The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study

Abstract

Background: There is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson's disease (PD). Objective: To evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency. Methods: Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a doubleblinded, randomized cognitive testing during stimulation at (1) 130e135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. Results: Theta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests. Conclusion:In this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation

“…However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize the effects of this promising approach. Our study followed up on our previous work demonstrating enhanced brainstem response to taVNS delivered in the cymba conchae of the left ear during the exhalation phase of respiration (RAVANS [4,7,26]), and characterized the brainstem Fig. 3.…”

“…First-level General Linear Model (GLM) analyses were carried out for each subject and each scan run using an event-related design and the fMRI Expert Analysis Tool (FEAT v6.00, FSL). For each scan run, stimulation timings (recorded via Labview computer) were convolved with a set of three basis functions chosen by the FMRIB's Linear Optimal Basis Set (FLOBS, FSL) algorithm to account for the potential deviation of the brainstem response from the canonical hemodynamic impulse response function as well as the systematic influence of hemodynamic response to the prior exhalation/stimulus event, as in our previous brainstem-focused analyses [26]. Additional regressors of no interest were used for censoring of motion outliers (as estimated through the fsl_motio-n_outliers tool) and for cardiogenic pulsatility reduction in fMRI signals by convolving heart rate with the previously-reported cardiac response function [36].…”

“…2). As in our previous work [26], a search volume defined in the ipsilateral (left) dorsal medulla was applied to evaluate responses at the site of primary synapse for vagal afference, e.g. NTS.…”

“…The EAI, introduced for brainstem ROI analyses in our previous paper [26], prevents very significant but spatially limited (i.e., a few voxels) activations from driving the outcome metric, using a multiplicative factor calculated at the group level for each contrast (RAVANS e Sham) to weigh the average value of the summary statistics extracted at the single subject level. The EAI indices for the different ROIs were then compared across different stimulus frequencies using linear mixed-effects models.…”

“…Our own studies have described another, less commonly explored stimulation parameter, respiratory phase of stimulation, finding that stimulation during the exhalatory phase produced more robust NTS, as well as locus coeruleus and raphe nuclei response in the brainstem [7,26]. While Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) has been found to enhance brainstem targeting for taVNS, parameter optimization within this framework with other important stimulus variables, such as burst frequency, are unknown.…”