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Emerging findings of glutamate–glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies

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Abstract

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into ‘children and adolescents’ and ‘adults’ and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle–Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

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References

  1. Association AP (2013) Diagnostic and statistical manual of mental disorders, 5th edition: Dsm-5, 5th edn. American Psychiatric Publishing

    Book  Google Scholar 

  2. Wolraich ML, Hagan JF, Allan C et al (2019) Subcommittee on children and adolescents with attention-deficit/hyperactive disorder clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 144(4):e20192528. https://doi.org/10.1542/peds.2019-3997 (Pediatrics 145)

    Article  PubMed  Google Scholar 

  3. Rohde LA, Biederman J, Busnello EA et al (1999) ADHD in a school sample of Brazilian adolescents: a study of prevalence, comorbid conditions, and impairments. J Am Acad Child Adolesc Psychiatry 38:716–722. https://doi.org/10.1097/00004583-199906000-00019

    Article  CAS  PubMed  Google Scholar 

  4. Polanczyk G, de Lima MS, Horta BL et al (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164:942–948. https://doi.org/10.1176/ajp.2007.164.6.942

    Article  PubMed  Google Scholar 

  5. Thomas R, Sanders S, Doust J et al (2015) Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics 135:e994-1001. https://doi.org/10.1542/peds.2014-3482

    Article  PubMed  Google Scholar 

  6. Kessler RC, Adler L, Barkley R et al (2006) The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 163:716–723. https://doi.org/10.1176/ajp.2006.163.4.716

    Article  PubMed  PubMed Central  Google Scholar 

  7. Fayyad J, De Graaf R, Kessler R et al (2007) Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190:402–409. https://doi.org/10.1192/bjp.bp.106.034389

    Article  CAS  PubMed  Google Scholar 

  8. Barkley RA, Fischer M, Smallish L, Fletcher K (2002) The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol 111:279–289

    Article  PubMed  Google Scholar 

  9. Vitola ES, Bau CHD, Salum GA et al (2017) Exploring DSM-5 ADHD criteria beyond young adulthood: phenomenology, psychometric properties and prevalence in a large three-decade birth cohort. Psychol Med 47:744–754. https://doi.org/10.1017/S0033291716002853

    Article  CAS  PubMed  Google Scholar 

  10. Danckaerts M, Sonuga-Barke EJS, Banaschewski T et al (2010) The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. Eur Child Adolesc Psychiatry 19:83–105. https://doi.org/10.1007/s00787-009-0046-3

    Article  PubMed  Google Scholar 

  11. Biederman J, Faraone SV (2006) The effects of attention-deficit/hyperactivity disorder on employment and household income. MedGenMed 8:12

    PubMed  PubMed Central  Google Scholar 

  12. Faraone SV, Asherson P, Banaschewski T et al (2015) Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 1:15020. https://doi.org/10.1038/nrdp.2015.20

    Article  PubMed  Google Scholar 

  13. Foley P (2007) Succi nervorum: a brief history of neurochemistry. J Neural Transm Suppl. https://doi.org/10.1007/978-3-211-73574-9_2

    Article  PubMed  Google Scholar 

  14. Dunn GA, Nigg JT, Sullivan EL (2019) Neuroinflammation as a risk factor for attention deficit hyperactivity disorder. Pharmacol Biochem Behav 182:22–34. https://doi.org/10.1016/j.pbb.2019.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Del Sole A, Gambini A, Falini A et al (2002) In vivo neurochemistry with emission tomography and magnetic resonance spectroscopy: clinical applications. Eur Radiol 12:2582–2599. https://doi.org/10.1007/s00330-002-1419-x

    Article  PubMed  Google Scholar 

  16. Wang X, Hu X, Xie P et al (2015) Comparison of magnetic resonance spectroscopy and positron emission tomography in detection of tumor recurrence in posttreatment of glioma: a diagnostic meta-analysis. Asia Pac J Clin Oncol 11:97–105. https://doi.org/10.1111/ajco.12202

    Article  PubMed  Google Scholar 

  17. Stagg C, Rothman D (2014) Magnetic resonance spectroscopy—tools for neuroscience research and emerging clinical applications, 1st edn. Elsevier, London

    Google Scholar 

  18. Yan H-D, Ishihara K, Serikawa T, Sasa M (2003) Activation by N-acetyl-l-aspartate of acutely dissociated hippocampal neurons in rats via metabotropic glutamate receptors. Epilepsia 44:1153–1159. https://doi.org/10.1046/j.1528-1157.2003.49402.x

    Article  CAS  PubMed  Google Scholar 

  19. Kantarci K, Petersen RC, Boeve BF et al (2004) 1H MR spectroscopy in common dementias. Neurology 63:1393–1398. https://doi.org/10.1212/01.wnl.0000141849.21256.ac

    Article  CAS  PubMed  Google Scholar 

  20. Gillaspy GE (2011) The cellular language of myo-inositol signaling. New Phytol 192:823–839. https://doi.org/10.1111/j.1469-8137.2011.03939.x

    Article  CAS  PubMed  Google Scholar 

  21. Davanzo P, Thomas MA, Yue K et al (2001) Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology 24:359–369. https://doi.org/10.1016/S0893-133X(00)00207-4

    Article  CAS  PubMed  Google Scholar 

  22. Rango M, Cogiamanian F, Marceglia S et al (2008) Myoinositol content in the human brain is modified by transcranial direct current stimulation in a matter of minutes: a 1H-MRS study. Magn Reson Med 60:782–789. https://doi.org/10.1002/mrm.21709

    Article  CAS  PubMed  Google Scholar 

  23. Xu S, Yang J, Li CQ et al (2005) Metabolic alterations in focally activated primary somatosensory cortex of alpha-chloralose-anesthetized rats measured by 1H MRS at 11.7 T. Neuroimage 28:401–409. https://doi.org/10.1016/j.neuroimage.2005.06.016

    Article  PubMed  Google Scholar 

  24. Hesslinger B, Thiel T, Tebartz van Elst L et al (2001) Attention-deficit disorder in adults with or without hyperactivity: where is the difference? A study in humans using short echo (1)H-magnetic resonance spectroscopy. Neurosci Lett 304:117–119. https://doi.org/10.1016/s0304-3940(01)01730-x

    Article  CAS  PubMed  Google Scholar 

  25. Perlov E, Philipsen A, Matthies S et al (2009) Spectroscopic findings in attention-deficit/hyperactivity disorder: review and meta-analysis. World J Biol Psychiatry 10:355–365. https://doi.org/10.1080/15622970802176032

    Article  PubMed  Google Scholar 

  26. Aoki Y, Inokuchi R, Suwa H, Aoki A (2013) Age-related change of neurochemical abnormality in attention-deficit hyperactivity disorder: a meta-analysis. Neurosci Biobehav Rev 37:1692–1701. https://doi.org/10.1016/j.neubiorev.2013.04.019

    Article  CAS  PubMed  Google Scholar 

  27. Bae S, Han DH, Kim SM et al (2016) Neurochemical correlates of internet game play in adolescents with attention deficit hyperactivity disorder: a proton magnetic resonance spectroscopy (MRS) study. Psychiatry Res Neuroimaging 254:10–17. https://doi.org/10.1016/j.pscychresns.2016.05.006

    Article  PubMed  Google Scholar 

  28. Bauer J, Werner A, Kohl W et al (2018) Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex. World J Biol Psychiatry 19:538–546. https://doi.org/10.1080/15622975.2016.1262060

    Article  PubMed  Google Scholar 

  29. Benamor L (2014) (1)H-Magnetic resonance spectroscopy study of stimulant medication effect on brain metabolites in French Canadian children with attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat 10:47–54. https://doi.org/10.2147/NDT.S52338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bollmann S, Ghisleni C, Poil SS et al (2015) Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry 5:e589. https://doi.org/10.1038/tp.2015.79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ende G, Cackowski S, Van Eijk J et al (2016) Impulsivity and aggression in female BPD and ADHD patients: association with ACC glutamate and GABA concentrations. Neuropsychopharmacology 41:410–418. https://doi.org/10.1038/npp.2015.153

    Article  CAS  PubMed  Google Scholar 

  32. Endres D, Perlov E, Maier S et al (2015) Normal neurochemistry in the prefrontal and cerebellar brain of adults with attention-deficit hyperactivity disorder. Front Behav Neurosci 9:242. https://doi.org/10.3389/fnbeh.2015.00242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hai T, Duffy H, Lemay J-F et al (2020) Neurochemical correlates of executive function in children with attention-deficit/hyperactivity disorder. J Can Acad Child Adolesc Psychiatry 29:15–25

    PubMed  PubMed Central  Google Scholar 

  34. Maltezos S, Horder J, Coghlan S et al (2014) Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Transl Psychiatry 4:e373. https://doi.org/10.1038/tp.2014.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Naaijen J, Forde NJ, Lythgoe DJ et al (2017) Fronto-striatal glutamate in children with Tourette’s disorder and attention-deficit/hyperactivity disorder. Neuroimage Clin 13:16–23. https://doi.org/10.1016/j.nicl.2016.11.013

    Article  PubMed  Google Scholar 

  36. Naaijen J, Lythgoe DJ, Zwiers MP et al (2018) Anterior cingulate cortex glutamate and its association with striatal functioning during cognitive control. Eur Neuropsychopharmacol 28:381–391. https://doi.org/10.1016/j.euroneuro.2018.01.002

    Article  CAS  PubMed  Google Scholar 

  37. Puts NA, Ryan M, Oeltzschner G et al (2020) Reduced striatal GABA in unmedicated children with ADHD at 7T. Psychiatry Res Neuroimaging 301:111082. https://doi.org/10.1016/j.pscychresns.2020.111082

    Article  PubMed  Google Scholar 

  38. Tafazoli S, O’Neill J, Bejjani A et al (2013) 1H MRSI of middle frontal gyrus in pediatric ADHD. J Psychiatr Res 47:505–512. https://doi.org/10.1016/j.jpsychires.2012.11.011

    Article  PubMed  Google Scholar 

  39. O’Neill J, O’Connor MJ, Yee V et al (2019) Differential neuroimaging indices in prefrontal white matter in prenatal alcohol-associated ADHD versus idiopathic ADHD. Birth Defects Res 111:797–811. https://doi.org/10.1002/bdr2.1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jamie N (2014) Spectral quantification and pitfalls in interpreting magnetic resonance spectroscopy data: what to look out for. In: Stagg C, Rothman D (eds) Magnetic resonance spectroscopy: tools for neuroscience research and emerging clinical applications, 1st edn. Elsevier, London, pp 49–67

    Google Scholar 

  41. Vidor MV, Panzenhagen AC, Martins AR et al (2021) Attention-deficit/hyperactivity disorder and brain metabolites from proton magnetic resonance spectroscopy: a systematic review and meta-analysis protocol. Trends Psychiatry Psychother 43:1–8. https://doi.org/10.47626/2237-6089-2019-0111

    Article  PubMed  PubMed Central  Google Scholar 

  42. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700. https://doi.org/10.1136/bmj.b2700

    Article  PubMed  PubMed Central  Google Scholar 

  43. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535. https://doi.org/10.1136/bmj.b2535

    Article  PubMed  PubMed Central  Google Scholar 

  44. Higgins JPT, Thomas J, Chandler J, et al (2020) Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). http://www.training.cochrane.org/handbook. Accessed 28 Jul 2020

  45. Pires GN, Bezerra AG, Tufik S, Andersen ML (2016) Effects of experimental sleep deprivation on anxiety-like behavior in animal research: systematic review and meta-analysis. Neurosci Biobehav Rev 68:575–589. https://doi.org/10.1016/j.neubiorev.2016.06.028

    Article  PubMed  Google Scholar 

  46. Pires GN, Bezerra AG, Tufik S, Andersen ML (2016) Effects of acute sleep deprivation on state anxiety levels: a systematic review and meta-analysis. Sleep Med 24:109–118. https://doi.org/10.1016/j.sleep.2016.07.019

    Article  PubMed  Google Scholar 

  47. Ankit R (2020) WebPlotDigitizer. Automeris, Pacifica, California, USA

  48. Li BSY, Wang H, Gonen O (2003) Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy. Magn Reson Imaging 21:923–928. https://doi.org/10.1016/s0730-725x(03)00181-4

    Article  CAS  PubMed  Google Scholar 

  49. The Ottawa Hospital (2019) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 22 Nov 2019

  50. Sterne JAC, Sutton AJ, Ioannidis JPA et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002. https://doi.org/10.1136/bmj.d4002

    Article  PubMed  Google Scholar 

  51. Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. https://doi.org/10.1002/sim.1186

    Article  PubMed  Google Scholar 

  52. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration (2014) Review Manager (RevMan)

  53. Haynes W (2013) Benjamini–Hochberg method. In: Dubitzky W, Wolkenhauer O, Cho K-H, Yokota H (eds) Encyclopedia of systems biology. Springer, New York, pp 78–78

    Chapter  Google Scholar 

  54. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc: Ser B (Methodol) 57:289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x

    Article  Google Scholar 

  55. Alvarado A, Zapata G, Diaz L et al (2003) Proton magnetic resonance spectroscopy and electroencephalographicactivity in attention deficit disorder. Vitae Academia Biomédica Digital

  56. Arcos-Burgos M, Londoño AC, Pineda DA et al (2012) Analysis of brain metabolism by proton magnetic resonance spectroscopy (1H-MRS) in attention-deficit/hyperactivity disorder suggests a generalized differential ontogenic pattern from controls. Atten Defic Hyperact Disord 4:205–212. https://doi.org/10.1007/s12402-012-0088-0

    Article  PubMed  PubMed Central  Google Scholar 

  57. Carrey NJ, MacMaster FP, Gaudet L, Schmidt MH (2007) Striatal creatine and glutamate/glutamine in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 17:11–17. https://doi.org/10.1089/cap.2006.0008

    Article  PubMed  Google Scholar 

  58. Colla M, Ende G, Alm B et al (2008) Cognitive MR spectroscopy of anterior cingulate cortex in ADHD: elevated choline signal correlates with slowed hit reaction times. J Psychiatr Res 42:587–595. https://doi.org/10.1016/j.jpsychires.2007.06.006

    Article  PubMed  Google Scholar 

  59. Courvoisie H, Hooper SR, Fine C et al (2004) Neurometabolic functioning and neuropsychological correlates in children with ADHD-H: preliminary findings. J Neuropsychiatry Clin Neurosci 16:63–69. https://doi.org/10.1176/jnp.16.1.63

    Article  CAS  PubMed  Google Scholar 

  60. Dramsdahl M, Ersland L, Plessen KJ et al (2011) Adults with attention-deficit/hyperactivity disorder—a brain magnetic resonance spectroscopy study. Front Psychiatry 2:65. https://doi.org/10.3389/fpsyt.2011.00065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Edden RAE, Crocetti D, Zhu H et al (2012) Reduced GABA concentration in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 69:750–753. https://doi.org/10.1001/archgenpsychiatry.2011.2280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fayed N, Modrego PJ (2005) Comparative study of cerebral white matter in autism and attention-deficit/hyperactivity disorder by means of magnetic resonance spectroscopy. Acad Radiol 12:566–569. https://doi.org/10.1016/j.acra.2005.01.016

    Article  PubMed  Google Scholar 

  63. Fayed N, Modrego PJ, Castillo J, Dávila J (2007) Evidence of brain dysfunction in attention deficit-hyperactivity disorder: a controlled study with proton magnetic resonance spectroscopy. Acad Radiol 14:1029–1035. https://doi.org/10.1016/j.acra.2007.05.017

    Article  PubMed  Google Scholar 

  64. Ferreira PEMS, Palmini A, Bau CHD et al (2009) Differentiating attention-deficit/hyperactivity disorder inattentive and combined types: a (1)H-magnetic resonance spectroscopy study of fronto-striato-thalamic regions. J Neural Transm 116:623–629. https://doi.org/10.1007/s00702-009-0191-3

    Article  PubMed  Google Scholar 

  65. Hammerness P, Biederman J, Petty C et al (2012) Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study. CNS Neurosci Ther 18:34–40. https://doi.org/10.1111/j.1755-5949.2010.00226.x

    Article  CAS  PubMed  Google Scholar 

  66. Jin Z, Zang YF, Zeng YW et al (2001) Striatal neuronal loss or dysfunction and choline rise in children with attention-deficit hyperactivity disorder: a 1H-magnetic resonance spectroscopy study. Neurosci Lett 315:45–48. https://doi.org/10.1016/s0304-3940(01)02315-1

    Article  CAS  PubMed  Google Scholar 

  67. MacMaster FP, Carrey N, Sparkes S, Kusumakar V (2003) Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder. Biol Psychiatry 53:184–187. https://doi.org/10.1016/s0006-3223(02)01401-4

    Article  PubMed  Google Scholar 

  68. Moore CM, Biederman J, Wozniak J et al (2006) Differences in brain chemistry in children and adolescents with attention deficit hyperactivity disorder with and without comorbid bipolar disorder: a proton magnetic resonance spectroscopy study. Am J Psychiatry 163:316–318. https://doi.org/10.1176/appi.ajp.163.2.316

    Article  PubMed  PubMed Central  Google Scholar 

  69. Perlov E, Philipsen A, Hesslinger B et al (2007) Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder—a magnet resonance spectroscopy study. J Psychiatr Res 41:934–941. https://doi.org/10.1016/j.jpsychires.2006.12.007

    Article  CAS  PubMed  Google Scholar 

  70. Perlov E, Tebarzt van Elst L, Buechert M et al (2010) H1-MR-spectroscopy of cerebellum in adult attention deficit/hyperactivity disorder. J Psychiatr Res 44:938–943. https://doi.org/10.1016/j.jpsychires.2010.02.016

    Article  CAS  PubMed  Google Scholar 

  71. Soliva JC, Moreno A, Fauquet J et al (2010) Cerebellar neurometabolite abnormalities in pediatric attention/deficit hyperactivity disorder: a proton MR spectroscopic study. Neurosci Lett 470:60–64. https://doi.org/10.1016/j.neulet.2009.12.056

    Article  CAS  PubMed  Google Scholar 

  72. Sparkes SJ, MacMaster FP, Carrey NC (2004) Proton magnetic resonance spectroscopy and cognitivefunction in pediatric attention-deficit/hyperactive disorder

  73. Sun L, Jin Z, Zang Y et al (2005) Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study. Brain Dev 27:340–344. https://doi.org/10.1016/j.braindev.2004.09.004

    Article  PubMed  Google Scholar 

  74. de Vasconcelos MM (2005) Utilidade da espectroscopia por RM no diagnóstico do TDAH. Doctoral dissertation, Universidade Federal Fluminense

  75. Yang P, Wu M-T, Dung S-S, Ko C-W (2010) Short-TE proton magnetic resonance spectroscopy investigation in adolescents with attention-deficit hyperactivity disorder. Psychiatry Res 181:199–203. https://doi.org/10.1016/j.pscychresns.2009.10.001

    Article  PubMed  Google Scholar 

  76. Yeo RA, Hill DE, Campbell RA et al (2003) Proton magnetic resonance spectroscopy investigation of the right frontal lobe in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 42:303–310. https://doi.org/10.1097/00004583-200303000-00010

    Article  PubMed  Google Scholar 

  77. Bechara A, Damasio H, Damasio AR, Lee GP (1999) Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making. J Neurosci 19:5473–5481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bechara A, Tranel D, Damasio H (2000) Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain 123(Pt 11):2189–2202. https://doi.org/10.1093/brain/123.11.2189

    Article  PubMed  Google Scholar 

  79. Hänsel A, von Känel R (2008) The ventro-medial prefrontal cortex: a major link between the autonomic nervous system, regulation of emotion, and stress reactivity? Biopsychosoc Med 2:21. https://doi.org/10.1186/1751-0759-2-21

    Article  PubMed  PubMed Central  Google Scholar 

  80. Shamay-Tsoory SG, Tomer R, Berger BD, Aharon-Peretz J (2003) Characterization of empathy deficits following prefrontal brain damage: the role of the right ventromedial prefrontal cortex. J Cogn Neurosci 15:324–337. https://doi.org/10.1162/089892903321593063

    Article  CAS  PubMed  Google Scholar 

  81. Beadle JN, Paradiso S, Tranel D (2018) Ventromedial prefrontal cortex is critical for helping others who are suffering. Front Neurol 9:288. https://doi.org/10.3389/fneur.2018.00288

    Article  PubMed  PubMed Central  Google Scholar 

  82. Boes AD, Bechara A, Tranel D et al (2009) Right ventromedial prefrontal cortex: a neuroanatomical correlate of impulse control in boys. Soc Cogn Affect Neurosci 4:1–9. https://doi.org/10.1093/scan/nsn035

    Article  PubMed  Google Scholar 

  83. Faraone SV, Biederman J, Mick E (2006) The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med 36:159–165. https://doi.org/10.1017/S003329170500471X

    Article  PubMed  Google Scholar 

  84. Mitchell ND, Baker GB (2010) An update on the role of glutamate in the pathophysiology of depression. Acta Psychiatr Scand 122:192–210. https://doi.org/10.1111/j.1600-0447.2009.01529.x

    Article  CAS  PubMed  Google Scholar 

  85. Ramadan S, Lin A, Stanwell P (2013) Glutamate and glutamine: a review of in vivo MRS in the human brain. NMR Biomed 26:1630–1646. https://doi.org/10.1002/nbm.3045

    Article  CAS  PubMed  Google Scholar 

  86. Maria YL, Price AN, Puts NAJ et al (2021) Simultaneous quantification of GABA, Glx and GSH in the neonatal human brain using magnetic resonance spectroscopy. Neuroimage 233:117930. https://doi.org/10.1016/j.neuroimage.2021.117930

    Article  CAS  PubMed  Google Scholar 

  87. Sonnewald U, Schousboe A (2016) Introduction to the Glutamate–Glutamine cycle. Adv Neurobiol 13:1–7. https://doi.org/10.1007/978-3-319-45096-4_1

    Article  PubMed  Google Scholar 

  88. Erecińska M, Silver IA (1990) Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 35:245–296. https://doi.org/10.1016/0301-0082(90)90013-7

    Article  PubMed  Google Scholar 

  89. Cooper AJL (2012) The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis. Neurochem Res 37:2439–2455. https://doi.org/10.1007/s11064-012-0803-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. de Graaf AA, Deutz NE, Bosman DK et al (1991) The use of in vivo proton NMR to study the effects of hyperammonemia in the rat cerebral cortex. NMR Biomed 4:31–37. https://doi.org/10.1002/nbm.1940040106

    Article  PubMed  Google Scholar 

  91. Bosman DK, Deutz NE, De Graaf AA et al (1990) Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 12:281–290. https://doi.org/10.1002/hep.1840120215

    Article  CAS  PubMed  Google Scholar 

  92. Balkhi HM, Gul T, Banday MZ, Haq E (2014) Glutamate excitotoxicity: an insight into the mechanism. Int J Adv Res 2:361–373

    Google Scholar 

  93. Shaw P, Gornick M, Lerch J et al (2007) Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 64:921–931. https://doi.org/10.1001/archpsyc.64.8.921

    Article  PubMed  Google Scholar 

  94. Verma A, Kumar I, Verma N et al (2016) Magnetic resonance spectroscopy—revisiting the biochemical and molecular milieu of brain tumors. BBA Clin 5:170–178. https://doi.org/10.1016/j.bbacli.2016.04.002

    Article  PubMed  PubMed Central  Google Scholar 

  95. Ross B, Bluml S (2001) Magnetic resonance spectroscopy of the human brain. Anat Rec 265:54–84. https://doi.org/10.1002/ar.1058

    Article  CAS  PubMed  Google Scholar 

  96. Xin L, Tkáč I (2017) A practical guide to in vivo proton magnetic resonance spectroscopy at high magnetic fields. Anal Biochem 529:30–39. https://doi.org/10.1016/j.ab.2016.10.019

    Article  CAS  PubMed  Google Scholar 

  97. Jordan HS, Bert R, Chew P, et al (2003) Magnetic resonance spectroscopy for brain tumors. Agency for Healthcare Research and Quality (US), Rockville

  98. AIM Specialty Health (2017) Appropriate use criteria: magnetic resonance spectroscopy. AIM Specialty Health

  99. Glunde K, Jiang L, Moestue SA, Gribbestad IS (2011) MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer. NMR Biomed 24:673–690. https://doi.org/10.1002/nbm.1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. De Stefano N, Filippi M, Miller D et al (2007) Guidelines for using proton MR spectroscopy in multicenter clinical MS studies. Neurology 69:1942–1952. https://doi.org/10.1212/01.wnl.0000291557.62706.d3

    Article  PubMed  Google Scholar 

  101. Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates, 7th edn. Academic Press, Amsterdam

    Google Scholar 

  102. Ferry B, Gervasoni D, Vogt C (2014) Stereotaxic neurosurgery in laboratory rodent. Springer Paris, Paris

    Book  Google Scholar 

  103. De Vloo P, Nuttin B (2019) Stereotaxy in rat models: current state of the art, proposals to improve targeting accuracy and reporting guideline. Behav Brain Res 364:457–463. https://doi.org/10.1016/j.bbr.2017.10.035

    Article  PubMed  Google Scholar 

  104. Carrey N, MacMaster FP, Fogel J et al (2003) Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study. Clin Neuropharmacol 26:218–221. https://doi.org/10.1097/00002826-200307000-00013

    Article  PubMed  Google Scholar 

  105. Wiguna T, Guerrero APS, Wibisono S, Sastroasmoro S (2012) Effect of 12-week administration of 20-mg long-acting methylphenidate on Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the prefrontal cortices of school-age children in Indonesia: a study using 1H magnetic resonance spectroscopy (MRS). Clin Neuropharmacol 35:81–85. https://doi.org/10.1097/WNF.0b013e3182452572

    Article  CAS  PubMed  Google Scholar 

  106. Spencer TJ, Brown A, Seidman LJ et al (2013) Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies. J Clin Psychiatry 74:902–917. https://doi.org/10.4088/JCP.12r08287

    Article  PubMed  PubMed Central  Google Scholar 

  107. Licata SC, Renshaw PF (2010) Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. Ann N Y Acad Sci 1187:148–171. https://doi.org/10.1111/j.1749-6632.2009.05143.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schmaal L, Veltman DJ, Nederveen A et al (2012) N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 37:2143–2152. https://doi.org/10.1038/npp.2012.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bolton J, Moore GJ, MacMillan S et al (2001) Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD. J Am Acad Child Adolesc Psychiatry 40:903–906. https://doi.org/10.1097/00004583-200108000-00011

    Article  CAS  PubMed  Google Scholar 

  110. Taylor M, Murphy SE, Selvaraj S et al (2008) Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectroscopy. J Psychopharmacol (Oxford) 22:473–476. https://doi.org/10.1177/0269881107081510

    Article  CAS  Google Scholar 

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Author notes

  1. Marcos Vinícius Vidor and Alana Castro Panzenhagen have contributed equally to this work.

Authors and Affiliations

  1. Programa de Transtornos de Déficit de Atenção/Hiperatividade em Adultos (ProDAH-A), Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil

    Marcos Vinícius Vidor, Alana Castro Panzenhagen, Renata Basso Cupertino, Cibele Edom Bandeira, Felipe Almeida Picon, Bruna Santos da Silva, Eduardo Schneider Vitola, Diego Luiz Rovaris, Claiton Henrique Dotto Bau & Eugênio Horácio Grevet

  2. Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, 2400, 2º andar, Porto Alegre, RS, 90035-003, Brazil

    Marcos Vinícius Vidor, Luis Augusto Rohde & Eugênio Horácio Grevet

  3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, RS, Brazil

    Alana Castro Panzenhagen

  4. Serdil-Clínica de Radiologia e Diagnóstico de Imagem, Porto Alegre, RS, Brazil

    Alexandre Ribeiro Martins

  5. Department of Psychiatry, University of Vermont, Burlington, VT, USA

    Renata Basso Cupertino

  6. Departamento de Genética, Instituto de Biociências, UFRGS, Porto Alegre, RS, Brazil

    Cibele Edom Bandeira & Claiton Henrique Dotto Bau

  7. Instituto Nacional de Psiquiatria do Desenvolvimento (INPD), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Porto Alegre, RS, Brazil

    Luis Augusto Rohde

  8. Instituto de Ciências Biomédicas, Departamento de Fisiologia e Biofísica, Universidade de São Paulo (USP), São Paulo, SP, Brazil

    Diego Luiz Rovaris

Authors
  1. Marcos Vinícius Vidor
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  2. Alana Castro Panzenhagen
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  3. Alexandre Ribeiro Martins
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  4. Renata Basso Cupertino
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  5. Cibele Edom Bandeira
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  6. Felipe Almeida Picon
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  7. Bruna Santos da Silva
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  8. Eduardo Schneider Vitola
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  9. Luis Augusto Rohde
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  11. Claiton Henrique Dotto Bau
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  12. Eugênio Horácio Grevet
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Corresponding author

Correspondence to Eugênio Horácio Grevet.

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Conflict of interest

Mr. Vidor is the recipient of a PhD scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—PBE-DPM, Bolsa Especial para Doutorado em Pesquisa Médica). Mr. Martins is affiliated to private companies related to clinical imaging services. Luis Augusto Rohde has received honoraria, has been on the speakers’ bureau/advisory board, and/or has acted as a consultant for Medice, Novartis/Sandoz, and Shire/Takeda in the last two years; and receives authorship royalties from OxfordPress and ArtMed. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him has received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Janssen-Cilag, Novartis/Sandoz, and Shire/Takeda. Eugênio Horácio Grevet has served as a speakers’ bureau/advisory board for Shire Pharmaceuticals in the past 3 years; and has received travel awards from Shire for taking part in psychiatric meetings. Ms. Panzenhagen, Dr. Cupertino, Ms. Bandeira, Dr. Picon, Dr. Silva, Dr. Vitola, Dr. Rovaris, and Dr. Bau reported no biomedical financial interests or potential conflicts of interest.

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Vidor, M.V., Panzenhagen, A.C., Martins, A.R. et al. Emerging findings of glutamate–glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies. Eur Arch Psychiatry Clin Neurosci 272, 1395–1411 (2022). https://doi.org/10.1007/s00406-022-01397-6

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