Abstract
Brain monoaminergic function is involved in the pathophysiology of psychiatric disorders. The loudness dependence (LD) of the N1/P2 component of auditory evoked potentials has been proposed as a noninvasive indicator of central serotonergic function, whereas single photon emission computed tomography (SPECT) and [123I]β-CIT can be used to visualize both serotonin (SERT) and dopamine transporters (DAT). The aim of the study was to correlate LD and SPECT measures in patients with obsessive-compulsive disorder, a condition with evidence for a serotonergic dysfunction. A total of 10 subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities. The LD of the relevant subcomponents (tangential dipoles) was investigated using dipole source analysis. SPECT was performed 20–24 h after injection of a mean 140 MBq [123I]β-CIT. As a measure of brain SERT and DAT availabilities, a ratio of specific to nonspecific [123I]β-CIT binding for the midbrain·pons region (SERT) and the striatum (DAT) was used. The LD of the right tangential dipole correlated significantly with both SERT and DAT availabilities (Pearson's correlations: ρ=0.69, p<0.05, and ρ=0.80, p<0.01, respectively). The correlations remained significant after controlling for the effects of age, gender, and severity of clinical symptoms. Associations between LD and both SERT and DAT availabilities further validate the use of neurophysiological approaches as noninvasive indirect measures of neurochemical brain function and point at a hypothesized interconnection of central monoaminergic systems.
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References
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC.
Baxter Jr LR, Schwartz JM, Bergman KS, Szuba MP, Guze BH, Mazziotta JC et al (1992). Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry 49: 681–689.
Beck AT, Ward CH, Mendelson J, Mock J, Erbaugh J (1961). An inventory for measuring depression. Arch Gen Psychiatry 4: 564–571.
Berger B, Gaspar P, Verney C (1991). Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci 14: 21–27.
Boja JW, Mitchell WM, Patel A, Kopajtic TA, Carroll FI, Lewin AH et al (1992). High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 12: 27–36.
Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I (1993). SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT. Binding kinetics in the human brain. J Neural Transm Gen Sect 94: 137–146.
Bruneau N, Barthelemy C, Jouve J, Lelord G (1986). Frontal auditory-evoked potential augmenting-reducing and urinary homovanillic acid. Neuropsychobiology 16: 78–84.
Chang LT (1978). A method of attenuation correction in radionuclide computed tomography. IEEE Trans Nucl Sci 25: 638–643.
Croft RJ, Klugman A, Baldeweg T, Gruzelier JH (2001). Electrophysiological evidence of serotonergic impairment in long-term MDMA (‘ecstasy’) users. Am J Psychiatry 158: 1687–1692.
Frankle WG, Huang Y, Hwang DR, Talbot PS, Slifstein M, Van Heertum R et al (2004). Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med 45: 682–694.
Gallinat J, Bottlender R, Juckel G, Munke-Puchner A, Stotz G, Kuss HJ et al (2000). The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression. Psychopharmacology 148: 404–411.
Gallinat J, Senkowski D, Wernicke C, Juckel G, Becker I, Sander T et al (2003). Allelic variants of the functional promoter polymorphism of the human serotonin transporter gene is associated with auditory cortical stimulus processing. Neuropsychopharmacology 28: 530–532.
Gaspar P, Berger B, Febvret A, Vigny A, Henry JP (1989). Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase. J Comp Neurol 279: 249–271.
Goodman WK (1999). Obsessive-compulsive disorder: diagnosis and treatment. J Clin Psychiatry 60: 27–32.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR et al (1989a). The Yale–Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 46: 1012–1016.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al (1989b). The Yale–Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 46: 1006–1011.
Hegerl U, Gallinat J, Juckel G (2001). Event-related potentials. Do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J Affect Disord 62: 93–100.
Hegerl U, Gallinat J, Mrowinski D (1994). Intensity dependence of auditory evoked dipole source activity. Int J Psychophysiol 17: 1–13.
Hegerl U, Juckel G (1993). Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 33: 173–187.
Heinz A, Ragan P, Jones DW, Hommer D, Williams W, Knable MB et al (1998). Reduced central serotonin transporters in alcoholism. Am J Psychiatry 155: 1544–1549.
Hervé D, Pickel VM, Joh TH, Beaudet A (1987). Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 435: 71–83.
Innis RB, Baldwin RM, Sybirska E, Zea Y, Laruelle M, Al-Tikriti M et al (1991). Single photon emission computed tomography imaging of monoamine reuptake sites in primate brain with [123I]CIT. Eur J Pharmacol 200: 369–370.
Innis RB, Seibyl JP, Scanley BE, Laruelle M, Abi-Dargham A, Wallace E et al (1993). Single photon emission computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson disease. Proc Natl Acad Sci USA 90: 11965–11969.
Jacobsen LK, Staley JK, Malison RT, Zoghbi SS, Seibyl JP, Kosten TR et al (2000). Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients. Am J Psychiatry 157: 1134–1140.
Juckel G, Hegerl U, Molnar M, Csepe V, Karmos G (1999). Auditory evoked potentials reflect serotonergic neuronal activity—a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus. Neuropsychopharmacology 21: 710–716.
Juckel G, Molnar M, Hegerl U, Csepe V, Karmos G (1997). Auditory-evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats. Biol Psychiatry 41: 1181–1195.
Kauppinen T, Bergstrom K, Heikman P, Hiltunen J, Ahonen A (2003). Biodistribution and radiation dosimetry of 123I ADAM in healthy subjects: preliminary results. Eur J Nucl Med Mol Imaging 30: 132–136.
Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM et al (2003). Changes in human in vivo serotonin and dopamine transporter availability during chronic antidepressant administration. Neuropsychopharmacology 28: 413–420.
Kuikka JT, Bergstrom KA, Vanninen E, Laulumaa V, Hartikainen P, Lansimies E (1993). Initial experience with single-photon emission tomography using iodine-123-labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane in human brain. Eur J Nucl Med 20: 783–786.
Laruelle M, Baldwin RM, Malison RT, Zea-Ponce Y, Zoghbi SS, Al-Tikriti MS et al (1993). SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT: pharmacological characterization of brain uptake in nonhuman primates. Synapse 13: 295–309.
Laruelle M, Wallace E, Seibyl JP, Baldwin RM, Zea-Ponce Y, Zoghbi SS et al (1994). Graphical, kinetic, and equilibrium analyses of in vivo [123I]beta-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab 14: 982–994.
Leonard H, Swedo S, Rapoport JL, Coffey M, Cheslow D (1988). Treatment of childhood obsessive compulsive disorder with clomipramine and desmethylimipramine: a double-blind crossover comparison. Psychopharmacol Bull 24: 93–95.
Lewis DA, Campbell MJ, Foote SL, Goldstein M, Morrison JH (1987). The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific. J Neurosci 7: 279–290.
Lewis DA, Campbell MJ, Foote SL, Morrison JH (1986). The monoaminergic innervation of primate neocortex. Hum Neurobiol 5: 181–188.
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L et al (1998). Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44: 1090–1098.
Meyer JH, Wilson AA, Ginovart N, Goulding V, Hussey D, Hood K et al (2001). Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. Am J Psychiatry 158: 1843–1849.
Moukhles H, Bosler O, Bolam JP, Vallee A, Umbriaco D, Geffard M et al (1997). Quantitative and morphometric data indicate precise cellular interactions between serotonin terminals and postsynaptic targets in rat substantia nigra. Neuroscience 76: 1159–1171.
Mozley PD, Kim HJ, Gur RC, Tatsch K, Muenz LR, McElgin WT et al (1996). Iodine-123-IPT SPECT imaging of CNS dopamine transporters: nonlinear effects of normal aging on striatal uptake values. J Nucl Med 37: 1965–1970.
Mulert C, Juckel G, Augustin H, Hegerl U (2002). A tomographic method for the loudness dependence analysis of the auditory evoked N1/P2-response in the primary auditory cortex. Clin Neurophysiol 113: 1566–1572.
Murphy DL (1990). Peripheral indices of central serotonin function in human. Ann NY Acad Sci 600: 282–296.
Näätänen R, Picton T (1987). The N1 wave of the human electric and magnetic response to sound: a review and an analysis of the component structure. Psychophysiology 24: 375–425.
Norra C, Mrazek M, Tuchtenhagen F, Gobbele R, Buchner H, Sass H et al (2003). Enhanced intensity dependence as a marker of low serotonergic neurotransmission in borderline personality disorder. J Psychiatr Res 37: 23–33.
Oya S, Choi SR, Hou C, Mu M, Kung MP, Acton PD et al (2000). 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand. Nucl Med Biol 27: 249–254.
Parsey RV, Kegeles LS, Hwang DR, Simpson N, Abi-Dargham A, Mawlawi O et al (2000). In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652. J Nucl Med 41: 1465–1477.
Parsons LH, Justice Jr JB (1993). Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res 606: 195–199.
Pirker W, Asenbaum S, Hauk M, Kandlhofer S, Tauscher J, Willeit M et al (2000). Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging. J Nucl Med 41: 36–44.
Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G et al (1995). Beta-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect 100: 247–256.
Pogarell O, Hamann C, Pöpperl G, Juckel G, Choukèr M, Zaudig M et al (2003). Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biol Psychiatry 54: 1406–1413.
Ryding E, Lindstrom M, Bradvik B, Grabowski M, Bosson P, Traskman-Bendz L et al (2004). A new model for separation between brain dopamine and serotonin transporters in 123I-β-CIT SPECT measurements: normal values and sex and age dependence. Eur J Nucl Med Mol Imaging print copy in press (originally published online March 11, 2004, at http://springerlink.metapress.com/media/3D32QPRRVQCFD7NWDRWQ/Contributions/U/U/H/J/UUHJWMJPP1066495_html/fulltext.html).
Saxena S, Brody AL, Maidment KM, Dunkin JJ, Colgan M, Alborzian S et al (1999). Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder. Neuropsychopharmacology 21: 683–693.
Saxena S, Rauch SL (2000). Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin N Am 23: 563–586.
Scherg M, Berg P (1996). New concepts of brain source imaging and localization. Electroencephalogr Clin Neurophysiol Suppl 46: 127–137.
Scherg M, Picton TW (1991). Separation and identification of event-related potential components by brain electric source analysis. Electroencephalogr Clin Neurophysiol Suppl 42: 24–37.
Scherg M, Vajsar J, Picton TW (1989). Source analysis of the late human auditory evoked potentials. J Cogn Neurosci 4: 336–355.
Staley JK, Basile M, Flynn DD, Mash DC (1994). Visualizing dopamine and serotonin transporters in the human brain with the potent cocaine analogue [125I]RTI-55: in vitro binding and autoradiographic characterization. J Neurochem 62: 549–556.
Stein DJ (2002). Obsessive-compulsive disorder. Lancet 360: 397–405.
Tatsch K, Asenbaum S, Bartenstein P, Catafau A, Halldin C, Pilowski L et al (2002). EANM procedure guidelines for brain neurotransmission SPET using 123 I-labelled dopamine transporter ligands. Eur J Nucl Med Mol Imaging 29: BP30–BP35.
Tauscher J, Pirker W, de Zwaan M, Asenbaum S, Brucke T, Kasper S (1999). In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment. Eur Neuropsychopharmacol 9: 177–179.
Tauscher J, Pirker W, Willeit M, de Zwaan M, Bailer U, Neumeister A et al (2001). [123I] beta-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa. Biol Psychiatry 49: 326–332.
Tuchtenhagen F, Daumann J, Norra C, Gobbele R, Becker S, Pelz S et al (2000). High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users. Neuropsychopharmacology 22: 608–617.
Von Knorring L, Perris C (1981). Biochemistry of the augmenting-reducing response in visual evoked potentials. Neuropsychobiology 7: 1–8.
Willeit M, Praschak-Rieder N, Neumeister A, Pirker W, Asenbaum S, Vitouch O et al (2000). [123I]-beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol Psychiatry 47: 482–489.
Wilson AA, Ginovart N, Hussey D, Meyer J, Houle S (2002). In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography. Nucl Med Biol 29: 509–515.
Wittchen HU, Zaudig M, Fydrich T (1997). SKID—Strukturiertes Klinisches Interview Für DSM IV. Achse I and II: Handanweisungen. Hogrefe Verlag: Goettingen, Germany.
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This work was supported by a grant from the Faculty of Medicine of the Ludwig-Maximilians-University of Munich (FöFoLe No. 119).
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Pogarell, O., Tatsch, K., Juckel, G. et al. Serotonin and Dopamine Transporter Availabilities Correlate with the Loudness Dependence of Auditory Evoked Potentials in Patients with Obsessive-Compulsive Disorder. Neuropsychopharmacol 29, 1910–1917 (2004). https://doi.org/10.1038/sj.npp.1300537
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