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Importance: Major depressive disorder (MDD) is characterized by a substantial burden on health, including changes in appetite and body weight. Heterogeneity of depressive symptoms has hampered the identification of biomarkers that robustly generalize to most patients, thus calling for symptom-based mapping.Objective: To define the functional architecture of the reward circuit subserving increases vs decreases in appetite and body weight in patients with MDD by specifying their contributions and influence on disease biomarkers using resting-state functional connectivity (FC).Design, Setting, and Participants: In this case-control study, functional magnetic resonance imaging (fMRI) data were taken from the Marburg-Münster FOR 2107 Affective Disorder Cohort Study (MACS), collected between September 2014 and November 2016. Cross-sectional data of patients with MDD (n = 407) and healthy control participants (n = 400) were analyzed from March 2018 to June 2022.Main Outcomes and Measures: Changes in appetite during the depressive episode and their association with FC were examined using fMRI. By taking the nucleus accumbens (NAcc) as seed of the reward circuit, associations with opposing changes in appetite were mapped, and a sparse symptom-specific elastic-net model was built with 10-fold cross-validation.Results: Among 407 patients with MDD, 249 (61.2%) were women, and the mean (SD) age was 36.79 (13.4) years. Reduced NAcc-based FC to the ventromedial prefrontal cortex (vmPFC) and the hippocampus was associated with reduced appetite (vmPFC: bootstrap r = 0.13; 95% CI, 0.02-0.23; hippocampus: bootstrap r = 0.15; 95% CI, 0.05-0.26). In contrast, reduced NAcc-based FC to the insular ingestive cortex was associated with increased appetite (bootstrap r = -0.14; 95% CI, -0.24 to -0.04). Critically, the cross-validated elastic-net model reflected changes in appetite based on NAcc FC and explained variance increased with increasing symptom severity (all patients: bootstrap r = 0.24; 95% CI, 0.16-0.31; patients with Beck Depression Inventory score of 28 or greater: bootstrap r = 0.42; 95% CI, 0.25-0.58). In contrast, NAcc FC did not classify diagnosis (MDD vs healthy control).Conclusions and Relevance: In this study, NAcc-based FC reflected important individual differences in appetite and body weight in patients with depression that can be leveraged for personalized prediction. However, classification of diagnosis using NAcc-based FC did not exceed chance levels. Such symptom-specific associations emphasize the need to map biomarkers onto more confined facets of psychopathology to improve the classification and treatment of MDD. [ABSTRACT FROM AUTHOR]

Maintaining energy homeostasis is vital and supported by vagal signaling between digestive organs and the brain. Previous research has established a gastric network in the brain that is phase synchronized with the rhythm of the stomach, but tools to perturb its function were lacking. To evaluate whether stomach-brain coupling can be acutely increased by non-invasively stimulating vagal afferent projections to the brain. Using a single-blind randomized crossover design, we investigated the effect of acute right-sided transcutaneous auricular vagus nerve stimulation (taVNS) versus sham stimulation on stomach-brain coupling. In line with preclinical research, taVNS increased stomach-brain coupling in the nucleus of the solitary tract (NTS) and the midbrain while boosting coupling across the brain. Crucially, in the cortex, taVNS-induced changes in coupling occurred primarily in transmodal regions and were associated with changes in hunger ratings as indicators of the subjective metabolic state. taVNS increases stomach-brain coupling via an NTS-midbrain pathway that signals gut-induced reward, indicating that communication between the brain and the body is effectively modulated by vago-vagal signaling. Such insights may help us better understand the role of vagal afferents in orchestrating the recruitment of the gastric network which could pave the way for novel neuromodulatory treatments. [Display omitted] • Transcutaneous auricular vagus nerve stimulation (taVNS) can emulate interoceptive signals. • taVNS boosts stomach-brain coupling in the brainstem, midbrain, and transmodal cortex. • taVNS-induced changes in stomach-brain coupling mirror changes in hunger ratings. [ABSTRACT FROM AUTHOR]

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. 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. We used a single-blind, randomized crossover design in 30 patients with MDD and 29 matched (age, sex, and BMI) healthy control participants (HCP). 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 < 0.001). However, invigoration remained elevated in all participants, and no acute changes were observed in Session 2 (Δinvigoration = 3.3, p =.12). Crucially, throughout Session 1, we found taVNS-induced increases in effort invigoration (p boot = 0.008) and wanting (p boot = 0.010) in patients with MDD, with gains in wanting maintained across sessions (Δwanting = 0.06, p =.97). 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. [Display omitted] • Anhedonia is a core symptom of major depressive disorder that is hard to treat. • Vagus nerve stimulation (VNS) has increased motivation in healthy participants. • We extend this work using non-invasive VNS (tVNS) in participants with depression. • tVNS increases wanting and invigoration in Session 1 over trials in depression. • Gains in motivation from Session 1 are maintained until Session 2. [ABSTRACT FROM AUTHOR]

Metabolic feedback between the gut and the brain relayed via the vagus nerve contributes to energy homeostasis. We investigated in healthy adults whether non-invasive stimulation of vagal afferents impacts energy homeostasis via efferent effects on metabolism or digestion. In a randomized crossover design, we applied transcutaneous auricular vagus nerve stimulation (taVNS) while recording efferent metabolic effects using simultaneous electrogastrography (EGG) and indirect calorimetry. We found that taVNS reduced gastric myoelectric frequency (p =.008), but did not alter resting energy expenditure. We conclude that stimulating vagal afferents induces gastric slowing via vagal efferents without acutely affecting net energy expenditure at rest. Collectively, this highlights the potential of taVNS to modulate digestion by activating the dorsal vagal complex. Thus, taVNS-induced changes in gastric frequency are an important peripheral marker of brain stimulation effects. Image 1 • Metabolic feedback via the vagus nerve contributes to energy homeostasis. • taVNS reduced gastric frequency without altering resting energy expenditure. • Gastric frequency could be a promising peripheral marker of brain stimulation. [ABSTRACT FROM AUTHOR]