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Noninvasive Methodology (NMR)

  • Mitul A. MehtaEmail author
Living reference work entry
First Online:

Abstract

Neuroimaging with MRI provides a noninvasive means to assess drug effects in vivo. In addition to the discovery of potential markers of psychopathology, MRI methods can be used to test existing and novel compounds. The assessments can be of metabolite levels, task-based brain activation, brain connectivity, drug-related activation, and quantitative perfusion. These methods are pharmacodynamic in nature and can also be used to describe pharmacokinetic–pharmacodynamic relationships. They complement emission tomography assessments of brain penetration and dose-occupancy relationships and can extend or even be a substitute for these methods when ligands are not available, with particular value when the desired outcome is intermediate markers of function. Limitations and challenges of these methods are intrinsic to the measurement, such as vascular artifacts, but they can be overcome with additional assessments.

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References and Further Reading

  1. Abbott CC, Jaramillo A, Wilcox CE, Hamilton DA (2013) Antipsychotic drug effects in schizophrenia: a review of longitudinal fmri investigations and neural interpretations. Curr Med Chem 20:428–437PubMedPubMedCentralGoogle Scholar
  2. Allen P, Azis M, Modinos G, Bossong MG, Bonoldi I, Samson C, Quinn B, Kempton MJ, Howes OD, Stone JM, Calem M, Perez J, Bhattacharayya S, Broome MR, Grace AA, Zelaya F, Mcguire P (2017) Increased resting hippocampal and basal ganglia perfusion in people at ultra high risk for psychosis: replication in a second cohort. Schizophr Bull.  https://doi.org/10.1093/schbul/sbx169
  3. Alsop DC, Detre JA, Golay X, Gunther M, Hendrikse J, Hernandez-Garcia L, Lu H, Macintosh BJ, Parkes LM, Smits M, Van Osch MJ, Wang DJ, Wong EC, Zaharchuk G (2015) Recommended implementation of arterial spin-labeled perfusion mri for clinical applications: a consensus of the ismrm perfusion study group and the european consortium for asl in dementia. Magn Reson Med 73:102–116CrossRefPubMedGoogle Scholar
  4. Arthurs OJ, Stephenson CM, Rice K, Lupson VC, Spiegelhalter DJ, Boniface SJ, Bullmore ET (2004) Dopaminergic effects on electrophysiological and functional mri measures of human cortical stimulus-response power laws. Neuroimage 21:540–546CrossRefPubMedGoogle Scholar
  5. Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE (1997) Acute effects of cocaine on human brain activity and emotion. Neuron 19:591–611CrossRefPubMedGoogle Scholar
  6. Bullmore E, Sporns O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 10:186–198CrossRefGoogle Scholar
  7. Buonocore MH, Maddock RJ (2015) Magnetic resonance spectroscopy of the brain: a review of physical principles and technical methods. Rev Neurosci 26:609–632CrossRefPubMedGoogle Scholar
  8. Cohen ER, Ugurbil K, Kim SG (2002) Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fmri response. J Cereb Blood Flow Metab 22:1042–1053CrossRefPubMedGoogle Scholar
  9. Coimbra A, Baumgartner R, Schwarz AJ (2013) Pharmacological FMRI in drug discovery and development. In: Garrido L, Beckmann L (eds) New applications of NMR in drug discovery and development Royal Society Of ChemstryGoogle Scholar
  10. Dai W, Garcia D, De Bazelaire C, Alsop DC (2008) Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields. Magn Reson Med 60:1488–1497CrossRefPubMedPubMedCentralGoogle Scholar
  11. De Simoni S, Schwarz AJ, O’daly OG, Marquand AF, Brittain C, Gonzales C, Stephenson S, Williams SC, Mehta MA (2013) Test-retest reliability of the bold pharmacological mri response to ketamine in healthy volunteers. Neuroimage 64:75–90CrossRefPubMedGoogle Scholar
  12. Deakin JF, Lees J, Mckie S, Hallak JE, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry 65:154–164CrossRefPubMedGoogle Scholar
  13. Doyle OM, De Simoni S, Schwarz AJ, Brittain C, O’daly OG, Williams SC, Mehta MA (2013) Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents. J Pharmacol Exp Ther 345:151–160CrossRefPubMedGoogle Scholar
  14. Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley B, Oathes DJ, Etkin A, Schatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM, Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ, Liston C (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28–38CrossRefPubMedGoogle Scholar
  15. Duff EP, Vennart W, Wise RG, Howard MA, Harris RE, Lee M, Wartolowska K, Wanigasekera V, Wilson FJ, Whitlock M, Tracey I, Woolrich MW, Smith SM (2015) Learning to identify cns drug action and efficacy using multistudy FMRI data. Sci Transl Med 7:274ra16CrossRefPubMedGoogle Scholar
  16. Dukart J, Holiga S, Chatham C, Hawkins P, Forsyth A, Mcmillan R, Myers J, Lingford-Hughes AR, Nutt DJ, Merlo-Pich E, Risterucci C, Boak L, Umbricht D, Schobel S, Liu T, Mehta MA, Zelaya FO, Williams SC, Brown G, Paulus M, Honey GD, Muthukumaraswamy S, Hipp J, Bertolino A, Sambataro F (2018) Cerebral blood flow predicts differential neurotransmitter activity. Sci Rep 8:4074CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fonseka TM, Macqueen GM, Kennedy SH (2018) Neuroimaging biomarkers as predictors of treatment outcome in major depressive disorder. J Affect Disord 233:21–35CrossRefPubMedGoogle Scholar
  18. Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ (1997) Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6:218–229CrossRefPubMedGoogle Scholar
  19. Godlewska BR, Norbury R, Selvaraj S, Cowen PJ, Harmer CJ (2012) Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients. Psychol Med 42:2609–2617CrossRefPubMedPubMedCentralGoogle Scholar
  20. Handley R, Zelaya FO, Reinders AA, Marques TR, Mehta MA, O’gorman R, Alsop DC, Taylor H, Johnston A, Williams S, Mcguire P, Pariante CM, Kapur S, Dazzan P (2013) Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (RCBF) in the human brain. Hum Brain Mapp 34:272–282CrossRefPubMedGoogle Scholar
  21. Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (2012) 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 70:185–98Google Scholar
  22. Huettel SA, Song AW, Mccarthy G (2014) Functional magnetic resonance imaging, 3rd edn. Sunderland, Sinauer AssociatesGoogle Scholar
  23. Insel TR, Cuthbert BN (2015) Medicine. Brain disorders? Precisely. Science 348:499–500CrossRefPubMedGoogle Scholar
  24. Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Corlett PR, Rothman DL, Mason G, Qiu M, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman JA (2018) Utility of imaging-based biomarkers for glutamate-targeted drug development in psychotic disorders: a randomized clinical trial. JAMA Psychiatry 75:11–19CrossRefPubMedGoogle Scholar
  25. Jelen LA, King S, Mullins PG, Stone JM (2018) Beyond static measures: a review of functional magnetic resonance spectroscopy and its potential to investigate dynamic glutamatergic abnormalities in schizophrenia. J Psychopharmacol 32:497–508CrossRefPubMedGoogle Scholar
  26. Jonckers E, Shah D, Hamaide J, Verhoye M, Van Der Linden A (2015) The power of using functional FMRI on small rodents to study brain pharmacology and disease. Front Pharmacol 6:231CrossRefPubMedPubMedCentralGoogle Scholar
  27. Joules R, Doyle OM, Schwarz AJ, O’daly OG, Brammer M, Williams SC, Mehta MA (2015) Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile. Psychopharmacology 232:4205–4218CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kannurpatti SS, Motes MA, Biswal BB, Rypma B (2014) Assessment of unconstrained cerebrovascular reactivity marker for large age-range FMRI studies. PLoS One 9:E88751CrossRefPubMedPubMedCentralGoogle Scholar
  29. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive nmda antagonist, ketamine, in humans. psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214CrossRefPubMedGoogle Scholar
  30. Leppanen JM (2006) Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings. Curr Opin Psychiatry 19:34–39CrossRefPubMedGoogle Scholar
  31. Li Z, Vidorreta M, Katchmar N, Alsop DC, Wolf DH, Detre JA (2018) Effects of resting state condition on reliability, trait specificity, and network connectivity of brain function measured with arterial spin labeled perfusion MRI. Neuroimage 173:165–175CrossRefPubMedPubMedCentralGoogle Scholar
  32. Mandeville JB (2012) Iron FMRI measurements of CBV and implications for BOLD signal. Neuroimage 62:1000–1008CrossRefPubMedPubMedCentralGoogle Scholar
  33. Marquand AF, O’daly OG, De Simoni S, Alsop DC, Maguire RP, Williams SC, Zelaya FO, Mehta MA (2012) Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach. Neuroimage 60:1015–1024CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mathias EJ, Kenny A, Plank MJ, David T (2018) Integrated models of neurovascular coupling and BOLD signals: responses for varying neural activations. Neuroimage 174:69–86CrossRefPubMedGoogle Scholar
  35. Mccutcheon R, Beck K, Jauhar S, Howes OD (2017) Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophr BullGoogle Scholar
  36. Mehta MA, Schmechtig A, Kotoula V, Mccolm J, Jackson K, Brittain C, Tauscher-Wisniewski S, Kinon BJ, Morrison PD, Pollak T, Mant T, Williams SCR, Schwarz AJ (2018) Group II metabotropic glutamate receptor agonist prodrugs Ly2979165 and Ly2140023 attenuate the functional imaging response to ketamine in healthy subjects. Psychopharmacology 235:1875–1886CrossRefPubMedGoogle Scholar
  37. Merritt K, Egerton A, Kempton MJ, Taylor MJ, Mcguire PK (2016) Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73:665–674CrossRefGoogle Scholar
  38. Murphy K, Birn RM, Bandettini PA (2013) Resting-state FMRI confounds and cleanup. Neuroimage 80:349–359CrossRefPubMedPubMedCentralGoogle Scholar
  39. Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A, Howard MA (2016) A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 79:693–705CrossRefPubMedGoogle Scholar
  40. Petzold GC, Murthy VN (2011) Role of astrocytes in neurovascular coupling. Neuron 71:782–797CrossRefPubMedGoogle Scholar
  41. Pruim RHR, Mennes M, Van Rooij D, Llera A, Buitelaar JK, Beckmann CF (2015) ICA-aroma: a robust ICA-based strategy for removing motion artifacts from FMRI data. Neuroimage 112:267–277CrossRefPubMedGoogle Scholar
  42. Roalf DR, Nanga RPR, Rupert PE, Hariharan H, Quarmley M, Calkins ME, Dress E, Prabhakaran K, Elliott MA, Moberg PJ, Gur RC, Gur RE, Reddy R, Turetsky BI (2017) Glutamate imaging (glucest) reveals lower brain glucest contrast in patients on the psychosis spectrum. Mol Psychiatry 22:1298–1305CrossRefPubMedPubMedCentralGoogle Scholar
  43. Schulz KP, Bedard AV, Fan J, Hildebrandt TB, Stein MA, Ivanov I, Halperin JM, Newcorn JH (2017) Striatal activation predicts differential therapeutic responses to methylphenidate and atomoxetine. J Am Acad Child Adolesc Psychiatry 56:602–609. E2CrossRefPubMedGoogle Scholar
  44. Schwarz AJ, Becerra L, Upadhyay J, Anderson J, Baumgartner R, Coimbra A, Evelhoch J, Hargreaves R, Robertson B, Iyengar S, Tauscher J, Bleakman D, Borsook D (2011) A procedural framework for good imaging practice in pharmacological FMRI studies applied to drug development #1: processes and requirements. Drug Discov Today 16:583–593CrossRefPubMedGoogle Scholar
  45. Schwerk A, Alves FD, Pouwels PJ, Van Amelsvoort T (2014) Metabolic alterations associated with schizophrenia: a critical evaluation of proton magnetic resonance spectroscopy studies. J Neurochem 128:1–87CrossRefPubMedGoogle Scholar
  46. Smith SM, Vidaurre D, Beckmann CF, Glasser MF, Jenkinson M, Miller KL, Nichols TE, Robinson EC, Salimi-Khorshidi G, Woolrich MW, Barch DM, Ugurbil K, Van Essen DC (2013) Functional connectomics from resting-state FMRI. Trends Cogn Sci 17:666–682CrossRefPubMedPubMedCentralGoogle Scholar
  47. Snitz BE, Macdonald A 3rd, Cohen JD, Cho RY, Becker T, Carter CS (2005) Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naive state and effects of short-term atypical antipsychotic treatment. Am J Psychiatry 162:2322–2329CrossRefPubMedGoogle Scholar
  48. Warbrick T, Mobascher A, Brinkmeyer J, Musso F, Stoecker T, Shah NJ, Fink GR, Winterer G (2012) Nicotine effects on brain function during a visual oddball task: a comparison between conventional and EEG-Informed FMRI analysis. J Cogn Neurosci 24:1682–1694CrossRefPubMedGoogle Scholar
  49. Williams LM, Korgaonkar MS, Song YC, Paton R, Eagles S, Goldstein-Piekarski A, Grieve SM, Harris AW, Usherwood T, Etkin A (2015) Amygdala reactivity to emotional faces in the prediction of general and medication-specific responses to antidepressant treatment in the randomized iSPOT-D trial. Neuropsychopharmacology 40:2398–2408CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wolke S (2018) Mechanisms of reward in depression: an intervention study investigating the acute effects of lurasidone on cerebral blood flow and the neural correlates of reward and penalty processing. Phd, King’s College LondonGoogle Scholar
  51. Wong EC, Buxton RB, Frank LR (1997) Implementation of quantitative perfusion imaging techniques for functional brain mapping using pulsed arterial spin labeling. NMR Biomed 10:237–249CrossRefPubMedGoogle Scholar
  52. Zelaya FO, Fernández-Seara MA, Black KJ, Williams SCR, Mehta MA (2015) Perfusion in pharmacologic imaging. In: Bammer R (ed) MR & CT perfusion imaging: clinical applications and theoretical principles. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of NeuroimagingInstitute of Psychiatry, Psychology & Neuroscience, King’s College LondonLondonUK

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