Toward a Noninvasive Automatic Seizure Control System in Rats With Transcranial Focal Stimulations via Tripolar Concentric Ring Electrodes

Epilepsy affects approximately 1% of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We are developing a noninvasive, or minimally invasive, transcranial focal electrical stimulation system through our novel tripolar concentric ring electrodes to control seizures. In this study, we demonstrate feasibility of an automatic seizure control system in rats with pentylenetetrazole-induced seizures through single and multiple stimulations. These stimulations are automatically triggered by a real-time electrographic seizure activity detector based on a disjunctive combination of detections from a cumulative sum algorithm and a generalized likelihood ratio test. An average seizure onset detection accuracy of 76.14% was obtained for the test set (n = 13). Detection of electrographic seizure activity was accomplished in advance of the early behavioral seizure activity in 76.92% of the cases. Automatically triggered stimulation significantly (p = 0.001) reduced the electrographic seizure activity power in the once stimulated group compared to controls in 70% of the cases. To the best of our knowledge this is the first closed-loop automatic seizure control system based on noninvasive electrical brain stimulation using tripolar concentric ring electrode electrographic seizure activity as feedback

A Novel Long-term, Multi-Channel and Non-invasive Electrophysiology Platform for Zebrafish.

Zebrafish are a popular vertebrate model for human neurological disorders and drug discovery. Although fecundity, breeding convenience, genetic homology and optical transparency have been key advantages, laborious and invasive procedures are required for electrophysiological studies. Using an electrode-integrated microfluidic system, here we demonstrate a novel multichannel electrophysiology unit to record multiple zebrafish. This platform allows spontaneous alignment of zebrafish and maintains, over days, close contact between head and multiple surface electrodes, enabling non-invasive long-term electroencephalographic recording. First, we demonstrate that electrographic seizure events, induced by pentylenetetrazole, can be reliably distinguished from eye or tail movement artifacts, and quantifiably identified with our unique algorithm. Second, we show long-term monitoring during epileptogenic progression in a scn1lab mutant recapitulating human Dravet syndrome. Third, we provide an example of cross-over pharmacology antiepileptic drug testing. Such promising features of this integrated microfluidic platform will greatly facilitate high-throughput drug screening and electrophysiological characterization of epileptic zebrafish

Network Properties Revealed during Multi-Scale Calcium Imaging of Seizure Activity in Zebrafish.

Seizures are characterized by hypersynchronization of neuronal networks. Understanding these networks could provide a critical window for therapeutic control of recurrent seizure activity, i.e., epilepsy. However, imaging seizure networks has largely been limited to microcircuits in vitro or small "windows" in vivo. Here, we combine fast confocal imaging of genetically encoded calcium indicator (GCaMP)-expressing larval zebrafish with local field potential (LFP) recordings to study epileptiform events at whole-brain and single-neuron levels in vivo. Using an acute seizure model (pentylenetetrazole, PTZ), we reliably observed recurrent electrographic ictal-like events associated with generalized activation of all major brain regions and uncovered a well-preserved anterior-to-posterior seizure propagation pattern. We also examined brain-wide network synchronization and spatiotemporal patterns of neuronal activity in the optic tectum microcircuit. Brain-wide and single-neuronal level analysis of PTZ-exposed and 4-aminopyridine (4-AP)-exposed zebrafish revealed distinct network dynamics associated with seizure and non-seizure hyperexcitable states, respectively. Neuronal ensembles, comprised of coactive neurons, were also uncovered during interictal-like periods. Taken together, these results demonstrate that macro- and micro-network calcium motifs in zebrafish may provide a greater understanding of epilepsy

High-Frequency Oscillations Recorded on the Scalp of Patients With Epilepsy Using Tripolar Concentric Ring Electrodes

Epilepsy is the second most prevalent neurological disorder (~1% prevalence) affecting ~67 million people worldwide with up to 75% from developing countries. The conventional electroencephalogram is plagued with artifacts from movements, muscles, and other sources. Tripolar concentric ring electrodes automatically attenuate muscle artifacts and provide improved signal quality. We performed basic experiments in healthy humans to show that tripolar concentric ring electrodes can indeed record the physiological alpha waves while eyes are closed. We then conducted concurrent recordings with conventional disc electrodes and tripolar concentric ring electrodes from patients with epilepsy. We found that we could detect high frequency oscillations, a marker for early seizure development and epileptogenic zone, on the scalp surface that appeared to become more narrow-band just prior to seizures. High frequency oscillations preceding seizures were present in an average of 35.5% of tripolar concentric ring electrode data channels for all the patients with epilepsy whose seizures were recorded and absent in the corresponding conventional disc electrode data. An average of 78.2% of channels that contained high frequency oscillations were within the seizure onset or irritative zones determined independently by three epileptologists based on conventional disc electrode data and videos

A Novel Spike-Wave Discharge Detection Framework Based on the Morphological Characteristics of Brain Electrical Activity Phase Space in an Animal Model

Background: Animal models of absence epilepsy are widely used in childhood absence epilepsy studies. Absence seizures appear in the brain’s electrical activity as a specific spike wave discharge (SWD) pattern. Reviewing long-term brain electrical activity is time-consuming and automatic methods are necessary. On the other hand, nonlinear techniques such as phase space are effective in brain electrical activity analysis. In this study, we present a novel SWD-detection framework based on the geometrical characteristics of the phase space.Methods: The method consists of the following steps: (1) Rat stereotaxic surgery and cortical electrode implantation, (2) Long-term brain electrical activity recording, (3) Phase space reconstruction, (4) Extracting geometrical features such as volume, occupied space, and curvature of brain signal trajectories, and (5) Detecting SDWs based on the thresholding method. We evaluated the approach with the accuracy of the SWDs detection method.Results: It has been demonstrated that the features change significantly in transition from a normal state to epileptic seizures. The proposed approach detected SWDs with 98% accuracy.Conclusion: The result supports that nonlinear approaches can identify the dynamics of brain electrical activity signals

Automatic Seizure Detection in Rats Using Laplacian EEG and Verification with Human Seizure Signals

Automated detection of seizures is still a challenging problem. This study presents an approach to detect seizure segments in Laplacian electroencephalography (tEEG) recorded from rats using the tripolar concentric ring electrode (TCRE) configuration. Three features, namely, median absolute deviation, approximate entropy, and maximum singular value were calculated and used as inputs into two different classifiers: support vector machines and adaptive boosting. The relative performance of the extracted features on TCRE tEEG was examined. Results are obtained with an overall accuracy between 84.81 and 96.51%. In addition to using TCRE tEEG data, the seizure detection algorithm was also applied to the recorded EEG signals from Andrzejak et al. database to show the efficiency of the proposed method for seizure detection