The mechanisms of seizure emergence, and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research and clinical epileptology. Our study shows that the transition to seizure is not a sudden phenomenon, but a slow process characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon observable in systems characterized by transitions between contrasting dynamical regimes. In epilepsy, this complex process is modulated by the synchronous synaptic input from IEDs. IEDs are external perturbations that produce phasic changes in the slow transition process and can exert opposing effects on the dynamics of a seizuregenerating network, causing either stabilizing anti-seizure or destabilizing pro-seizure effects. We show that the multifaceted nature of IEDs is defined by the dynamical state of the seizuregenerating network at the moment of the discharge occurrence, not necessarily by the existence of distinct cellular mechanisms.

Interictal epileptiform discharges (spikes, IEDs) are electrographic markers of epileptic tissue and their quantification is utilized in planning of surgical resection. Visual analysis of long-term multi-channel intracranial recordings is extremely laborious and prone to bias. Development of new and reliable techniques of automatic spike detection represents a crucial step towards increasing the information yield of intracranial recordings and to improve surgical outcome. In this study, we designed a novel and robust detection algorithm that adaptively models statistical distributions of signal envelopes and enables discrimination of signals containing IEDs from signals with background activity. This detector demonstrates performance superior both to human readers and to an established detector. It is even capable of identifying low-amplitude IEDs which are often missed by experts and which may represent an important source of clinical information. Application of the detector to non-epileptic intracranial data from patients with intractable facial pain revealed the existence of sharp transients with waveforms reminiscent of interictal discharges that can represent biological sources of false positive detections. Identification of these transients enabled us to develop and propose secondary processing steps, which may exclude these transients, improving the detector's specificity and having important implications for future development of spike detectors in general.

Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioral inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behavior and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a hand-held device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes, and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from 9 humans and 8 canines with epilepsy, and then implemented prospectively in out-of-sample testing in 2 pet canines and 4 humans with drug resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures, and correlation with patient behavioral reports. In the future correlation of spikes and seizures with behavior will allow more detailed investigation of the clinical impact of spikes and seizures on patients.