The Presynaptic Regulation of Dopamine and Norepinephrine Synthesis Has Dissociable Effects on Different Kinds of Cognitive Conflicts

  • Wiebke Bensmann
  • Nicolas Zink
  • Larissa Arning
  • Christian Beste
  • Ann-Kathrin StockEmail author


Goal-directed behavior requires the ability to resolve subliminally or consciously induced response conflicts, both of which may benefit from catecholamine-induced increases in gain control. We investigated the effects of presynaptic differences in dopamine and norepinephrine synthesis with the help of the tyrosine hydroxylase (TH) rs10770141 and the dopamine-β-hydroxylase (DBH) rs1611115, rs6271, and rs1611122 polymorphisms. Conscious and subliminal response conflicts were induced with flanker and prime distractors in (n = 207) healthy young participants while neurophysiological data (EEG) was recorded. The results demonstrated that the increased presynaptic catecholamine synthesis associated with the TH rs10770141 TT genotype improves cognitive control in case of consciously perceived (flanker) conflicts, but not in case of subliminally processed (prime) conflicts. Only norepinephrine seemed to also modulate subliminal conflict processing, as evidenced by better performance of the DBH rs1611122 CC genotype in case of high subliminal conflict load. Better performance was linked to larger conflict-induced modulations in post-response alpha band power arising from parietal and inferior frontal regions, which likely helps to suppress the processing of distracting information. In summary, presynaptic catecholamine synthesis benefits consciously perceived conflicts by improving the suppression of distracting information following a conflict. Subliminal conflicts were modulated via the same mechanism, but only by norepinephrine.


Conflict DBH Dopamine Norepinephrine Subliminal TH 



This study was funded by a grant from the Deutsche Forschungsgemeinschaft (DFG) SFB940 B8 to AS and CB.

Compliance with Ethical Standards

Conflict of Interests

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Beste C, Mückschel M, Rosales R, Domingo A, Lee L, Ng A, Klein C, Münchau A (2017) The basal ganglia striosomes affect the modulation of conflicts by subliminal information-evidence from X-linked dystonia parkinsonism. Cereb Cortex N Y N 1991:1–10. Google Scholar
  2. 2.
    Eimer M, Schlaghecken F (2003) Response facilitation and inhibition in subliminal priming. Biol Psychol 64:7–26. CrossRefGoogle Scholar
  3. 3.
    Goschke T, Dreisbach G (2008) Conflict-triggered goal shielding: response conflicts attenuate background monitoring for prospective memory cues. Psychol Sci 19:25–32. CrossRefGoogle Scholar
  4. 4.
    Keye D, Wilhelm O, Oberauer K, Stürmer B (2013) Individual differences in response conflict adaptations. Front Psychol 4.
  5. 5.
    McBride J, Boy F, Husain M, Sumner P (2012) Automatic motor activation in the executive control of action. Front Hum Neurosci 6.
  6. 6.
    Parkinson J, Haggard P (2014) Subliminal priming of intentional inhibition. Cognition 130:255–265. CrossRefGoogle Scholar
  7. 7.
    Schlaghecken F, Eimer M (2004) Masked prime stimuli can bias “free” choices between response alternatives. Psychon Bull Rev 11:463–468. CrossRefGoogle Scholar
  8. 8.
    Stock A-K, Wolff N, Beste C (2017) Opposite effects of binge drinking on consciously vs. subliminally induced cognitive conflicts. NeuroImage 162:117–126. CrossRefGoogle Scholar
  9. 9.
    Ulrich R, Schröter H, Leuthold H, Birngruber T (2015) Automatic and controlled stimulus processing in conflict tasks: superimposed diffusion processes and delta functions. Cogn Psychol 78:148–174. CrossRefGoogle Scholar
  10. 10.
    Boy F, Husain M, Sumner P (2010) Unconscious inhibition separates two forms of cognitive control. Proc Natl Acad Sci 107:11134–11139. CrossRefGoogle Scholar
  11. 11.
    Stock A-K, Friedrich J, Beste C (2016) Subliminally and consciously induced cognitive conflicts interact at several processing levels. Cortex J Devoted Study Nerv Syst Behav 85:75–89. CrossRefGoogle Scholar
  12. 12.
    Li SC, Lindenberger U, Sikström S (2001) Aging cognition: from neuromodulation to representation. Trends Cogn Sci 5:479–486CrossRefGoogle Scholar
  13. 13.
    Servan-Schreiber D, Printz H, Cohen JD (1990) A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior. Science 249:892–895CrossRefGoogle Scholar
  14. 14.
    Yousif N, Fu RZ, Abou-El-Ela Bourquin B et al (2016) Dopamine activation preserves visual motion perception despite noise interference of human V5/MT. J Neurosci 36:9303–9312. CrossRefGoogle Scholar
  15. 15.
    Ziegler S, Pedersen ML, Mowinckel AM, Biele G (2016) Modelling ADHD: a review of ADHD theories through their predictions for computational models of decision-making and reinforcement learning. Neurosci Biobehav Rev 71:633–656. CrossRefGoogle Scholar
  16. 16.
    Nieuwenhuis S, Aston-Jones G, Cohen JD (2005) Decision making, the P3, and the locus coeruleus--norepinephrine system. Psychol Bull 131:510–532. CrossRefGoogle Scholar
  17. 17.
    Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450. CrossRefGoogle Scholar
  18. 18.
    Adelhöfer N, Gohil K, Passow S, Teufert B, Roessner V, Li SC, Beste C (2018) The system-neurophysiological basis for how methylphenidate modulates perceptual-attentional conflicts during auditory processing. Hum Brain Mapp 39:5050–5061. CrossRefGoogle Scholar
  19. 19.
    Beste C, Adelhöfer N, Gohil K, Passow S, Roessner V, Li SC (2018) Dopamine modulates the efficiency of sensory evidence accumulation during perceptual decision making. Int J Neuropsychopharmacol 21:649–655. CrossRefGoogle Scholar
  20. 20.
    Chmielewski WX, Mückschel M, Ziemssen T, Beste C (2017) The norepinephrine system affects specific neurophysiological subprocesses in the modulation of inhibitory control by working memory demands. Hum Brain Mapp 38:68–81. CrossRefGoogle Scholar
  21. 21.
    Mückschel M, Gohil K, Ziemssen T, Beste C (2017) The norepinephrine system and its relevance for multi-component behavior. NeuroImage 146:1062–1070. CrossRefGoogle Scholar
  22. 22.
    Priebe NJ, Ferster D (2002) A new mechanism for neuronal gain control (or how the gain in brains has mainly been explained). Neuron 35:602–604. CrossRefGoogle Scholar
  23. 23.
    Mitchell SJ, Silver RA (2003) Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38:433–445CrossRefGoogle Scholar
  24. 24.
    Papasavvas CA, Wang Y, Trevelyan AJ, Kaiser M (2015) Gain control through divisive inhibition prevents abrupt transition to chaos in a neural mass model. Phys Rev E 92.
  25. 25.
    Klein P-A, Petitjean C, Olivier E, Duque J (2014) Top-down suppression of incompatible motor activations during response selection under conflict. NeuroImage 86:138–149. CrossRefGoogle Scholar
  26. 26.
    Ocklenburg S, Güntürkün O, Beste C (2011) Lateralized neural mechanisms underlying the modulation of response inhibition processes. NeuroImage 55:1771–1778. CrossRefGoogle Scholar
  27. 27.
    Stürmer B, Siggelkow S, Dengler R, Leuthold H (2000) Response priming in the Simon paradigm. A transcranial magnetic stimulation study. Exp Brain Res 135:353–359CrossRefGoogle Scholar
  28. 28.
    Verleger R, Kuniecki M, Möller F, Fritzmannova M, Siebner HR (2009) On how the motor cortices resolve an inter-hemispheric response conflict: an event-related EEG potential-guided TMS study of the flankers task. Eur J Neurosci 30:318–326. CrossRefGoogle Scholar
  29. 29.
    Leblois A (2006) Competition between feedback loops underlies normal and pathological dynamics in the basal ganglia. J Neurosci 26:3567–3583. CrossRefGoogle Scholar
  30. 30.
    Mückschel M, Chmielewski W, Ziemssen T, Beste C (2017) The norepinephrine system shows information-content specific properties during cognitive control – evidence from EEG and pupillary responses. NeuroImage 149:44–52. CrossRefGoogle Scholar
  31. 31.
    Bensmann W, Roessner V, Stock A-K, Beste C (2018) Catecholaminergic modulation of conflict control depends on the source of conflicts. Int J Neuropsychopharmacol 21:901–909. CrossRefGoogle Scholar
  32. 32.
    Elshoff J-P, Braun M, Andreas J-O, Middle M, Cawello W (2012) Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies. Clin Ther 34:966–978. CrossRefGoogle Scholar
  33. 33.
    Schirinzi T, Pisani V, Imbriani P, di Lazzaro G, Scalise S, Pisani A (2018) Long-term treatment with rotigotine in drug-naïve PSP patients. Acta Neurol Belg 119:113–116. CrossRefGoogle Scholar
  34. 34.
    Skirrow C, McLoughlin G, Banaschewski T, Brandeis D, Kuntsi J, Asherson P (2015) Normalisation of frontal theta activity following methylphenidate treatment in adult attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol 25:85–94. CrossRefGoogle Scholar
  35. 35.
    Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Dewey SL, Hitzemann R et al (1999) Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high”. J Pharmacol Exp Ther 288:14–20Google Scholar
  36. 36.
    Iversen LL, Iversen SD, Bloom FE, Roth RH (2009) Introduction to neuropsychopharmacology. Oxford University Press, New YorkCrossRefGoogle Scholar
  37. 37.
    Prandovszky E, Gaskell E, Martin H, Dubey JP, Webster JP, McConkey GA (2011) The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS One 6:e23866. CrossRefGoogle Scholar
  38. 38.
    Kobayashi K, Nagatsu T (2005) Molecular genetics of tyrosine 3-monooxygenase and inherited diseases. Biochem Biophys Res Commun 338:267–270. CrossRefGoogle Scholar
  39. 39.
    Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem 239:2910–2917Google Scholar
  40. 40.
    Barrie ES, Weinshenker D, Verma A, Pendergrass SA, Lange LA, Ritchie MD, Wilson JG, Kuivaniemi H et al (2014) Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circ Res 115:1017–1025. CrossRefGoogle Scholar
  41. 41.
    Rao F, Zhang L, Wessel J, Zhang K, Wen G, Kennedy BP, Rana BK, Das M et al (2007) Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. Circulation 116:993–1006. CrossRefGoogle Scholar
  42. 42.
    Combarros O, Warden DR, Hammond N, Cortina-Borja M, Belbin O, Lehmann MG, Wilcock GK, Brown K et al (2010) The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer’s disease in the Epistasis Project. BMC Med Genet 11.
  43. 43.
    Cubells JF, Sun X, Li W, Bonsall RW, McGrath JA, Avramopoulos D, Lasseter VK, Wolyniec PS et al (2011) Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia. Hum Genet 130:635–643. CrossRefGoogle Scholar
  44. 44.
    Cavanagh JF, Zambrano-Vazquez L, Allen JJB (2012) Theta lingua franca: a common mid-frontal substrate for action monitoring processes. Psychophysiology 49:220–238. CrossRefGoogle Scholar
  45. 45.
    Cavanagh JF, Frank MJ (2014) Frontal theta as a mechanism for cognitive control. Trends Cogn Sci 18:414–421. CrossRefGoogle Scholar
  46. 46.
    Chmielewski WX, Mückschel M, Dippel G, Beste C (2016) Concurrent information affects response inhibition processes via the modulation of theta oscillations in cognitive control networks. Brain Struct Funct 221:3949–3961. CrossRefGoogle Scholar
  47. 47.
    Cohen MX (2014) A neural microcircuit for cognitive conflict detection and signaling. Trends Neurosci 37:480–490. CrossRefGoogle Scholar
  48. 48.
    De Blasio FM, Barry RJ (2013) Prestimulus delta and theta determinants of ERP responses in the Go/NoGo task. Int J Psychophysiol Off J Int Organ Psychophysiol 87:279–288. Google Scholar
  49. 49.
    Harper J, Malone SM, Bernat EM (2014) Theta and delta band activity explain N2 and P3 ERP component activity in a go/no-go task. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 125:124–132. CrossRefGoogle Scholar
  50. 50.
    Mückschel M, Stock A-K, Dippel G, Chmielewski W, Beste C (2016) Interacting sources of interference during sensorimotor integration processes. NeuroImage 125:342–349. CrossRefGoogle Scholar
  51. 51.
    Cohen MX, Donner TH (2013) Midfrontal conflict-related theta-band power reflects neural oscillations that predict behavior. J Neurophysiol 110:2752–2763. CrossRefGoogle Scholar
  52. 52.
    Klimesch W (2012) α-Band oscillations, attention, and controlled access to stored information. Trends Cogn Sci 16:606–617. CrossRefGoogle Scholar
  53. 53.
    Klimesch W (2011) Evoked alpha and early access to the knowledge system: the P1 inhibition timing hypothesis. Brain Res 1408:52–71. CrossRefGoogle Scholar
  54. 54.
    Klimesch W, Sauseng P, Hanslmayr S (2007) EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev 53:63–88. CrossRefGoogle Scholar
  55. 55.
    Cohen MX, Ridderinkhof KR (2013) EEG source reconstruction reveals frontal-parietal dynamics of spatial conflict processing. PLoS One 8:e57293. CrossRefGoogle Scholar
  56. 56.
    Bauer M, Oostenveld R, Peeters M, Fries P (2006) Tactile spatial attention enhances gamma-band activity in somatosensory cortex and reduces low-frequency activity in parieto-occipital areas. J Neurosci 26:490–501. CrossRefGoogle Scholar
  57. 57.
    Hoogenboom N, Schoffelen J-M, Oostenveld R, Parkes LM, Fries P (2006) Localizing human visual gamma-band activity in frequency, time and space. NeuroImage 29:764–773. CrossRefGoogle Scholar
  58. 58.
    Schneider TR, Debener S, Oostenveld R, Engel AK (2008) Enhanced EEG gamma-band activity reflects multisensory semantic matching in visual-to-auditory object priming. NeuroImage 42:1244–1254. CrossRefGoogle Scholar
  59. 59.
    Botvinick MM, Cohen JD, Carter CS (2004) Conflict monitoring and anterior cingulate cortex: an update. Trends Cogn Sci 8:539–546. CrossRefGoogle Scholar
  60. 60.
    Bari A, Robbins TW (2013) Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 108:44–79. CrossRefGoogle Scholar
  61. 61.
    Aron AR, Robbins TW, Poldrack RA (2014) Inhibition and the right inferior frontal cortex: one decade on. Trends Cogn Sci 18:177–185. CrossRefGoogle Scholar
  62. 62.
    Allen C, Singh KD, Verbruggen F, Chambers CD (2018) Evidence for parallel activation of the pre-supplementary motor area and inferior frontal cortex during response inhibition: a combined MEG and TMS study. R Soc Open Sci 5:171369. CrossRefGoogle Scholar
  63. 63.
    Horiguchi M, Ohi K, Hashimoto R, Hao Q, Yasuda Y, Yamamori H, Fujimoto M, Umeda-Yano S et al (2014) Functional polymorphism (C-824T) of the tyrosine hydroxylase gene affects IQ in schizophrenia: TH SNP affects IQ in schizophrenia. Psychiatry Clin Neurosci 68:456–462. CrossRefGoogle Scholar
  64. 64.
    Sadahiro R, Suzuki A, Shibuya N, Kamata M, Matsumoto Y, Goto K, Otani K (2010) Association study between a functional polymorphism of tyrosine hydroxylase gene promoter and personality traits in healthy subjects. Behav Brain Res 208:209–212. CrossRefGoogle Scholar
  65. 65.
    Nunez PL, Pilgreen KL (1991) The spline-Laplacian in clinical neurophysiology: a method to improve EEG spatial resolution. J Clin Neurophysiol Off Publ Am Electroencephalogr Soc 8:397–413Google Scholar
  66. 66.
    Perrin F, Pernier J, Bertrand O, Echallier JF (1989) Spherical splines for scalp potential and current density mapping. Electroencephalogr Clin Neurophysiol 72:184–187CrossRefGoogle Scholar
  67. 67.
    Tallon-Baudry C, Bertrand O, Delpuech C, Permier J (1997) Oscillatory gamma-band (30-70 Hz) activity induced by a visual search task in humans. J Neurosci 17:722–734CrossRefGoogle Scholar
  68. 68.
    Cooper PS, Darriba Á, Karayanidis F, Barceló F (2016) Contextually sensitive power changes across multiple frequency bands underpin cognitive control. NeuroImage 132:499–511. CrossRefGoogle Scholar
  69. 69.
    Gross J, Kujala J, Hamalainen M, Timmermann L, Schnitzler A, Salmelin R (2001) Dynamic imaging of coherent sources: Studying neural interactions in the human brain. Proc Natl Acad Sci 98:694–699. CrossRefGoogle Scholar
  70. 70.
    Oostenveld R, Fries P, Maris E, Schoffelen J-M (2011) FieldTrip: Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Comput Intell Neurosci 2011:156869. CrossRefGoogle Scholar
  71. 71.
    Evans AC, Collins DL, Milner B, Milner B (1992) An MRI-based stereotactic atlas from 250 young normal subjectsGoogle Scholar
  72. 72.
    Doppelmayr M, Klimesch W, Hödlmoser K, Sauseng P, Gruber W (2005) Intelligence related upper alpha desynchronization in a semantic memory task. Brain Res Bull 66:171–177. CrossRefGoogle Scholar
  73. 73.
    Sauseng P, Klimesch W, Gruber W, Doppelmayr M, Stadler W, Schabus M (2002) The interplay between theta and alpha oscillations in the human electroencephalogram reflects the transfer of information between memory systems. Neurosci Lett 324:121–124CrossRefGoogle Scholar
  74. 74.
    Bonnefond M, Jensen O (2013) The role of gamma and alpha oscillations for blocking out distraction. Commun Integr Biol 6:e22702. CrossRefGoogle Scholar
  75. 75.
    Wolff N, Zink N, Stock A-K, Beste C (2017) On the relevance of the alpha frequency oscillation’s small-world network architecture for cognitive flexibility. Sci Rep 7:13910. CrossRefGoogle Scholar
  76. 76.
    Wolff N, Giller F, Buse J, Roessner V, Beste C (2018) When repetitive mental sets increase cognitive flexibility in adolescent obsessive-compulsive disorder. J Child Psychol Psychiatry 59:1024–1032. CrossRefGoogle Scholar
  77. 77.
    Kiefer M (2008) Top-down modulation of unconscious “automatic” processes: a gating framework. Adv Cogn Psychol 3:289–306. CrossRefGoogle Scholar
  78. 78.
    Kiefer M, Ansorge U, Haynes J-D, Hamker F, Mattler U, Verleger R, Niedeggen M (2011) Neuro-cognitive mechanisms of conscious and unconscious visual perception: from a plethora of phenomena to general principles. Adv Cogn Psychol 7:55–67. CrossRefGoogle Scholar
  79. 79.
    Muhle-Karbe PS, Duncan J, De Baene W et al (2017) Neural coding for instruction-based task sets in human frontoparietal and visual cortex. Cereb Cortex N Y N 1991 27:1891–1905. Google Scholar
  80. 80.
    Popov T, Westner BU, Silton RL, Sass SM, Spielberg JM, Rockstroh B, Heller W, Miller GA (2018) Time course of brain network reconfiguration supporting inhibitory control. J Neurosci 38:4348–4356. CrossRefGoogle Scholar
  81. 81.
    Spielberg JM, Miller GA, Heller W, Banich MT (2015) Flexible brain network reconfiguration supporting inhibitory control. Proc Natl Acad Sci 112:10020–10025. CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine Carl Gustav CarusTU DresdenDresdenGermany
  2. 2.Department of Human Genetics, Faculty of MedicineRuhr-Universität BochumBochumGermany

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