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  • Hippocampal Response to Ultra Low-Frequency Electrical Stimulation is Both Stimulation Parameter- and Brain State-Dependent: Lessons from Sensing-Enabled Neurostimulation in Idiopathic Nonhuman Primat

    Final Number:

    Thomas A Wozny BS; Witold J Lipski BS, PhD; Ahmad Alhourani MD; Efstathios Kondylis; Mark Richardson

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: The use of implantable neurostimulators to deliver high-frequency electrical stimulation (>100Hz) has garnered considerable interest for the treatment of intractable epilepsy, with two separate devices showing modest efficacy in clinical trials [1,2]. In contrast, low-frequency stimulation (LFS, <10Hz) remains relatively under-explored despite offering the advantage of considerably lower current requirements and extended battery life. In this study, we analyzed the neural response to stimulation to guide LFS parameter selection for seizure prevention.

    Methods: A sensing-enabled, implanted neurostimulator (Activa RC+S) was used to record local field potentials (LFP) while LFS was delivered in an awake, normally behaving rhesus macaque implanted with bilateral hippocampal DBS leads. 2Hz stimulation frequency was used for all experiments as it was the lowest frequency the neurostimulator could deliver and was efficacious in previous studies [3]. Stimulation trains of variable duration were delivered in a trial-wise fashion while pulse width and current amplitude were varied. The neural response to stimulation was quantified and used to select a parameter combination for chronic testing.

    Results: LFS at current amplitudes >1mA and pulse widths >50usec evoked a brief LFP response immediately after each stimulation pulse, which was followed by a longer window of LFP suppression. Stimulation became more effective at suppressing LFP energy as the duration of the pulse train increased (up to 15sec) but diminished in efficacy as pulse trains became very long (>1hr). LFS delivered continuously for 2 weeks revealed that the neural response to stimulation varied with circadian rhythm and time relative to seizure onset.

    Conclusions: LFS of the hippocampus shows a promising ability to suppress LFP energy for short pulse trains, but this efficacy is lost for very long pulse trains. This finding suggests that cycling LFS between the on and off state may be effective at suppressing hippocampal excitability while avoiding the observed attenuation in stimulation-induced neural response.

    Patient Care: Deep-brain stimulation is becoming an option for an increasing number of neurologic conditions, including epilepsy. The current study attempts to demonstrate how advancements in implantable neurostimulator technology can allow for the utilization of intracranial recordings to empirically optimize stimulation settings in an efficient, patient-specific manner.

    Learning Objectives: By the end of this session, participants should be able to: 1) Describe the current state of implantable neurostimulators FDA-approved for intractable epilepsy, 2) Describe the range of clinically relevant electrical stimulation parameter settings and their differential effects on neural activity, 3) Discuss the utility of sensing-enabled implantable neurostimulators in optimizing stimulation therapy for epilepsy.

    References: [1] Fisher, Robert, et al. "Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy." Epilepsia 51.5 (2010): 899-908. [2] Heck, Christianne N., et al. "Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial." Epilepsia55.3 (2014): 432-441. [3] Toprani, Sheela, and Dominique M. Durand. "Fiber tract stimulation can reduce epileptiform activity in an in-vitro bilateral hippocampal slice preparation." Experimental neurology 240 (2013): 28-43.

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