Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression

Background Major depressive disorder (MDD) is often marked by impaired motivation and reward processing, known as anhedonia. Many patients do not respond to first-line treatments, and improvements in motivation can be slow, creating an urgent need for rapid interventions. Recently, we demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) acutely boosts effort invigoration in healthy participants, but its effects on depression remain unclear. Objective To assess the impact of taVNS on effort invigoration and maintenance in a sample that includes patients with MDD, evaluating the generalizability of our findings. Methods We used a single-blind, randomized crossover design in 30 patients with MDD and 29 matched (age, sex, and BMI) healthy control participants (HCP). Results Consistent with prior findings, taVNS increased effort invigoration for rewards in both groups during Session 1 ( p =.040), particularly for less wanted rewards in HCP ( p boot <.001). However, invigoration remained elevated in all participants, and no acute changes were observed in Session 2 (Δinvigoration=3.52, p =.093). Crucially, throughout Session 1, we found taVNS-induced increases in effort invigoration ( p boot =.008) and wanting ( p boot =.010) in patients with MDD, with gains in wanting maintained across sessions (Δwanting=0.06, p =.97). Conclusions Our study replicates the invigorating effects of taVNS in Session 1 and reveals its generalizability to depression. Furthermore, we expand upon previous research by showing taVNS-induced conditioning effects on invigoration and wanting within Session 1 in patients that were largely sustained. While enduring motivational improvements present challenges for crossover designs, they are highly desirable in interventions and warrant further follow-up research. Graphical abstract