Article | Published:

The myeloarchitecture of impulsivity: premature responding in youth is associated with decreased myelination of ventral putamen

Neuropsychopharmacology (2019) | Download Citation

Abstract

Impulsivity has been suggested as a neurocognitive endophenotype conferring risk across a number of neuropsychiatric conditions, including substance and behavioural addictions, eating disorders, and attention deficit/hyperactivity disorder. We used a paradigm with interspecies translation validity (the four-choice serial reaction time task, 4CSRTT) to assess ‘waiting’ impulsivity in a youth sample (N = 99, aged 16–26 years). We collected magnetization prepared two rapid acquisition gradient echo (MP2RAGE) scans, which enabled us to measure R1, the longitudinal relaxation rate, a parameter closely related to tissue myelin content, as well as quantify grey matter volume. We also assessed inhibitory control (commission errors) on a Go/NoGo task and measured decisional impulsivity (delay discounting) using the Monetary Choice Questionnaire (MCQ). We found R1 of the bilateral ventral putamen was negatively correlated with premature responding, the index of waiting impulsivity on the 4CSRTT. Heightened impulsivity in youth was significantly and specifically associated with lower levels of myelination in the ventral putamen. Impulsivity was not associated with grey matter volume. The association with myelination was specific to waiting impulsivity: R1 was not associated with decisional impulsivity on the MCQ or inhibitory control on the Go/NoGo task. We report that heightened waiting impulsivity, measured as premature responding on the 4CSRTT, is specifically associated with lower levels of ventral putaminal myelination, measured using R1. This may represent a neural signature of vulnerability to diseases associated with excessive impulsivity and demonstrates the added explanatory power of quantifying the mesoscopic organization of the human brain, over and above macroscopic volumetric measurements.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry. 2003;160:1041–52.

  2. 2.

    Foulkes L, Blakemore S-J Studying individual differences in human adolescent brain development. Nat Neurosci. 2018;21:315–23.

  3. 3.

    Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD. Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci. 2012;16:81–91.

  4. 4.

    Daruna JH, Barnes PA. A neurodevelopmental view of impulsivity. In: McCown WG, Johnson JL, Shure MB, editors. The impulsive client: theory, research, and treatment. Washington, DC, USA: American Psychological Association; 1993. p. 23–37.

  5. 5.

    Dalley JW, Robbins TW. Fractionating impulsivity: neuropsychiatric implications. Nat Rev Neurosci. 2017;18:158.

  6. 6.

    Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69:680–94.

  7. 7.

    Thomsen KR, Joensson M, Lou HC, Møller A, Gross J, Kringelbach ML, et al. Altered paralimbic interaction in behavioral addiction. Proc Natl Acad Sci USA. 2013;110:4744–9.

  8. 8.

    Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW. Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits. Biol Psychiatry. 2010;68:770–3.

  9. 9.

    Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci. 2005;8:1481–9.

  10. 10.

    Voon V, Dalley JW. (2015). Translatable and back-translatable measurement of impulsivity and compulsivity: convergent and divergent processes. In: Robbins TW, Sahakian BJ, (eds.) Translational Neuropsychopharmacology. Curr Top Behav Neurosci, vol 28. Springer, Cham.

  11. 11.

    Robbins T. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacol (Berl). 2002;163:362–80.

  12. 12.

    Voon V, Irvine MA, Derbyshire K, Worbe Y, Lange I, Abbott S, et al. Measuring “waiting” impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task. Biol Psychiatry. 2014;75:148–55.

  13. 13.

    Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol. 2013;108:44–79.

  14. 14.

    Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Lääne K, et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315:1267–70.

  15. 15.

    Caprioli D, Sawiak SJ, Merlo E, Theobald DE, Spoelder M, Jupp B, et al. Gamma aminobutyric acidergic and neuronal structural markers in the nucleus accumbens core underlie trait-like impulsive behavior. Biol Psychiatry. 2014;75:115–23.

  16. 16.

    Cole BJ, Robbins TW. Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal. Behav Brain Res. 1989;33:165–79.

  17. 17.

    Morris LS, Kundu P, Baek K, Irvine MA, Mechelmans DJ, Wood J, et al. Jumping the gun: mapping neural correlates of waiting impulsivity and relevance across alcohol misuse. Biol Psychiatry. 2016;79:499–507.

  18. 18.

    Mechelmans DJ, Strelchuk D, Doñamayor N, Banca P, Robbins TW, Baek K, et al. Reward sensitivity and waiting impulsivity: shift towards reward valuation away from action control. Int J Neuropsychopharmacol. 2017;20:971–8.

  19. 19.

    Caravaggio F, Plitman E, Chung JK, Gerretsen P, Kim J, Iwata Y, et al. Trait impulsiveness is related to smaller post‐commissural putamen volumes in males but not females. Eur J Neurosci. 2017;46:2253–64.

  20. 20.

    Guo Y, Chen Z, Feng T. The effect of future time perspective on delay discounting is mediated by the gray matter volume of vmPFC. Neuropsychologia. 2017;102:229–36.

  21. 21.

    Owens MM, Gray JC, Amlung MT, Oshri A, Sweet LH, MacKillop J. Neuroanatomical foundations of delayed reward discounting decision making. Neuroimage. 2017;161:261–70.

  22. 22.

    Tschernegg M, Pletzer B, Schwartenbeck P, Ludersdorfer P, Hoffmann U, Kronbichler M. Impulsivity relates to striatal gray matter volumes in humans: evidence from a delay discounting paradigm. Front Hum Neurosci. 2015;9:384.

  23. 23.

    Yip SW, Worhunsky PD, Xu J, Morie KP, Constable RT, Malison RT, et al. Gray‐matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions. Addict Biol. 2018;23:394–402.

  24. 24.

    Andres T, Ernst T, Oishi K, Greenstein D, Nakama H, Chang L. Brain microstructure and impulsivity differ between current and past methamphetamine users. J Neuroimmune Pharmacol. 2016;11:531–41.

  25. 25.

    Fields RD. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci. 2015;16:756.

  26. 26.

    Edwards LJ, Kirilina E, Mohammadi S, Weiskopf N. Microstructural imaging of human neocortex in vivo. Neuroimage. 2018;182:184–206.

  27. 27.

    Stueber C, Morawski M, Schäfer A, Labadie C, Wähnert M, Leuze C, et al. Myelin and iron concentration in the human brain: a quantitative study of MRI contrast. Neuroimage. 2014;93:95–106.

  28. 28.

    Kim S, Knösche TR. Intracortical myelination in musicians with absolute pitch: Quantitative morphometry using 7‐T MRI. Hum Brain Mapp. 2016;37:3486–501.

  29. 29.

    Amunts K, Zilles K. Architectonic mapping of the human brain beyond Brodmann. Neuron. 2015;88:1086–107.

  30. 30.

    Micheva KD, Wolman D, Mensh BD, Pax E, Buchanan J, Smith SJ, et al. A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. eLife. 2016;5:e15784.

  31. 31.

    Ziegler G, Hauser T, Moutoussis M, Bullmore ET, Goodyer IM, Fonagy P, et al. Compulsivity and impulsivity are linked to distinct aberrant developmental trajectories of fronto-striatal myelination. BioRxiv. 2018:328146.

  32. 32.

    Reynolds B, Ortengren A, Richards JB, de Wit H. Dimensions of impulsive behavior: Personality and behavioral measures. Personal Individ Differ. 2006;40:305–15.

  33. 33.

    Rømer Thomsen K, Callesen MB, Hesse M, Kvamme TL, Pedersen MM, Pedersen MU, et al. Impulsivity traits and addiction-related behaviors in youth. J Behav Addict. 2018;7:317–30.

  34. 34.

    Pedersen MU, Thomsen KR, Pedersen MM, Hesse M. Mapping risk factors for substance use: Introducing the YouthMap12. Addict Behav. 2017;65:40–50.

  35. 35.

    Fischer JA, Najman JM, Williams GM, Clavarino AM. Childhood and adolescent psychopathology and subsequent tobacco smoking in young adults: findings from an Australian birth cohort. Addiction. 2012;107:1669–76.

  36. 36.

    Heron J, Barker ED, Joinson C, Lewis G, Hickman M, Munafò M, et al. Childhood conduct disorder trajectories, prior risk factors and cannabis use at age 16: birth cohort study. Addiction. 2013;108:2129–38.

  37. 37.

    Miettunen J, Murray G, Jones P, Mäki P, Ebeling H, Taanila A, et al. Longitudinal associations between childhood and adulthood externalizing and internalizing psychopathology and adolescent substance use. Psychol Med. 2014;44:1727–38.

  38. 38.

    Lecrubier Y, Sheehan DV, Weiller E, Amorim P, Bonora I, Sheehan KH, et al. The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. Eur Psychiatry. 1997;12:224–31.

  39. 39.

    Kirby KN, Petry NM, Bickel WK. Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. J Exp Psychol Gen. 1999;128:78.

  40. 40.

    Gray JC, Amlung MT, Palmer AA, MacKillop J. Syntax for calculation of discounting indices from the monetary choice questionnaire and probability discounting questionnaire. J Exp Anal Behav. 2016;106:156–63.

  41. 41.

    Houben K, Havermans RC, Nederkoorn C, Jansen A. Beer à No‐Go: Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction. 2012;107:1280–7.

  42. 42.

    Kvamme T, Rømer Thomsen K, Callesen M, Donamayor N, Jensen M, Pedersen M, et al. Distraction towards contextual alcohol cues and craving are associated with levels of alcohol use among youth. BMC Psychiatry. 2018;18:354

  43. 43.

    Peirce JW. PsychoPy—psychophysics software in Python. J Neurosci Methods. 2007;162:8–13.

  44. 44.

    Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele P-F, Gruetter R. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 2010;49:1271–81.

  45. 45.

    Lutti A, Dick F, Sereno MI, Weiskopf N. Using high-resolution quantitative mapping of R1 as an index of cortical myelination. Neuroimage. 2014;93:176–88.

  46. 46.

    Marques JP, Khabipova D, Gruetter R. Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R 1, R 2* and magnetic susceptibility. Neuroimage. 2017;147:152–63.

  47. 47.

    Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, et al. A multi-modal parcellation of human cerebral cortex. Nature. 2016;536:171–8.

  48. 48.

    Keuken M, Bazin P-L, Backhouse K, Beekhuizen S, Himmer L, Kandola A, et al. Effects of aging on T1, T2*, and QSM MRI values in the subcortex. Brain Struct Funct. 2017;222:2487–505.

  49. 49.

    Worsley KJ, Evans AC, Marrett S, Neelin P. A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab. 1992;12:900–18.

  50. 50.

    Belsley DA, Kuh E, Welsch RE. (2004). Regression diagnostics: identifying influential data and sources of collinearity. Vol. 571. John Wiley & Sons, Hoboken, New Jersey.

  51. 51.

    Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008;320:1352–5.

  52. 52.

    Jupp B, Caprioli D, Saigal N, Reverte I, Shrestha S, Cumming P, et al. Dopaminergic and GABA‐ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex. Eur J Neurosci. 2013;37:1519–28.

  53. 53.

    Eagle DM, Baunez C, Hutcheson DM, Lehmann O, Shah AP, Robbins TW. Stop-signal reaction-time task performance: role of prefrontal cortex and subthalamic nucleus. Cereb Cortex. 2007;18:178–88.

  54. 54.

    Moreno-López L, Catena A, Fernández-Serrano MJ, Delgado-Rico E, Stamatakis EA, Pérez-García M, et al. Trait impulsivity and prefrontal gray matter reductions in cocaine dependent individuals. Drug Alcohol Depend. 2012;125:208–14.

  55. 55.

    Jacobsen LK, Giedd JN, Gottschalk C, Kosten TR, Krystal JH. Quantitative morphology of the caudate and putamen in patients with cocaine dependence. Am J Psychiatry. 2001;158:486–9.

  56. 56.

    Ersche KD, Jones PS, Williams GB, Turton AJ, Robbins TW, Bullmore ET. Abnormal brain structure implicated in stimulant drug addiction. Science. 2012;335:601–4.

  57. 57.

    Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C. Microstructural maturation of the human brain from childhood to adulthood. Neuroimage. 2008;40:1044–55.

  58. 58.

    Costa A, la Fougère C, Pogarell O, Möller H-J, Riedel M, Ettinger U. Impulsivity is related to striatal dopamine transporter availability in healthy males. Psychiatry Res Neuroimaging. 2013;211:251–6.

  59. 59.

    Bongarzone ER, Howard SG, Schonmann V, Campagnoni AT. Identification of the dopamine D3 receptor in oligodendrocyte precursors: potential role in regulating differentiation and myelin formation. J Neurosci. 1998;18:5344–53.

  60. 60.

    Feng Y. Convergence and divergence in the etiology of myelin impairment in psychiatric disorders and drug addiction. Neurochem Res. 2008;33:1940–9.

  61. 61.

    Desmond KL, Al‐Ebraheem A, Janik R, Oakden W, Kwiecien JM, Dabrowski W, et al. Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination. NMR Biomed. 2016;29:985–98.

  62. 62.

    Okubo G, Okada T, Yamamoto A, Fushimi Y, Okada T, Murata K, et al. Relationship between aging and T1 relaxation time in deep gray matter: A voxel‐based analysis. J Magn Reson Imaging. 2017;46:724–31.

  63. 63.

    Perales JC, Verdejo-García A, Moya M, Lozano Ó, Pérez-García M. Bright and dark sides of impulsivity: performance of women with high and low trait impulsivity on neuropsychological tasks. J Clin Exp Neuropsychol. 2009;31:927–44.

  64. 64.

    Stevens L, Verdejo-García A, Roeyers H, Goudriaan AE, Vanderplasschen W. Delay discounting, treatment motivation and treatment retention among substance-dependent individuals attending an in inpatient detoxification program. J Subst Abus Treat. 2015;49:58–64.

  65. 65.

    Vassileva J, Georgiev S, Martin E, Gonzalez R, Segala L. Psychopathic heroin addicts are not uniformly impaired across neurocognitive domains of impulsivity. Drug Alcohol Depend. 2011;114:194–200.

Download references

Funding and Disclosures

This work was supported by Aarhus University Research Foundation, Assistant Professor Starting Grant–R46-A4016 (KRT, MBC, VV, MUP), Danish Ministry for Social Affairs and the Interior–9173-0003 (KRT, MBC, MUP), and a Medical Research Council Senior Clinical Fellowship (Grant Number MR/P008747/1 to VV). This work was also supported by NIHR Cambridge Biomedical Research Centre. The authors declare no competing interests.

Author information

Author notes

  1. These authors contributed equally: Camilla L. Nord, Seung-Goo Kim, Kristine Rømer Thomsen and Valerie Voon.

Affiliations

  1. Department of Psychiatry, University of Cambridge, Cambridge, UK

    • Camilla L. Nord
    • , Seung-Goo Kim
    • , Timo L. Kvamme
    •  & Valerie Voon
  2. MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK

    • Camilla L. Nord
  3. Department of Psychology and Neuroscience, Duke University, Durham, NC, USA

    • Seung-Goo Kim
  4. Centre for Alcohol and Drug Research, School of Business and Social Sciences, University of Aarhus, Aarhus, Denmark

    • Mette Buhl Callesen
    • , Timo L. Kvamme
    • , Mads Uffe Pedersen
    •  & Kristine Rømer Thomsen
  5. Center of Functionally Integrative Neuroscience, MINDLab, Aarhus University, Aarhus, Denmark

    • Timo L. Kvamme
    •  & Mads Jensen
  6. Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

    • Valerie Voon

Authors

  1. Search for Camilla L. Nord in:

  2. Search for Seung-Goo Kim in:

  3. Search for Mette Buhl Callesen in:

  4. Search for Timo L. Kvamme in:

  5. Search for Mads Jensen in:

  6. Search for Mads Uffe Pedersen in:

  7. Search for Kristine Rømer Thomsen in:

  8. Search for Valerie Voon in:

Corresponding author

Correspondence to Camilla L. Nord.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41386-019-0343-6