Abstract
Dopamine transmission remains central to our understanding of neurocircuitry models
of schizophrenia, and to the mechanism of action of typical antipsychotic medications,
which preferentially block D2-receptors in striatum. In cerebral cortex, D2- and D1- mediated transmission modulates information processing, and tunes the activity of
the cortico-striato-thalamic loops, in which dopaminergic, glutamatergic, GABAergic
and serotonergic projections are integrated and interconnected. Molecular imaging
techniques, especially positron emission tomography, have been used to investigate
the spatial pattern of the binding properties of antipsychotic medications. We now
summarize the state of development of molecular imaging, integrated into a model of
schizophrenia emphasizing dysfunction of a complex loop, rather than a discrete abnormality
in the basal ganglia, as had been implicitly assumed in the classic dopamine model
of psychosis. Finally, hypotheses are proposed to explain differences between first-
and second generation antipsychotics with respect of regional selectivity for dopamine
and serotonin neurons.
References
- 1
Aalto S, Hirvonen J, Kajander J. et al .
Ketamine does not decrease striatal dopamine D2 receptor binding in man.
Psychopharmacology.
2002;
164
401-406
- 2
Abi-Dargham A, Gil R, Krystal J. et al .
Increased striatal dopamine transmission in schizophrenia: confirmation in a second
cohort.
Am J Psychiat.
1998;
155
761-767
- 3
Abi-Dargham A, Rodenhiser J, Printz D. et al .
Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.
Proc Natl Acad Sci USA.
2000;
97
8104-8109
- 4
Abi-Dargham A, Mawlawi O, Lombardo I. et al .
Prefrontal dopamine D1 receptors and working memory in schizophrenia.
J Neurosci.
2002;
22
3708-3719
- 5
Agid O, Mamo D, Ginovart N. et al .
Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response – a double-blind
PET study in schizophrenia.
Neuropsychopharmacology.
2007;
32
1209-1215
- 6
Andreasen NC.
A unitary model of schizophrenia: Bleuler's “fragmented phrene” as schizencephaly.
Arch Gen Psychiat.
1999;
56
781-787
- 7
Bäumler H.
Veränderungen des Thalamus bei Schizophrenie.
Journal für Hirnforschung.
1954;
1
156-169
- 8
Bartlett EJ, Brodie JD, Simkowitz P. et al .
Effects of haloperidol challenge on regional cerebral glucose utilization in normal
human subjects.
Am J Psychiat.
1994;
151
681-686
- 9
Bartlett EJ, Brodie JD, Simkowitz P. et al .
Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive
and nonresponsive schizophrenic patients.
Am J Psychiat.
1998;
155
337-343
- 10
Bortolozzi A, Diaz-Mataix L, Scorza MC, Celada P, Artigas F.
The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity.
J Neurochem.
2005;
95
1597-1607
- 11
Braus DF, Weber-Fahr W, Tost H, Ruf M, Henn FA.
Sensory information processing in neuroleptic-naive first-episode schizophrenic patients:
a functional magnetic resonance imaging study.
Arch Gen Psychiat.
2002;
59
696-701
- 12
Bressan RA, Erlandsson K, Jones HM. et al .
Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic
effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients.
Am J Psychiat.
2003;
160
1413-1420
- 13
Brown RM, Crane AM, Goldman PS.
Regional distribution of monoamines in the cerebral cortex and subcortical structures
of the rhesus monkey: concentrations and in vivo synthesis rates.
Brain Research.
1979;
168
133-150
- 14
Buchsbaum MS, Someya T, Teng CY. et al .
PET and MRI of the thalamus in never-medicated patients with schizophrenia.
Am J Psychiat.
1996;
153
191-199
- 15
Buchsbaum MS, Christian BT, Lehrer DS. et al .
D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients
with schizophrenia.
Schizophrenia Research.
2006;
85
232-244
- 16
Buchsbaum MS, Haznedar MM, Aronowitz J. et al .
FDG-PET in never-previously medicated psychotic adolescents treated with olanzapine
or haloperidol.
Schizophrenia Research.
2007;
94
293-305
- 17
Byne W, Buchsbaum MS, Mattiace LA. et al .
Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia.
Am J Psychiat.
2002;
159
59-65
- 18
Carlsson A.
Speculations on the control of mental and motor functions by dopamine-modulated cortico-striato-thalamo-cortical
feedback loops.
The Mount Sinai J Med, New York.
1988;
55
6-10
- 19
Carlsson A, Waters N, Carlsson ML.
Neurotransmitter interactions in schizophrenia-therapeutic implications.
Eur Arch Psychiat Clin Neurosci.
1999;
249
((Suppl 4))
37-43
- 20
Carlsson A.
The neurochemical circuitry of schizophrenia.
Pharmacopsychiatry.
2006;
39
((Suppl 1))
S10-14
- 21
Crespo-Facorro B, Paradiso S, Andreasen NC. et al .
Recalling word lists reveals “cognitive dysmetria” in schizophrenia: a positron emission
tomography study.
Am J Psychiat.
1999;
156
386-392
- 22
Csomor PA, Stadler RR, Feldon J. et al .
Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy
humans stratified for low and high gating levels.
Neuropsychopharmacology.
2008;
33
497-512
- 23
Cullen TJ, Walker MA, Parkinson N. et al .
A postmortem study of the mediodorsal nucleus of the thalamus in schizophrenia.
Schizophrenia Research.
2003;
60
157-166
- 24
Deakin JF, Lees J, MacKie S. et al .
Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic
resonance imaging study.
Arch Gen Psychiat.
2008;
65
154-164
- 25
Deep P, Dagher A, Sadikot A, Gjedde A, Cumming P.
Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary
to NMDA receptor antagonism with a low dose of amantadine.
Synapse.
1999;
34
313-318
- 26
Pietro NC Di, Seamans JK.
Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic
drugs and their mechanism of action.
Pharmacopsychiatry.
2007;
40
((Suppl 1))
S27-33
- 27
Dunwiddie TV, Masino SA.
The role and regulation of adenosine in the central nervous system.
Annu Rev Neurosci.
2001;
24
31-55
- 28
Fajolles C, Boireau A, Ponchant M, Laduron PM.
3 H]RP 62203, a ligand of choice to label in vivo brain 5-HT2 receptors.
Eur J Pharmacol.
1992;
216
53-57
- 29
Farde L, Nordström AL, Wiesel FA. et al .
Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy
in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal
side effects.
Arch Gen Psychiat.
1992;
49
538-544
- 30
Frankle WG.
Neuroreceptor imaging studies in schizophrenia.
Harvard Rev Psychiat.
2007;
15
212-232
- 31
Fünfgeld E.
ber histologische Unterschungen des Thalamus bei Katatonie.
Klinische Wochenschrift.
1924;
3
69-70
- 32
Gaffan D, Parker A.
Mediodorsal thalamic function in scene memory in rhesus monkeys.
Brain.
2000;
123
(( Pt 4))
816-827
- 33
Gallinat J, Obermayer K, Heinz A.
Systems Neurobiology of the Dysfunctional Brain: Schizophrenia.
Pharmacopsychiatry.
2007;
40
S40-S44
- 34
Gefvert O, Lundberg T, Wieselgren IM. et al .
D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia:
a PET study.
Eur Neuropsychopharmacol.
2001;
11
105-110
- 35
Gefvert O, Lindstrom LH, Waters N. et al .
Different corticostriatal patterns of L-DOPA utilization in patients with untreated
schizophrenia and patients treated with classical antipsychotics or clozapine.
Scand J Psychol.
2003;
44
289-292
- 36
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR.
Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits
in schizophrenia: a decade in review.
Psychopharmacology.
2001;
156
117-154
- 37
Goldsmith SK, Shapiro RM, Joyce JN.
Disrupted pattern of D2 dopamine receptors in the temporal lobe in schizophrenia.
A postmortem study.
Arch Gen Psychiat.
1997;
54
649-658
- 38
Gründer G, Yokoi F, Offord SJ. et al .
Time course of 5-HT2A receptor occupancy in the human brain after a single oral dose
of the putative antipsychotic drug MDL 100,907 measured by positron emission tomography.
Neuropsychopharmacology.
1997;
17
175-185
- 39
Gründer G, Landvogt C, Vernaleken I. et al .
The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients
with schizophrenia.
Neuropsychopharmacology.
2006;
31
1027-1035
- 40
Gründer G, Fellows C, Janouschek H. et al .
Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia:
An [18F]Fallypride PET Study.
Am J Psychiat.
2008;
- 41
Gulledge AT, Jaffe DB.
Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal
cortex.
J Neurosci.
1998;
18
9139-9151
- 42
Hall H, Farde L, Halldin C. et al .
Autoradiographic localization of extrastriatal D2-dopamine receptors in the human
brain using [125I]epidepride.
Synapse.
1996;
23
115-123
- 43
Hazlett EA, Buchsbaum MS, Kemether E. et al .
Abnormal glucose metabolism in the mediodorsal nucleus of the thalamus in schizophrenia.
Am J Psychiat.
2004;
161
305-314
- 44
Hernandez LF, Segovia G, Mora F.
Effects of activation of NMDA and AMPA glutamate receptors on the extracellular concentrations
of dopamine, acetylcholine, and GABA in striatum of the awake rat: a microdialysis
study.
Neurochemical Research.
2003;
28
1819-1827
- 45
Hietala J, Syvalahti E, Vuorio K. et al .
Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients.
Lancet.
1995;
346
1130-1131
- 46
Hirvonen J, Erp TG van, Huttunen J. et al .
Brain dopamine d1 receptors in twins discordant for schizophrenia.
Am J Psychiat.
2006;
163
1747-1753
- 47
Holcomb HH, Cascella NG, Thaker GK. et al .
Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with
and without haloperidol.
Am J Psychiat.
1996;
153
41-49
- 48 Huber G.
Pneumencephalographische und psychopathologische Bilder bei endogenen Psychosen. Berlin, Göttingen, Heidelberg: Springer 1957
- 49
Hurlemann R, Matusch A, Kuhn KU. et al .
5-HT2A receptor density is decreased in the at-risk mental state.
Psychopharmacology.
2008;
195
579-590
- 50
Kapur S, Zipursky RB, Remington G.
Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine,
risperidone, and olanzapine in schizophrenia.
Am J Psychiat.
1999;
156
286-293
- 51
Kargieman L, Santana N, Mengod G, Celada P, Artigas F.
Antipsychotic drugs reverse the disruption in prefrontal cortex function produced
by NMDA receptor blockade with phencyclidine.
Proc Natl Acad Sci USA.
2007;
104
14843-14848
- 52
Karlsson P, Farde L, Halldin C, Sedvall G.
PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia.
Am J Psychiat.
2002;
159
761-767
- 53
Kim JJ, Kim DJ, Kim TG. et al .
Volumetric abnormalities in connectivity-based subregions of the thalamus in patients
with chronic schizophrenia.
Schizophrenia Research.
2007;
97
226-235
- 54
Kumakura Y, Cumming P, Vernaleken I. et al .
Elevated [18F]fluoro-dopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study.
J Neurosci.
2007;
27
8080-8087
- 55
Laruelle M, Abi-Dargham A.
Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies.
J Psychopharmacol.
1999;
13
358-371
- 56
Lawler CP, Prioleau C, Lewis MM. et al .
Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and
serotonin receptor subtypes.
Neuropsychopharmacology.
1999;
20
612-627
- 57
Lawrie SM, Whalley HC, Abukmeil SS. et al .
Brain structure, genetic liability, and psychotic symptoms in subjects at high risk
of developing schizophrenia.
Biol Psychiat.
2001;
49
811-823
- 58
Lee FJ, Xue S, Pei L. et al .
Dual regulation of NMDA receptor functions by direct protein-protein interactions
with the dopamine D1 receptor.
Cell.
2002;
111
219-230
- 59
Leviel V, Gobert A, Guibert B.
Direct observation of dopamine compartmentation in striatal nerve terminal by ‘in
vivo’ measurement of the specific activity of released dopamine.
Brain Res.
1989;
499
205-213
- 60
Mamo D, Kapur S, Shammi CM. et al .
A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with
schizophrenia treated with therapeutic doses of ziprasidone.
Am J Psychiat.
2004;
161
818-825
- 61
Mamo D, Graff A, Mizrahi R. et al .
Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy
in patients with schizophrenia: a triple tracer PET study.
Am J Psychiat.
2007;
164
1411-1417
- 62
Manoach DS, Gollub RL, Benson ES. et al .
Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex
and basal ganglia during working memory performance.
Biol Psychiat.
2000;
48
99-109
- 63
Meltzer HY, Matsubara S, Lee JC.
The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical
antipsychotic drugs.
Psychopharmacology Bulletin.
1989;
25
390-392
- 64
Meyer-Lindenberg A, Miletich RS, Kohn PD. et al .
Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in
schizophrenia.
Nat Neurosci.
2002;
5
267-271
- 65
Minuzzi L, Nomikos GG, Wade MR. et al .
Interaction between LSD and dopamine D2/3 binding sites in pig brain.
Synapse.
2005;
56
198-204
- 66
Nordström AL, Farde L, Wiesel FA. et al .
Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects:
a double-blind PET study of schizophrenic patients.
Biol Psychiat.
1993;
33
227-235
- 67
O’Connor WT.
Functional neuroanatomy of the basal ganglia as studied by dual-probe microdialysis.
Nucl Med Biol.
1998;
25
743-746
- 68
O’Connor WT.
Functional neuroanatomy of the ventral striopallidal GABA pathway. New sites of interventin
in the treatment of schizophrenia.
J Neurosci Meth.
2001;
109
31-39
- 69
Oke AF, Adams RN.
Elevated thalamic dopamine: possible link to sensory dysfunctions in schizophrenia.
Schizophrenia Bulletin.
1987;
13
589-604
- 70
Oke AF, Putz C, Adams RN, Bird ED.
Neuroleptic treatment is an unlikely cause of elevated dopamine in thalamus of schizophrenic
subjects.
Psychiat Res.
1992;
45
203-208
- 71
Okubo Y, Suhara T, Suzuki K. et al .
Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET.
Nature.
1997;
385
634-636
- 72
Penit-Soria J, Audinat E, Crepel F.
Excitation of rat prefrontal cortical neurons by dopamine: an in vitro electrophysiological
study.
Brain Res.
1987;
425
263-274
- 73
Petit-Taboue MC, Landeau B, Barre L. et al .
Parametric PET imaging of 5HT2A receptor distribution with 18F-setoperone in the normal
human neocortex.
J Nucl Med.
1999;
40
25-32
- 74
Preuss UW, Zetzsche T, Jager M. et al .
Thalamic volume in first-episode and chronic schizophrenic subjects: a volumetric
MRI study.
Schizophrenia Research.
2005;
73
91-101
- 75
Reith J, Benkelfat C, Sherwin A. et al .
Elevated dopa decarboxylase activity in living brain of patients with psychosis.
Proc Natl Acad Sci USA.
1994;
91
11651-11654
- 76
Salgado-Pineda P, Baeza I, Perez-Gomez M. et al .
Sustained attention impairment correlates to gray matter decreases in first episode
neuroleptic-naive schizophrenic patients.
NeuroImage.
2003;
19
365-375
- 77
Seamans JK, Gorelova N, Durstewitz D, Yang CR.
Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal
neurons.
J Neurosci.
2001;
21
3628-3638
- 78
Seamans JK, Yang CR.
The principal features and mechanisms of dopamine modulation in the prefrontal cortex.
Prog Neurobiol.
2004;
74
1-58
- 79
Seeman P, Lee T.
Antipsychotic drugs: direct correlation between clinical potency and presynaptic action
on dopamine neurons.
Science.
1975;
188
1217-1219
- 80
Seeman P.
Atypical antipsychotics: mechanism of action.
Can J Psychiat.
2002;
47
27-38
- 81
Slifstein M, Kolachana B, Simpson EH. et al .
COMT genotype predicts cortical-limbic D1 receptor availability measured with [(11)C]NNC112
and PET.
Mol Psychiat.
2008;
- 82
Smith GS, Dewey SL, Brodie JD. et al .
Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects.
Am J Psychiat.
1997;
154
490-496
- 83
Soares JC, Innis RB.
Neurochemical brain imaging investigations of schizophrenia.
Biol Psychiat.
1999;
46
600-615
- 84 Steriade M, Jones EG, MacCormick DA.
Thalamus: organization and function. Amsterdam: Elsevier 1997
- 85
Stone JM, Davis JM, Leucht S, Pilowsky LS.
Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs
– An Original Patient Data Meta-analysis of the SPECT and PET In Vivo Receptor Imaging
Literature.
Schizophrenia Bulletin.
2008;
- 86
Strungas S, Christensen JD, Holcomb JM, Garver DL.
State-related thalamic changes during antipsychotic treatment in schizophrenia: preliminary
observations.
Psychiat Res.
2003;
124
121-124
- 87
Suhara T, Okubo Y, Yasuno F. et al .
Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia.
Arch Gen Psychiat.
2002;
59
25-30
- 88
Taber MT, Baker GB, Fibiger HC.
Glutamate receptor agonists decrease extracellular dopamine in the rat nucleus accumbens
in vivo.
Synapse.
1996;
24
165-172
- 89
Takahashi H, Higuchi M, Suhara T.
The role of extrastriatal dopamine D2 receptors in schizophrenia.
Biol Psychiat.
2006;
59
919-928
- 90
Tallerico T, Novak G, Liu IS, Ulpian C, Seeman P.
Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex.
Brain Res Mol Brain Res.
2001;
87
160-165
- 91
Talvik M, Nordstrom AL, Olsson H, Halldin C, Farde L.
Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia:
a PET study with [11C]FLB 457.
Int J Neuropsychopharmacol.
2003;
6
361-370
- 92
Tsukada H, Harada N, Nishiyama S. et al .
Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static
dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric
PET studies combined with microdialysis analysis.
Synapse.
2000;
37
95-103
- 93
Tuppurainen H, Kuikka J, Viinamaki H. et al .
Extrastriatal dopamine D 2/3 receptor density and distribution in drug-naive schizophrenic
patients.
Mol Psychiat.
2003;
8
453-455
- 94
Varty GB, Higgins GA.
Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence
for a role of D3 receptors?.
Behav Pharmacol.
1998;
9
445-455
- 95
Vernaleken I, Siessmeier T, Buchholz HG. et al .
High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain
of patients with schizophrenia.
Int J Neuropsychopharmacol.
2004;
7
421-430
- 96
Vernaleken I, Buchholz HG, Kumakura Y. et al .
Prefrontal’ cognitive performance of healthy subjects positively correlates with cerebral
FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation.
Hum Brain Mapp.
2007;
28
931-939
- 97
Vernaleken I, Kumakura Y, Buchholz HG. et al .
Baseline [(18)F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine
turnover and cognitive performance: A positron emission tomography study in healthy
subjects.
NeuroImage.
2008;
40
1222-1231
- 98
Vernaleken I, Gründer G.
Elevated D2/3-Receptor Availability in Schizophrenia: A [18F]Fallypride Study.
[Abstract] NeuroImage.
, ; in press
- 99
Vollenweider FX, Leenders KL, Scharfetter C. et al .
Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using
positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG).
Eur Neuropsychopharmacol.
1997;
7
9-24
- 100
Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL.
Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans.
J Psychiat Res.
2000;
34
35-43
- 101
Wan FJ, Swerdlow NR.
Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions
in the nucleus accumbens core and shell subregions.
Brain Res.
1996;
722
168-176
- 102 Weinberger DR, Laruelle M. Neurochemical and neuropharmacological imaging in schizophrenia. In:
Davis KL, Charney DS, Coyle JT, Nemeroff C (eds).
Neuropharmacology—the fifth generation of progress. Philadelphia: Lippincott, Williams, & Wilkins 2001
- 103
Wilson CJ.
Striatal D2 receptors and LTD: yes, but not where you thought they were.
Neuron.
2006;
50
347-348
- 104
Winterer G.
Prefrontal Dopamine Signaling in Schizophrenia - The Corticocentric Model.
Pharmacopsychiatry.
2007;
40
S45-S53
- 105
Xiberas X, Martinot JL, Mallet L. et al .
Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new
antipsychotic drugs in patients with schizophrenia.
Brit J Psychiat.
2001;
179
503-508
- 106
Yang CR, Seamans JK.
Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro:
modulation of dendritic-somatic signal integration.
J Neurosci.
1996;
16
1922-1935
- 107
Young KA, Randall PK, Wilcox RE.
Startle and sensorimotor correlates of ventral thalamic dopamine and GABA in rodents.
Neuroreport.
1995;
6
2495-2499
- 108
Young KA, Manaye KF, Liang C, Hicks PB, German DC.
Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia.
Biol Psychiat.
2000;
47
944-953
Correspondence
I. VernalekenMD
Department of Psychiatry and Psychotherapy
RWTH Aachen University
Pauwelsstraße 30
52074 Aachen
Germany
Phone: +49/241/80 89 65 4
Fax: +49/241/80 33 89 65 4
Email: ivernaleken@ukaachen.de