from 20 patients with epilepsy, examine their sensitivity to quantifiable properties such as the signal amplitude and autocorrelation, and investigate the influence of embedding and filtering strategies on their performance. The results are compared against those obtained from surrogate time series. Our conclusion is that neither the correlation dimension nor the correlation integral has predictive power for seizures.

Network system for automated seizure detection and contingent delivery of therapy

Summary The authors describe an integrated bedside system for real-time seizure detection and automated delivery of electrical stimulation directly to the brain of subjects undergoing invasive epilepsy surgery evaluation. These stimulations were triggered by specific detections following a prespecified pattern. The system uses a commercially available EEG unit, two personal computers, two Grass S-12 stimulators, and other custom-built units to enable interfacing between these components. To date, more than 9,500 hours of electrocorticographic data have been acquired, displayed, and analyzed, and more than 900 closed-loop stimulations for seizure blockage have been delivered safely and reliably to eight subjects with intractable epilepsy. This system generates on-line reports containing information about seizures that provide the epileptologist with timely, valuable data while allowing adaptation of the algorithm detection parameters to improve its performance if necessary. Additionally, it can control the output of any therapeutic device and administrate automatically cognitive tests or radioactive tracers for neuroimaging purposes. This network system, which can be replicated at a relatively low cost by others, is proof of concept for a portable or implantable device that could serve identical functions. Widespread availability of this type of system will advance the fields of clinical and basic epilepsy rapidly and considerably.

Observations on the application of the correlation dimension and correlation integral to the prediction of seizures.

Summary: The authors reexamine the correlation integral and the related correlation dimension in the context of EEG analysis with application to seizure prediction. They identify dependencies of the correlation integral and the correlation dimension on frequency and amplitude of the signal, which may result in a reinterpretation of the dynamic importance of these measures and may cast doubts on their predictive abilities for certain classes of seizures. The relevance, for clinical and research purposes, of the distinction between retrospective and prospective inference (prediction) is addressed briefly. The authors point to the need for further research, consisting of long time series, containing multiple seizures, and for the development of objective prediction criteria.

Controversies in epilepsy: Debates held during the Fourth International Workshop on Seizure Prediction

Debates on six controversial topics were held during the Fourth International Workshop on Seizure Prediction (IWSP4) convened in Kansas City, KS, USA, July 4-7, 2009. The topics were (1) Ictogenesis: Focus versus Network? (2) Spikes and Seizures: Step-relatives or Siblings? (3) Ictogenesis: A Result of Hyposynchrony? (4) Can Focal Seizures Be Caused by Excessive Inhibition? (5) Do High-Frequency Oscillations Provide Relevant Independent Information? (6) Phase Synchronization: Is It Worthwhile as Measured? This article, written by the IWSP4 organizing committee and the debaters, summarizes the arguments presented during the debates.