Temporally unstructured electrical stimulation to the amygdala suppresses behavioral chronic seizures of the pilocarpine animal model Jasiara Carla de Oliveira a , Daniel de Castro Medeiros b , Gustavo Henrique de Souza e Rezende b , Márcio Flávio Dutra Moraes b , Vinícius Rosa Cota a, ⁎ a Laboratório Interdiciplinar de Neuroengenharia e Neurociências, Departamento de Engenharia de Biossistemas (DEPEB), Universidade Federal de São João Del-Rei, Pça. Dom Helvécio, 74, 36301-160 São João Del-Rei, MG, Brazil b Núcleo de Neurociências, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, CEP 31270-901 Belo Horizonte, MG, Brazil abstract article info Article history: Received 17 January 2014 Revised 30 April 2014 Accepted 6 May 2014 Available online 13 June 2014 Keywords: Temporal lobe epilepsy Pilocarpine Electrical stimulation Temporal coding Basolateral amygdala Desynchronization Chronic seizures 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: pe- riodic 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 im- plantation of a bipolar electrical stimulation electrode in the right basolateral amygdala and were allowed to re- cover for seven days. The animals were then placed in a glass box, and their behaviors were recorded daily on DVD for 6 h 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 stimula- tion may wield its effect by desynchronizing neural networks involved in the ictogenic process. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Epilepsy is a chronic neurological disorder characterized by recur- rent and spontaneous seizures caused by hypersynchronous and exces- sive neural activity [1]. It has high prevalence, affecting about fifty million people worldwide [2]. Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy [3], which accounts for about 60% of all patients [4]. It has a focal onset, and it is the most common type of drug-resistant epilepsy [5]. Intracranial electrical stimulation has long been considered a poten- tially viable therapy for patients with drug-resistant epilepsy who are not eligible for ablative surgery [6]. Currently, electrical stimulation (i.e., current or voltage pulses) may be applied to the peripheral nervous system, in structures such as the vagus nerve (vagus nerve stimulation) [7] and the trigeminal nerve (trigeminal nerve stimulation) [8], or di- rectly to the central nervous system, in substrates such as the anterior thalamic nucleus [9], subthalamic nuclei [10], and epileptogenic focus itself [11]. Although the literature reports an overwhelming amount of data showing the effect of electrical stimulation on seizure suppression (for a review, see [6]), its mechanisms of action on neural network modula- tion need further investigation. While debatable, the most widely accepted framework for its therapeutic effectiveness posits that electri- cal stimulation would recruit substrates and/or neural networks capable of modulating seizure-like activity in areas involved in ictogenesis or rather by impairing the coupling of neural oscillators necessary to prop- agate and sustain aberrant activity [12,13]. Among others, in silico stud- ies have shown that neural circuits that fire synchronously are coupled in a positive feedback fashion [14], that synaptic weights increase in proportion to the coincidence in neuronal firing [15], corroborating Hebbian postulates [16], and that this coincidence may be increased or decreased by a synchronizing or desynchronizing electrical stimulation, respectively [15]. Finally, Medeiros et al. have shown that electrical Epilepsy & Behavior 36 (2014) 159–164 ⁎ Corresponding author at: DEPEB, Pça. Dom Helvécio, 74, B. Fábricas, 36301-160 São João Del-Rei, MG, Brazil. Tel.: +55 32 3379 2541 (office), +55 32 8861 8074 (mobile). E-mail addresses: vrcota@ufsj.edu.br, vrcota@pq.cnpq.br, vrcota@gmail.com (V.R. Cota). http://dx.doi.org/10.1016/j.yebeh.2014.05.005 1525-5050/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh