Transcutaneous vagus nerve stimulation increases locus coeruleus function and memory performance in older individuals

Abstract

AbstractBackgroundAnimal studies reported that vagus nerve stimulation increases noradrenalin release in target areas of the locus coeruleus (LC). Furthermore, after stimulation, animals exhibited improved retention performance. Evidence for memory improvement using transcutaneous vagus nerve stimulation (tVNS), a non‐invasive alternative, is scarce. Given that the LC is affected by tau pathology early in life, we aimed to examine 1) whether tVNS can improve memory performance in older individuals and 2) whether tVNS targets the LC in older individuals.MethodTwo separate cross‐over single‐blind randomized studies were performed. In study one, 30 healthy older individuals (Mean age:60.57 years, 50% male) underwent tVNS and Sham during face‐name learning. Bias‐corrected scores across the experimental conditions were analyzed using a repeated measures ANOVA. In study two, 16 older individuals (median age:71.15 years, 56% male) underwent respiratory‐gated tVNS and Sham during 2 sessions of 7T fMRI involving a face‐name learning task. The bias‐corrected behavioral scores were compared using LME. The BOLD data were motion, distortion and ICA‐FIX denoised and we fitted a GLM for stimulation on> stimulation off within session, within participant (tVNS>Sham). The group‐average tVNS effect was estimated. For the LC, we performed analyses within a small volume search space at p<0.05. For the rest of the brain, cluster‐wise correction was applied.ResultBoth studies demonstrated higher scores on the memory task during tVNS as compared to the sham condition (tVNS versus Sham, p=0.037, Cohen’s d=0.35) but effect sizes were greater for the respiratory gated tVNS experiment (tVNS versus Sham: p=0.04, Cohen’s d=0.55). The BOLD map showed bilateral activation of the caudal LC during tVNS compared to Sham (peak z‐value=3.44). Positive clusters (tVNS>Sham) were also observed in several regions, including the prefrontal and temporal cortex, insula, thalamus, hippocampus and putamen. Negative clusters were observed in the basolateral amygdala and cornu ammonis 1.ConclusionIn older individuals, alterations in the functioning of the locus coeruleus network may mediate the positive effects of tVNS on memory performance in older individuals. Our previous work demonstrated that noradrenalin‐dysregulation was associated with greater tau. Future work will explore the efficacy and disease‐modifying potential of tVNS in cognitively impaired individuals.