Association between Attention Deficit Hyperactivity Disorder and the Autonomic Nervous System: An Update

Abstract

This article constitutes a review of the research on the relationship between Attention Deficit Hyperactivity Disorder (ADHD) and autonomic nervous system (ANS) functionality. It also explores the possibility of using heart rate variability (HRV) to investigate the link between ADHD and autonomic dysfunction. One line of inquiry that has been the focus of sudies on the pathogensis of ADHD is the dysfunction of the autonomic system. The physiological measurements used to evaluate autonomic dysfunction are concentrated in the cardiovascular system. Databases were searched to identify studies published prior to August 2020. Studies that examined ANS with regard to medication use/treatment were excluded, while those related to ADHD etiopathogenesis were prioritized. In the present article, 52 studies, three of which were systematic reviews and meta-analyses, were evaluated. In general, although the etiopathogenetic association between ADHD and autonomic dysfunction (especially reduced parasympathetic activity) is remarkable, the findings are nonetheless contradictory. Heterogeneity, subtypes, and comorbidities in cases of ADHD appear to complicate the relationship with autonomic dysfunction.

Keywords

• attention deficit hyperactivity disorder
• autonomic dysfunction
• central autonomic network
• autonomic nervous system
• heart rate variability

Dikkat Eksikliği Hiperaktivite Bozukluğu İle Otonom Sinir Sisteminin İlişkisi: Bir Güncelleme

Abstract

Bu makale, Dikkat Eksikliği Hiperaktivite Bozukluğu (DEHB) ile otonom sinir sistemi (OSS) işlevselliği arasındaki ilişki üzerine yapılan araştırmaların bir derlemesini oluşturmaktadır. Ayrıca DEHB ve otonomik işlev bozukluğu arasındaki bağlantıyı araştırmak için kalp hızı değişkenliğini (KHD) kullanma olasılığını ele almaktadır. DEHB'nin patogenezine ilişkin araştırmaların odak noktası olan bir araştırma alanı otonom sistemin işlev bozukluğudur. Otonom disfonksiyonu değerlendirmek için kullanılan fizyolojik ölçümler kardiyovasküler sistemde yoğunlaşmıştır. Ağustos 2020'den önce yayınlanan çalışmaları belirlemek için veri tarandı. OSS'yi ilaç kullanımı/tedavisi açısından inceleyen çalışmalar hariç tutulurken, DEHB etyopatogenezi ile ilgili olanlar önceliklendirildi. . Bu makalede, üçü sistematik derleme ve meta-analiz olan 52 çalışma değerlendirilmiştir. Genel olarak, DEHB ile otonomik disfonksiyon (özellikle azalmış parasempatik aktivite) arasındaki etyopatogenetik ilişki dikkat çekici olsa da, bulgular yine de çelişkilidir. DEHB vakalarında heterojenlik, alt tipler ve komorbiditeler otonomik disfonksiyon ile ilgili yorumları zorlaştırıyor gibi görünmektedir.

Keywords

• dikkat eksikliği hiperaktivite bozukluğu
• otonom disfonksiyon
• merkezi otonom ağ
• otonom sinir sistemi
• kalp hızı değişkenliği

References

1. 1. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub; American Psychiatric Association 2013.
2. 2. Akay A, Ercan ES. Çocuk ve ergen ruh sağlığı ve hastalıkları 2. baskı. . Ankara: Çocuk ve Gençlik Ruh Sağlığı Derneği Yayınları; 2016.
3. 3. Banaschewski T, Becker K, Scherag S, Franke B, Coghill D. Molecular genetics of attention-deficit/hyperactivity disorder: an overview. European child & adolescent psychiatry. 2010;19(3):237-57.
4. 4. Wilens TE. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. Journal of clinical psychopharmacology. 2008;28(3):S46-S53.
5. 5. Cortese S. The neurobiology and genetics of attention-deficit/hyperactivity disorder (ADHD): what every clinician should know. European journal of paediatric neurology. 2012;16(5):422-33.
6. 6. Seidman LJ, Valera EM, Makris N, Monuteaux MC, Boriel DL, Kelkar K et al. Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biological psychiatry. 2006;60(10):1071-80.
7. 7. Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. Jama. 2002;288(14):1740-8.
8. 8. Makris N, Biederman J, Valera EM, Bush G, Kaiser J, Kennedy DN et al. Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cerebral Cortex. 2006;17(6):1364-75.

9. 9. Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA psychiatry. 2013;70(2):185-98.
10. 10. Dickstein SG, Bannon K, Xavier Castellanos F, Milham MP. The neural correlates of attention deficit hyperactivity disorder: An ALE meta‐analysis. Journal of Child Psychology and Psychiatry. 2006;47(10):1051-62.
11. 11. Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset. New England Journal of Medicine. 1990;323(20):1361-6.
12. 12. Faraone SV, Rostain AL, Blader J, Busch B, Childress AC, Connor DF et al. Practitioner Review: Emotional dysregulation in attention‐deficit/hyperactivity disorder–implications for clinical recognition and intervention. Journal of Child Psychology and Psychiatry. 2019;60(2):133-50.
13. 13. Hanć T, Cortese S. Attention deficit/hyperactivity-disorder and obesity: A review and model of current hypotheses explaining their comorbidity. Neuroscience & Biobehavioral Reviews. 2018;92:16-28.
14. 14. Guyton AC, Hall JE, Tuan DXA, Coquery S. Précis de physiologie médicale. Piccin; 2003.
15. 15. Taner D. Fonksiyonel anatomi. ODTÜ Geliştirme Vakfı Yayıncılık ve İletişim AŞ-Metu Press-Yayınları, Ankara. 2013:231-2.
16. 16. Thayer JF, Lane RD. Claude Bernard and the heart–brain connection: Further elaboration of a model of neurovisceral integration. Neuroscience & Biobehavioral Reviews. 2009;33(2):81-8.
17. 17. Saha S. Role of the central nucleus of the amygdala in the control of blood pressure: descending pathways to medullary cardiovascular nuclei. Clinical and Experimental Pharmacology and Physiology. 2005;32(5‐6):450-6.
18. 18. Guideri F, Acampa M, Hayek C, Zappella M, Di Perri T. Reduced heart rate variability in patients affected with Rett syndrome. A possible explanation for sudden death. Neuropediatrics. 1999;30(03):146-8.
19. 19. Ming X, Julu PO, Brimacombe M, Connor S, Daniels ML. Reduced cardiac parasympathetic activity in children with autism. Brain and Development. 2005;27(7):509-16.
20. 20. Bienias P, Łusakowska A, Ciurzyński M, Rymarczyk Z, Irzyk K, Konwerski M et al. Cardiac autonomic function in type 1 and type 2 myotonic dystrophy. Clinical Autonomic Research. 2017;27(3):193-202.
21. 21. BENARROCH EE, editor. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clinic Proceedings; 1993: Elsevier.
22. 22. Porges SW. Orienting in a defensive world: Mammalian modifications of our evolutionary heritage. A polyvagal theory. Psychophysiology. 1995;32(4):301-18.
23. 23. Whedon M, Perry NB, Calkins SD, Bell MA. Cardiac vagal regulation in infancy predicts executive function and social competence in preschool: Indirect effects through language. Developmental psychobiology. 2018;60(5):595-607.
24. 24. Beauchaine T. Vagal tone, development, and Gray's motivational theory: Toward an integrated model of autonomic nervous system functioning in psychopathology. Development and psychopathology. 2001;13(2):183-214.
25. 25. Hastings PD, Nuselovici JN, Utendale WT, Coutya J, McShane KE, Sullivan C. Applying the polyvagal theory to children's emotion regulation: Social context, socialization, and adjustment. Biological psychology. 2008;79(3):299-306.
26. 26. Beauchaine TP, Gatzke-Kopp L, Mead HK. Polyvagal theory and developmental psychopathology: Emotion dysregulation and conduct problems from preschool to adolescence. Biological psychology. 2007;74(2):174-84.
27. 27. Rukmani MR, Seshadri SP, Thennarasu K, Raju TR, Sathyaprabha TN. Heart rate variability in children with attention-deficit/hyperactivity disorder: a pilot study. Annals of neurosciences. 2016;23(2):81-8.
28. 28. Maeda E, Iwata T, Murata K. Effects of work stress and home stress on autonomic nervous function in Japanese male workers. Industrial health. 2014.
29. 29. Agarwal SK, Norby FL, Whitsel EA, Soliman EZ, Chen LY, Loehr LR et al. Cardiac autonomic dysfunction and incidence of atrial fibrillation: results from 20 years follow-up. Journal of the American College of Cardiology. 2017;69(3):291-9.
30. 30. Ng GA. Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death. Autonomic Neuroscience. 2016;199:66-79.
31. 31. Axelrod FB. Hereditary sensory and autonomic neuropathies. Clinical Autonomic Research. 2002;12.
32. 32. Trang H, Girard A, Laude D, Elghozi J-L. Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine's curse). Clinical Science. 2005;108(3):225-30.
33. 33. Goodman B. Autonomic Dysfunction in Autism Spectrum Disorders (ASD)(P5. 117). AAN Enterprises; 2016.
34. 34. Beauchaine TP, Neuhaus E, Gatzke-Kopp LM, Reid MJ, Chipman J, Brekke A et al. Electrodermal responding predicts responses to, and may be altered by, preschool intervention for ADHD. Journal of Consulting and Clinical Psychology. 2015;83(2):293.
35. 35. Herpertz SC, Wenning B, Mueller B, Qunaibi M, Sass H, Herpertz-Dahlmann B. Psychophysiological responses in ADHD boys with and without conduct disorder: implications for adult antisocial behavior. Journal of the American Academy of Child & Adolescent Psychiatry. 2001;40(10):1222-30.
36. 36. El-Sheikh M, Keiley M, Erath S, Dyer WJ. Marital conflict and growth in children's internalizing symptoms: The role of autonomic nervous system activity. Developmental Psychology. 2013;49(1):92.
37. 37. Kara K, Karaman D, Erdem U, Congologlu MA, Durukan I, Ilhan A. Investigation of autonomic nervous system functions by pupillometry in children with attention deficit hyperactivity disorder. Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology. 2013;23(1):49-56.
38. 38. Kim J-S, Lee S-H, Oh Y-S, Park J-W, An J-Y, Choi H-S et al. Arterial stiffness and cardiovascular autonomic dysfunction in patients with Parkinson's disease. Neurodegenerative Diseases. 2017;17(2-3):89-96.
39. 39. Silverman N. Quantitative methods to enhance morphological information using M-mode Doppler and cross sectional ultrasound. Pediatric echocardiography. Williams & Wilkins Baltimore, MD; 1993. p. 35-108.
40. 40. Kelly AS, Rudser KD, Dengel DR, Kaufman CL, Reiff MI, Norris AL et al. Cardiac autonomic dysfunction and arterial stiffness among children and adolescents with attention deficit hyperactivity disorder treated with stimulants. The Journal of pediatrics. 2014;165(4):755-9.
41. 41. Bélanger S, Warren A, Hamilton R, Gray C, Sanatani S, Côté J et al. Cardiac risk assessment before the use of stimulant medications in children and youth. Paediatrics & child health. 2009;14(9):579-85.
42. 42. Negrao BL, Crafford D, Viljoen M. The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder. Cardiovascular journal of Africa. 2009;20(5):296.
43. 43. Hammerness P, Georgiopoulos A, Doyle RL, Utzinger L, Schillinger M, Martelon M et al. An open study of adjunct OROS-methylphenidate in children who are atomoxetine partial responders: II. Tolerability and pharmacokinetics. Journal of child and adolescent psychopharmacology. 2009;19(5):493-9.
44. 44. Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. American Journal of Psychiatry. 2008;165(6):721-30.
45. 45. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. European Neuropsychopharmacology. 2013;23(6):534-41.
46. 46. Sert A, Gokcen C, Aypar E, Odabas D. Effects of atomoxetine on cardiovascular functions and on QT dispersion in children with attention deficit hyperactivity disorder. Cardiology in the Young. 2012;22(2):158-61.
47. 47. Thapar A, Cooper M, Eyre O, Langley K. Practitioner review: what have we learnt about the causes of ADHD? Journal of Child Psychology and Psychiatry. 2013;54(1):3-16. 48. Millichap JG. Etiologic classification of attention-deficit/hyperactivity disorder. Pediatrics. 2008;121(2):e358-e65.
48. 49. Kim HJ, Yang J, Lee M-S. Changes of heart rate variability during methylphenidate treatment in attention-deficit hyperactivity disorder children: A 12-week prospective study. Yonsei medical journal. 2015;56(5):1365-71.
49. 50. Griffiths KR, Quintana DS, Hermens DF, Spooner C, Tsang TW, Clarke S et al. Sustained attention and heart rate variability in children and adolescents with ADHD. Biological psychology. 2017;124:11-20.
50. 51. Hailpern SM, Egan BM, Lewis KD, Wagner C, Shattat GF, Al Qaoud DI et al. Blood pressure, heart rate, and CNS stimulant medication use in children with and without ADHD: analysis of NHANES data. Frontiers in pediatrics. 2014;2:100.
51. 52. Meyer T, Becker A, Sundermann J, Rothenberger A, Herrmann-Lingen C. Attention deficit-hyperactivity disorder is associated with reduced blood pressure and serum vitamin D levels: results from the nationwide German Health Interview and Examination Survey for Children and Adolescents (KiGGS). European child & adolescent psychiatry. 2017;26(2):165-75.
52. 53. Fuemmeler BF, Østbye T, Yang C, McClernon FJ, Kollins SH. Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study. International journal of obesity. 2011;35(6):852.
53. 54. Karpuz D, Hallıoğlu O, Toros F, Taşdelen B. Dikkat eksikliği ve hiperaktivite bozukluğu olan çocuklarda metilfenidat tedavisinin kalp hızı değişkenliği üzerine etkisi. Cukurova Medical Journal. 2017;42(2):271-6.
54. 55. Imeraj L, Antrop I, Roeyers H, Deschepper E, Bal S, Deboutte D. Diurnal variations in arousal: a naturalistic heart rate study in children with ADHD. European child & adolescent psychiatry. 2011;20(8):381-92.
55. 56. Tonhajzerová I, Ondrejka I, Farský I, Višňovcová Z, Mešťaník M, Javorka M et al. Attention deficit/hyperactivity disorder (ADHD) is associated with altered heart rate asymmetry. Physiol Res. 2014;63(Suppl 4):S509-19.
56. 57. Buchhorn R, Conzelmann A, Willaschek C, Störk D, Taurines R, Renner TJ. Heart rate variability and methylphenidate in children with ADHD. ADHD Attention Deficit and Hyperactivity Disorders. 2012;4(2):85-91.
57. 58. Altay MA. Does attention deficit hyperactivity disorder have cardiac arrhythmia potential? Anatolian Journal of Psychiatry. 2018;19(6):624-30.
58. 59. Negrao BL, Bipath P, Van der Westhuizen D, Viljoen M. Autonomic correlates at rest and during evoked attention in children with attention-deficit/hyperactivity disorder and effects of methylphenidate. Neuropsychobiology. 2011;63(2):82-91.
59. 60. Mahle WT, Hebson C, Strieper MJ. Electrocardiographic screening in children with attention-deficit hyperactivity disorder. The American journal of cardiology. 2009;104(9):1296-9.
60. 61. Nahshoni E, Sclarovsky S, Spitzer S, Zalsman G, Strasberg B, Weizman A. Early repolarization in young children with attention-deficit/hyperactivity disorder versus normal controls: a retrospective preliminary chart review study. Journal of child and adolescent psychopharmacology. 2009;19(6):731-5.
61. 62. Thomas PE, Carlo WF, Decker JA, Cannon BC, Kertesz NJ, Friedman RA et al. Impact of the American Heart Association Scientific Statement on screening electrocardiograms and stimulant medications. Archives of pediatrics & adolescent medicine. 2011;165(2):166-70.
62. 63. Shahani SA, Evans WN, Mayman GA, Thomas VC. Attention deficit hyperactivity disorder screening electrocardiograms: a community-based perspective. Pediatric cardiology. 2014;35(3):485-9.
63. 64. Koenig J, Rash JA, Kemp AH, Buchhorn R, Thayer JF, Kaess M. Resting state vagal tone in attention deficit (hyperactivity) disorder: a meta-analysis. The World Journal of Biological Psychiatry. 2017;18(4):256-67.
64. 65. Lackschewitz H, Hüther G, Kröner-Herwig B. Physiological and psychological stress responses in adults with attention-deficit/hyperactivity disorder (ADHD). Psychoneuroendocrinology. 2008;33(5):612-24.
65. 66. Oliver ML, Nigg JT, Cassavaugh ND, Backs RW. Behavioral and cardiovascular responses to frustration during simulated driving tasks in young adults with and without attention disorder symptoms. Journal of attention disorders. 2012;16(6):478-90.
66. 67. de Carvalho TD, Wajnsztejn R, de Abreu LC, Vanderlei LCM, Godoy MF, Adami F et al. Analysis of cardiac autonomic modulation of children with attention deficit hyperactivity disorder. Neuropsychiatric disease and treatment. 2014;10:613.
67. 68. Crowell SE, Beauchaine TP, Gatzke-Kopp L, Sylvers P, Mead H, Chipman-Chacon J. Autonomic correlates of attention-deficit/hyperactivity disorder and oppositional defiant disorder in preschool children. Journal of abnormal psychology. 2006;115(1):174.
68. 69. Karalunas SL, Fair D, Musser ED, Aykes K, Iyer SP, Nigg JT. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. JAMA psychiatry. 2014;71(9):1015-24.
69. 70. Luman M, Oosterlaan J, Hyde C, Van Meel CS, Sergeant JA. Heart rate and reinforcement sensitivity in ADHD. Journal of Child Psychology and Psychiatry. 2007;48(9):890-8.
70. 71. Wang T-S, Huang W-L, Kuo TB, Lee G-S, Yang CC. Inattentive and hyperactive preschool-age boys have lower sympathetic and higher parasympathetic activity. The Journal of Physiological Sciences. 2013;63(2):87-94.
71. 72. Eisenberg J. Heart rate variability during a continuous performance test in children with problems of attention. The Israel journal of psychiatry and related sciences. 2011;48(1):19.
72. 73. Tonhajzerova I, Ondrejka I, Adamik P, Hruby R, Javorka M, Trunkvalterova Z et al. Changes in the cardiac autonomic regulation in children with attention deficit hyperactivity disorder (ADHD). Indian Journal of Medical Research. 2009;130(1):44.
73. 74. Semrud-Clikeman M, Pliszka SR, Bledsoe J, Lancaster J. Volumetric MRI differences in treatment naive and chronically treated adolescents with ADHD-combined type. Journal of attention disorders. 2014;18(6):511-20.
74. 75. Castellanos FX. Toward a pathophysiology of attention-deficit/hyperactivint disorder. Clinical Pediatrics. 1997;36(7):381-93.
75. 76. Schrimsher GW, Billingsley RL, Jackson EF, Moore BD. Caudate nucleus volume asymmetry predicts attention-deficit hyperactivity disorder (ADHD) symptomatology in children. Journal of Child Neurology. 2002;17(12):877-84.
76. 77. Qureshi MNI, Min B, Jo HJ, Lee B. Multiclass classification for the differential diagnosis on the ADHD subtypes using recursive feature elimination and hierarchical extreme learning machine: structural MRI study. PloS one. 2016;11(8):e0160697.
77. 78. Solanto MV, Schulz KP, Fan J, Tang CY, Newcorn JH. Event‐related FMRI of inhibitory control in the predominantly inattentive and combined subtypes of ADHD. Journal of Neuroimaging. 2009;19(3):205-12.
78. 79. Park B-y, Kim M, Seo J, Lee J-m, Park H. Connectivity analysis and feature classification in attention deficit hyperactivity disorder sub-types: a task functional magnetic resonance imaging study. Brain topography. 2016;29(3):429-39.
79. 80. Ercan ES, Suren S, Bacanlı A, Yazıcı KU, Callı C, Ardic UA et al. Altered structural connectivity is related to attention deficit/hyperactivity subtypes: A DTI study. Psychiatry Research: Neuroimaging. 2016;256:57-64.
80. 81. Beauchaine TP, Gatzke-Kopp L, Neuhaus E, Chipman J, Reid MJ, Webster-Stratton C. Sympathetic-and parasympathetic-linked cardiac function and prediction of externalizing behavior, emotion regulation, and prosocial behavior among preschoolers treated for ADHD. Journal of consulting and clinical psychology. 2013;81(3):481.
81. 82. Musser ED, Backs RW, Schmitt CF, Ablow JC, Measelle JR, Nigg JT. Emotion regulation via the autonomic nervous system in children with attention-deficit/hyperactivity disorder (ADHD). Journal of abnormal child psychology. 2011;39(6):841-52.
82. 83. Bunford N, Evans SW, Zoccola PM, Owens JS, Flory K, Spiel CF. Correspondence between heart rate variability and emotion dysregulation in children, including children with ADHD. Journal of abnormal child psychology. 2017;45(7):1325-37.
83. 84. McQuade JD, Breaux RP. Are elevations in ADHD symptoms associated with physiological reactivity and emotion dysregulation in children? Journal of abnormal child psychology. 2017;45(6):1091-103.
84. 85. Musser ED, Galloway-Long HS, Frick PJ, Nigg JT. Emotion regulation and heterogeneity in attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2013;52(2):163-71. e2.
85. 86. Ward AR, Alarcón G, Nigg JT, Musser ED. Variation in parasympathetic dysregulation moderates short-term memory problems in childhood attention-deficit/hyperactivity disorder. Journal of abnormal child psychology. 2015;43(8):1573-83.
86. 87. Beauchaine TP, Katkin ES, Strassberg Z, Snarr J. Disinhibitory psychopathology in male adolescents: discriminating conduct disorder from attention-deficit/hyperactivity disorder through concurrent assessment of multiple autonomic states. Journal of abnormal psychology. 2001;110(4):610.
87. 88. Robe A, Dobrean A, Cristea IA, Păsărelu C-R, Predescu E. Attention-deficit/hyperactivity disorder and task-related heart rate variability: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2019.
88. 89. Yüksel T, Özcan Ö. Heart rate variability as an indicator of autonomous nervous system activity in children with attention deficit hyperactivity disorder. Anatolian Journal of Psychiatry/Anadolu Psikiyatri Dergisi. 2018;19(5).
89. 90. Du Rietz E, James S-N, Banaschewski T, Brandeis D, Asherson P, Kuntsi J. Autonomic Arousal Profiles in Young Individuals with ADHD as a Function of Recording Context. 2018.
90. 91. Sekaninova N, Mestanik M, Mestanikova A, Hamrakova A, Tonhajzerova I. Novel Approach to Evaluate Central Autonomic Regulation in Attention Deficit/Hyperactivity Disorder (ADHD). Physiological research. 2019;68(4):531-45.