Blood viscosity is associated with smoking status rather than the presence of chronic obstructive pulmonary disease: findings from the Korea COPD Subgroup Study (KOCOSS).

Obesity is characterized by chronic low-grade peripheral inflammation (metaflammation). Several studies have shown elevated cytokine levels and alterations in circulating immune cells in individuals with overweight or obesity [, , , , , ]. In addition, obesity is associated with central inflammation, such as increased cellularity and edema [, , ]. Beyond the well-established impact of obesity on metabolic and cardiovascular function [], obesity is often also comorbid with mental disorders, such as depression [, ]. Emerging evidence supports a mechanistic role for inflammation in driving mood and motivational disturbances. In animal [, , ] and human studies [, , , ], inflammatory stimuli induce depressive-like behavior and alter dopamine or reward-related signaling in the brain. Higher levels of inflammatory markers have also been linked to reduced functional connectivity within the cortico-striatal motivational circuit in patients with depression, which was associated with higher anhedonia and psychomotor slowing []. Likewise, higher inflammation has been linked to altered reward anticipation [] and elevated central inflammation has been found in the dopaminergic midbrain of patients with depression compared to healthy control participants []. Similar to the effects of inflammation, diet-induced obesity is also associated with altered dopamine transmission, reward deficiency, and depressive behavior both in animals [, , , ] and humans [, , , ]. Recent evidence has associated low-grade inflammation in obesity with reduced overall motivation to expend effort for rewards []. Taken together, this indicates that obesity-associated inflammation may mechanistically contribute to the higher incidence of motivational and mood disturbances in people with obesity. This positions overweight and obesity as a potential model condition for anti-inflammatory interventions. While Glucagon-like Peptide-1 (GLP-1) receptor agonists (RA) have led to striking improvements in weight reduction interventions [], there remains an unmet need for alternative treatments in individuals with overweight or class-I obesity due to potential negative health effects, including inflammation and mental symptoms. This applies to both at-risk individuals before they are eligible for GLP-1 RAs or during a maintenance phase after initial weight loss. To counteract inflammatory effects, neuromodulation of the cholinergic anti-inflammatory pathway (CAIP, []) via electrical vagus nerve stimulation (VNS) has emerged as a promising approach. Recently, invasive VNS has received FDA approval for the treatment of rheumatoid arthritis []. In addition, prolonged VNS is effective in treatment-resistant depression [, , ], although it is not clear whether this is due to anti-inflammatory effects. Transcutaneous VNS (tVNS) provides a non-invasive and well-tolerated alternative to invasive VNS [, , ]. Acute tVNS has been demonstrated to improve mood recovery [] and effort invigoration [, ]. tVNS has been shown to successfully activate the nucleus tractus solitarii, the primary target of vagal afferents in the brain, in humans [, , , ]. In addition, tVNS elicits efferent effects on peripheral organs, as indexed by changes in gastric myoelectric activity [, ], suggesting that CAIP could be activated. Accordingly, tVNS reduces inflammation in rodents when administered during acute immune challenges [] and during chronic inflammation []. In humans, tVNS has been shown to reduce inflammation mainly in acute inflammation [, , ], while findings for chronic inflammation are inconsistent [, , , ]. The current evidence might be limited due to small sample sizes, variable stimulation settings [], and a lack of comprehensive inflammatory phenotyping. Sufficiently powered studies investigating the prolonged effects of daily conventional auricular tVNS administration on chronic low-grade peripheral and central inflammation, such as in people with overweight/obesity, are lacking. To address this translational gap, this study uses prolonged (≥ 30 min of daily stimulation over ~ 14 days), self-administered tVNS with high-intensity stimulation as active condition and low-intensity stimulation as a control condition in 60 participants with overweight or class-I obesity. We will evaluate midterm effects on both peripheral and central inflammation, as well as on mood and motivation, while recording and monitoring potential side effects of the intervention. By simultaneously assessing inflammatory markers and behavioral outcome measures, the study investigates potential therapeutic effects of tVNS and provides insights into the pathomechanisms linking obesity-related inflammation with disturbances in mood and motivation.