Professor of Neurology University of Alabama School of Medicine Birmingham, Alabama
This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: The VNS mechanism of action (MOA) is unclear. It is possible that different VNS stimulation protocols may elicit different clinical and brain responses. Phase 1 study (NCT03446664) investigates with fMRI the effect of standard versus novel microburst stimulation parameters in stimulation-naïve epilepsy patients. Methods: Up to 40 participants will be implanted with VNS. At two weeks post-implantation 3T fMRI session is conducted (three scans). Prior to undergoing each scan, the maximum tolerated stimulation intensity is determined starting at 0.125mA with 0.125mA increments. In each block design fMRI scan stimulation is provided for 30s (ON), followed by no stimulation for 30s (OFF). Each set of VNS parameters is assessed for 5 min (i.e. 5 ON/OFF blocks); the protocol allows investigation of up to 6 parameter sets during each 30-min fMRI. Scan 1 utilizes standard VNS stimulation while Scan 2 utilizes microburst stimulation. Scan 3 optimizes the microburst parameters to determine the personalized VNS settings for the patient. Automated fMRI data processing pipeline in AFNI was developed for individual on-site processing to convert data to NIfTI format, remove non-brain voxels, align anatomical and fMRI scans, and normalize to Talairach reference space. FMRI underwent slice-timing and motion correction, spatial normalization, spatial smoothing, and percent signal change calculation. A general linear model of ON vs. OFF blocks was performed to determine VNS-related fMRI activation per stimulation setting. An individual activation map for each setting was thresholded at a significance level of 5% for a 2-tailed test and 2-voxel minimum. Anatomical thalamic mask was used to extract mean t-value for each thalamic cluster meeting minimum thresholds, and the stimulation setting yielding highest mean thalamic t-value over significant clusters is selected as the Peak. One sample t-tests, covarying for enrolment site (i.e., scanner type), were performed to create group average maps for the peak thalamic activation of Scan 1 (standard VNS) and Scan 3 (optimized microburst VNS). Paired t-test compared scans 1 and 3 to examine brains’ responses to each stimulation type. Activation on group maps were significant at corrected p< 0.05 (voxelwise p=0.05, cluster extent threshold of 3402 mm3). Results: Twenty-six patients with refractory epilepsy from nine sites were implanted with VNS to date and underwent 3T fMRI at 2 weeks post-implantation. Quality data were obtained in all scan sessions. Group activation maps of peak thalamic activation for standard (0.41 mA ± 0.27) and optimized microburst VNS (0.38 mA ± 0.25; p=0.52) showed widespread thalamic and cortical activation (Figure 1AB). Comparison of stimulation types revealed greater cerebellar and brain stem fMRI signal changes in microburst VNS compared to standard VNS (Fig. 1C). Conclusions: Standard and optimized microburst VNS elicit similar patterns of thalamic activation. However, microburst stimulation also engages the cerebellum and brain stem, which may be uniquely involved in its MOA. Relationship between fMRI activation patterns and clinical response as a potential MOA of microburst stimulation and implications thereof warrant further investigation. Funding: Please list any funding that was received in support of this abstract.: LivaNova
