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Effect of Tolcapone on Brain Activity During a Variable Attentional Control Task: A Double-Blind, Placebo-Controlled, Counter-Balanced Trial in Healthy Volunteers

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Abstract

Background

Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC.

Objective

In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task.

Study Design

We performed a double-blinded, placebo-controlled, counter-balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083).

Setting

The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009.

Patients

Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated.

Intervention

Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH.

Main Outcome Measure

Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors.

Results

There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing).

Conclusion

Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance.

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References

  1. MacDonald AWI, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science. 2000;288(5472):1835–8.

    Article  PubMed  CAS  Google Scholar 

  2. Durston S, Davidson MC, Thomas KM, Worden MS, Tottenham N, Martinez A, et al. Parametric manipulation of conflict and response competition using rapid mixed-trial event-related fMRI. NeuroImage. 2003;20(4):2135–41.

    Article  PubMed  CAS  Google Scholar 

  3. Blasi G, Goldberg TE, Elvevåg B, Rasetti R, Bertolino A, Cohen J, et al. Differentiating allocation of resources and conflict detection within attentional control processing. Eur J Neurosci. 2007;25(2):594–602.

    Article  PubMed  Google Scholar 

  4. Weissman DH, Giesbrecht B, Song AW, Mangun GR, Woldorff MG. Conflict monitoring in the human anterior cingulate cortex during selective attention to global and local object features. Neuroimage. 2003;19(4):1361–8.

    Article  PubMed  CAS  Google Scholar 

  5. Kerns JG, Cohen JD, MacDonald AW 3, Cho RY, Stenger VA, Carter CS. Anterior cingulate conflict monitoring and adjustments in control. Science. 2004; 303(5660):1023–6.

    Google Scholar 

  6. Cohen RA, Kaplan RF, Moser DJ, Jenkins MA, Wilkinson H. Impairments of attention after cingulotomy. Neurology. 1999;53(4):819–24.

    Article  PubMed  CAS  Google Scholar 

  7. Danckert J, Maruff P, Ymer C, Kinsella G, Yucel M, de Graaff S, et al. Goal-directed selective attention and response competition monitoring: Evidence from unilateral parietal and anterior cingulate lesion. Neuropsychology. 2000;14(1):16–28.

    Article  PubMed  CAS  Google Scholar 

  8. Bartus RT, Levere TE. Frontal decortication in rhesus monkeys: a test of the interference hypothesis. Brain Res. 1977;119(1):233–48.

    Article  PubMed  CAS  Google Scholar 

  9. Wilkins AJ, Shallice T, McCarthy R. Frontal lesions and sustained attention. Neuropsychologia. 1987;25(2):359–65.

    Article  PubMed  CAS  Google Scholar 

  10. Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, et al. Fronto-striatal cognitive deficits at different stages of Parkinson’s disease. Brain. 1992;115:1727–51.

    Article  PubMed  Google Scholar 

  11. Owen AM, Sahakian BJ, Semple J, Polkey CE, Robbins TW. Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia. 1995;33(1):1–24.

    Article  PubMed  CAS  Google Scholar 

  12. Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20(11):4320–4.

    PubMed  CAS  Google Scholar 

  13. Deuel RK, Regan DJ. Parietal hemineglect and motor deficits in the monkey. Neuropsychologia. 1985;23(3):305–14.

    Article  PubMed  CAS  Google Scholar 

  14. King VR, Corwin JV. Comparisons of hemi-inattention produced by unilateral lesions of the posterior parietal cortex or medial agranular prefrontal cortex in rats: Neglect, extinction, and the role of stimulus distance. Behav Brain Res. 1993;54(2):117–31.

    Article  PubMed  CAS  Google Scholar 

  15. Danckert J, Stöttinger E, Quehl N, Anderson B. Right hemisphere brain damage impairs strategy updating. Cereb Cortex. 2012;22(12):2745–60.

    Article  PubMed  Google Scholar 

  16. Yücel M, Volker C, Collie A, Maruff P, Danckert J, Velakoulis D, et al. Impairments of response conflict monitoring and resolution in schizophrenia. Psychol Med. 2002;32(7):1251–60.

    Article  PubMed  Google Scholar 

  17. Weiss EM, Golaszewski S, Mottaghy FM, Hofer A, Hausmann A, Kemmler G, et al. Brain activation patterns during a selective attention test-a functional MRI study in healthy volunteers and patients with schizophrenia. Psychiatry Res. 2003;123(1):1–15.

    Article  PubMed  Google Scholar 

  18. Heckers S, Weiss AP, Deckersbach T, Goff DC, Morecraft RJ, Bush G. Anterior cingulate cortex activation during cognitive interference in schizophrenia. Am J Psychiatry. 2004;161(4):707–15.

    Article  PubMed  Google Scholar 

  19. Kerns JG, Cohen JD, MacDonald AW 3, Johnson MK, Stenger VA, Aizenstein H, et al. Decreased conflict- and error-related activity in the anterior cingulate cortex in subjects with schizophrenia. Am J Psychiatry. 2005; 162(10): 1833–9.

    Google Scholar 

  20. Weiss EM, Siedentopf C, Golaszewski S, Mottaghy FM, Hofer A, Kremser C, et al. Brain activation patterns during a selective attention test—a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia. Psychiatry Res. 2007;154(1):31–40.

    Article  PubMed  Google Scholar 

  21. Blasi G, Taurisano P, Papazacharias A, Caforio G, Romano R, Lobianco L, Fazio L, Di Giorgio A, Latorre V, Sambataro F, Popolizio T, Nardini M, Mattay VS, Weinberger DR, Bertolino A. Nonlinear response of the anterior cingulate and prefrontal cortex in schizophrenia as a function of variable attentional control. Cereb Cortex. 2010;20(4):837–45.

    Article  PubMed  Google Scholar 

  22. Delawalla Z, Csernansky JG, Barch DM. Prefrontal cortex function in nonpsychotic siblings of individuals with schizophrenia. Biol Psychiatry. 2008;63(5):490–7.

    Article  PubMed  Google Scholar 

  23. Cools R, Rogers R, Barker RA, Robbins TW. Top-down attentional control in Parkinson’s disease: salient considerations. J Cognitive Neurosci. 2010;22(5):848–59.

    Article  Google Scholar 

  24. Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009;23(Suppl 1):33–41.

    Article  PubMed  CAS  Google Scholar 

  25. Nieoullon A. Dopamine and the regulation of cognition and attention. Prog Neurobiol. 2002;67(1):53–83.

    Article  PubMed  CAS  Google Scholar 

  26. Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004;74(1):1–58.

    Article  PubMed  CAS  Google Scholar 

  27. Goldman-Rakic PS, Muly EC 3, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000;31(2–3):295–301.

    Google Scholar 

  28. Devilbiss DM, Berridge CW. Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry. 2008;64(7):626–35.

    Article  PubMed  CAS  Google Scholar 

  29. Daniel DG, Weinberger DR, Jones DW, Zigun JR, Coppola R, Handel S, Bigelow LB, Goldberg TE, Berman KF, Kleinman JE. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci. 1991;11(7):1907–17.

    PubMed  CAS  Google Scholar 

  30. Mattay VS, Berman KF, Ostrem JL, Esposito G, Van Horn JD, Bigelow LB, Weinberger DR. Dextroamphetamine enhances “neural network-specific” physiological signals: a positron-emission tomography rCBF study. J Neurosci. 1996;16(15):4816–22.

    PubMed  CAS  Google Scholar 

  31. Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci. 2000; 20(6): RC65.

    Google Scholar 

  32. Tomasi D, Volkow ND, Wang GJ, Wang R, Telang F, Caparelli EC, Wong C, Jayne M, Fowler JS. Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls. Neuroimage. 2011;54(4):3101–10.

    Article  PubMed  CAS  Google Scholar 

  33. Karoum F, Chrapusta SJ, Egan MF. 3-methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: Reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem. 1994;63(3):972–9.

    Article  PubMed  CAS  Google Scholar 

  34. Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci. 1998;18:2697–2708.

    Google Scholar 

  35. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-O-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004;24(23):5331–5.

    Article  PubMed  CAS  Google Scholar 

  36. Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR, et al. Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci. 2008;28(35):8709–23.

    Article  PubMed  CAS  Google Scholar 

  37. Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res. 1997; 82(2): 202–202.

  38. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007;32(5):1011–20.

    Article  PubMed  CAS  Google Scholar 

  39. Blasi G, Mattay VS, Bertolino A, Elvevåg B, Callicott JH, Das S, et al. Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci. 2005;25(20):5038–45.

    Article  PubMed  CAS  Google Scholar 

  40. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al. Effect of COMT Val108/158 met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA. 2001;98(12):6912–22.

    Article  Google Scholar 

  41. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA. 2003;100(10):6186–91.

    Article  PubMed  CAS  Google Scholar 

  42. Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev. 1999;51(4):593–628.

    PubMed  CAS  Google Scholar 

  43. Gasparini M, Fabrizio E, Bonifati V, Meco G. Cognitive improvement during tolcapone treatment in Parkinson’s disease. J Neural Transm. 1997;104(8–9):887–94.

    Article  PubMed  CAS  Google Scholar 

  44. Farrell SM, Tunbridge EM, Braeutigam S, Harrison PJ. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biol Psychiatry. 2012;71(6):538–534.

    Google Scholar 

  45. Goldman-Rakic P. The cortical dopamine system: role in memory and cognition Adv. Pharmacol. 1998;42:707–11.

    CAS  Google Scholar 

  46. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5.

    Article  PubMed  CAS  Google Scholar 

  47. McNair DM, Lorr M, Droppleman LF. Revised manual for the profile of mood states. San Diego: Educational and Industrial Testing Service; 1992.

    Google Scholar 

  48. Jorga K, Fotteler B, Heizmann P, Gasser R. Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. Br J Clin Pharmacol. 1999;48(4):513–20.

    Article  PubMed  CAS  Google Scholar 

  49. Jorga KM. Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers. Neurology. 1998;50(5 Suppl 5):S31–8.

    Article  PubMed  CAS  Google Scholar 

  50. Friston KJ, Zarahn E, Josephs O, Henson RN, Dale AM. Stochastic designs in event-related fMRI. Neuroimage. 1999;10(5): 607–19.

    Google Scholar 

  51. Cognition and Brain Sciences Unit. DataDiagnostics - MRC CBU Imaging Wiki. [homepage on the Internet]. 2009 [cited 2011 Jun 23]. Available from: Medical Research Council. http://imaging.mrc-cbu.cam.ac.uk/imaging/DataDiagnostics

  52. Oldfield R. The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia. 1971;9:97–113.

    Article  PubMed  CAS  Google Scholar 

  53. Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G, Sambataro F, et al. Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology. 2010;35(10):2101–9.

    Article  PubMed  CAS  Google Scholar 

  54. Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, et al. Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex. 1999;9(1): 20–26.

    Google Scholar 

  55. Paskavitz JF, Sweet LH, Wellen J, Helmer KG, Rao SM, Cohen RA. Recruitment and stabilization of brain activation within a working memory task; an FMRI study. Brain Imaging Behav. 2010;4(1):5–21.

    Article  PubMed  Google Scholar 

  56. Spence SA, Green RD, Wilkinson ID, Hunter MD. Modafinil modulates anterior cingulate function in chronic schizophrenia. Br J Psychiatry. 2005;187:55–61.

    Article  PubMed  Google Scholar 

  57. Hunter MD, Ganesan V, Wilkinson ID, Spence SA. Impact of modafinil on prefrontal executive function in schizophrenia. Am J Psychiatry. 2006;163(12):2184–6.

    Article  PubMed  Google Scholar 

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Acknowledgments

Sophia C. Magalona and Roberta Rasetti contributed equally to the manuscript.

Sophia C. Magalona, Roberta Rasetti, Jingshan Chen, Qiang Chen, Ian Gold, Heather Decot, Joseph H. Callicott, Karen F. Berman, José A. Apud, Daniel R. Weinberger, and Venkata S. Mattay declare that they have no conflict of interest.

This research was supported by direct funding of the Weinberger Lab in the Intramural Research Program of the National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. and the Lieber Institute for Brain Development.

We thank Saumitra Das, MS for his help with data acquisition.

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Authors and Affiliations

  1. Clinical Brain Disorders Branch (CBDB), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA

    Sophia C. Magalona, Roberta Rasetti, Jingshan Chen, Ian Gold, Heather Decot, Joseph H. Callicott, Karen F. Berman & José A. Apud

  2. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Baltimore, MD, 21205, USA

    Qiang Chen, Daniel R. Weinberger & Venkata S. Mattay

  3. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

  5. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

  6. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

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  1. Sophia C. Magalona
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  2. Roberta Rasetti
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  9. José A. Apud
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  11. Venkata S. Mattay
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Correspondence to Venkata S. Mattay.

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Magalona, S.C., Rasetti, R., Chen, J. et al. Effect of Tolcapone on Brain Activity During a Variable Attentional Control Task: A Double-Blind, Placebo-Controlled, Counter-Balanced Trial in Healthy Volunteers. CNS Drugs 27, 663–673 (2013). https://doi.org/10.1007/s40263-013-0082-x

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