{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:12:54Z","timestamp":1793293974447,"version":"4.5.0"},"reference-count":192,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006602","name":"Air Force Research Laboratory","doi-asserted-by":"publisher","award":["FA8650-18-2-5402"],"award-info":[{"award-number":["FA8650-18-2-5402"]}],"id":[{"id":"10.13039\/100006602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-\u03b1 and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions.<\/jats:p>","DOI":"10.3390\/brainsci16010008","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:27:51Z","timestamp":1766586471000},"page":"8","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transcutaneous Auricular Vagus Nerve Stimulation for Treating Emotional Dysregulation and Inflammation in Common Neuropsychiatric Disorders"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7758-5022","authenticated-orcid":false,"given":"William J.","family":"Tyler","sequence":"first","affiliation":[{"name":"Center for Neuroengineering and Brain Computer Interfaces, Department of Biomedical Engineering, School of Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101675","DOI":"10.1016\/j.eclinm.2022.101675","article-title":"Quantifying the global burden of mental disorders and their economic value","volume":"54","author":"Arias","year":"2022","journal-title":"eClinicalMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1001\/jamapsychiatry.2023.5051","article-title":"Worldwide Prevalence and Disability From Mental Disorders Across Childhood and Adolescence: Evidence From the Global Burden of Disease Study","volume":"81","author":"Kieling","year":"2024","journal-title":"JAMA Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"GBD 2019 Mental Disorders Collaborators (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry, 9, 137\u2013150.","DOI":"10.1016\/S2215-0366(21)00395-3"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103014","DOI":"10.1016\/j.eclinm.2024.103014","article-title":"Dynamic changes and future trend predictions of the global burden of anxiety disorders: Analysis of 204 countries and regions from 1990 to 2021 and the impact of the COVID-19 pandemic","volume":"79","author":"Chen","year":"2025","journal-title":"eClinicalMedicine"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bechter, K. (2020). The Challenge of Assessing Mild Neuroinflammation in Severe Mental Disorders. Front. Psychiatry, 11.","DOI":"10.3389\/fpsyt.2020.00773"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.psychres.2015.06.009","article-title":"Examining the role of neuroinflammation in major depression","volume":"229","author":"Furtado","year":"2015","journal-title":"Psychiatry Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hassamal, S. (2023). Chronic stress, neuroinflammation, and depression: An overview of pathophysiological mechanisms and emerging anti-inflammatories. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1130989"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1001\/jamapsychiatry.2024.3543","article-title":"Neuroinflammation, Stress-Related Suicidal Ideation, and Negative Mood in Depression","volume":"82","author":"Herzog","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/s41577-019-0190-z","article-title":"Sleep and inflammation: Partners in sickness and in health","volume":"19","author":"Irwin","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/S2215-0366(20)30255-8","article-title":"Neuroinflammation in psychiatric disorders: PET imaging and promising new targets","volume":"7","author":"Meyer","year":"2020","journal-title":"Lancet Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"S\u0103lcudean, A., Bodo, C.-R., Popovici, R.-A., Cozma, M.-M., P\u0103curar, M., Cr\u0103ciun, R.-E., Crisan, A.-I., Enatescu, V.-R., Marinescu, I., and Cimpian, D.-M. (2025). Neuroinflammation\u2014A Crucial Factor in the Pathophysiology of Depression\u2014A Comprehensive Review. Biomolecules, 15.","DOI":"10.3390\/biom15040502"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5071786","DOI":"10.1155\/2017\/5071786","article-title":"Modulating Neuroinflammation to Treat Neuropsychiatric Disorders","volume":"2017","author":"Radtke","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1146\/annurev.neuro.28.061604.135709","article-title":"An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance","volume":"28","author":"Cohen","year":"2005","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/s41583-020-0360-9","article-title":"Locus coeruleus: A new look at the blue spot","volume":"21","author":"Poe","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"van der Linden, D., Tops, M., and Bakker, A.B. (2021). The Neuroscience of the Flow State: Involvement of the Locus Coeruleus Norepinephrine System. Front. Psychol., 12.","DOI":"10.3389\/fpsyg.2021.645498"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2398212820930321","DOI":"10.1177\/2398212820930321","article-title":"The role of the locus coeruleus in the generation of pathological anxiety","volume":"4","author":"Morris","year":"2020","journal-title":"Brain Neurosci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e70111","DOI":"10.1111\/ejn.70111","article-title":"The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders","volume":"61","author":"Reyes","year":"2025","journal-title":"Eur. J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/S0006-3223(99)00127-4","article-title":"Role of norepinephrine in the pathophysiology and treatment of mood disorders","volume":"46","author":"Ressler","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41398-022-02297-y","article-title":"Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression","volume":"13","author":"Guo","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/mp.2016.3","article-title":"A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression","volume":"21","author":"Goldsmith","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s12974-022-02492-0","article-title":"Microglia in depression: An overview of microglia in the pathogenesis and treatment of depression","volume":"19","author":"Wang","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Brites, D., and Fernandes, A. (2015). Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front. Cell. Neurosci., 9.","DOI":"10.3389\/fncel.2015.00476"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.tins.2015.08.001","article-title":"Depression as a Microglial Disease","volume":"38","author":"Yirmiya","year":"2015","journal-title":"Trends Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1001\/jamapsychiatry.2014.2427","article-title":"Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes","volume":"72","author":"Setiawan","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tyler, W.J. (2025). Auricular bioelectronic devices for health, medicine, and human-computer interfaces. Front. Electron., 6.","DOI":"10.3389\/felec.2025.1503425"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lopez Blanco, C., and Tyler, W.J. (2025). The vagus nerve: A cornerstone for mental health and performance optimization in recreation and elite sports. Front. Psychol., 16.","DOI":"10.3389\/fpsyg.2025.1639866"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/joa.13122","article-title":"The anatomical basis for transcutaneous auricular vagus nerve stimulation","volume":"236","author":"Butt","year":"2020","journal-title":"J. Anat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22055","DOI":"10.1038\/s41598-022-25864-1","article-title":"Safety of transcutaneous auricular vagus nerve stimulation (taVNS): A systematic review and meta-analysis","volume":"12","author":"Kim","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.brs.2021.06.002","article-title":"Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans","volume":"14","author":"Urbin","year":"2021","journal-title":"Brain Stimul."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.brs.2014.11.018","article-title":"Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans","volume":"8","author":"Frangos","year":"2015","journal-title":"Brain Stimul."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e70011","DOI":"10.1111\/psyp.70011","article-title":"Three Hundred Hertz Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) Impacts Pupil Size Non-Linearly as a Function of Intensity","volume":"62","author":"Phillips","year":"2025","journal-title":"Psychophysiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1523\/JNEUROSCI.1361-20.2020","article-title":"Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations","volume":"41","author":"Sharon","year":"2021","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s42234-019-0021-3","article-title":"Collateral benefits of studying the vagus nerve in bioelectronic medicine","volume":"5","author":"Pavlov","year":"2019","journal-title":"Bioelectron. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nrendo.2012.189","article-title":"The vagus nerve and the inflammatory reflex\u2014Linking immunity and metabolism","volume":"8","author":"Pavlov","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1016\/j.neuron.2022.09.003","article-title":"Bioelectronic medicine: Preclinical insights and clinical advances","volume":"110","author":"Pavlov","year":"2022","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bbi.2005.03.015","article-title":"The cholinergic anti-inflammatory pathway","volume":"19","author":"Pavlov","year":"2005","journal-title":"Brain Behav. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1093\/intimm\/dxab073","article-title":"Control of inflammation using non-invasive neuromodulation: Past, present and promise","volume":"34","author":"Tynan","year":"2021","journal-title":"Int. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0006-3223(99)00140-7","article-title":"Role of locus coeruleus in attention and behavioral flexibility","volume":"46","author":"Rajkowski","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/(SICI)1096-9861(19960115)364:3<523::AID-CNE10>3.0.CO;2-Q","article-title":"Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain","volume":"364","author":"Colago","year":"1996","journal-title":"J. Comp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1046\/j.1365-2826.1998.00254.x","article-title":"Amygdaloid corticotropin-releasing factor targets locus coeruleus dendrites: Substrate for the co-ordination of emotional and cognitive limbs of the stress response","volume":"10","author":"Colago","year":"1998","journal-title":"J. Neuroendocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/npp.2012.50","article-title":"Corticotropin-Releasing Factor Acting at the Locus Coeruleus Disrupts Thalamic and Cortical Sensory-Evoked Responses","volume":"37","author":"Devilbiss","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0006-3223(99)00164-X","article-title":"Corticotropin-releasing factor, norepinephrine, and stress","volume":"46","author":"Koob","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_43","first-page":"119","article-title":"Biological peripheral correlates of anxiety","volume":"8","author":"Boulenger","year":"1982","journal-title":"Encephale"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/S0306-4522(99)00319-X","article-title":"Stress-induced c-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation","volume":"94","author":"Hahn","year":"1999","journal-title":"Neuroscience"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1038\/nn.2682","article-title":"Tuning arousal with optogenetic modulation of locus coeruleus neurons","volume":"13","author":"Carter","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.neuron.2015.07.002","article-title":"CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety","volume":"87","author":"McCall","year":"2015","journal-title":"Neuron"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e18247","DOI":"10.7554\/eLife.18247","article-title":"Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior","volume":"6","author":"McCall","year":"2017","journal-title":"Elife"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1152\/physrev.1983.63.3.844","article-title":"Nucleus locus ceruleus: New evidence of anatomical and physiological specificity","volume":"63","author":"Foote","year":"1983","journal-title":"Physiol. Rev."},{"key":"ref_49","first-page":"129","article-title":"Forebrain norepinephrine: Role in controlled information processing in the rat","volume":"7","author":"Cole","year":"1992","journal-title":"Neuropsychopharmacology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0301-0511(96)05222-2","article-title":"Arousal systems and attentional processes","volume":"45","author":"Robbins","year":"1997","journal-title":"Biol. Psychol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/2041318a0","article-title":"Inhibition of uptake of tritiated-noradrenaline in the intact rat brain by imipramine and structurally related compounds","volume":"204","author":"Glowinski","year":"1964","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"212286","DOI":"10.7573\/dic.212286","article-title":"Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder","volume":"4","author":"Belkin","year":"2015","journal-title":"Drugs Context"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhang, H., Cui, M., Cao, J.L., and Han, M.H. (2022). The Role of Beta-Adrenergic Receptors in Depression and Resilience. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102378"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Maletic, V., Eramo, A., Gwin, K., Offord, S.J., and Duffy, R.A. (2017). The Role of Norepinephrine and Its \u03b1-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review. Front. Psychiatry, 8.","DOI":"10.3389\/fpsyt.2017.00042"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6277","DOI":"10.1523\/JNEUROSCI.0450-11.2011","article-title":"\u03b2-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat","volume":"31","author":"Wohleb","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"42676","DOI":"10.1038\/srep42676","article-title":"Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/j.1365-2826.2010.01988.x","article-title":"The Brainstem Noradrenergic Systems in Stress, Anxiety and Depression","volume":"22","author":"Itoi","year":"2010","journal-title":"J. Neuroendocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Townsend, L.K. (2025). Peripheral adrenergic activity contributes to anxiety. Nat. Rev. Endocrinol.","DOI":"10.1038\/s41574-025-01210-z"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1001\/archpsyc.1984.01790190025003","article-title":"Noradrenergic Function in Panic Anxiety: Effects of Yohimbine in Healthy Subjects and Patients With Agoraphobia and Panic Disorder","volume":"41","author":"Charney","year":"1984","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0165-1781(89)90132-7","article-title":"Noradrenergic function in generalized anxiety disorder: Effects of yohimbine in healthy subjects and patients with generalized anxiety disorder","volume":"27","author":"Charney","year":"1989","journal-title":"Psychiatry Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1001\/archpsyc.1984.01790190045005","article-title":"Adrenergic function in patients with panic anxiety","volume":"41","author":"Nesse","year":"1984","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1001\/archpsyc.1989.01810020072012","article-title":"Behavioral and Physiologic Effects of Short-term and Long-term Administration of Clonidine in Panic Disorder","volume":"46","author":"Uhde","year":"1989","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0006-3223(92)90200-J","article-title":"Noradrenergic function in panic disorder effects of intravenous clonidine pretreatment on lactate induced panic","volume":"31","author":"Coplan","year":"1992","journal-title":"Biol. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1001\/archpsyc.1981.01780370029003","article-title":"Platelet \u03b12-Adrenergic Receptors in Major Depressive Disorder: Binding of Tritiated Clonidine Before and After Tricyclic Antidepressant Drug Treatment","volume":"38","author":"Zis","year":"1981","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/0006-3223(92)90259-3","article-title":"\u03b12-Adrenoceptors in the brain of suicide victims: Increased receptor density associated with major depression","volume":"31","author":"Barturen","year":"1992","journal-title":"Biol. Psychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0006-3223(02)01728-6","article-title":"Elevated agonist binding to \u03b12-adrenoceptors in the locus coeruleus in major depression","volume":"53","author":"Ordway","year":"2003","journal-title":"Biol. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1016\/j.neubiorev.2012.07.011","article-title":"\u03b12 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy","volume":"36","author":"Cottingham","year":"2012","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4875","DOI":"10.1523\/JNEUROSCI.21-13-04875.2001","article-title":"The \u03b12A-Adrenergic Receptor Plays a Protective Role in Mouse Behavioral Models of Depression and Anxiety","volume":"21","author":"Schramm","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Uys, M.M., Shahid, M., and Harvey, B.H. (2017). Therapeutic Potential of Selectively Targeting the \u03b12C-Adrenoceptor in Cognition, Depression, and Schizophrenia\u2014New Developments and Future Perspective. Front. Psychiatry, 8.","DOI":"10.3389\/fpsyt.2017.00144"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0165-1781(79)90061-1","article-title":"Changes in lymphocyte beta-adrenergic receptors in depression and mania","volume":"1","author":"Extein","year":"1979","journal-title":"Psychiatry Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1056\/NEJM198509193131202","article-title":"Reduced Sensitivity of Lymphocyte Beta-Adrenergic Receptors in Patients with Endogenous Depression and Psychomotor Agitation","volume":"313","author":"Mann","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1600-0773.1985.tb02500.x","article-title":"Beta adrenergic receptor function in depression and the effect of antidepressant drugs","volume":"56","author":"Pandey","year":"1985","journal-title":"Acta Pharmacol. Toxicol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/BF00735875","article-title":"Lymphocyte \u03b2-adrenergic receptor binding in panic disorder","volume":"94","author":"Brown","year":"1988","journal-title":"Psychopharmacology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0091-3057(93)90078-8","article-title":"\u03b2-adrenergic receptors are involved in stress-related behavioral changes","volume":"45","author":"Dunn","year":"1993","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1189\/jlb.0306164","article-title":"DAMPs, PAMPs and alarmins: All we need to know about danger","volume":"81","author":"Bianchi","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"437","DOI":"10.4103\/2319-4170.104408","article-title":"Alarmins, inflammasomes and immunity","volume":"35","author":"Ojcius","year":"2012","journal-title":"Biomed. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1124\/pr.113.008144","article-title":"Neuroinflammation and Comorbidity of Pain and Depression","volume":"66","author":"Walker","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nrn2297","article-title":"From inflammation to sickness and depression: When the immune system subjugates the brain","volume":"9","author":"Dantzer","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nri.2015.5","article-title":"The role of inflammation in depression: From evolutionary imperative to modern treatment target","volume":"16","author":"Miller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12974-021-02100-7","article-title":"On inflammatory hypothesis of depression: What is the role of IL-6 in the middle of the chaos?","volume":"18","author":"Roohi","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.biopsych.2022.10.017","article-title":"A Sticky Situation: The Link Between Peripheral Inflammation, Neuroinflammation, and Severe Mental Illness","volume":"93","author":"Tomasik","year":"2023","journal-title":"Biol. Psychiatry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1017\/S0033291712000554","article-title":"Generalized anxiety and C-reactive protein levels: A prospective, longitudinal analysis","volume":"42","author":"Copeland","year":"2012","journal-title":"Psychol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"100410","DOI":"10.1016\/j.bbih.2021.100410","article-title":"The association of anxiety and stress-related disorders with C-reactive protein (CRP) within UK Biobank","volume":"19","author":"Kennedy","year":"2022","journal-title":"Brain Behav. Immun.-Health"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15318","DOI":"10.1007\/s12035-025-05177-w","article-title":"PET Imaging Unveils Neuroinflammatory Mechanisms in Psychiatric Disorders: From Microglial Activation to Therapeutic Innovation","volume":"62","author":"Liu","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1600-0447.2007.00967.x","article-title":"Pathophysiology of hypercortisolism in depression","volume":"115","author":"Carroll","year":"2007","journal-title":"Acta Psychiatr. Scand. Suppl."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"30187","DOI":"10.1038\/srep30187","article-title":"Prolonged secretion of cortisol as a possible mechanism underlying stress and depressive behaviour","volume":"6","author":"Qin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1097\/01.psy.0000163456.22154.d2","article-title":"Hypercortisolemia and depression","volume":"67","author":"Gillespie","year":"2005","journal-title":"Psychosom. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.tins.2013.01.005","article-title":"Gut\u2013brain axis: How the microbiome influences anxiety and depression","volume":"36","author":"Foster","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Kumar, A., Pramanik, J., Goyal, N., Chauhan, D., Sivamaruthi, B.S., Prajapati, B.G., and Chaiyasut, C. (2023). Gut Microbiota in Anxiety and Depression: Unveiling the Relationships and Management Options. Pharmaceuticals, 16.","DOI":"10.3390\/ph16040565"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/s41398-021-01443-2","article-title":"A diet high in sugar and fat influences neurotransmitter metabolism and then affects brain function by altering the gut microbiota","volume":"11","author":"Guo","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1001\/jamapsychiatry.2025.2579","article-title":"Soft Drink Consumption and Depression Mediated by Gut Microbiome Alterations","volume":"82","author":"Ribeiro","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zhang, L., Sun, H., Liu, Z., Yang, J., and Liu, Y. (2024). Association between dietary sugar intake and depression in US adults: A cross-sectional study using data from the National Health and Nutrition Examination Survey 2011\u20132018. BMC Psychiatry, 24.","DOI":"10.1186\/s12888-024-05531-7"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/s41398-022-01922-0","article-title":"Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders","volume":"12","author":"Horn","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Jackler, R.K. (2019). Ear Surgery Illustrated: A Comprehensive Atlas of Otologic Microsurgical Techniques, Thieme. [1st ed.].","DOI":"10.1055\/b-0039-171421"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/ca.1089","article-title":"The nerve supply of the human auricle","volume":"15","author":"Peuker","year":"2002","journal-title":"Clin. Anat."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/ana.410070209","article-title":"Cold face test in the assessment of trigeminal-brainstem-vagal function in humans","volume":"7","author":"Khurana","year":"1980","journal-title":"Ann. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Lapi, D., Scuri, R., and Colantuoni, A. (2016). Trigeminal Cardiac Reflex and Cerebral Blood Flow Regulation. Front. Neurosci., 10.","DOI":"10.3389\/fnins.2016.00470"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e484","DOI":"10.1097\/MD.0000000000000484","article-title":"Trigeminal cardiac reflex: New thinking model about the definition based on a literature review","volume":"94","author":"Meuwly","year":"2015","journal-title":"Medicine"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13865","DOI":"10.1038\/srep13865","article-title":"Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans","volume":"5","author":"Tyler","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e14183","DOI":"10.1111\/psyp.14183","article-title":"The diving response and cardiac vagal activity: A systematic review and meta-analysis","volume":"60","author":"Ackermann","year":"2023","journal-title":"Psychophysiology"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Panneton, W.M., and Gan, Q. (2020). The Mammalian Diving Response: Inroads to Its Neural Control. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00524"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1152\/jappl.1967.22.4.800","article-title":"Simulated diving in man: Comparison of facial stimuli and response in arrhythmia","volume":"22","author":"Whayne","year":"1967","journal-title":"J. Appl. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/BF02425070","article-title":"Anatomic basis of Arnold\u2019s ear-cough reflex","volume":"8","author":"Gupta","year":"1986","journal-title":"Surg. Radiol. Anat."},{"key":"ref_105","first-page":"253","article-title":"A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold\u2019s ear-cough reflex","volume":"20","author":"Tekdemir","year":"1998","journal-title":"Surg. Radiol. Anat."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1007\/s12565-014-0231-4","article-title":"Origin, course and distribution of the nerves to the posterosuperior wall of the external acoustic meatus","volume":"89","author":"Kiyokawa","year":"2014","journal-title":"Anat. Sci. Int."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Mao, Y., Chen, C., Falahpour, M., MacNiven, K.H., Heit, G., Sharma, V., Alataris, K., and Liu, T.T. (2022). Effects of Sub-threshold Transcutaneous Auricular Vagus Nerve Stimulation on Cingulate Cortex and Insula Resting-state Functional Connectivity. Front. Hum. Neurosci., 16.","DOI":"10.3389\/fnhum.2022.862443"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/ner.12541","article-title":"Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI","volume":"20","author":"Yakunina","year":"2017","journal-title":"Neuromodul. Technol. Neural Interface"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"101971","DOI":"10.1016\/j.nicl.2019.101971","article-title":"Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: An fMRI study","volume":"24","author":"Zhang","year":"2019","journal-title":"NeuroImage Clin."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.brs.2025.06.014","article-title":"Locus coeruleus fMRI response to transcutaneous auricular vagus nerve stimulation is coupled to changes in salivary alpha amylase","volume":"18","author":"Schneider","year":"2025","journal-title":"Brain Stimul."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0022-3956(03)00074-8","article-title":"A review of functional neuroimaging studies of vagus nerve stimulation (VNS)","volume":"37","author":"Chae","year":"2003","journal-title":"J. Psychiatr. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.brs.2015.02.003","article-title":"Acute Vagal Nerve Stimulation Lowers \u03b12 Adrenoceptor Availability: Possible Mechanism of Therapeutic Action","volume":"8","author":"Landau","year":"2015","journal-title":"Brain Stimul. Basic Transl. Clin. Res. Neuromodul."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"21645","DOI":"10.1038\/s41598-021-00976-2","article-title":"Local activation of \u03b12 adrenergic receptors is required for vagus nerve stimulation induced motor cortical plasticity","volume":"11","author":"Tseng","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.brs.2025.05.051","article-title":"Beta-receptor blockades during high-intensity vagus nerve stimulation enable enhanced cortical plasticity, and provide insight into the mechanism of VNS-mediated plasticity","volume":"18","author":"Neifert","year":"2025","journal-title":"Brain Stimul. Basic Transl. Clin. Res. Neuromodul."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Chen, Y., Lu, X., and Hu, L. (2023). Transcutaneous Auricular Vagus Nerve Stimulation Facilitates Cortical Arousal and Alertness. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20021402"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"He, J.-K., Jia, B.-H., Wang, Y., Li, S.-Y., Zhao, B., Zhou, Z.-G., Bi, Y.-Z., Wu, M.-Z., Li, L., and Zhang, J.-L. (2022). Transcutaneous Auricular Vagus Nerve Stimulation Modulates the Prefrontal Cortex in Chronic Insomnia Patients: fMRI Study in the First Session. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.827749"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e31808","DOI":"10.1097\/MD.0000000000031808","article-title":"Transcutaneous auricular vagus nerve stimulation in disorders of consciousness: A mini-narrative review","volume":"101","author":"Jang","year":"2022","journal-title":"Medicine"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1038\/s41467-020-17344-9","article-title":"Vagus nerve stimulation boosts the drive to work for rewards","volume":"11","author":"Neuser","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1037\/neu0000735","article-title":"The effects of transcutaneous auricular vagal nerve stimulation on cognition in healthy individuals: A meta-analysis","volume":"35","author":"Ridgewell","year":"2021","journal-title":"Neuropsychology"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Sun, J., Ma, Y., Du, Z., Wang, Z., Guo, C., Luo, Y., Chen, L., Gao, D., Li, X., and Xu, K. (2022). Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.923783"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41398-025-03352-0","article-title":"Ready for translation: Non-invasive auricular vagus nerve stimulation inhibits psychophysiological indices of stimulus-specific fear and facilitates responding to repeated exposure in phobic individuals","volume":"15","author":"Szeska","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Zhang, S., He, J.-K., Zhong, G.-L., Wang, Y., Zhao, Y.-N., Wang, L., Li, S.-Y., Xiao, X., Yang, Z.-Y., and Zhao, B. (2022). Prolonged Longitudinal Transcutaneous Auricular Vagus Nerve Stimulation Effect on Striatal Functional Connectivity in Patients with Major Depressive Disorder. Brain Sci., 12.","DOI":"10.21203\/rs.3.rs-1837921\/v1"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1152\/jn.00057.2020","article-title":"A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: Challenges and future directions","volume":"123","author":"Colzato","year":"2020","journal-title":"J. Neurophysiol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"680","DOI":"10.3758\/s13415-018-0596-2","article-title":"Transcutaneous vagus nerve stimulation (tVNS) enhances conflict-triggered adjustment of cognitive control","volume":"18","author":"Fischer","year":"2018","journal-title":"Cogn. Affect. Behav. Neurosci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s13311-022-01318-4","article-title":"The Effects of Transcutaneous Vagus Nerve Stimulation on Functional Connectivity Within Semantic and Hippocampal Networks in Mild Cognitive Impairment","volume":"20","author":"Murphy","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Kong, J., Fang, J., Park, J., Li, S., and Rong, P. (2018). Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Front. Psychiatry, 9.","DOI":"10.3389\/fpsyt.2018.00020"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12974-020-01732-5","article-title":"Neural networks and the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation in depression","volume":"17","author":"Liu","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jad.2016.02.031","article-title":"Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study","volume":"195","author":"Rong","year":"2016","journal-title":"J. Affect. Disord."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1007\/s00268-020-05543-w","article-title":"Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve Attenuates the Acute Inflammatory Response After Lung Lobectomy","volume":"44","author":"Salama","year":"2020","journal-title":"World J. Surg."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Corr\u00eaa, F.I., Souza, P.H.L., Uehara, L., Ritti-Dias, R.M., Oliveira da Silva, G., Segheto, W., Pacheco-Barrios, K., Fregni, F., and Corr\u00eaa, J.C.F. (2022). Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial. Life, 12.","DOI":"10.3390\/life12101644"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.brs.2023.02.008","article-title":"Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: An open double-blind, sham-controlled, pilot study","volume":"16","author":"Wu","year":"2023","journal-title":"Brain Stimul."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.3171\/2024.10.JNS241643","article-title":"Auricular vagus nerve stimulation for mitigation of inflammation and vasospasm in subarachnoid hemorrhage: A single-institution randomized controlled trial","volume":"142","author":"Huguenard","year":"2025","journal-title":"J. Neurosurg."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Laurido-Soto, O.J., Tan, G., Nielsen, S.S., Huguenard, A.L., Donovan, K., Xu, I., Giles, J., Dhar, R., Adeoye, O., and Lee, J.-M. (2025). Transcutaneous Auricular Vagus Nerve Stimulation Reduces Inflammatory Biomarkers and May Improve Outcomes after Large Vessel Occlusion Strokes: Results of the Randomized Clinical Trial NUVISTA. medRxiv.","DOI":"10.1101\/2025.03.06.25323500"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s42234-024-00162-5","article-title":"Exploring the efficacy of Transcutaneous Auricular Vagus nerve stimulation (taVNS) in modulating local and systemic inflammation in experimental models of colitis","volume":"10","author":"Hesampour","year":"2024","journal-title":"Bioelectron. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2634","DOI":"10.1111\/cns.14207","article-title":"Anti-neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression-like behaviors via hypothalamic \u03b17nAchR\/JAK2\/STAT3\/NF-\u03baB pathway in rats exposed to chronic unpredictable mild stress","volume":"29","author":"Chen","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e14614","DOI":"10.1111\/cns.14614","article-title":"Transcutaneous auricular vagus nerve stimulation ameliorates adolescent depressive- and anxiety-like behaviors via hippocampus glycolysis and inflammation response","volume":"30","author":"Sun","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Song, X., Zhu, H., Chen, Z., Wang, Y., Zhang, J., Wang, Y., Rong, P., and Wang, J. (2025). Transcutaneous auricular vagus nerve stimulation alleviates inflammation-induced depression by modulating peripheral-central inflammatory cytokines and the NF-\u03baB pathway in rats. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1536056"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Bremner, J.D., Gurel, N.Z., Wittbrodt, M.T., Shandhi, M.H., Rapaport, M.H., Nye, J.A., Pearce, B.D., Vaccarino, V., Shah, A.J., and Park, J. (2020). Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders. J. Pers. Med., 10.","DOI":"10.3390\/jpm10030119"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Geng, D., Liu, X., Wang, Y., and Wang, J. (2022). The effect of transcutaneous auricular vagus nerve stimulation on HRV in healthy young people. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0263833"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.brs.2014.07.031","article-title":"Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity","volume":"7","author":"Clancy","year":"2014","journal-title":"Brain Stimul."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1111\/ejn.16305","article-title":"Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity","volume":"59","author":"Yokota","year":"2024","journal-title":"Eur. J. Neurosci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e70251","DOI":"10.14814\/phy2.70251","article-title":"Transcutaneous auricular vagus nerve stimulation inhibits mental stress-induced cortisol release-Potential implications for inflammatory conditions","volume":"13","author":"Goyes","year":"2025","journal-title":"Physiol. Rep."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e14250","DOI":"10.1111\/psyp.14250","article-title":"Effects of non-invasive vagus nerve stimulation on cognitive and autonomic correlates of perseverative cognition","volume":"60","author":"Ottaviani","year":"2023","journal-title":"Psychophysiology"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Le Roy, B., Martin-Krumm, C., Gille, A., Jacob, S., Vigier, C., Laborde, S., Claverie, D., Besnard, S., and Trousselard, M. (2023). Evaluation of taVNS for extreme environments: An exploration study of health benefits and stress operationality. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1286919"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Tyler, W.J., Wyckoff, S., Hearn, T., and Hool, N. (2019). The Safety and Efficacy of Transdermal Auricular Vagal Nerve Stimulation Earbud Electrodes for Modulating Autonomic Arousal, Attention, Sensory Gating, and Cortical Brain Plasticity in Humans. bioRxiv, 732529.","DOI":"10.1101\/732529"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1017\/S0033291720005073","article-title":"Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion","volume":"52","author":"Ferstl","year":"2022","journal-title":"Psychol. Med."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Borges, U., Knops, L., Laborde, S., Klatt, S., and Raab, M. (2020). Transcutaneous Vagus Nerve Stimulation May Enhance Only Specific Aspects of the Core Executive Functions. A Randomized Crossover Trial. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00523"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Pihlaja, M., Failla, L., Per\u00e4kyl\u00e4, J., and Hartikainen, K.M. (2020). Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation\u2014More Efficient Cognitive Control?. Front. Hum. Neurosci., 14.","DOI":"10.3389\/fnhum.2020.561780"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"108614","DOI":"10.1016\/j.neuropsychologia.2023.108614","article-title":"The effect of transcutaneous auricular vagus nerve stimulation (taVNS) on cognitive control in multitasking","volume":"187","author":"Sommer","year":"2023","journal-title":"Neuropsychologia"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Mena-Chamorro, P., Espinoza-Palavicino, T., Barramu\u00f1o-Medina, M., Romero-Arias, T., and G\u00e1lvez-Garc\u00eda, G. (2025). Impact of transcutaneous auricular vagus nerve stimulation (taVNS) on cognitive flexibility as a function of task complexity. Front. Hum. Neurosci., 19.","DOI":"10.3389\/fnhum.2025.1569472"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"100462","DOI":"10.1016\/j.ijchp.2024.100462","article-title":"Transcutaneous auricular vagus nerve stimulation enhanced emotional inhibitory control via increasing intrinsic prefrontal couplings","volume":"24","author":"Zhu","year":"2024","journal-title":"Int. J. Clin. Health Psychol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.1109\/TCSS.2025.3564035","article-title":"Exploring the Alleviating Effects of taVNS on Negative Emotions: An EEG Study","volume":"12","author":"Jin","year":"2025","journal-title":"IEEE Trans. Comput. Soc. Syst."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"7636","DOI":"10.1523\/JNEUROSCI.2329-20.2021","article-title":"Establishment of Emotional Memories Is Mediated by Vagal Nerve Activation: Evidence from Noninvasive taVNS","volume":"41","author":"Wirkner","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"327","DOI":"10.5606\/tftrd.2023.11174","article-title":"The effects of transcutaneous auricular vagus nerve stimulation on visual memory performance and fatigue","volume":"69","year":"2023","journal-title":"Turk. J. Phys. Med. Rehabil."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0167-8760(01)00162-3","article-title":"The polyvagal theory: Phylogenetic substrates of a social nervous system","volume":"42","author":"Porges","year":"2001","journal-title":"Int. J. Psychophysiol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/wps.20871","article-title":"Cardiac vagal tone: A neurophysiological mechanism that evolved in mammals to dampen threat reactions and promote sociality","volume":"20","author":"Porges","year":"2021","journal-title":"World Psychiatry"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jad.2024.11.077","article-title":"Transcutaneous vagus nerve stimulation improves emotional processing","volume":"372","author":"Zhao","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Kim, W.-J., Lee, Y.-S., Hong, K.H., Choi, H., Song, J.-J., and Hwang, H.-J. (2025). Effect of transcutaneous auricular vagus nerve stimulation on stress regulation: An EEG and questionnaire study. Front. Digit. Health, 7.","DOI":"10.3389\/fdgth.2025.1593614"},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Ricci, L., Croce, P., Lanzone, J., Boscarino, M., Zappasodi, F., Tombini, M., Di Lazzaro, V., and Assenza, G. (2020). Transcutaneous Vagus Nerve Stimulation Modulates EEG Microstates and Delta Activity in Healthy Subjects. Brain Sci., 10.","DOI":"10.3390\/brainsci10100668"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"4076","DOI":"10.1109\/TNSRE.2024.3497893","article-title":"The Neural Basis of the Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Emotion Regulation Related Brain Regions: An rs-fMRI Study","volume":"32","author":"Zhang","year":"2024","journal-title":"IEEE Trans. Neural Syst. Rehabil. Eng."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Ma, Y., Wang, Z., He, J., Sun, J., Guo, C., Du, Z., Chen, L., Luo, Y., Gao, D., and Hong, Y. (2022). Transcutaneous auricular vagus nerve immediate stimulation treatment for treatment-resistant depression: A functional magnetic resonance imaging study. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.931838"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Guo, Z.-P., Liao, D., Chen, L., Wang, C., Qu, M., Lv, X.-Y., Fang, J.-L., and Liu, C.-H. (2024). Transcutaneous auricular vagus nerve stimulation modulating the brain topological architecture of functional network in major depressive disorder: An fMRI study. Brain Sci., 14.","DOI":"10.3390\/brainsci14090945"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/ner.13528","article-title":"A Comprehensive Review of Vagus Nerve Stimulation for Depression","volume":"25","author":"Austelle","year":"2022","journal-title":"Neuromodul. J. Int. Neuromodul. Soc."},{"key":"ref_164","first-page":"3","article-title":"The Future Is Noninvasive: A Brief Review of the Evolution and Clinical Utility of Vagus Nerve Stimulation","volume":"20","author":"Badran","year":"2022","journal-title":"Focus (Am. Psychiatr. Publ.)"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"usaf063","DOI":"10.1093\/milmed\/usaf063","article-title":"Transcutaneous Auricular Vagus Nerve Stimulation: Efficacy, Applications, and Challenges in Mood Disorders and Autonomic Regulation\u2014A Narrative Review","volume":"190","author":"Croft","year":"2025","journal-title":"Mil. Med."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"555","DOI":"10.12740\/PP\/OnlineFirst\/115191","article-title":"Use of transcutaneous auricular vagus nerve stimulation (taVNS) in the treatment of drug-resistant depression\u2014A pilot study, presentation of five clinical cases","volume":"55","author":"Kaczmarczyk","year":"2021","journal-title":"Psychiatr. Pol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.neurom.2021.10.021","article-title":"Comparative Effectiveness of Transcutaneous Auricular Vagus Nerve Stimulation vs Citalopram for Major Depressive Disorder: A Randomized Trial","volume":"25","author":"Li","year":"2022","journal-title":"Neuromodul. Technol. Neural Interface"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00702-012-0908-6","article-title":"Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study","volume":"120","author":"Hein","year":"2013","journal-title":"J. Neural Transm."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jad.2022.07.068","article-title":"Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder with peripartum onset: A multicenter, open-label, controlled proof-of-concept clinical trial (DELOS-1)","volume":"316","author":"Deligiannidis","year":"2022","journal-title":"J. Affect. Disord."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.neurom.2025.02.003","article-title":"Accelerated Transcutaneous Auricular Vagus Nerve Stimulation for Inpatient Depression and Anxiety: The iWAVE Open Label Pilot Trial","volume":"28","author":"Austelle","year":"2025","journal-title":"Neuromodulation"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/ner.13366","article-title":"Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study","volume":"25","author":"Evensen","year":"2022","journal-title":"Neuromodul. J. Int. Neuromodul. Soc."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/s41598-020-58412-w","article-title":"Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training","volume":"10","author":"Szeska","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"e13891","DOI":"10.1111\/jsr.13891","article-title":"Preliminary evidence of transcutaneous vagus nerve stimulation effects on sleep in veterans with post-traumatic stress disorder","volume":"33","author":"Bottari","year":"2024","journal-title":"J. Sleep Res."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/j.biopsych.2012.10.021","article-title":"Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation","volume":"73","author":"Engineer","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"100264","DOI":"10.1016\/j.ynstr.2020.100264","article-title":"Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial","volume":"13","author":"Gurel","year":"2020","journal-title":"Neurobiol. Stress"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"113718","DOI":"10.1016\/j.expneurol.2021.113718","article-title":"Vagus nerve stimulation enhances fear extinction as an inverted-U function of stimulation intensity","volume":"341","author":"Souza","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s42843-023-00089-6","article-title":"Vagal Nerve Stimulation for Patients With Stress-Related Psychiatric Disorders and Addictions","volume":"49","author":"Bremner","year":"2023","journal-title":"J. Health Serv. Psychol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/j.brs.2021.10.368","article-title":"At-home telemedicine controlled taVNS twice daily for 4 weeks reduces long COVID symptoms of anxiety and fatigue","volume":"14","author":"Austelle","year":"2021","journal-title":"Brain Stimul. Basic Transl. Clin. Res. Neuromodul."},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Ferreira, L.M.A., Brites, R., Frai\u00e3o, G., Pereira, G., Fernandes, H., de Brito, J.A.A., Pereira Generoso, L., Maziero Capello, M.G., Pereira, G.S., and Scoz, R.D. (2024). Transcutaneous auricular vagus nerve stimulation modulates masseter muscle activity, pain perception, and anxiety levels in university students: A double-blind, randomized, controlled clinical trial. Front. Integr. Neurosci., 18.","DOI":"10.3389\/fnint.2024.1422312"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.jad.2024.06.083","article-title":"Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson\u2019s disease with anxiety","volume":"361","author":"Zhang","year":"2024","journal-title":"J. Affect. Disord."},{"key":"ref_181","first-page":"1149","article-title":"Effect of vagus nerve stimulation (taVNS) on anxiety and sleep disturbances among elderly health care workers in the post COVID-19 pandemic","volume":"78","author":"Srinivasan","year":"2024","journal-title":"Work"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Black, B., Hunter, S., Cottrell, H., Dar, R., Takahashi, N., Ferguson, B.J., Valter, Y., Porges, E., Datta, A., and Beversdorf, D.Q. (2023). Remotely supervised at-home delivery of taVNS for autism spectrum disorder: Feasibility and initial efficacy. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1238328"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"152488","DOI":"10.1016\/j.comppsych.2024.152488","article-title":"Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression","volume":"132","author":"Ferstl","year":"2024","journal-title":"Compr. Psychiatry"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.biopsycho.2019.01.014","article-title":"Transcutaneous vagus nerve stimulation reduces spontaneous but not induced negative thought intrusions in high worriers","volume":"142","author":"Burger","year":"2019","journal-title":"Biol. Psychol."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Wang, Y.-M., Xu, Y.-Y., Zhai, Y., Wu, Q.-Q., Huang, W., Liang, Y., Sun, Y.-H., and Xu, L.-Y. (2021). Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Protracted Alcohol Withdrawal Symptoms in Male Alcohol-Dependent Patients. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.678594"},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Wu, Y., Song, L., Wang, X., Li, N., Zhan, S., Rong, P., Wang, Y., and Liu, A. (2022). Transcutaneous Vagus Nerve Stimulation Could Improve the Effective Rate on the Quality of Sleep in the Treatment of Primary Insomnia: A Randomized Control Trial. Brain Sci., 12.","DOI":"10.3390\/brainsci12101296"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"116344","DOI":"10.1016\/j.biopha.2024.116344","article-title":"Preventive noninvasive vagal nerve stimulation reduces insufficient sleep-induced depression by improving the autonomic nervous system","volume":"173","author":"Ma","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"zsaf152","DOI":"10.1093\/sleep\/zsaf152","article-title":"Optimizing transcutaneous vagus nerve stimulation parameters for sleep and autonomic function in veterans with posttraumatic stress disorder with or without mild traumatic brain injury","volume":"48","author":"Bottari","year":"2025","journal-title":"Sleep"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s00702-007-0755-z","article-title":"BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation","volume":"114","author":"Kraus","year":"2007","journal-title":"J. Neural Transm."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.brs.2018.11.013","article-title":"The effect of transcutaneous auricular vagus nerve stimulation on treatment-resistant depression monitored by resting-state fMRI and MRS: The first case report","volume":"12","author":"Li","year":"2019","journal-title":"Brain Stimul."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jad.2016.08.003","article-title":"Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression","volume":"205","author":"Liu","year":"2016","journal-title":"J. Affect. Disord."},{"key":"ref_192","first-page":"93","article-title":"Mapping the modulating effect of transcutaneous auricular vagus nerve stimulation on voxel-based analyses in patients with first-episode major depressive disorder: A resting-state functional magnetic resonance imaging study","volume":"45","author":"He","year":"2023","journal-title":"Braz. J. Psychiatry"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/1\/8\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:43:53Z","timestamp":1766587433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/1\/8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,20]]},"references-count":192,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["brainsci16010008"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16010008","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,20]]}}}