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Positron emission tomography studies in adult patients with attention-deficit/hyperactivity disorder

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, motor hyperactivity, impulsivity, and psychosocial as well as cognitive dysfunction. Although characteristic clinical manifestations have been described, no definitive biomarkers to diagnose ADHD have been established. In this review article, we summarize positron emission tomography (PET) studies conducted in adult patients with ADHD. We found that, although, disturbances of dopamine, serotonin, and norepinephrine functions have been implicated in ADHD, no characteristic findings have been identified from PET studies in patients with ADHD. Several previous PET studies on the central dopaminergic transmission-related ligands in patients with ADHD have shown altered binding of dopamine markers in the basal ganglia. However, no consistent results were observed in the binding characteristics for dopamine transporters and receptors. Findings from PET studies with ligands related to serotonin and norepinephrine pathways showed either unclear clinical significance or low replicability. Therefore, whether alterations of monoamine function may be involved in the pathophysiological mechanism remains to be clarified. The limitations of previous PET studies include their small sample sizes, focus on several kinds of existing ligands, and a questionable validity of the diagnosis (lack of biological diagnostic criteria). To determine the characteristic findings for diagnosing ADHD, further research is needed, and particularly, studies that evaluate new active ligands with specific binding to monoamine pathways should be undertaken.

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Data sharing is not applicable to this article as no new data were created or analyzed in this study.

References

  1. Posner J, Polanczyk GV, Sonuga-Barke E. Attention-deficit hyperactivity disorder. Lancet. 2020;395:450–62. https://doi.org/10.1016/S0140-6736(19)33004-1.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164:942–8. https://doi.org/10.1176/ajp.2007.164.6.942.

    Article  PubMed  Google Scholar 

  3. Simon V, Czobor P, Bálint S, Mészáros A, Bitter I. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry. 2009;194:204–11. https://doi.org/10.1192/bjp.bp.107.048827.

    Article  PubMed  Google Scholar 

  4. Takahashi N, Ishizuka K, Inada T. Peripheral biomarkers of attention-deficit hyperactivity disorder: current status and future perspective. J Psychiatr Res. 2021;137:465–70. https://doi.org/10.1016/j.jpsychires.2021.03.012.

    Article  PubMed  Google Scholar 

  5. Nikolaus S, Mamlins E, Giesel FL, Schmitt D, Müller HW. Monoaminergic hypo- or hyperfunction in adolescent and adult attention-deficit hyperactivity disorder? Rev Neurosci. 2022;33:347–64. https://doi.org/10.1515/revneuro-2021-0083.

    Article  CAS  PubMed  Google Scholar 

  6. Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L, et al. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:1380–7. https://doi.org/10.1016/j.biopsych.2006.07.032.

    Article  CAS  PubMed  Google Scholar 

  7. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry. 1995;52:456–63. https://doi.org/10.1001/archpsyc.1995.03950180042006.

    Article  CAS  PubMed  Google Scholar 

  8. Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, et al. Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacol (Berl). 1997;131:71–8. https://doi.org/10.1007/s002130050267.

    Article  CAS  Google Scholar 

  9. Volkow ND, Wang GJ, Fowler JS, Logan J, Franceschi D, Maynard L, et al. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse. 2002;43:181–7. https://doi.org/10.1002/syn.10038.

    Article  CAS  PubMed  Google Scholar 

  10. Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ. Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord. 2002;6(Suppl 1):S31-43. https://doi.org/10.1177/070674370200601s05.

    Article  PubMed  Google Scholar 

  11. Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D, Clark L, et al. Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory. J Neurosci. 2009;29:4690–6. https://doi.org/10.1523/JNEUROSCI.3266-08.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry. 2010;68:854–60. https://doi.org/10.1016/j.biopsych.2010.06.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;69:e145–57. https://doi.org/10.1016/j.biopsych.2011.02.036.

    Article  CAS  PubMed  Google Scholar 

  14. Drgon T, Lin Z, Wang GJ, Fowler J, Pablo J, Mash DC, et al. Common human 5′ dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol. 2006;26:875–89. https://doi.org/10.1007/s10571-006-9014-3.

    Article  CAS  PubMed  Google Scholar 

  15. Spencer TJ, Biederman J, Madras BK, Dougherty DD, Bonab AA, Livni E, et al. Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using Altropane. Biol Psychiatry. 2007;62:1059–61. https://doi.org/10.1016/j.biopsych.2006.12.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Volkow ND, Wang GJ, Newcorn J, Fowler JS, Telang F, Solanto MV, et al. Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage. 2007;34:1182–90. https://doi.org/10.1016/j.neuroimage.2006.10.014.

    Article  PubMed  Google Scholar 

  17. Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang F, et al. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA. 2009;302:1084–91. https://doi.org/10.1001/jama.2009.1308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Volkow ND, Wang GJ, Newcorn JH, Kollins SH, Wigal TL, Telang F, et al. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol Psychiatry. 2011;16:1147–54. https://doi.org/10.1038/mp.2010.97.

    Article  CAS  PubMed  Google Scholar 

  19. Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U. Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry. 2012;169:264–72. https://doi.org/10.1176/appi.ajp.2011.11060940.

    Article  PubMed  Google Scholar 

  20. Wiers CE, Lohoff FW, Lee J, Muench C, Freeman C, Zehra A, et al. Methylation of the dopamine transporter gene in blood is associated with striatal dopamine transporter availability in ADHD: A preliminary study. Eur J Neurosci. 2018;48:1884–95. https://doi.org/10.1111/ejn.14067.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Volkow ND, Wang GJ, Newcorn J, Telang F, Solanto MV, Fowler JS, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007;64:932–40. https://doi.org/10.1001/archpsyc.64.8.932.

    Article  CAS  PubMed  Google Scholar 

  22. Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci. 2012;32:841–9. https://doi.org/10.1523/JNEUROSCI.4461-11.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. del Campo N, Fryer TD, Hong YT, Smith R, Brichard L, Acosta-Cabronero J, et al. A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment. Brain. 2013;136:3252–70. https://doi.org/10.1093/brain/awt263.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cherkasova MV, Faridi N, Casey KF, O’Driscoll GA, Hechtman L, Joober R, et al. Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD. Neuropsychopharmacology. 2014;39:1498–507. https://doi.org/10.1038/npp.2013.349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Badgaiyan RD, Sinha S, Sajjad M, Wack DS. Attenuated tonic and enhanced phasic release of dopamine in attention deficit hyperactivity disorder. PLoS ONE. 2015;10: e0137326. https://doi.org/10.1371/journal.pone.0137326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cherkasova MV, Faridi N, Casey KF, Larcher K, O’Driscoll GA, Hechtman L, et al. Differential associations between cortical thickness and striatal dopamine in treatment-naive adults with ADHD vs. healthy controls. Front Hum Neurosci. 2017;11:421. https://doi.org/10.3389/fnhum.2017.00421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yokokura M, Takebasashi K, Takao A, Nakaizumi K, Yoshikawa E, Futatsubashi M, et al. In vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study. Mol Psychiatry. 2021;26:4958–67. https://doi.org/10.1038/s41380-020-0784-7.

    Article  CAS  PubMed  Google Scholar 

  28. Ernst M, Zametkin AJ, Matochik JA, Jons PH, Cohen RM. DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A [fluorine-18]fluorodopa positron emission tomographic study. J Neurosci. 1998;18:5901–7. https://doi.org/10.1523/JNEUROSCI.18-15-05901.1998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ludolph AG, Kassubek J, Schmeck K, Glaser C, Wunderlich A, Buck AK, et al. Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study. Neuroimage. 2008;41:718–27. https://doi.org/10.1016/j.neuroimage.2008.02.025.

    Article  PubMed  Google Scholar 

  30. Karlsson L, Tuominen L, Huotarinen A, Leppämäki S, Sihvola E, Helin S, et al. Serotonin transporter in attention-deficit hyperactivity disorder–preliminary results from a positron emission tomography study. Psychiatry Res. 2013;212:164–5. https://doi.org/10.1016/j.pscychresns.2013.02.001.

    Article  CAS  PubMed  Google Scholar 

  31. Vanicek T, Kutzelnigg A, Philippe C, Sigurdardottir HL, James GM, Hahn A, et al. Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET. Hum Brain Mapp. 2017;38:792–802. https://doi.org/10.1002/hbm.23418.

    Article  PubMed  Google Scholar 

  32. Vanicek T, Spies M, Rami-Mark C, Savli M, Höflich A, Kranz GS, et al. The norepinephrine transporter in attention-deficit/hyperactivity disorder investigated with positron emission tomography. JAMA Psychiat. 2014;71:1340–9. https://doi.org/10.1001/jamapsychiatry.2014.1226.

    Article  Google Scholar 

  33. Sigurdardottir HL, Kranz GS, Rami-Mark C, James GM, Vanicek T, Gryglewski G, et al. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET. Hum Brain Mapp. 2016;37:884–95. https://doi.org/10.1002/hbm.23071.

    Article  PubMed  Google Scholar 

  34. Sigurdardottir HL, Kranz GS, Rami-Mark C, James GM, Vanicek T, Gryglewski G, et al. Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity-impulsivity symptoms in ADHD measured with PET. Mol Psychiatry. 2021;26:1009–18. https://doi.org/10.1038/s41380-019-0461-x.

    Article  CAS  PubMed  Google Scholar 

  35. Ulke C, Rullmann M, Huang J, Luthardt J, Becker GA, Patt M, et al. Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S, S)-O-[11C]methylreboxetine positron emission tomography study. Transl Psychiatry. 2019;9:301. https://doi.org/10.1038/s41398-019-0619-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J, et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med. 1990;323:1361–6. https://doi.org/10.1056/NEJM199011153232001.

    Article  CAS  PubMed  Google Scholar 

  37. Ernst M, Zametkin AJ, Matochik JA, Liebenauer L, Fitzgerald GA, Cohen RM. Effects of intravenous dextroamphetamine on brain metabolism in adults with attention-deficit hyperactivity disorder (ADHD) Preliminary findings. Psychopharmacol Bull. 1994;30:219–25.

    CAS  PubMed  Google Scholar 

  38. Matochik JA, Liebenauer LL, King AC, Szymanski HV, Cohen RM, Zametkin AJ. Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry. 1994;151:658–64. https://doi.org/10.1176/ajp.151.5.658.

    Article  CAS  PubMed  Google Scholar 

  39. Ernst M, Zametkin AJ, Phillips RL, Cohen RM. Age-related changes in brain glucose metabolism in adults with attention-deficit/hyperactivity disorder and control subjects. J Neuropsychiatry Clin Neurosci. 1998;10:168–77. https://doi.org/10.1176/jnp.10.2.168.

    Article  CAS  PubMed  Google Scholar 

  40. Hansen FH, Skjørringe T, Yasmeen S, Arends NV, Sahai MA, Erreger K, et al. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. J Clin Invest. 2014;124:3107–20. https://doi.org/10.1172/JCI73778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schweitzer JB, Faber TL, Grafton ST, Tune LE, Hoffman JM, Kilts CD. Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2000;157:278–80. https://doi.org/10.1176/appi.ajp.157.2.278.

    Article  CAS  PubMed  Google Scholar 

  42. Schweitzer JB, Lee DO, Hanford RB, Tagamets MA, Hoffman JM, Grafton ST, et al. A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response. Neuropsychopharmacology. 2003;28:967–73. https://doi.org/10.1038/sj.npp.1300110.

    Article  CAS  PubMed  Google Scholar 

  43. Moffitt TE, Houts R, Asherson P, Belsky DW, Corcoran DL, Hammerle M, et al. Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence from a four-decade longitudinal cohort study. Am J Psychiatry. 2015;172:967–77. https://doi.org/10.1176/appi.ajp.2015.14101266.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Caye A, Rocha TB, Anselmi L, Murray J, Menezes AM, Barros FC, et al. Attention-deficit/hyperactivity disorder trajectories from childhood to young adulthood: evidence from a birth cohort supporting a late-onset syndrome. JAMA Psychiat. 2016;73:705–12. https://doi.org/10.1001/jamapsychiatry.2016.0383.

    Article  Google Scholar 

  45. Agnew-Blais JC, Polanczyk GV, Danese A, Wertz J, Moffitt TE, Arseneault L. Evaluation of the persistence, remission, and emergence of attention-deficit/hyperactivity disorder in young adulthood. JAMA Psychiat. 2016;73:713–20. https://doi.org/10.1001/jamapsychiatry.2016.0465.

    Article  Google Scholar 

  46. Cortese S, Castellanos FX. Neuroimaging of attention-deficit/hyperactivity disorder: current neuroscience-informed perspectives for clinicians. Curr Psychiatry Rep. 2012;14:568–78. https://doi.org/10.1007/s11920-012-0310-y.

    Article  PubMed  Google Scholar 

  47. Montgomery AJ, Asselin MC, Farde L, Grasby PM. Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET. J Cereb Blood Flow Metab. 2007;27:369–77. https://doi.org/10.1038/sj.jcbfm.9600339.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partly supported by JSPS KAKENHI [Grant Number JP21K07498].

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Authors and Affiliations

  1. Department of Psychiatry, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya-Shi, Aichi, 466-8560, Japan

    Maeri Yamamoto

  2. Department of Psychiatry, Graduate School of Medicine, Nagoya University, 65 Tsurumai-Cho, Showa-Ku, Nagoya-Shi, Aichi, 466-8550, Japan

    Toshiya Inada

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  1. Maeri Yamamoto
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MY and TI conceived and designed the study, wrote the first draft of the manuscript, revised and approved the final version of the manuscript.

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Correspondence to Toshiya Inada.

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The authors declare that they have no competing financial interests. The authors contacted the drug information offices of pharmaceutical companies (namely, Jansen, Lilly, and Shionogi) in Japan that market drugs for ADHD (namely, methylphenidate hydrochloride, atomoxetine hydrochloride, guanfacine hydrochloride, and lisdexamfetamine mesylate) to check whether they have any literature reporting PET studies in patients with ADHD and received information from them.

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Not applicable. This is a review article. No human or animal studies were conducted for this manuscript.

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Yamamoto, M., Inada, T. Positron emission tomography studies in adult patients with attention-deficit/hyperactivity disorder. Jpn J Radiol 41, 382–392 (2023). https://doi.org/10.1007/s11604-022-01368-w

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