Dokument

Zusammenfassung:
Hintergrund: Kognitive Defizite in der akuten Phase einer Depression sind hinreichend belegt, sowohl empirisch als auch durch Bildgebungsstudien (Nair et al. 1999, Harvey et al. 2004). Kaum erforscht ist, ob neuronale Auffälligkeiten nachweisbar sind, wenn die depressive Symptomatik zurückgegangen ist. Die vorliegende fMRT-Studie ist eine der wenigen, die remittierte Patienten untersucht. Besonderes Augenmerk liegt auf Gehirn-arealen, die in der akuten Phase während Arbeitsgedächtnisaufgaben hyperaktiviert sind: Der präfrontale Kortex und das anteriore Cingulum (Fossati et al. 2002). Heutzutage geht man von einer multifaktoriellen Genese depressiver Symptomatik aus. Es gibt Hinweise darauf, dass verschiedene genetische Polymorphismen Vulnerabili-tätsmarker darstellen. Kandidatengene sind folgende: Der funktionelle Polymorphismus in der Promotorregion des 5HTTLPR-Gens (Hariri et al. 2002), der funktionelle Poly-morphismus des Serotoninrezeptors 5HT1A (Domschke et al. 2006), Allelvarianten in der Promotorregion des MAO-A-Gens (Brummett et al. 2007) und der funktionelle Einzel-nukleotidpolymorphismus Val/Met im COMT-Gen (O’Hara et al. 1998). Fragestellung: Es gilt zu überprüfen, ob neuronale Auffälligkeiten auch in Remission belegbar sind und ob ein Zusammenhang der hypothetischen „Depressionsmarker“ 5HTTLPR, 5HT1A, MAO-A und COMT mit der Erkrankung aufgezeigt werden kann. Material und Methoden: 28 remittierte Patienten mit depressivem Syndrom und 28 sorgfältig gematchte Kontrollprobanden wurden rekrutiert. Es wurde eine fMRT-Messung mit geblocktem n-zurück-Paradigma (0-, 1- und 2-zurück) durchgeführt. Anschließend wurde Blut abgenommen und die Genetikanalyse ausgeführt. Die funkti-onellen Daten wurden mittels SPM 5 Software ausgewertet. Die statistische Datenerhe-bung erfolgte mit der SPSS 18.0 Software. Ergebnisse: Alle Probanden aktivierten während der n-zurück-Aufgabe ein für das verbale Arbeitsgedächtnis typisches fronto-parietales Netzwerk. Patienten wiesen verglichen mit den Kontrollprobanden bei vergleichbarer Leistung signifikant vermehrte Aktivierung im Cingulum auf. Träger der Risikoallele des HTTLPR-Polymorphismus zeigten gegenüber Nichtrisikoallelträgern ebenso eine Hyperaktivierung im cingulären Kortex. Auch bei gesonderter Betrachtung der Kontrollprobandengruppe spiegelte sich der Effekt Risikoallelträger als gesteigerte cinguläre Aktivierung wider. Der funktionelle Polymorphismus 5HT1A hatte keine signifikante Auswirkung auf die neuronale Aktivie-rung. Aufgrund ungleicher Allelverteilungen innerhalb der Stichprobe wurden die Analysen zu den Polymorphismen COMT Val/Met und MAO-A VNRT nicht weiterge-führt. Fazit: Im Vergleich zu Patienten in der akuten Phase der Erkrankung weisen remittierte Patienten im Cingulum ebenfalls eine Hyperaktivierung auf, während der PFC nicht vermehrt aktiviert ist. Diese Resultate sprechen entweder für eine langsamere Normali-sierung in den limbischen Strukturen oder für eine bleibende oder für eine vorbestehen-de neuronale Auffälligkeit. Gesunde Kontrollprobanden mit den HTTLPR-Risikoallelen weisen ähnliche Hyperaktivierungen auf. Diese Ergebnisse legen nahe, dass der HTTLPR-Polymorphismus einen Vulnerabilitätsmarker für die Entstehung depressiver Symptomatik darstellt.

Bibliographie / References

1. McGuffin, P., R. Katz, et al. (1996). "A hospital-based twin register of the heritability of DSM-IV unipolar depression." Arch Gen Psychiatry 53(2): 129-136.
2. Owen, A. M., K. M. McMillan, et al. (2005). "N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies." Hum Brain Mapp 25(1): 46-59.
3. Springer Medizin Verlag Schoning, S., P. Zwitserlood, et al. (2009). "Working-memory fMRI reveals cingulate hyperactivation in euthymic major depression." Hum Brain Mapp 30(9): 2746- 2756.
4. Smith EE, Jonides J. (1997) "Working Memory: A View from Neuroimaging" COGNITIVE PSYCHOLOGY 33, 5–42s
5. Gruber, O., T. Muller, et al. (2007). "Dynamic interactions between neural systems underlying different components of verbal working memory." J Neural Transm 114(8): 1047-1050.
6. Sander, J. B. and C. A. McCarty (2005). "Youth depression in the family context: familial risk factors and models of treatment." Clin Child Fam Psychol Rev 8(3): 203-219.
7. Marcos T, Salamero M et al. (1997) "Cognitive dysfunctions in recovered melancholic patients " Journal of Affective Disorders 32, 133-137
8. Tunbridge, E. M., P. J. Harrison, et al. (2006). "Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond." Biol Psychiatry 60(2): 141- 151.
9. Cerasa, A., M. C. Gioia, et al. (2008). "Ventro-lateral prefrontal activity during working memory is modulated by MAO A genetic variation." Brain Res 1201: 114-121.
10. Sheldrick, A. J., A. Krug, et al. (2008). "Effect of COMT val158met genotype on cognition and personality." Eur Psychiatry 23(6): 385-389.
11. Schermuly I, Fellgiebel A, Wagner S et al. (2010) " Association between cingulum bundle structure and cognitive performance: an observational study in major de- pression. " Eur Psychiatry. 25(6):355-60
12. Weiland-Fiedler P, Erickson K et al. (2004). "Evidence for continuing neuropsychological impairments in depression." J Affect Disord. 15;82(2):253-8
13. Castaneda AE, Tuulio-Henriksson A, et al. (2008). "A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults". J Affect Disord. 106(1-2):1-27. Epub 2007 Aug 20.
14. Harvey PO, Le Bastard G, et al. (2004). "Executive functions and updating of the contents of working memory in unipolar depression." J Psychiatr Res.38(6):567- 76.
15. Liu F, Zheng XL, Li BM. (2009) " The anterior cingulate cortex is involved in retrieval of long-term/long-lasting but not short-term memory for step-through inhibitory avoidance in rats. " Neurosci Lett. 460(2):175-9.
16. Zhang Y, Fukushima H, et al. (2011). " Induction and requirement of gene expression in the anterior cingulate cortex and medial prefrontal cortex for the consolidation of inhibitory avoidance memory. " Mol Brain. 4(1):4. Quellenverzeichnis 108
17. Medalla1 M, Barbas H (2009) " Synapses with inhibitory neurons differentiate anterior cingulate from dorsolateral prefrontal pathways associated with cognitive con- trol " Neuron. 61(4): 609–620.
18. Mitchell, R. L. and L. H. Phillips (2007). "The psychological, neurochemical and functional neuroanatomical mediators of the effects of positive and negative mood on executive functions." Neuropsychologia 45(4): 617-629.
19. Curtisa CE, Zald DH et al. (2000) "Organization of working memory within the human prefrontal cortex: a PET study of self-ordered object working memory". Neuropsychologia 38
20. Ranganath C, Johnson MK et al. (2003) "Prefrontal activity associated with working memory and episodic long-term memory". Neuropsychologia 41
21. Hadland KA, Rushworth MF et al. (2003) " The effect of cingulate lesions on social behaviour and emotion. " Neuropsychologia. 41(8):919-31.
22. Manuck, S. B., J. D. Flory, et al. (2000). "A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity." Psychiatry Res 95(1): 9-23.
23. Bush G, Luu P et al (2000).: " Cognitive and emotional influences in anterior cingulate cortex. " Trends in Cognitive Sciences – Vol.4,No.6
24. Trichard C, Martinot JL et al. (1995). "Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study." Psy- chol Med. 25(1):79-85.
25. Channon S, Baker JE, et al. (1993). "Working memory in clinical depression: an exper- imental study." Psychol Med. 23(1):87-91.
26. Kessing LV, et al. (1998) "Cognitive impairment in the euthymic phase of affective disorder." Psychol Med. 28(5):1027-38.
27. Miller, G. A. (1956). "The magical number seven plus or minus two: some limits on our capacity for processing information." Psychol Rev 63(2): 81-97.
28. Hariri, A. R. and D. R. Weinberger (2003). "Functional neuroimaging of genetic variation in serotonergic neurotransmission." Genes Brain Behav 2(6): 341-349.
29. Veiel HO et al. (1997). "A preliminary profile of neuropsychological deficits associated with major depression." J Clin Exp Neuropsychol. 19(4):587-603
30. Frodl T, Scheuerecker J et al. (2009) " Neuronal correlates of emotional processing in patients with major depression " World J Biol Psychiatry. 10(3):202-8.
31. Ohara, K., M. Nagai, et al. (1998). "Low activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression." Neuroreport 9(7): 1305-1308.
32. Dannlowski, U., P. Ohrmann, et al. (2007). "Serotonergic genes modulate amygdala activity in major depression." Genes Brain Behav 6(7): 672-676.
33. Surguladze, S. A., A. Elkin, et al. (2008). "Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces." Genes Brain Behav 7(5): 543-551.
34. Chai SC, Kung JC, Shyu BC (2010) " Roles of the anterior cingulate cortex and medial thalamus in short-term and long-term aversive information processing " Molecu- lar Pain 6:42
35. Isayama, S., Y. Sugimoto, et al. (2001). "Effects of histidine on working memory deficits induced by the 5-HT1A-receptor agonist 8-OH-DPAT." Jpn J Pharmacol 86(4): 451-453.
36. Heinz, A. and M. N. Smolka (2006). "The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks." Rev Neurosci 17(3): 359-367.
37. Niendam TA, Laird AR et al. (2012) "Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions". Cogn Affect Behav Neurosci 12:241–268
38. Wingen, M., K. P. Kuypers, et al. (2007). "Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI." J Psychopharmacol 21(5): 477-485.
39. Sabol, S. Z., S. Hu, et al. (1998). "A functional polymorphism in the monoamine oxidase A gene promoter." Hum Genet 103(3): 273-279.
40. Pezawas, L., A. Meyer-Lindenberg, et al. (2005). "5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression." Nat Neurosci 8(6): 828-834.
41. Karow, T., Lang-Roth, R. (2007) "Allgemeine und Spezielle Pharmakologie und Toxikologie -Vorlesungsorientierte Darstellung und klinischer Leitfaden." Thieme & Frohberg GmbH.
42. Walsh, N. D., S. C. Williams, et al. (2007). "A longitudinal functional magnetic resonance imaging study of verbal working memory in depression after antidepressant therapy." Biol Psychiatry 62(11): 1236-1243.
43. Nair J, Nair SS et al. (1999). "Analysis of the symptoms of depression--a neural network approach." Psychiatry Res. 11;87(2-3):193-201
44. Kim J, Matthews N et al. (2010). "An Event-Related fMRI Study of Phonological Verbal Working Memory in Schizophrenia". PLoS ONE Quellenverzeichnis 103
45. Medalla M, Barbas H (2010) " Anterior cingulate synapses in prefrontal areas 10 and 46 suggest differential influence in cognitive control. " J Neurosci. 30(48):16068-81
46. Hamilton, M. (1960). "A rating scale for depression." J Neurol Neurosurg Psychiatry 23: 56-62.
47. Schulze, T. G., D. J. Muller, et al. (2000). "Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder." Am J Med Genet 96(6): 801-803.
48. Lachman, H. M., B. Morrow, et al. (1996). "Association of codon 108/158 catechol-O- methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome." Am J Med Genet 67(5): 468-472.
49. Karnath HO, Thier P (2003, 2006). "Neuropsychologie". S. 471, 491. Springer Medizin Verlag Kersting, A., K. Kroker, et al. (2007). "Association of MAO-A variant with complicated grief in major depression." Neuropsychobiology 56(4): 191-196.
50. Hautzinger, M., Bailer, M., Worall & H., Keller, F. (1994)."Beck-Depressions-Inventar (BDI)." Bearbeitung der deutschen Ausgabe. Testhandbuch. Bern, Göttingen, Toronto, Seattle: Huber. Quellenverzeichnis 102
51. Smolka, M. N., G. Schumann, et al. (2005). "Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex." J Neurosci 25(4): 836-842.
52. Jacob, C. P., J. Muller, et al. (2005). "Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity." Neuropsychopharmacology 30(9): 1711-1718.
53. Harvey PO, Fossati P, et al. (2005). "Cognitive control and brain resources in major depression: an fMRI study using the n-back task." Neuroimage 26(3): 860-869.
54. Ravnkilde B, Videbech P (2002). "Cognitive deficits in major depression." Scand J Psychol. 43(3):239-51.
55. Burt DB, Zembar MJ, et al., (1995). "Depression and memory impairment: a meta- analysis of the association, its pattern, and specificity." Psychol Bull. 117(2):285-305.
56. Müller, N. und Storbach, D. (2005). "Depressionen-Krankheitsbild und Therapie." Govi-Verlag; Auflage: 1.
57. Frodl TS, Koutsouleris N (2008) " Depression-Related Variation in Brain Morphology Over 3 Years Effects of Stress? " ARCH GEN PSYCHIATRY VOL 65 (NO. 10)
58. Wittchen, H.-U. (1997). Diagnostik und Epidemiologie der "Wahnhaften Depression".
59. Möller, H.-J., Laux, G., Deister, A. (2005). "Duale Reihe: Psychiatrie und Psychotherapie." Thieme, Stuttgart; Auflage: 4., überarbeitete Auflage.
60. Takenouchi K, Nishijo H et al. (1999) " Emotional and behavioral correlates of the anterior cingulate cortex during associative learning in rats " Neuroscience. 93(4):1271-87
61. Seligman, M. E. P. (1979). Erlernte Hilflosigkeit. München, Wien, Baltimore: Urban und Schwarzenberg.
62. Chen, J., B. K. Lipska, et al. (2004). "Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain." Am J Hum Genet 75(5): 807-821.
63. Johnston SJ, Linden DEJ et al. (2012) "Functional Imaging Reveals Working Memory and Attention Interact to Produce the Attentional Blink" J Cogn Neurosci.
64. Callicott, J. H., N. F. Ramsey, et al. (1998). "Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia." Neuropsychopharmacology 18(3): 186-196.
65. Schneider F, Fink GR et al. (2007) "Funktionelle MRT in Psychiatrie und Neurologie".
66. Gallinat, J., M. Bauer, et al. (2008). "Genes and neuroimaging: advances in psychiatric research." Neurodegener Dis 5(5): 277-285.
67. Sullivan, P. F., M. C. Neale, et al. (2000). "Genetic epidemiology of major depression: review and meta-analysis." Am J Psychiatry 157(10): 1552-1562.
68. Hariri AR, Weinberger DR. (2003) "Imaging genomics" British Medical Bulletin; 65: 259–270
69. Savitz JB, Drevets WC (2009) " Imaging Phenotypes of Major Depressive Disorder: Genetic Correlates " Neuroscience. 164(1): 300–330.
70. Lemonde, S., G. Turecki, et al. (2003). "Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide." J Neurosci 23(25): 8788-8799.
71. Caspi, A., K. Sugden, et al. (2003). "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene." Science 301(5631): 386-389.
72. Meyer-Lindenberg, A. and D. R. Weinberger (2006). "Intermediate phenotypes and genetic mechanisms of psychiatric disorders." Nat Rev Neurosci 7(10): 818-827.
73. Hautzinger, M (2003). "Kognitive Verhaltenstherapie bei Depressionen: Behandlungsanleitungen und Materialien". BeltzPVU; Auflage: 6., überarbeitete Auflage.
74. Lehrl, S. (2005). Mehrfachwahl-Wortschatz-Intelligenztest MWT-B. Balingen: Spitta Verlag,, 5. unveränderte Aufl..
75. Zhang Z, Séguéla P et al. (2010). " Metabotropic induction of persistent activity in layers II/III of anterior cingulate cortex. " Cereb Cortex. 20(12):2948-57.
76. Shih, J. C., K. Chen, et al. (1999). "Monoamine oxidase: from genes to behavior." Annu Rev Neurosci 22: 197-217.
77. Youdim, M. B. and Y. S. Bakhle (2006). "Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness." Br J Pharmacol 147 Suppl 1: S287-296.
78. Harvey PD et al. (2011). "Mood symptoms, cognition, and everyday functioning: in major depression, bipolar disorder, and schizophrenia." Innov Clin Neurosci. 8(10):14-8.
79. Serretti, A., C. Cusin, et al. (2003). "Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders." Psychiatr Genet 13(2): 121-126.
80. Smith DJ, Muir WJ et al. (2006). Neurocognitive impairment in euthymic young adults with bipolar spectrum disorder and recurrent major depressive disorder." Bipolar Disord. 8(1):40-6
81. Wager, T. D. and E. E. Smith (2003). "Neuroimaging studies of working memory: a meta-analysis." Cogn Affect Behav Neurosci 3(4): 255-274.
82. Landrø NI, Stiles TC, et al. (2001) "Neuropsychological function in nonpsychotic unipolar major depression." Neuropsychiatry Neuropsychol Behav Neurol. 14(4):233-40.
83. Zakzanis, K. K., L. Leach, et al. (1998). "On the nature and pattern of neurocognitive function in major depressive disorder." Neuropsychiatry Neuropsychol Behav Neurol 11(3): 111-119.
84. Matsuo, K., D. C. Glahn, et al. (2007). "Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder." Mol Psychiatry 12(2): 158-166.
85. Tranter R, O'Donovan C et al. (2002). "Prevalence and outcome of partial remission in depression". J Psychiatry Neurosci; 27(4)
86. Möller, Laux, Kampfhammer. (2002) "Psychiatrie und Psychotherapie". Springer Verlag; 2. Auflage; S. 1175-1177.
87. Owen AM, Herrod NJ et al. (1999) "Redefining the functional organization of working memory processes within human lateral prefrontal cortex" European Journal of Neuroscience, Vol. 11, pp. 567–574
88. Hariri, A. R., V. S. Mattay, et al. (2002). "Serotonin transporter genetic variation and the response of the human amygdala." Science 297(5580): 400-403.
89. O'Hara, R., C. M. Schroder, et al. (2007). "Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol." Mol Psychiatry 12(6): 544-555.
90. Wendland, J., B. Martin, et al. (2006). "Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531." Mol Psychiatry. 11(3): 224-226.
91. Oldfield, R. C. (1971). "The assessment and analysis of handedness: the Edinburgh inventory." Neuropsychologia 9(1): 97-113.
92. Coppen, A. (1967). "The biochemistry of affective disorders." Br J Psychiatry 113(504): 1237-1264.
93. Sackeim, H. A. (2001). "The definition and meaning of treatment-resistant depression." J Clin Psychiatry 62 Suppl 16: 10-17.
94. Christopher G, MacDonald J, et al. (2005) "The impact of clinical depression on working memory." Cogn Neuropsychiatry. 10(5):379-99.
95. McMahon, F. J., S. Buervenich, et al. (2006). "Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment." Am J Hum Genet 78(5): 804-814.
96. Papaleo, F., J. N. Crawley, et al. (2008). "Genetic dissection of the role of catechol-O- methyltransferase in cognition and stress reactivity in mice." J Neurosci 28(35): 8709-8723.
97. Massat, I., D. Souery, et al. (2005). "Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study." Mol Psychiatry 10(6): 598-605.
98. Heinz, A., D. F. Braus, et al. (2005). "Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter." Nat Neurosci 8(1): 20-21.
99. Holmes AJ, Bogdan R, Pizzagalli D (2010) " Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression " Neuropsychopharmacology. 35(5): 1186–1197.
100. Hariri, A. R., E. M. Drabant, et al. (2006). "Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing." Biol Psychiatry 59(10): 888-897.
101. Paelecke-Habermann Y, Pohl J, et al. (2005) " Attention and executive functions in remitted major depression patients." J Affect Disord. 89(1-3):125-35.
102. Lee RS, Hermens DF, et al.(2011). "A meta-analysis of cognitive deficits in first- episode Major Depressive Disorder." J Affect Disord.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten