Investigation of Neopterin and Neurophysiological Measurements as Biomarkers of Anxiety and Stress


  • Rouxzan Cronje
  • Johanni Beukes
  • Andries Masenge
  • Peet du Toit
  • Priyesh Bipath Department of Physiology, University of Pretoria



anxiety, biomarkers, brainwaves, heart rate variability, inflammation, neopterin, stress


The aim of this study was to investigate whether the inflammatory marker neopterin and certain neurophysiological measurements could be used as complementary markers for stress and anxiety symptoms as determined by the Depression, Anxiety, and Stress Scale (DASS-21) questionnaire. A cohort of 158 respondents completed the DASS-21 and biographical questionnaire which were used to stratify health sciences university students between Group A (n = 20), who had high levels of symptoms, and Group B (n = 20) who had normal levels of stress and anxiety. Neurophysiological measurements were taken from these participants, namely heart rate variability (HRV), blood pressure (BP), blood-volume pulse (BVP), electrodermal activity (EDA), and quantitative electroencephalography (qEEG). Each participant also donated a urine sample which was tested for neopterin concentration using an enzyme-linked immunosorbent assay (ELISA). Neopterin positively correlated with the stress and anxiety scores, while HRV and BVP were negatively correlated with these scores. In terms of qEEG, delta and hibeta wave activity increased in the left and frontal brain regions of participants with high mental health scores, whereas alpha wave activity decreased in these regions. High DASS scores were associated with elevated neopterin concentration and neurophysiological changes (brain waves, HRV, and BVP).


Akin, A., & Çetin, B. (2007). The Depression Anxiety and Stress Scale (DASS): The study of validity and reliability. Kuram ve Uygulamada Egitim Bilimleri, 7(1), 260–268.

Albert, P. R., Benkelfat, C., & Descarries, L. (2012). The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1601), 2378–2381.

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

An, E., Nolty, A. A. T., Amano, S. S., Rizzo, A. A., Buckwalter, J. G., & Rensberger, J. (2020). Heart rate variability as an index of resilience. Military Medicine, 185(3–4), 363–369.

Antony, M., Bieling, P., Cox, B., Enns, M., & Swinson, R. (1998). Psychometric properties of the 42-item and 21-item versions of the Depression Anxiety Stress Scales in clinical groups and a community sample. Psychological Assessment, 10(2), 176–181.

Arias, D., Saxena, S., & Verguet, S. (2022). Quantifying the global burden of mental disorders and their economic value. eClinicalMedicine, 54, Article 101675.

Atmaca, M., Kuloglu, M., Tezcan, E., Onal, S. l., & Ustundag, B. (2002). Neopterin levels and dexamethasone suppression test in posttraumatic stress disorder. European Archives of Psychiatry and Clinical Neuroscience, 252(4), 161–165.

Awadalla, S., Davies, E. B., & Glazebrook, C. (2020). A longitudinal cohort study to explore the relationship between depression, anxiety and academic performance among Emirati university students. BMC Psychiatry, 20(1), Article 448.

Bagdy, G. (1998). Serotonin, anxiety, and stress hormones: Focus on 5-HT receptor subtypes, species and gender differencesa. Annals of the New York Academy of Sciences, 851(1), 357–363.

Bankier, B., Barajas, J., Martinez-Rumayor, A., & Januzzi, J. L. (2008). Association between C-reactive protein and generalized anxiety disorder in stable coronary heart disease patients. European Heart Journal, 29(18), 2212–2217.

Bauer, M. E., & Teixeira, A. L. (2019). Inflammation in psychiatric disorders: What comes first? Annals of the New York Academy of Sciences, 1437(1), 57–67.

Beaufort, I. N., De Weert-Van Oene, G. H., Buwalda, V. A. J., de Leeuw, J. R. J., & Goudriaan, A. E. (2017). The Depression, Anxiety and Stress Scale (DASS-21) as a screener for depression in substance use disorder inpatients: A pilot study. European Addiction Research, 23(5), 260–268.

Berdowska, A., & Zwirska-Korczala, K. (2001). Neopterin measurement in clinical diagnosis. Journal of Clinical Pharmacy and Therapeutics, 26(5), 319–329.

Blackhart, G. C., Minnix, J. A., & Kline, J. P. (2006). Can EEG asymmetry patterns predict future development of anxiety and depression?: A preliminary study. Biological Psychology, 72(1), 46–50.

Blokland, A., Lieben, C., & Deutz, N. E. P. (2002). Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat. Journal of Psychopharmacology, 16(1), 39–49.

Bouayed, J., Rammal, H., & Soulimani, R. (2009). Oxidative stress and anxiety: Relationship and cellular pathways. Oxidative Medicine and Cellular Longevity, 2(2), 63–67.

Brown, R. R., Lee, C. M., Kohler, P. C., Hank, J. A., Storer, B. E., & Sondel, P. M. (1989). Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 21. Cancer Research, 49(17), 4941–4944.

Buist–Bouwman, M. A., De Graaf, R., Vollebergh, W. A. M., Alonso, J., Bruffaerts, R., Ormel, J., & ESEMeD/MHEDEA 2000 Investigators (2006). Functional disability of mental disorders and comparison with physical disorders: A study among the general population of six European countries. Acta Psychiatrica Scandinavica, 113(6), 492–500.

Capuron, L., & Castanon, N. (2016). Role of inflammation in the development of neuropsychiatric symptom domains: Evidence and mechanisms. In R. Dantzer & L. Capuron (Eds.), Inflammation-associated depression: Evidence, mechanisms and implications (pp. 31–44). Current topics in behavioral neurosciences (vol. 31). Springer, Cham.

Chalmers, J. A., Quintana, D. S., Abbott, M. J., & Kemp, A. H. (2014). Anxiety disorders are associated with reduced heart rate variability: A meta-analysis. Frontiers in Psychiatry, 5, Article 80.

Charmandari, E., Tsigos, C., & Chrousos, G. (2005). Endocrinology of the stress response. Annual Review of Physiology, 67, 259–284.

Chu, B., Marwaha, K., Sanvictores, T., & Ayers, D. (2022). Physiology, stress reaction. StatPearls. StatPearls Publishing.

Cohen, B. E., Edmondson, D., & Kronish, I. M. (2015). State of the art review: Depression, stress, anxiety, and cardiovascular disease. American Journal of Hypertension, 28(11), 1295–1302.

Crawford, J. R., & Henry, J. D. (2003). The Depression Anxiety Stress Scales (DASS): Normative data and latent structure in a large non-clinical sample. British Journal of Clinical Psychology, 42(2), 111–131.

Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J. M., Lüscher, B., & Mohler, H. (1999). Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neuroscience, 2(9), 833–839.

Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56.

De Beurs, E., Van Dyck, R., Marquenie, Lange, A., & Blonk, R. (2001). De DASS: Een vragenlijst voor het meten van epressivee, angst en stress [The DASS: A questionnaire for the measurement of depression, anxiety, and stress]. Gedragstherapie, 34(1), 35–53.

Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., & Lanctôt, K. L. (2010). A meta-analysis of cytokines in major depression. Biological Psychiatry, 67(5), 446–457.

Dreyer, Z., Henn, C., & Hill, C. (2019). Validation of the Depression Anxiety Stress Scale-21 (DASS-21) in a non-clinical sample of South African working adults. Journal of Psychology in Africa, 29(4), 346–353.

Dunbar, P. R., Hill, J., & Neale, T. J. (1993). Urinary neopterin quantification indicates altered cell-mediated immunity in healthy subjects under psychological stress. Australian & New Zealand Journal of Psychiatry, 27(3), 495–501.

Dunbar, P. R., Hill, J., Neale, T. J., & Mellsop, G. W. (1992). Neopterin measurement provides evidence of altered cell-mediated immunity in patients with depression, but not with schizophrenia. Psychological Medicine, 22(4), 1051–1057.

Dunn, A. J. (2006). Effects of cytokines and infections on brain neurochemistry. Clinical Neuroscience Research, 6(1–2), 52–68.

Dyrbye, L. N., Massie, F. S., Eacker, A., Harper, W., Power, D., Durning, S. J., Thomas, M. R., Moutier, C., Satele, D., Sloan, J., & Shanafelt, T. D. (2010). Relationship between burnout and professional conduct and attitudes among US medical students. JAMA, 304(11), 1173–1180.

Dyrbye, L. N., Thomas, M. R., & Shanafelt, T. D. (2005). Medical student distress: Causes, consequences, and proposed solutions. Mayo Clinic Proceedings, 80(12), 1613–1622.

Dyrbye, L. N., Thomas, M. R., & Shanafelt, T. D. (2006). Systematic review of depression, anxiety, and other indicators of psychological distress among U.S. and Canadian medical students. Academic Medicine, 81(4), 354–373.

Edwards, K. M., Wilson, K. L., Sadja, J., Ziegler, M. G., & Mills, P. J. (2011). Effects on blood pressure and autonomic nervous system function of a 12-week exercise or exercise plus DASH-diet intervention in individuals with elevated blood pressure. Acta Physiologica, 203(3), 343–350.

Eisenberg, D., Golberstein, E., & Hunt, J. (2009). Mental Health and Academic Success in College. The B. E. Journal of Economic Analysis & Policy, 9(1), Article 40.

Eisenhut, M. (2013). Neopterin in diagnosis and monitoring of infectious diseases. Journal of Biomarkers, 2013, Article 196432.

Fares, J., Al Tabosh, H., Saadeddin, Z., El Mouhayyar, C., & Aridi, H. (2016). Stress, burnout and coping strategies in preclinical medical students. North American Journal of Medical Sciences, 8(2), 75–81.

Ferrari, A. J., Santomauro, D. F., Mantilla Herrera, A. M., Shadid, J., Ashbaugh, C., Erskine, H. E., Charlson, F. J., Degenhardt, L., Scott, J. G., McGrath, J. J., Allebeck, P., Benjet, C., Breitborde, N. J. K., Brugha, T., Dai, X., Dandona, L., Dandona, R., Fischer, F., Haagsma, J. A., … Whiteford, H. A. (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry, 9(2), 137–150.

Forgione, F. A. (2018). Diagnostic dissent: Experiences of perceived misdiagnosis and stigma in persons diagnosed with schizophrenia. Journal of Humanistic Psychology, 59(1), 69–98.

Fuchs, D., Avanzas, P., Arroyo-Espliguero, R., Jenny, M., Consuegra-Sánchez, L., & Kaski, J. (2009). The role of neopterin in atherogenesis and cardiovascular risk assessment. Current Medicinal Chemistry, 16, 4644–4653.

Gao, K., Mu, C.-L., Farzi, A., & Zhu, W.-Y. (2020). Tryptophan metabolism: A link between the gut microbiota and brain. Advances in Nutrition, 11(3), 709–723.

García-Gutiérrez, M. S., Navarrete, F., Sala, F., Gasparyan, A., Austrich-Olivares, A., & Manzanares, J. (2020). Biomarkers in psychiatry: Concept, definition, types and relevance to the clinical reality. Frontiers in Psychiatry, 11, Article 432.

Gass, P., Reichardt, H. M., Strekalova, T., Henn, F., & Tronche, F. (2001). Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: Models for depression and anxiety? Physiology & Behavior, 73(5), 811–825.

Ghisoni, K., de Paula Martins R., Barbeito, L., & Latini, A. (2015). Neopterin as a potential cytoprotective brain molecule. Journal of Psychiatric Research, 71, 134–139.

Gieseg, S. P., Baxter-Parker, G., & Lindsay, A. (2018). Neopterin, inflammation, and oxidative stress: What could we be missing? Antioxidants, 7(7), Article 80.

Godoy, L. D., Rossignoli, M. T., Delfino-Pereira, P., Garcia-Cairasco, N., & de Lima Umeoka, E. H. (2018). A comprehensive overview on stress neurobiology: Basic concepts and clinical implications. Frontiers in Behavioral Neuroscience, 12, Article 127.

Goebert, D., Thompson, D., Takeshita, J., Beach, C., Bryson, P., Ephgrave, K., Kent, A., Kunkel, M., Schechter, J., & Tate, J. (2009). Depressive symptoms in medical students and residents: A multischool study. Academic Medicine, 84(2), 236–241.

Gordan, R., Gwathmey, J. K., & Xie, L.-H. (2015). Autonomic and endocrine control of cardiovascular function. World Journal of Cardiology, 7(4), 204–214.

Guest, P. C. (2017). Biomarkers and mental illness: It's not all in the mind. Copernicus Books.

Guy-Evans, O. (2021, April 13). Temporal lobe: Definition, functions, and location. Simple Psychology. Retrieved January 22.

Hamerlinck, F. F. V. (1999). Neopterin: A review. Experimental Dermatology, 8(3), 167–176.

Handouzi, W., Maaoui, C., Pruski, A., & Moussaoui, A. (2014). Objective model assessment for short-term anxiety recognition from blood volume pulse signal. Biomedical Signal Processing and Control, 14, 217–227.

Haroon, E., Raison, C. L., & Miller, A. H. (2012). Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior. Neuropsychopharmacology, 37(1), 137–162.

Henry, J. D., & Crawford, J. R. (2005). The short-form version of the Depression Anxiety Stress Scales (DASS-21): Construct validity and normative data in a large non-clinical sample. British Journal of Clinical Psychology, 44(2), 227–239.

Hillebrand, S., Gast, K. B., de Mutsert, R., Swenne, C. A., Jukema, J. W., Middeldorp, S., Rosendaal, F. R., & Dekkers, O. M. (2013). Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: Meta-analysis and dose–response meta-regression. EP Europace, 15(5), 742–749.

Ho, T. C., Pham, H. T., Miller, J. G., Kircanski, K., & Gotlib, I. H. (2020). Sympathetic nervous system dominance during stress recovery mediates associations between stress sensitivity and social anxiety symptoms in female adolescents. Development and Psychopathology, 32(5), 1914–1925.

Hodes, G. E., Kana, V., Menard, C., Merad, M., & Russo, S. J. (2015). Neuroimmune mechanisms of depression. Nature Neuroscience, 18(10), 1386–1393.

Hoehn–Saric, R., & McLeod, D. R. (1988). The peripheral sympathetic nervous system. Its role in normal and pathologic anxiety. Psychiatric Clinics of North America, 11(2), 375–386.

Hoge, E. A., Brandstetter, K., Moshier, S., Pollack, M. H., Wong, K. K., & Simon, N. M. (2009). Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depression and Anxiety, 26(5), 447–455.

Hojat, M., Mangione, S., Nasca, T. J., Rattner, S., Erdmann, J. B., Gonnella, J. S., & Magee, M. (2004). An empirical study of decline in empathy in medical school. Medical Education, 38(9), 934–941.

Holwerda, S. W., Luehrs, R. E., Gremaud, A. L., Wooldridge, N. A., Stroud, A. K., Fiedorowicz, J. G., Abboud, F. M., & Pierce, G. L. (2018). Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety. Journal of Neurophysiology, 120(1), 11–22.

Hourani, L. L., Davila, M. I., Morgan, J., Meleth, S., Ramirez, D., Lewis, G., Kizakevich, P. N., Eckhoff, R., Morgan, T., Strange, L., Lane, M., Weimer, B., & Lewis, A. (2020). Mental health, stress, and resilience correlates of heart rate variability among military reservists, guardsmen, and first responders. Physiology & Behavior, 214, Article 112734.

Huber, C., Batchelor, J. R., Fuchs, D., Hausen, A., Lang, A., Niederwieser, D., Reibnegger, G., Swetly, P., Troppmair, J., & Wachter, H. (1984). Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. Journal of Experimental Medicine, 160(1), 310–316.

Inserra, A., Mastronardi, C. A., Rogers, G., Licinio, J., & Wong, M. L. (2019). Neuroimmunomodulation in major depressive disorder: Focus on caspase 1, inducible nitric oxide synthase, and interferon-gamma. Molecular Neurobiology, 56(6), 4288–4305.

Jamil, H., Alakkari, M., Al-Mahini, M. S., Alsayid, M., & Al Jandali, O. (2022). The impact of anxiety and depression on academic performance: A cross-sectional study among medical students in Syria. Avicenna Journal of Medicine, 12(3), 111–119.

Jiang, L.-C., Yan, Y.-J., Jin, Z.-S., Hu, M.-L., Wang, L., Song, Y., Li, N.-N., Su, J., Wu, D.-X., & Xiao, T. (2020). The Depression Anxiety Stress Scale-21 in Chinese hospital workers: Reliability, latent structure, and measurement invariance across genders. Frontiers in Psychology, 11, Article 247.

Johnson, J. D., Barnard, D. F., Kulp, A. C., & Mehta, D. M. (2019). Neuroendocrine regulation of brain cytokines after psychological stress. Journal of the Endocrine Society, 3(7), 1302–1320.

Kanda, P. A. M., Anghinah, R., Smidth, M. T., & Silva, J. M. (2009). The clinical use of quantitative EEG in cognitive disorders. Dementia & Neuropsychologia, 3(3), 195–203.

Karason, K., Mølgaard, H., Wikstrand, J., & Sjöström, L. (1999). Heart rate variability in obesity and the effect of weight loss. The American Journal of Cardiology, 83(8), 1242–1247.

Kemp, A. H., Quintana, D. S., Felmingham, K. L., Matthews, S., & Jelinek, H. F. (2012). Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk. PLoS ONE, 7(2), Article e30777.

Kemp, A. H., Quintana, D. S., Gray, M. A., Felmingham, K. L., Brown, K., & Gatt, J. M. (2010). Impact of depression and antidepressant treatment on heart rate variability: A review and meta-analysis. Biological Psychiatry, 67(11), 1067–1074.

Kessler, R. C. (1997). The effects of stressful life events on depression. Annual Review of Psychology, 48, 191–214.

Klaus, F., Guetter, K., Schlegel, R., Seifritz, E., Rassi, A., Thöny, B., Cathomas, F., & Kaiser, S. (2021). Peripheral biopterin and neopterin in schizophrenia and depression. Psychiatry Research, 297, Article 113745.

Kreibig, S. (2010). Autonomic nervous system activity in emotion: A review. Biological Psychology, 84(3), 394–421.

Kubota, Y., Chen, L. Y., Whitsel, E. A., & Folsom, A. R. (2017). Heart rate variability and lifetime risk of cardiovascular disease: The atherosclerosis risk in communities study. Annals of Epidemiology, 27(10), 619–625.e2.

Kudat, H., Akkaya, V., Sozen, A. B., Salman, S., Demirel, S., Ozcan, M., Atilgan, D., Yilmaz, M. T., & Guven, O. (2006). Heart rate variability in diabetes patients. Journal of International Medical Research, 34(3), 291–296.

Kushki, A., Fairley, J., Merja, S., King, G., & Chau, T. (2011). Comparison of blood volume pulse and skin conductance responses to mental and affective stimuli at different anatomical sites. Physiological Measurement, 32(10), 1529–1539.

Lanser, L., Kink, P., Egger, E. M., Willenbacher, W., Fuchs, D., Weiss, G., & Kurz, K. (2020). Inflammation-induced tryptophan breakdown is related with anemia, fatigue, and depression in cancer. Frontiers in Immunology, 11, Article 249.

Lovibond, S. H., & Lovibond, P. F. (1995). Manual for the depression anxiety stress scales (2nd Ed.). Psychology Foundation of Australia.

Macaluso, M., & Preskorn, S. H. (2012). How biomarkers will change psychiatry: From clinical trials to practice. Part I: Introduction. Journal of Psychiatric Practice, 18(2), 118–121.

Maes, M., Scharpé, S., Meltzer, H. Y., Okayli, G., Bosmans, E., D'Hondt, P., Vanden Bossche, B. V., & Cosyns, P. (1994). Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: Further evidence for an immune response. Psychiatry Research, 54(2), 143–160.

Maes, M., Song, C., Lin, A., De Jongh, R., Van Gastel, A., Kenis, G., Bosmans, E., De Meester, I., Benoy, I., Neels, H., Demedts, P., Janca, A., Scharpé, S., & Smith, R. S. (1998). The effects of psychological stress on humans: Increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine, 10(4), 313–318.

Maes, M., Van der Planken, M., Stevens, W. J., Peeters, D., DeClerck, L. S., Bridts, C. H., Schotte, C., & Cosyns, P. (1992). Leukocytosis, monocytosis and neutrophilia: Hallmarks of severe depression. Journal of Psychiatric Research, 26(2), 125–134.

Maggi, E., Parronchi, P., Manetti, R., Simonelli, C., Piccinni, M. P., Rugiu, F. S., De Carli, M., Ricci, M., & Romagnani, S. (1992). Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. Journal of Immunology, 148(7), 2142–2147.

Malekshahi, A., Malekshahi, R., Czornik, M., Dax, J., Wolpert, S., Bauer, H., Braun, C., & Birbaumer, N. (2020). Real-time monitoring and regulating auditory cortex alpha activity in patients with chronic tinnitus. Journal of Neural Engineering, 17(1), Article 016032.

Maser, B., Danilewitz, M., Guérin, E., Findlay, L., & Frank, E. (2019). Medical student psychological distress and mental illness relative to the general population: A Canadian cross-sectional survey. Academic Medicine, 94(11), 1781–1791.

Mayberg, H. S. (1997). Limbic-cortical dysregulation: A proposed model of depression. The Journal of Neuropsychiatry and Clinical Neurosciences, 9(3), 471–481.

Maydych, V. (2019). The interplay between stress, inflammation, and emotional attention: Relevance for depression. Frontiers in Neuroscience, 13, Article 384.

McCraty, R., & Shaffer, F. (2015). Heart rate variability: New perspectives on physiological mechanisms, assessment of self-regulatory capacity, and health risk. Global Advances in Integrative Medicine and Health, 4(1), 46–61.

Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65(9), 732–741.

Mitra, R., & Sapolsky, R. M. (2008). Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 105(14), 5573–5578.

Mohammad, M. (2021). Risk factors associated with stress, anxiety, and depression among university undergraduate students. AIMS Public Health, 8(1), 36–65.

Monteiro, S., Ferreira, F. M., Pinto, V., Roque, S., Morais, M., de Sá-Calçada, D., Mota, C., Correia-Neves, M., & Cerqueira, J. J. (2016). Absence of IFNγ promotes hippocampal plasticity and enhances cognitive performance. Translational Psychiatry, 6(1), Article e707.

Müller, N., & Schwarz, M. J. (2007). The immune-mediated alteration of serotonin and glutamate: Towards an integrated view of depression. Molecular Psychiatry, 12(11), 988–1000.

Myint, A. M., Bondy, B., Baghai, T. C., Eser, D., Nothdurfter, C., Schüle, C., Zill, P., Müller, N., Rupprecht, R., & Schwarz, M. J. (2013). Tryptophan metabolism and immunogenetics in major depression: A role for interferon-γ gene. Brain, Behavior, and Immunity, 31, 128–133.

Myint, A. M., & Kim, Y. K. (2003). Cytokine–serotonin interaction through IDO: A neurodegeneration hypothesis of depression. Medical Hypotheses, 61(5–6), 519–525.

Nathan, C. F. (1986). Peroxide and pteridine: A hypothesis on the regulation of macrophage antimicrobial activity by interferon gamma. Interferon, 7, 125–143.

Neurofeedback Alliance. (2021). Understanding brain waves.

Nutt, D. J., & Malizia, A. L. (2001). New insights into the role of the GABAA–benzodiazepine receptor in psychiatric disorder. The British Journal of Psychiatry, 179(5), 390–396.

O'Connor, J. C., Lawson, M. A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K. W., & Dantzer, R. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Molecular Psychiatry, 14(5), 511–522.

Osimo, E. F., Pillinger, T., Rodriguez, I. M., Khandaker, G. M., Pariante, C. M., & Howes, O. D. (2020). Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behavior, and Immunity, 87, 901–909.

Pace, T. W., & Miller, A. H. (2009). Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Annals of the New York Academy of Sciences, 1179(1), 86–105.

Pace, T. W. W., Hu, F., & Miller, A. H. (2007). Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain, Behavior, and Immunity, 21(1), 9–19.

Pacileo, M., Cirillo, P., De Rosa, S., Ucci, G., Petrillo, G., Musto D’Amore, S., Sasso, L., Maietta, P., Spagnuolo, R., & Chiariello, M. (2007). The role of neopterin in cardiovascular disease. Archivio Monaldi per Le Malattie Del Torace [Monaldi Archives for Chest Disease], 68(2), 68–73.

Pêgo, J. M., Sousa, J. C., Almeida, O. F., & Sousa, N. (2010). Stress and the neuroendocrinology of anxiety disorders. In M. B. Stein & T. Steckler (Eds.), Behavioral neurobiology of anxiety and its treatment (pp. 97–118). Springer Science + Business Media.

Peper, E., Harvey, R., Lin, I.-M., Tylova, H., & Moss, D. (2007). Is there more to blood volume pulse than heart rate variability, respiratory sinus arrhythmia, and cardiorespiratory synchrony? Biofeedback, 35, 54–61.

Perlstein, W. M., Elbert, T., & Stenger, V. A. (2002). Dissociation in human prefrontal cortex of affective influences on working memory-related activity. Proceedings of the National Academy of Sciences, 99(3), 1736–1741.

Pinto, P. C. L., Marcelos, C. M., Mezzasalma, M. A., Osterne, F. J. V., de Melo Tavares de Lima, M. A., & Nardi, A. E. (2014). Tinnitus and its association with psychiatric disorders: Systematic review. The Journal of Laryngology & Otology, 128(8), 660–664.

Quagliato, L. A., & Nardi, A. E. (2018). Cytokine alterations in panic disorder: A systematic review. Journal of Affective Disorders, 228, 91–96.

Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends in Immunology, 27(1), 24–31.

Raison, C. L., & Miller, A. H. (2003). When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. The American Journal of Psychiatry, 160(9), 1554–1565.

Rajkumar, R. P. (2022). The correlates of government expenditure on mental health services: An analysis of data from 78 countries and regions. Cureus, 14(8), Article e28284.

Reader, B. F., Jarrett, B. L., McKim, D. B., Wohleb, E. S., Godbout, J. P., & Sheridan, J. F. (2015). Peripheral and central effects of repeated social defeat stress: Monocyte trafficking, microglial activation, and anxiety. Neuroscience, 289, 429–442.

Risbrough, V. B., & Stein, M. B. (2006). Role of corticotropin releasing factor in anxiety disorders: A translational research perspective. Hormones and Behavior, 50(4), 550–561.

Roffman, J. L. (2011). Biomarkers and personalized psychiatry. Harvard Review of Psychiatry, 19(3), 99–101.

Rojas, G. M., Alvarez, C., Montoya, C. E., de la Iglesia-Vayá, M., Cisternas, J. E., & Gálvez, M. (2018). Study of resting-state functional connectivity networks using EEG electrodes position as seed. Frontiers in Neuroscience, 12, Article 235.

Rössler, W. (2016). The stigma of mental disorders: A millennia-long history of social exclusion and prejudices. EMBO Rep, 17(9), 1250–1253.

Roth, G. A., Abate, D., Abate, K. H., Abay, S. M., Abbafati, C., Abbasi, N., Abbastabar, H., Abd-Allah, F., Abdela, J., Abdelalim, A., Abdollahpour, I., Abdulkader, R. S., Abebe, H. T., Abebe, M., Abebe, Z., Abejie, A. N., Abera, S. F., Abil, O. Z., Abraha, H. N., ... Murray, C. J. L. (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 392(10159), 1736–1788.

Salim, S. (2014). Oxidative stress and psychological disorders. Current Neuropharmacology, 12(2), 140–147.

Šalkevicius, J., Damaševičius, R., Maskeliunas, R., & Laukiene, I. (2019). Anxiety level recognition for virtual reality therapy system using physiological signals. Electronics, 8(9), Article 1039.

Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000). How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews, 21(1), 55–89.

Sarchiapone, M., Gramaglia, C., Iosue, M., Carli, V., Mandelli, L., Serretti, A., Marangon, D., & Zeppegno, P. (2018). The association between electrodermal activity (EDA), depression and suicidal behaviour: A systematic review and narrative synthesis. BMC Psychiatry, 18(1), Article 22.

Satyjeet, F., Naz, S., Kumar, V., Aung, N. H., Bansari, K., Irfan, S., & Rizwan, A. (2020). Psychological stress as a risk factor for cardiovascular disease: A case-control study. Cureus, 12(10), Article e10757.

Saxena, S., Sharan, P., & Saraceno, B. (2003). Budget and financing of mental health services: Baseline information on 89 countries from WH’'s project atlas. Journal of Mental Health Policy and Economics, 6(3), 135–143.

Schiweck, C., Piette, D., Berckmans, D., Claes, S., & Vrieze, E. (2019). Heart rate and high frequency heart rate variability during stress as biomarker for clinical depression. A systematic review. Psychological Medicine, 49(2), 200–211.

Schlee, W., Schecklmann, M., Lehner, A., Kreuzer, P. M., Vielsmeier, V., Poeppl, T. B., & Langguth, B. (2014). Reduced variability of auditory alpha activity in chronic tinnitus. Neural Plasticity, 2014, Article 436146.

Shaffer, F., & Ginsberg, J. P. (2017). An overview of heart rate variability metrics and norms. Frontiers in Public Health, 5, Article 258.

Shin, L. M., & Liberzon, I. (2010). The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology, 35(1), 169–191.

Shinba, T. (2017). Major depressive disorder and generalized anxiety disorder show different autonomic dysregulations revealed by heart-rate variability analysis in first-onset drug-naïve patients without comorbidity. Psychiatry and Clinical Neurosciences, 71(2), 135–145.

Silverman, M. N., Pearce, B. D., Biron, C. A., & Miller, A. H. (2005). Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunology, 18(1), 41–78.

Singla, S., Jhamb, S., Singh, K. D., & Kumar, A. (2020). Depression affects autonomic system of the body? Yes, it does! Journal of Education and Health Promotion, 9, Article 217.

Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience, 8(4), 383–395.

Sroykham, W., & Wongsawat, Y. (2019). Effects of brain activity, morning salivary cortisol, and emotion regulation on cognitive impairment in elderly people. Medicine, 98(26), Article e16114.

Steimer, T. (2002). The biology of fear- and anxiety-related behaviors. Dialogues in Clinical Neuroscience, 4(3), 231–249.

Strauß, A., Wöstmann, M., & Obleser, J. (2014). Cortical alpha oscillations as a tool for auditory selective inhibition. Frontiers in Human Neuroscience, 8, Article 350.

Tanaka, M., Yoshida, M., Emoto, H., & Ishii, H. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: Basic studies. European Journal of Pharmacology, 405(1–3), 397–406.

Teed, A. R., Feinstein, J. S., Puhl, M., Lapidus, R. C., Upshaw, V., Kuplicki, R. T., Bodurka, J., Ajijola, O. A., Kaye, W. H., Thompson, W. K., Paulus, M. P., & Khalsa, S. S. (2022). Association of generalized anxiety disorder with autonomic hypersensitivity and blunted ventromedial prefrontal cortex activity during peripheral adrenergic stimulation: A randomized clinical trial. JAMA Psychiatry, 79(4), 323–332.

Teplan, M. (2002). Fundamental of EEG measurement. Measurement Science Review, 2(2), 1–11.

Thomas, M. R., Dyrbye, L. N., Huntington, J. L., Lawson, K. L., Novotny, P. J., Sloan, J. A., & Shanafelt, T. D. (2007). How do distress and well-being relate to medical student empathy? A multicenter study. Journal of General Internal Medicine, 22(2), 177–183.

Tomlinson, M., Grimsrud, A. T., Stein, D. J., Williams, D. R., & Myer, L. (2009). The epidemiology of major depression in South Africa: Results from the South African stress and health study. South African Medical Journal, 99(5 Pt. 2), 367–373.

Tonsing, K. N. (2014). Psychometric properties and validation of Nepali version of the Depression Anxiety Stress Scales (DASS-21). Asian Journal of Psychiatry, 8, 63–66.

Torpy, J. M., Lynm, C., & Glass, R. M. (2007). Chronic stress and the heart. JAMA, 298(14), Article 1722.

Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G., & Mechawar, N. (2014). Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain, Behavior, and Immunity, 42, 50–59.

Tran, T. D., Tran, T., & Fisher, J. (2013). Validation of the depression anxiety stress scales (DASS) 21 as a screening instrument for depression and anxiety in a rural community-based cohort of northern Vietnamese women. BMC Psychiatry, 13(1), Article 24.

Trivedi, J. K. (2006). Cognitive deficits in psychiatric disorders: Current status. Indian Journal of Psychiatry, 48(1), 10–20.

Valkanova, V., Ebmeier, K. P., & Allan, C. L. (2013). CRP, IL-6 and depression: A systematic review and meta-analysis of longitudinal studies. Journal of Affective Disorders, 150(3), 736–744.

Vitasari, P., Wahab, M. N. A., Othman, A., Herawan, T., & Sinnadurai, S. K. (2010). the relationship between study anxiety and academic performance among engineering students. Procedia - Social and Behavioral Sciences, 8, 490–497.

Vogelzangs, N., Beekman, A. T., de Jonge, P., & Penninx, B. W. (2013). Anxiety disorders and inflammation in a large adult cohort. Translational Psychiatry, 3(4), Article e249.

Vogelzangs, N., Seldenrijk, A., Beekman, A. T. F., van Hout, H. P. J., de Jonge, P., & Penninx, B. W. J. H. (2010). Cardiovascular disease in persons with depressive and anxiety disorders. Journal of Affective Disorders, 125(1–3), 241–248.

Von Känel, R., Hepp, U., Kraemer, B., Traber, R., Keel, M., Mica, L., & Schnyder, U. (2007). Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. Journal of Psychiatric Research, 41(9), 744–752.

Wagner, F., Wagner, R. G., Kolanisi, U., Makuapane, L. P., Masango, M., & Gómez-Olivé, F. X. (2022). The relationship between depression symptoms and academic performance among first-year undergraduate students at a South African university: A cross-sectional study. BMC Public Health, 22(1), Article 2067.

Wakefield, J. C. (2010). Misdiagnosing normality: Psychiatry's failure to address the problem of false positive diagnoses of mental disorder in a changing professional environment. Journal of Mental Health, 19(4), 337–351.

Warner, S. (2013). Cheat sheet for neurofeedback. Stress Therapy Solutions. Retrieved January 23.

Watanabe, M. (2017). [Brodmann Areas 8 and 9 Including the Frontal Eye Field]. Brain and Nerve, 69(4), 347–354.

Weinstock, M. (2001). Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Progress in Neurobiology, 65(5), 427–451.

Weiss, C., Murr, C., Zoller, H., Haun, M., Widner,B., Ludescher, C., & Fuchs, D. (1999). Modulation of neopterin formation and tryptophan degradation by Th1- and Th2-derived cytokines in human monocytic cells. Clinical & Experimental Immunology, 116(3), 435–440.

Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., Charlson, F. J., Norman, R. E., Flaxman, A. D., Johns, N., Burstein, R., Murray, C. J. L., & Vos, T. (2013). Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010. Lancet, 382(9904), 1575–1586.

Widner, B., Laich, A., Sperner-Unterweger, B., Ledochowski, M., & Fuchs, D. (2002). Neopterin production, tryptophan degradation, and mental depression—What is the link? Brain Behavior and Immunity, 16(5), 590–595.

Wilmer, M. T., Anderson, K., & Reynolds, M. (2021). Correlates of quality of life in anxiety disorders: Review of recent research. Current Psychiatry Reports, 23(11), Article 77.

Wohleb, E. S., Powell, N. D., Godbout, J. P., & Sheridan, J. F. (2013). Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. Journal of Neuroscience, 33(34), 13820–13833.

Yang, X., Fang, Y., Chen, H., Zhang, T., Yin, X., Man, J., Yang, L., & Lu, M. (2021). Global, regional and national burden of anxiety disorders from 1990 to 2019: Results from the Global Burden of Disease Study 2019. Epidemiology and Psychiatric Sciences, 30, Article e36.

Zöger, S., Svedlund, J., & Holgers, K.-M. (2006). Relationship between tinnitus severity and psychiatric disorders. Psychosomatics, 47(4), 282–288.






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