Exploration of Neuroprotective Therapy

Table 1. Locus coeruleus-norepinephrine (LC-NE) system illustrating both tonic and phasic modes of activity.

Feature	Tonic mode	Phasic mode	References
Pattern	A slow, sustained, regular discharge of single spikes	A brief, high-frequency discharge with a rapid & high spiking activity	[47]
Frequency	0.1–5.0 Hz	10–20 Hz	[48]
Trigger	General behavioral state and arousal	Elicited by novel or salient polymodal sensory stimuli	[49, 50]
Function	Maintenance & Regulation of the general state of arousal, vigilance, and alertness	Facilitates the significance & relevance of an event and orients precise responses to allocate and prioritize resources to relevant information	[48]
Effect	Establishes the background level of norepinephrine release	Creates high frequency and sharp spikes in NE release	[51]

Return to article view

Declarations

Author contributions

TU: Conceptualization, Supervision. OHB: Methodology, Formal analysis. MMM: Supervision, Writing—original draft. SS: Investigation, Writing—original draft. FS: Resources, Writing—review & editing. ST: Project administration, Validation. SA: Writing—review & editing. RS: Formal analysis, Resources, Supervision. RSN: Supervision, Data curation. KYG: Supervision, Writing—original draft. MTH: Project administration. ATA: Supervision. TTI: Writing—review & editing. JF: Writing—original draft. FHA: Investigation, Methodology. All authors read and approved the submitted version.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research received no specific grant from any funding agency.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Goddard AW, Ball SG, Martinez J, Robinson MJ, Yang CR, Russell JM, et al. Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety. 2010;27:339–50. [DOI] [PubMed]

Ordway GA, Schwartz MA, Frazer A, editors. Brain norepinephrine: neurobiology and therapeutics. Cambridge: Cambridge University Press; 2007. [DOI]

Sanchez-Roige S, Gray JC, MacKillop J, Chen CH, Palmer AA. The genetics of human personality. Genes Brain Behav. 2018;17:e12439. [DOI] [PubMed] [PMC]

He Y, Song N, Xiao J, Cui L, McWhinnie CM. Levels of neuroticism differentially predict individual scores in the depression and anxiety dimensions of the tripartite model: A multiwave longitudinal study. Stress Health. 2018;34:435–9. [DOI] [PubMed]

Waldeck D, Pancani L, Holliman AJ, Karekla M, Tyndall I. Adaptability and Psychological Flexibility: Overlapping constructs? J Contextual Behav Sci. 2021;19:72–8. [DOI]

Neilson B, Devlin S, Drollinger S, Brown N, Sibley C, Foroughi C, et al. Pupil Dilation Variability as an Indicator of Arousal Regulation: Towards Understanding Operator Functional State. Ind Cognit Ergon Eng Psychol. 2022;35:30–7. [DOI]

Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament and character. Arch Gen Psychiatry. 1993;50:975–90. [DOI] [PubMed]

Gray JA. The Neuropsychology of Temperament. In: Strelau J, Angleitner A, editors. Explorations in Temperament: International Perspectives on Theory and Measurement. Boston: Springer; 1991. pp. 105–28. [DOI]

Safron A, DeYoung CG. Integrating Cybernetic Big Five Theory with the free energy principle: A new strategy for modeling personalities as complex systems. In: Wood D, Read SJ, Harms PD, Slaughter A, editors. Measuring and Modeling Persons and Situations. New York: Academic Press; 2021. pp. 617–49. [DOI]

10.

Depue RA, Collins PF. Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion. Behav Brain Sci. 1999;22:491–569. [DOI] [PubMed]

11.

Schwarz LA, Luo L. Organization of the locus coeruleus-norepinephrine system. Curr Biol. 2015;25:R1051–6. [DOI] [PubMed]

12.

Breton-Provencher V, Drummond GT, Sur M. Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets. Front Neural Circuits. 2021;15:638007. [DOI] [PubMed] [PMC]

13.

Dong J, Xiao T, Xu Q, Liang F, Gu S, Wang F, et al. Anxious Personality Traits: Perspectives from Basic Emotions and Neurotransmitters. Brain Sci. 2022;12:1141. [DOI] [PubMed] [PMC]

14.

Gu S, Wang W, Wang F, Huang JH. Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders. Neural Plast. 2016;2016:2609128. [DOI] [PubMed] [PMC]

15.

Robbins TW. Opinion on monoaminergic contributions to traits and temperament. Philos Trans R Soc Lond B Biol Sci. 2018;373:20170153. [DOI] [PubMed] [PMC]

16.

McCall JG, Siuda ER, Bhatti DL, Lawson LA, McElligott ZA, Stuber GD, et al. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior. Elife. 2017;6:e18247. [DOI] [PubMed] [PMC]

17.

Ormel J, Bastiaansen A, Riese H, Bos EH, Servaas M, Ellenbogen M, et al. The biological and psychological basis of neuroticism: current status and future directions. Neurosci Biobehav Rev. 2013;37:59–72. [DOI] [PubMed]

18.

Bouras NN, Mack NR, Gao WJ. Prefrontal modulation of anxiety through a lens of noradrenergic signaling. Front Syst Neurosci. 2023;17:1173326. [DOI] [PubMed] [PMC]

19.

Trofimova IN, Gaykalova AA. Emotionality vs. Other Biobehavioural Traits: A Look at Neurochemical Biomarkers for Their Differentiation. Front Psychol. 2021;12:781631. [DOI] [PubMed] [PMC]

20.

Kuo HI, Qi FX, Paulus W, Kuo MF, Nitsche MA. Noradrenergic Enhancement of Motor Learning, Attention, and Working Memory in Humans. Int J Neuropsychopharmacol. 2021;24:490–8. [DOI] [PubMed] [PMC]

21.

Lecas JC. Locus coeruleus activation shortens synaptic drive while decreasing spike latency and jitter in sensorimotor cortex. Implications for neuronal integration. Eur J Neurosci. 2004;19:2519–30. [DOI] [PubMed]

22.

Sullivan GM, Coplan JD, Kent JM, Gorman JM. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias. Biol Psychiatry. 1999;46:1205–18. [DOI] [PubMed]

23.

Dahl MJ, Mather M, Werkle-Bergner M. Noradrenergic modulation of rhythmic neural activity shapes selective attention. Trends Cogn Sci. 2022;26:38–52. [DOI] [PubMed] [PMC]

24.

Zhang Z, Cordeiro Matos S, Jego S, Adamantidis A, Séguéla P. Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors. PLoS One. 2013;8:e66122. [DOI] [PubMed] [PMC]

25.

Delvecchio G, Bellani M, Altamura AC, Brambilla P. The association between the serotonin and dopamine neurotransmitters and personality traits. Epidemiol Psychiatr Sci. 2016;25:109–12. [DOI] [PubMed] [PMC]

26.

Morris LS, McCall JG, Charney DS, Murrough JW. The role of the locus coeruleus in the generation of pathological anxiety. Brain Neurosci Adv. 2020;4:2398212820930321. [DOI] [PubMed] [PMC]

27.

Hajós M, Fleishaker JC, Filipiak-Reisner JK, Brown MT, Wong EHF. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. CNS Drug Rev. 2004;10:23–44. [DOI] [PubMed] [PMC]

28.

Weinshilboum RM, Thoa NB, Johnson DG, Kopin IJ, Axelrod J. Proportional release of norepinephrine and dopamine—hydroxylase from sympathetic nerves. Science. 1971;174:1349–51. [DOI] [PubMed]

29.

Azizi SA. Monoamines: Dopamine, Norepinephrine, and Serotonin, Beyond Modulation, “Switches” That Alter the State of Target Networks. Neuroscientist. 2022;28:121–43. [DOI] [PubMed]

30.

Gonzalez-Lopez E, Vrana KE. Dopamine beta-hydroxylase and its genetic variants in human health and disease. J Neurochem. 2020;152:157–81. [DOI] [PubMed]

31.

Nikolenko VN, Borminskaya ID, Nikitina AT, Golyshkina MS, Rizaeva NA, Oganesyan MV. Locus Coeruleus-Norepinephrine System: Spheres of Influence and Contribution to the Development of Neurodegenerative Diseases. Front Biosci (Landmark Ed). 2024;29:118. [DOI] [PubMed]

32.

Alnæs D, Sneve MH, Espeseth T, Endestad T, van de Pavert SH, Laeng B. Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus. J Vis. 2014;14:1. [DOI] [PubMed]

33.

Wagner-Altendorf TA, Fischer B, Roeper J. Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons. Eur J Neurosci. 2019;50:3772–85. [DOI] [PubMed]

34.

Molinoff PB. Alpha- and beta-adrenergic receptor subtypes properties, distribution and regulation. Drugs. 1984;28:1–15. [DOI] [PubMed]

35.

Thiele RH, Nemergut EC, Lynch CIII. The Clinical Implications of Isolated Alpha₁ Adrenergic Stimulation. Anesth. Analg. 2011;113:297–304. [DOI]

36.

Tsai SJ, Wang YC, Hong CJ. Norepinephrine transporter and alpha(2c) adrenoceptor allelic variants and personality factors. Am J Med Genet. 2002;114:649–51. [DOI] [PubMed]

37.

Smith A, Brice C, Nash J, Rich N, Nutt DJ. Caffeine and central noradrenaline: effects on mood, cognitive performance, eye movements and cardiovascular function. J Psychopharmacol. 2003;17:283–92. [DOI] [PubMed]

38.

Cahill L, van Stegeren A. Sex-related impairment of memory for emotional events with beta-adrenergic blockade. Neurobiol Learn Mem. 2003;79:81–8. [DOI] [PubMed]

39.

Handel EM, Jensen KA, Talbot JN, Rorabaugh BR. Alpha 1A-Adrenergic Receptor Signaling Promotes Antidepressant-Like Behavior and Increased Anxiety in the Mouse. FASEB J. 2008;22:904.11. [DOI]

40.

Pinggal E, Dockree PM, O’Connell RG, Bellgrove MA, Andrillon T. Pharmacological Manipulations of Physiological Arousal and Sleep-Like Slow Waves Modulate Sustained Attention. J Neurosci. 2022;42:8113–24. [DOI] [PubMed] [PMC]

41.

Lewis M. Issues in the Study of Personality Development. Psychol Inq. 2001;12:67–83. [DOI]

42.

Posner MI. Measuring alertness. Ann N Y Acad Sci. 2008;1129:193–9. [DOI] [PubMed]

43.

Sadaghiani S, D’Esposito M. Functional Characterization of the Cingulo-Opercular Network in the Maintenance of Tonic Alertness. Cereb Cortex. 2015;25:2763–73. [DOI] [PubMed] [PMC]

44.

Unsworth N, Robison MK. A locus coeruleus-norepinephrine account of individual differences in working memory capacity and attention control. Psychon Bull Rev. 2017;24:1282–311. [DOI] [PubMed]

45.

Grueschow M, Kleim B, Ruff CC. Functional Coupling of the Locus Coeruleus Is Linked to Successful Cognitive Control. Brain Sci. 2022;12:305. [DOI] [PubMed] [PMC]

46.

Biesanz JC, West SG, Kwok OM. Personality over time: Methodological approaches to the study of short-term and long-term development and change. J Pers. 2003;71:905–41. [DOI] [PubMed]

47.

Waterhouse BD, Moises HC, Woodward DJ. Phasic activation of the locus coeruleus enhances responses of primary sensory cortical neurons to peripheral receptive field stimulation. Brain Res. 1998;790:33–44. [DOI] [PubMed]

48.

Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403–50. [DOI] [PubMed]

49.

Devilbiss DM, Waterhouse BD. Phasic and tonic patterns of locus coeruleus output differentially modulate sensory network function in the awake rat. J Neurophysiol. 2011;105:69–87. [DOI] [PubMed] [PMC]

50.

O’Donnell J, Ding F, Nedergaard M. Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator? Curr Sleep Med Rep. 2015;1:1–8. [DOI] [PubMed] [PMC]

51.

Florin-Lechner SM, Druhan JP, Aston-Jones G, Valentino RJ. Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus. Brain Res. 1996;742:89–97. [DOI]

52.

Dobrek Ł, Thor P. Current concepts in clinical and laboratory assessments of autonomic nervous system activity. J Pre-Clinical Clin Res. 2015;9:63–8. [DOI]

53.

Viglione A, Mazziotti R, Pizzorusso T. From pupil to the brain: New insights for studying cortical plasticity through pupillometry. Front Neural Circuits. 2023;17:1151847. [DOI] [PubMed] [PMC]

54.

Zhou XA, Jiang Y, Napadow V, Yu X. Challenges and Perspectives of Mapping Locus Coeruleus Activity in the Rodent with High-Resolution fMRI. Brain Sci. 2022;12:1085. [DOI] [PubMed] [PMC]

55.

Ke JQ, Shao SM, Zheng YY, Fu FW, Zheng GQ, Liu CF. Sympathetic skin response and heart rate variability in predicting autonomic disorders in patients with Parkinson disease. Medicine (Baltimore). 2017;96:e6523. [DOI] [PubMed] [PMC]

56.

Huang WL, Ko LC, Liao SC. The association between heart rate variability and skin conductance: a correlation analysis in healthy individuals and patients with somatic symptom disorder comorbid with depression and anxiety. J Int Med Res. 2022;50:3000605221127104. [DOI] [PubMed] [PMC]

57.

Reimer J, McGinley MJ, Liu Y, Rodenkirch C, Wang Q, McCormick DA, et al. Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex. Nat Commun. 2016;7:13289. [DOI] [PubMed] [PMC]

58.

Mäki-Marttunen V, Espeseth T. Uncovering the locus coeruleus: Comparison of localization methods for functional analysis. Neuroimage. 2021;224:117409. [DOI] [PubMed]

59.

Thomas BL, Claassen N, Becker P, Viljoen M. Validity of Commonly Used Heart Rate Variability Markers of Autonomic Nervous System Function. Neuropsychobiology. 2019;78:14–26. [DOI] [PubMed]

60.

Su CW, Yang F, Lai R, Li Y, Naeem H, Yao N, et al. Unraveling the functional complexity of the locus coeruleus-norepinephrine system: insights from molecular anatomy to neurodynamic modeling. Cogn Neurodyn. 2025;19:29. [DOI] [PubMed]

61.

Philipp M, Brede M, Hein L. Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough. Am J Physiol Integr Comp Physiol. 2002;283:R287–95. [DOI]

62.

Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 1988;8:4287–98. [DOI] [PubMed] [PMC]

63.

Durán E, Novitskaya Y, Eschenko O. Receptor-specific noradrenergic modulation of oscillatory dynamics during non-rapid eye movement sleep in adult male rats. Neuropharmacology. 2026;282:110721. [DOI] [PubMed]

64.

Savitz DA, Wellenius GA. Can Cross-Sectional Studies Contribute to Causal Inference? It Depends. Am J Epidemiol. 2023;192:514–6. [DOI] [PubMed]

65.

Mortazavi N, Talwar P, Koshmanova E, Sharifpour R, Beckers E, Berger A, et al. REM sleep quality is associated with balanced tonic activity of the locus coeruleus during wakefulness. J Biomed Sci. 2025;32:35. [DOI] [PubMed] [PMC]

66.

Joshi S, Gold JI. Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex. Elife. 2022;11:e63490. [DOI] [PubMed] [PMC]

67.

Buenk C. Exploring the utility of pupillometry as a biomarker for relationships between early life stress, emotion regulation, and cognition [Dissertation]. Rondebosch: University of Cape Town; 2024.

68.

Oken BS, Salinsky MC, Elsas SM. Vigilance, alertness, or sustained attention: physiological basis and measurement. Clin Neurophysiol. 2006;117:1885–901. [DOI] [PubMed] [PMC]

69.

Mather M, Clewett D, Sakaki M, Harley CW. Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behav Brain Sci. 2016;39:e200. [DOI] [PubMed] [PMC]

70.

Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10:211–23. [DOI] [PubMed]

71.

Reyes BAS. The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders. Eur J Neurosci. 2025;61:e70111. [DOI] [PubMed] [PMC]

72.

Richardson L, Adams S. Cognitive Deficits in Patients With Depression. J Nurse Pract. 2018;14:437–43. [DOI]

73.

Hezemans FH, Wolpe N, O’Callaghan C, Ye R, Rua C, Jones PS, et al. Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes. PLoS Comput Biol. 2022;18:e1010079. [DOI] [PubMed] [PMC]

74.

Yamamoto T. The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type. Neurochem Res. 2022;47:2890–8. [DOI] [PubMed] [PMC]

75.

Fazlali Z, Ranjbar-Slamloo Y, Adibi M, Arabzadeh E. Correlation between Cortical State and Locus Coeruleus Activity: Implications for Sensory Coding in Rat Barrel Cortex. Front Neural Circuits. 2016;10:14. [DOI] [PubMed] [PMC]

76.

Ressler KJ, Nemeroff CB. Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol Psychiatry. 1999;46:1219–33. [DOI] [PubMed]

77.

Wang LY, Murphy RR, Hanscom B, Li G, Millard SP, Petrie EC, et al. Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span. Neurobiol Aging. 2013;34:2287–92. [DOI] [PubMed] [PMC]

78.

Chamberlain SR, Robbins TW. Noradrenergic modulation of cognition: therapeutic implications. J Psychopharmacol. 2013;27:694–718. [DOI] [PubMed]

79.

Gabay S, Pertzov Y, Henik A. Orienting of attention, pupil size, and the norepinephrine system. Atten Percept Psychophys. 2011;73:123–9. [DOI] [PubMed]

80.

Dahl MJ, Mather M, Sander MC, Werkle-Bergner M. Noradrenergic Responsiveness Supports Selective Attention across the Adult Lifespan. J Neurosci. 2020;40:4372–90. [DOI] [PubMed] [PMC]

81.

Qi M, Gao H. Acute psychological stress promotes general alertness and attentional control processes: An ERP study. Psychophysiology. 2020;57:e13521. [DOI] [PubMed]

82.

Enge S, Fleischhauer M, Lesch KP, Reif A, Strobel A. Variation in key genes of serotonin and norepinephrine function predicts gamma-band activity during goal-directed attention. Cereb Cortex. 2014;24:1195–205. [DOI] [PubMed]

83.

Southwick SM, Bremner JD, Rasmusson A, Morgan CA 3rd, Arnsten A, Charney DS. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;46:1192–204. [DOI] [PubMed]

84.

Hermans EJ, van Marle HJF, Ossewaarde L, Henckens MJAG, Qin S, van Kesteren MTR, et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science. 2011;334:1151–3. [DOI] [PubMed]

85.

Bayer H, Binette AN, Sweck SO, Juliano VAL, Plas SL, Ferst, LM, et al. Locus Coeruleus-Amygdala Circuit Disrupts Prefrontal Control to Impair Fear Extinction. Proc Natl Acad Sci U.S.A. 2026;123:e2528250123. [DOI]

86.

Hamati R. Insights into the Neurobiology of Anxiety and a Potential Target for Pharmacotherapy. J Neurosci. 2018;38:8919–21. [DOI] [PubMed] [PMC]

87.

Hood SD, Melichar JK, Taylor LG, Kalk N, Edwards TR, Hince DA, et al. Noradrenergic function in generalized anxiety disorder: impact of treatment with venlafaxine on the physiological and psychological responses to clonidine challenge. J Psychopharmacol. 2011;25:78–86. [DOI] [PubMed]

88.

See RE, Waters RP. Pharmacologically-induced stress: a cross-species probe for translational research in drug addiction and relapse. Am J Transl Res. 2010;3:81–9. [PubMed] [PMC]

89.

Datta D, Yang ST, Galvin VC, Solder J, Luo F, Morozov YM, et al. Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex. J Neurosci. 2019;39:2722–34. [DOI] [PubMed] [PMC]

90.

Baumann C, Schiele MA, Herrmann MJ, Lonsdorf TB, Zwanzger P, Domschke K, et al. Effects of an Anxiety-Specific Psychometric Factor on Fear Conditioning and Fear Generalization. Z Psychol. 2017;225:200–13. [DOI]

91.

Qin S, Hermans EJ, VAN Marle HJF, Luo J, Fernández G. Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex. Biol Psychiatry. 2009;66:25–32. [DOI] [PubMed]

92.

Itoi K, Sugimoto N. The brainstem noradrenergic systems in stress, anxiety and depression. J Neuroendocrinol. 2010;22:355–61. [DOI] [PubMed]

93.

Coplan JD, Liebowitz MR, Gorman JM, Fyer AJ, Dillon DJ, Campeas RB, et al. Noradrenergic function in panic disorder. Effects of intravenous clonidine pretreatment on lactate induced panic. Biol Psychiatry. 1992;31:135–46. [DOI] [PubMed]

94.

Onur OA, Walter H, Schlaepfer TE, Rehme AK, Schmidt C, Keysers C, et al. Noradrenergic enhancement of amygdala responses to fear. Soc Cogn Affect Neurosci. 2009;4:119–26. [DOI] [PubMed] [PMC]

95.

Slater C, Liu Y, Weiss E, Yu K, Wang Q. The Neuromodulatory Role of the Noradrenergic and Cholinergic Systems and Their Interplay in Cognitive Functions: A Focused Review. Brain Sci. 2022;12:890. [DOI] [PubMed] [PMC]

96.

Frøkjaer JB, Bergmann S, Brock C, Madzak A, Farmer AD, Ellrich J, et al. Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. Neurogastroenterol Motil. 2016;28:592–8. [DOI] [PubMed]

97.

Steinfurth ECK, Wendt J, Geisler F, Hamm AO, Thayer JF, Koenig J. Resting State Vagally-Mediated Heart Rate Variability Is Associated With Neural Activity During Explicit Emotion Regulation. Front Neurosci. 2018;12:794. [DOI] [PubMed] [PMC]

98.

Magnon V, Dutheil F, Vallet GT. Benefits from one session of deep and slow breathing on vagal tone and anxiety in young and older adults. Sci Rep. 2021;11:19267. [DOI] [PubMed] [PMC]

99.

Wareing L, Readman MR, Longo MR, Linkenauger SA, Crawford TJ. The Utility of Heartrate and Heartrate Variability Biofeedback for the Improvement of Interoception across Behavioural, Physiological and Neural Outcome Measures: A Systematic Review. Brain Sci. 2024;14:579. [DOI] [PubMed] [PMC]

100.

Tisdell EJ, Lukic B, Banerjee R, Liao D, Palmer C. The Effects of Heart Rhythm Meditation on Vagal Tone and Well-being: A Mixed Methods Research Study. Appl Psychophysiol Biofeedback. 2024;49:439–55. [DOI] [PubMed] [PMC]

101.

Kurhaluk N, Kołodziejska R, Kamiński P, Tkaczenko H. Integrative Neuroimmune Role of the Parasympathetic Nervous System, Vagus Nerve and Gut Microbiota in Stress Modulation: A Narrative Review. Int J Mol Sci. 2025;26:11706. [DOI] [PubMed] [PMC]

102.

Steenen SA, van Wijk AJ, van der Heijden GJMG, van Westrhenen R, de Lange J, de Jongh A. Propranolol for the treatment of anxiety disorders: Systematic review and meta-analysis. J Psychopharmacol. 2016;30:128–39. [DOI] [PubMed] [PMC]

103.

PROPRANOLOL HYDROCHLORIDE ER-propranolol hydrochloride capsule, extended release [Internet]. Semantic Scholar; [cited 2017 December 30]. Available from: https://api.semanticscholar.org/CorpusID:201666389

104.

Yu AJ, Dayan P. Uncertainty, neuromodulation, and attention. Neuron. 2005;46:681–92. [DOI] [PubMed]

105.

Gelbard-Sagiv H, Magidov E, Sharon H, Hendler T, Nir Y. Noradrenaline Modulates Visual Perception and Late Visually Evoked Activity. Curr Biol. 2018;28:2239–49. [DOI] [PubMed]

106.

Grupe DW, Nitschke JB. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci. 2013;14:488–501. [DOI] [PubMed] [PMC]

107.

Arnsten AFT, Raskind MA, Taylor FB, Connor DF. The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder. Neurobiol Stress. 2015;1:89–99. [DOI] [PubMed] [PMC]

108.

Ross JA, Van Bockstaele EJ. The Locus Coeruleus-Norepinephrine System in Stress and Arousal: Unraveling Historical, Current, and Future Perspectives. Front Psychiatry. 2021;11:601519. [DOI] [PubMed] [PMC]

109.

Baldi E, Bucherelli C. The inverted “u-shaped” dose-effect relationships in learning and memory: modulation of arousal and consolidation. Nonlinearity Biol Toxicol Med. 2005;3:9–21. [DOI] [PubMed] [PMC]

110.

Ford JD, Connor DF. ADHD and posttraumatic stress disorder. Curr Atten Disord Rep. 2009;1:60–6. [DOI]

111.

Southwick SM, Krystal JH, Morgan CA, Johnson D, Nagy LM, Nicolaou A, et al. Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50:266–74. [DOI] [PubMed]

112.

Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005;493:99–110. [DOI] [PubMed]

113.

Feraco T, Casali N, Ganzit E, Meneghetti C. Adaptability and emotional, behavioural and cognitive aspects of self-regulated learning: Direct and indirect relations with academic achievement and life satisfaction. Br J Educ Psychol. 2023;93:353–67. [DOI] [PubMed]

114.

Golland Y, Ben-David BM, Mather M, Keisari S. Playful brains: a possible neurobiological pathway to cognitive health in aging. Front Hum Neurosci. 2025;19:1490864. [DOI] [PubMed] [PMC]

115.

Grueschow M, Stenz N, Thörn H, Ehlert U, Breckwoldt J, Brodmann Maeder M, et al. Real-world stress resilience is associated with the responsivity of the locus coeruleus. Nat Commun. 2021;12:2275. [DOI] [PubMed] [PMC]

116.

Homberg JR, Kozicz T, Fernández G. Large-scale network balances in the transition from adaptive to maladaptive stress responses. Curr Opin Behav Sci. 2017;14:27–32. [DOI]

117.

Ressler KJ, Nemeroff CB. Role of norepinephrine in the pathophysiology of neuropsychiatric disorders. CNS Spectr. 2001;6:663–6. [DOI] [PubMed]

118.

Rothé M, Quilodran R, Sallet J, Procyk E. Coordination of high gamma activity in anterior cingulate and lateral prefrontal cortical areas during adaptation. J Neurosci. 2011;31:11110–7. [DOI] [PubMed] [PMC]

119.

Marzola P, Melzer T, Pavesi E, Gil-Mohapel J, Brocardo PS. Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration. Brain Sci. 2023;13:1610. [DOI] [PubMed] [PMC]

120.

Braun U, Schäfer A, Walter H, Erk S, Romanczuk-Seiferth N, Haddad L, et al. Dynamic reconfiguration of frontal brain networks during executive cognition in humans. Proc Natl Acad Sci U S A. 2015;112:11678–83. [DOI] [PubMed] [PMC]

121.

Beaty RE, Chen Q, Christensen AP, Qiu J, Silvia PJ, Schacter DL. Brain networks of the imaginative mind: Dynamic functional connectivity of default and cognitive control networks relates to openness to experience. Hum Brain Mapp. 2018;39:811–21. [DOI] [PubMed] [PMC]

122.

Bonanno GA, Burton CL. Regulatory Flexibility: An Individual Differences Perspective on Coping and Emotion Regulation. Perspect Psychol Sci. 2013;8:591–612. [DOI] [PubMed]

123.

Odacı H, Cikrikci Ö. Cognitive Flexibility Mediates the Relationship between Big Five Personality Traits and Life Satisfaction. Appl Res Qual Life. 2019;14:1229–46. [DOI]

124.

Casey BJ, Somerville LH, Gotlib IH, Ayduk O, Franklin NT, Askren MK, et al. Behavioral and neural correlates of delay of gratification 40 years later. Proc Natl Acad Sci U S A. 2011;108:14998–5003. [DOI] [PubMed] [PMC]

125.

Voss P, Thomas ME, Cisneros-franco JM, de Villers-Sidani É. Dynamic Brains and the Changing Rules of Neuroplasticity: Implications for Learning and Recovery. Front Psychol. 2017;8:1657. [DOI]

126.

Dave A, Ye S, Bätz LR, Lan X, Jacobs HIL, Ziaei M. Age-Related Increase in Locus Ceruleus Activity and Connectivity with the Prefrontal Cortex during Ambiguity Processing. J Neurosci. 2025;45:e2059242025. [DOI] [PubMed] [PMC]

127.

Huang R, Clewett D. The Locus Coeruleus: Where Cognitive and Emotional Processing Meet the Eye. In: Papesh MH, Goldinger SD, editors. Modern Pupillometry. Cham: Springer; 2024. pp. 3–75. [DOI]

128.

Takano H, Ito H, Takahashi H, Arakawa R, Okumura M, Kodaka F, et al. Serotonergic neurotransmission in the living human brain: a positron emission tomography study using [¹¹C]dasb and [¹¹C]WAY100635 in young healthy men. Synapse. 2011;65:624–33. [DOI] [PubMed]

129.

Lowry CA. Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J Neuroendocrinol. 2002;14:911–23. [DOI] [PubMed]

130.

Jawinski P, Markett S, Sander C, Huang J, Ulke C, Hegerl U, et al. The Big Five Personality Traits and Brain Arousal in the Resting State. Brain Sci. 2021;11:1272. [DOI] [PubMed] [PMC]

131.

Sarkisian KI, Ho L, Yang J, Mandelbaum R, Stanczyk FZ. Neuroendocrine, neurotransmitter, and gut microbiota imbalance contributing to potential psychiatric disorder prevalence in polycystic ovarian syndrome. F S Rep. 2023;4:337–42. [DOI] [PubMed] [PMC]

132.

España RA, Schmeichel BE, Berridge CW. Norepinephrine at the nexus of arousal, motivation and relapse. Brain Res. 2016;1641:207–16. [DOI] [PubMed] [PMC]

133.

Xing B, Li YC, Gao WJ. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex. Brain Res. 2016;1641:217–33. [DOI] [PubMed] [PMC]

134.

Chaby LE, Karavidha K, Lisieski MJ, Perrine SA, Liberzon I. Cognitive Flexibility Training Improves Extinction Retention Memory and Enhances Cortical Dopamine With and Without Traumatic Stress Exposure. Front Behav Neurosci. 2019;13:24. [DOI] [PubMed] [PMC]

135.

Blier P, Briley M. The noradrenergic symptom cluster: clinical expression and neuropharmacology. Neuropsychiatr Dis Treat. 2011;7:15–20. [DOI] [PubMed] [PMC]

136.

Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med. 2006;36:881–909. [DOI] [PubMed]

137.

Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22. [DOI] [PubMed] [PMC]

138.

McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873–904. [DOI] [PubMed]

139.

Robbins TW, Arnsten AFT. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci. 2009;32:267–87. [DOI] [PubMed] [PMC]

140.

Galgani A, Bartolini E, D’Amora M, Faraguna U, Giorgi FS. The Central Noradrenergic System in Neurodevelopmental Disorders: Merging Experimental and Clinical Evidence. Int J Mol Sci. 2023;24:5805. [DOI] [PubMed] [PMC]

141.

Hauser TU, Allen M, Purg N, Moutoussis M, Rees G, Dolan RJ. Noradrenaline blockade specifically enhances metacognitive performance. Elife. 2017;6:e24901. [DOI] [PubMed] [PMC]

142.

Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry. 2004;161:1256–63. [DOI] [PubMed]

143.

MacCormack JK, Armstrong-Carter EL, Gaudier-Diaz MM, Meltzer-Brody S, Sloan EK, Lindquist KA, et al. β-Adrenergic Contributions to Emotion and Physiology During an Acute Psychosocial Stressor. Psychosom Med. 2021;83:959–68. [DOI] [PubMed] [PMC]

144.

Millan MJ, Lejeune F, Gobert A, Brocco M, Auclair A, Bosc C, et al. S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine. J Pharmacol Exp Ther. 2000;295:1206–22. [PubMed]

145.

Reinhold JA, Mandos LA, Rickels K, Lohoff FW. Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother. 2011;12:2457–67. [DOI] [PubMed]

146.

Carl JR, Miller CB, Henry AL, Davis ML, Stott R, Smits JAJ, et al. Efficacy of digital cognitive behavioral therapy for moderate-to-severe symptoms of generalized anxiety disorder: A randomized controlled trial. Depress Anxiety. 2020;37:1168–78. [DOI] [PubMed]

147.

Srinivasan AV. Propranolol: A 50-Year Historical Perspective. Ann Indian Acad Neurol. 2019;22:21–6. [DOI] [PubMed] [PMC]

148.

Zverev Y, Mipando M. Some physiological and psychophysiological signs of neuroticism level in healthy persons. Cent Afr J Med. 1999;45:312–6. [DOI] [PubMed]

149.

Blase K, Vermetten E, Lehrer P, Gevirtz R. Neurophysiological Approach by Self-Control of Your Stress-Related Autonomic Nervous System with Depression, Stress and Anxiety Patients. Int J Environ Res Public Health. 2021;18:3329. [DOI] [PubMed] [PMC]

150.

De Benedittis G. Hypnotic Modulation of Autonomic Nervous System (ANS) Activity. Brain Sci. 2024;14:249. [DOI] [PubMed] [PMC]

151.

Hofmann SG, Asnaani A, Vonk IJJ, Sawyer AT, Fang A. The Efficacy of Cognitive Behavioral Therapy: A Review of Meta-analyses. Cognit Ther Res. 2012;36:427–40. [DOI] [PubMed] [PMC]

152.

Meiliana A, Dewi NM, Wijaya AY. Personalized Medicine: The Future of Health Care. Indones Biomed J. 2016;8:127–46. [DOI]

153.

Strianese O, Rizzo F, Ciccarelli M, Galasso G, D’Agostino Y, Salvati A, et al. Precision and Personalized Medicine: How Genomic Approach Improves the Management of Cardiovascular and Neurodegenerative Disease. Genes (Basel). 2020;11:747. [DOI] [PubMed] [PMC]

154.

Linden W, Lenz JW, Con AH. Individualized stress management for primary hypertension: a randomized trial. Arch Intern Med. 2001;161:1071–80. [DOI] [PubMed]

155.

Ghasemi F, Beversdorf DQ, Herman KC. Stress and stress responses: A narrative literature review from physiological mechanisms to intervention approaches. J Pacific Rim Psychol. 2024;18:1–20. [DOI]

156.

Nguyen JT, Srivastava SB. The Synergy of Mediation and Lifestyle Medication: A New Horizon in Mental Health Treatment. Am J Lifestyle Med. 2023;18:186–8. [DOI] [PubMed] [PMC]

157.

Holman D, Johnson S, O’Connor E. Stress Management Interventions: Improving Subjective Psychological Well-Being in the Workplace. In: Diener E, Oishi S, Tay L, editors. Handbook of well-being. Salt Lake City: DEF Publishers; 2018.

158.

Hariri AR. The neurobiology of individual differences in complex behavioral traits. Annu Rev Neurosci. 2009;32:225–47. [DOI] [PubMed] [PMC]

159.

Milivojevic V, Sinha R. Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability. Trends Mol Med. 2018;24:173–86. [DOI] [PubMed] [PMC]

160.

Billman GE, Hoskins RS. Time-series analysis of heart rate variability during submaximal exercise. Evidence for reduced cardiac vagal tone in animals susceptible to ventricular fibrillation. Circulation. 1989;80:146–57. [DOI] [PubMed]

161.

Megemont M, McBurney-Lin J, Yang H. Pupil diameter is not an accurate real-time readout of locus coeruleus activity. Elife. 2022;11:e70510. [DOI] [PubMed] [PMC]

162.

Zorawski M, Blanding NQ, Kuhn CM, LaBar KS. Effects of stress and sex on acquisition and consolidation of human fear conditioning. Learn Mem. 2006;13:441–50. [DOI] [PubMed] [PMC]

163.

Alvarez RP, Biggs A, Chen G, Pine DS, Grillon C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J Neurosci. 2008;28:6211–9. [DOI] [PubMed] [PMC]

164.

Schönfeld LM, Wojtecki L. Beyond Emotions: Oscillations of the Amygdala and Their Implications for Electrical Neuromodulation. Front Neurosci. 2019;13:366. [DOI] [PubMed] [PMC]

165.

Hommers LG, Richter J, Yang Y, Raab A, Baumann C, Lang K, et al. A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety. Transl Psychiatry. 2018;8:226. [DOI] [PubMed] [PMC]

166.

Wang HT, Dong XW, Li XL, Li YH. The Neural Mechanism Underlying Hyperarousal and Its Role in the Development of Posttraumatic Stress Disorder. Adv Psychol Sci. 2011;19:1651–7.

167.

Strawn JR, Geracioti TD Jr. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety. 2008;25:260–71. [DOI] [PubMed]

168.

Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract. 2007;13:72–8. [DOI] [PubMed]

169.

Mueller D, Cahill SP. Noradrenergic modulation of extinction learning and exposure therapy. Behav Brain Res. 2010;208:1–11. [DOI] [PubMed]

170.

Maren S. Unrelenting Fear Under Stress: Neural Circuits and Mechanisms for the Immediate Extinction Deficit. Front Syst Neurosci. 2022;16:888461. [DOI] [PubMed] [PMC]

171.

Wengler K, Trujillo P, Cassidy CM, Horga G. Neuromelanin-sensitive MRI for mechanistic research and biomarker development in psychiatry. Neuropsychopharmacology. 2024;50:137–52. [DOI] [PubMed] [PMC]

172.

Frangogiannis NG. Biomarkers: hopes and challenges in the path from discovery to clinical practice. Transl Res. 2012;159:197–204. [DOI] [PubMed] [PMC]

173.

Bernoni d’Aversa F, Gennarelli M. Genetics and Epigenetics of Obsessive-Compulsive Disorder. Genes (Basel). 2026;17:189. [DOI] [PubMed] [PMC]

174.

Zhao X, Lou Z, Shah PT, Wu C, Liu R, Xie W, et al. Integration of Multi-Modal Biosensing Approaches for Depression: Current Status, Challenges, and Future Perspectives. Sensors (Basel). 2025;25:4858. [DOI] [PubMed] [PMC]

175.

Cilia R, Arnaldi D, Ballanger B, Ceravolo R, De Micco R, Del Sole A, et al. Neuroimaging and Pathology Biomarkers in Parkinson’s Disease and Parkinsonism. Brain Sci. 2026;16:110. [DOI] [PubMed] [PMC]

176.

Loch AA, Lopes-Rocha AC, Fekih-Romdhane F, van de Bilt MT, Salazar de Pablo G, Fusar-Poli P. Inequality and barriers in psychosis prevention: A systematic review on clinical high-risk for psychosis studies from developing countries. Front Psychiatry. 2023;14:1148862. [DOI] [PubMed] [PMC]