Effect of Short‐Term Theta Frequency Stimulation of the Vagus Nerve on Cognition among Patients with Refractory Epilepsy: A Pilot Study
Authors: Strong E. Brandon , Scangos Katherine , Mefford Anthony , Lee Darrin , Shahlaie Kiarash 
Published: June 2021

ObjectiveThe purpose of this investigation is to collect preliminary data on the effect of theta frequency vagus nerve stimulation on cognitive measures, including memory retention, in patients with refractory epilepsy.BackgroundVagus nerve stimulation (VNS) was approved by the FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. VNS provides intermittent high frequency stimulation to the left vagus nerve, resulting in retrograde stimulation to centers in the brainstem. Research interest into alternative uses of VNS has increased in popularity over the past decade, including its effect on cognition.Initial short‐term studies (3–24 hours of stimulation) have provided information on how it may be working to alter cognitive function. Two pre‐clinical studies showed that rats displayed increased memory retention after 24 hours of VNS. Clinical studies have also demonstrated a significant increase in cognitive performance when VNS is administered during the memory consolidation period of a list learning task.The nucleus of the solitary tract (NST) in the brain stem is the primary relay station for afferent vagal nerve fibers. The NST has numerous projections to various areas of the forebrain and brain stem, including the hippocampus. Stimulation of the vagus nerve has been shown to alter the electrophysiological and metabolic profiles of the hippocampus, an area that plays a critical role in learning and memory functions. The hippocampus generates and maintains high amplitude oscillations in the theta frequency range (4–8 Hz), which play an important role in memory tasks. Furthermore, there is pre‐clinical evidence that theta oscillations are depressed in rodent models with temporal lobe epilepsy, and that reduced theta activity correlates with memory deficits. We hypothesize that theta frequency VNS will have a positive effect on memory retention.MethodsPatients with implanted VNS devices were identified in the medical records, consented, and screened via the Beck Depression Inventory (excluded if score > 20) and the Montreal Cognitive Assessment (excluded if score < 24). Participants then practiced cognitive tasks for 30 minutes, followed by three rounds of neurocognitive testing with different VNS settings (Figure 1). Only VNS frequency (theta: 5 Hz, beta: 25–30 Hz, and control: 0 Hz) was altered. Each round of neurocognitive testing included two tasks. The first was a memory encoding/retrieval task (California Verbal Learning Test, CVLT). The second was an executive function task administered between the encoding and retrieval portions of CVLT. Both participants and test administrators were blinded to VNS parameters.Results & DiscussionOver the course of one year, data was only collected from one patient. This was due to a combination of factors, including stringent exclusion criteria, difficult patient recruitment, and an understaffed research team. However, this patient did display a 23% increase in delayed free recall performance when treated with theta frequency stimulation (Figure 2). Furthermore, accuracy and reaction time decreased by 5% and >15% for both beta and theta stimulation (as compared to the control) during the executive function task (Stroop test). While generalizable conclusions are impossible to draw from this data, the preliminary results support our hypothesis. While we are in the process of collecting more data, we hope that this study can serve as a platform for researchers to build from.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.