Data-Driven Network Dynamical Model of Rat Brains During Acute Ictogenesis.

Epilepsy is one of the most common neurological disorders worldwide. Recent findings suggest that the brain is a complex system composed of a network of neurons, and seizure is considered an emergent property resulting from its interactions. Based on this perspective, network physiology has emerged as a promising approach to explore how brain areas coordinate, synchronize and integrate their dynamics, both under perfect health and critical illness conditions. Therefore, the objective of this paper is to present an application of (Dynamic) Bayesian Networks (DBN) to model Local Field Potentials (LFP) data on rats induced to epileptic seizures based on the number of arcs found using threshold analytics. Results showed that DBN analysis captured the dynamic nature of brain connectivity across ictogenesis and a significant correlation with neurobiology derived from pioneering studies employing techniques of pharmacological manipulation, lesion, and modern optogenetics. The arcs evaluated under the proposed approach achieved consistent results based on previous literature, in addition to demonstrating robustness regarding functional connectivity analysis. Moreover, it provided fascinating and novel insights, such as discontinuity between forelimb clonus and generalized tonic-clonic seizure (GTCS) dynamics. Thus, DBN coupled with threshold analytics may be an excellent tool for investigating brain circuitry and their dynamical interplay, both in homeostasis and dysfunction conditions.

Persistence of neural function in animals submitted to seizure-suppressing scale-free nonperiodic electrical stimulation applied to the amygdala.

Based on the rationale that neural hypersynchronization underlies epileptic phenomena, nonperiodic stimulation (NPS) was designed and successfully tested as an electrical stimulus with robust anticonvulsant action. Considering the scale-free temporal structure of NPS mimics natural-like activity, here we hypothesized its application to the amygdala would induce minor to none impairment of neural function in treated animals. Wistar rats underwent gold-standard behavioral tests such as open field (OF), elevated plus-maze (EPM), novel object recognition, and social interaction test in order to evaluate the functions of base-level anxiety, motor function, episodic memory, and sociability. We also performed daily (8 days, 6 h per day) electrophysiological recordings (local field potential/LFP and electromyography) to assess global forebrain dynamics and the sleep-wake cycle architecture and integrity. All animals displayed an increased proportion of time exploring new objects, spent more time in the closed arms of the EPM and in the periphery of the OF arena, with similar numbers of crossing between quadrants and no significant changes of social behaviors. In the sleep-wake cycle electrophysiology experiments, we found no differences regarding duration and proportion of sleep stages and the number of transitions between stages. Finally, the power spectrum of LFP recordings and neurodynamics were also unaltered. We concluded that NPS did not impair neural functions evaluated and thus, it may be safe for clinical studies. Additionally, results corroborate the notion that NPS may exert an on-demand only desynchronization effect by efficiently competing with epileptiform activity for the physiological and healthy recruitment of neural circuitry. Considering the very dynamical nature of circuit activation and functional activity underlying neural function in general (including cognition, processing of emotion, memory acquisition, and sensorimotor integration) and its corruption leading to disorder, such mechanism of action may have important implications in the investigation of neuropsychological phenomena and also in the development of rehabilitation neurotechnology.

The epileptic amygdala: Toward the development of a neural prosthesis by temporally coded electrical stimulation.

Many patients with epilepsy do not obtain proper control of their seizures through conventional treatment. We review aspects of the pathophysiology underlying epileptic phenomena, with a special interest in the role of the amygdala, stressing the importance of hypersynchronism in both ictogenesis and epileptogenesis. We then review experimental studies on electrical stimulation of mesiotemporal epileptogenic areas, the amygdala included, as a means to treat medically refractory epilepsy. Regular high-frequency stimulation (HFS) commonly has anticonvulsant effects and sparse antiepileptogenic properties. On the other hand, HFS is related to acute and long-term increases in excitability related to direct neuronal activation, long-term potentiation, and kindling, raising concerns regarding its safety and jeopardizing in-depth understanding of its mechanisms. In turn, the safer regular low-frequency stimulation (LFS) has a robust antiepileptogenic effect, but its pro- or anticonvulsant effect seems to vary at random among studies. As an alternative, studies by our group on the development and investigation of temporally unstructured electrical stimulation applied to the amygdala have shown that nonperiodic stimulation (NPS), which is a nonstandard form of LFS, is capable of suppressing both acute and chronic spontaneous seizures. We hypothesize two noncompetitive mechanisms for the therapeutic role of amygdala in NPS, 1) a direct desynchronization of epileptic circuitry in the forebrain and brainstem and 2) an indirect desynchronization/inhibition through nucleus accumbens activation. We conclude by reintroducing the idea that hypersynchronism, rather than hyperexcitability, may be the key for epileptic phenomena and epilepsy treatment.

Temporally unstructured electrical stimulation to the amygdala suppresses behavioral chronic seizures of the pilocarpine animal model.

Electrical stimulation applied to the basolateral amygdala in the pentylenetetrazole animal model of seizures may result in either a proconvulsant or an anticonvulsant effect depending on the interpulse intervals used: periodic or nonperiodic, respectively. We tested the effect of this electrical stimulation temporal coding on the spontaneous and recurrent behavioral seizures produced in the chronic phase of the pilocarpine animal model of temporal lobe epilepsy, an experimental protocol that better mimics the human condition. After 45 days of the pilocarpine-induced status epilepticus, male Wistar rats were submitted to a surgical procedure for the implantation of a bipolar electrical stimulation electrode in the right basolateral amygdala and were allowed to recover for seven days. The animals were then placed in a glass box, and their behaviors were recorded daily on DVD for 6h for 4 consecutive days (control period). Spontaneous recurrent behavioral seizures when showed in animals were further recorded for an extra 4-day period (treatment period), under periodic or nonperiodic electrical stimulation. The number, duration, and severity of seizures (according to the modified Racine's scale) during treatment were compared with those during the control period. The nonperiodically stimulated group displayed a significantly reduced total number and duration of seizures. There was no difference between control and treatment periods for the periodically stimulated group. Results corroborate previous findings from our group showing that nonperiodic electrical stimulation has a robust anticonvulsant property. In addition, results from the pilocarpine animal model further strengthen nonperiodic electrical stimulation as a valid therapeutic approach in current medical practice. Our working hypothesis is that temporally unstructured electrical stimulation may wield its effect by desynchronizing neural networks involved in the ictogenic process.