Publications (13)70.9 Total impact
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Article: Dopamine D2/D3 receptor availability and venturesomeness.
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ABSTRACT: The construct of impulsivity is considered as a major trait of personality. There is growing evidence that the mesolimbic dopamine system plays an important role in the modulation of impulsivity and venturesomeness, the two key components within the impulsivity-construct. The aim of the present study was to explore an association between trait impulsivity measured with self-assessment and the dopaminergic neurotransmission as measured by positron emission tomography (PET) in a cohort of healthy male subjects. In vivo D2/D3 receptor availability was determined with [(18)F]fallypride PET in 18 non-smoking healthy subjects. The character trait impulsivity was measured using the Impulsiveness-Venturesomeness-Empathy questionnaire (I7). Image processing and statistical analysis was performed on a voxel-by-voxel basis using statistical parametric mapping (SPM) software. The I7 subscale venturesomeness correlated positively with the D2/D3 receptor availability within the left temporal cortex and the thalamus. Measures on the I7 subscale impulsiveness and empathy did not correlate with the D2/D3 receptor availability in any brain region investigated. Our results suggest the involvement of extrastriatal dopaminergic neurotransmission in venturesomeness, a component of impulsivity.Psychiatry Research 06/2011; 193(2):80-4. · 2.52 Impact Factor -
Article: Alteration of dopamine D2/D3 receptor binding in patients with juvenile myoclonic epilepsy.
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ABSTRACT: To quantify extrastriatal and striatal D2/D3 receptor binding in patients with juvenile myoclonic epilepsy (JME) using the high-affinity dopamine D2/D3 receptor positron emission tomography (PET) ligand (18) F-Fallypride ([(18) F]FP). Twelve patients with JME and 21 age-matched control subjects were studied. Dynamic images (180 min) were acquired after injection of [(18) F]FP. Patients had been seizure-free of all seizure types for at least 10 days before scanning. Parametric images of binding potential (BP) were created using the simplified reference tissue model. The images were stereotactically normalized using a ligand-specific template. We performed a voxel-based analysis with statistical parametric mapping (SPM2). Region of interest (ROI) analysis was done comparing the BP of the thalamus, caudate nucleus, anterior (ventral) and posterior (dorsal) putamen, ventral striatum, and temporal lobe. Compared to controls, patients with JME showed a significant decrease in [(18) F]FP BP (SPM analysis corr. p < 0.001 at cluster level) restricted to the bilateral posterior putamen. There was no significant alteration of [(18) F]FP binding in other brains regions. ROI analysis revealed a significant (p < 0.05) decrease of [(18) F]FP BP in the left (mean -14.8%) and right (mean -16.9%) posterior putamen, but not in the anterior putamen, caudate, ventral striatum, thalamus, or temporal lobe. Patients with JME showed a reduction in D2/3 receptor binding restricted to the bilateral posterior putamen, suggesting a specific alteration of the dopaminergic system. Whether these changes can be regarded as merely functional or whether they relate to the pathophysiology of juvenile myoclonic epilepsy still remains unclear.Epilepsia 04/2010; 51(9):1699-706. · 3.96 Impact Factor -
Article: Human dopamine receptor D2/D3 availability predicts amygdala reactivity to unpleasant stimuli.
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ABSTRACT: Dopamine (DA) modulates the response of the amygdala. However, the relation between dopaminergic neurotransmission in striatal and extrastriatal brain regions and amygdala reactivity to affective stimuli has not yet been established. To address this issue, we measured DA D2/D3 receptor (DRD2/3) availability in twenty-eight healthy men (nicotine-dependent smokers and never-smokers) using positron emission tomography with [18F]fallypride. In the same group of participants, amygdala response to unpleasant visual stimuli was determined using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The effects of DRD2/3 availability in emotion-related brain regions and nicotine dependence on amygdala response to unpleasant stimuli were examined by multiple regression analysis. We observed enhanced prefrontal DRD2/3 availability in those individuals with higher amygdala response to unpleasant stimuli. As compared to never-smokers, smokers showed an attenuated amygdala BOLD response to unpleasant stimuli. Thus, individuals with high prefrontal DRD2/3 availability may be more responsive toward aversive and stressful information. Through this mechanism, dopaminergic neurotransmission might influence vulnerability for affective and anxiety disorders. Neuronal reactivity to unpleasant stimuli seems to be reduced by smoking. This observation could explain increased smoking rates in individuals with mental disorders.Human Brain Mapping 11/2009; 31(5):716-26. · 5.88 Impact Factor -
Article: In vivo imaging of dopamine receptors in a model of temporal lobe epilepsy.
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ABSTRACT: Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy. Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5). Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p < 0.05), but binding was unaffected in other striatal or extrastriatal regions. The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.Epilepsia 08/2009; 51(3):415-22. · 3.96 Impact Factor -
Article: Striatal and Extrastriatal D2/D3-Receptor-Binding Properties of Ziprasidone: A Positron Emission Tomography Study With [18F]Fallypride and [11C]Raclopride (D2/D3-Receptor Occupancy of Ziprasidone)
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ABSTRACT: To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [18F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [11C]raclopride-PET study, striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions (temporal cortex: 39 ng/mL; putamen: 64 ng/mL), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.Journal of Clinical Psychopharmacology 11/2008; 28(6):608-617. · 4.10 Impact Factor -
Article: Choice of reference area in studies of Alzheimer's disease using positron emission tomography with fluorodeoxyglucose-F18.
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ABSTRACT: At present, there is still no consensus on the choice of the reference area in positron emission tomography (PET) studies of Alzheimer's disease (AD). In this study, PET scans with fluorodeoxyglucose-F18 were carried out in the following groups of subjects: 47 patients with probable AD, 8 patients with mild cognitive impairment, and 15 age-similar healthy subjects. Scans normalized to the cerebral global mean (CGM), cerebellum (CBL), and the primary sensorimotor cortex (SMC). We evaluated the effect of the different count normalization procedures on the accuracy of (18)F-FDG PET to detect AD-specific metabolic abnormalities (voxel-based group comparison) and to differentiate between patients and healthy subjects (ROI-based discriminant analysis) with regard to the degree of clinical deterioration. Metabolic reductions in groups of very mildly, mildly and moderate-to-severely affected patients appeared, respectively, 2.2, 2.6, and 2.7 times greater in spatial extent when tracer uptake was normalized to SMC rather than to CGM. The overall accuracy of discrimination was 94%, 91%, and 80% after normalization to SMC, CBL, and CGM, respectively. In general, normalization to SMC was somewhat superior to cerebellar normalization, allowing the detection of more pronounced metabolic deficits and the more accurate discrimination of patients from non-patients. Normalization to CGM should be used with great caution not only in advanced stages of dementia, but also in very mild AD cases.Psychiatry Research 11/2008; 164(2):143-53. · 2.52 Impact Factor -
Article: Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse.
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ABSTRACT: All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers. In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation. Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex. Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.American Journal of Psychiatry 05/2008; 165(4):507-14. · 12.54 Impact Factor -
Article: Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria.
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ABSTRACT: Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. To test this hypothesis, we used positron emission tomography (PET) to measure the utilization of 6-[18F]fluoro-L-DOPA [corrected] (FDOPA) in the brain of adult patients suffering from PKU and in healthy controls. Dynamic 2-h long FDOPA emission recordings were obtained in seven adult PKU patients (five females, two males; age: 21 to 27 years) with elevated serum Phe levels, but lacking neurologic deficits. Seven age-matched, healthy volunteers were imaged under identical conditions. The utilization of FDOPA in striatum was calculated by linear graphical analysis (k3S, min(-1)), with cerebellum serving as a nonbinding reference region. The time to peak activity in all brain time-radioactivity curves was substantially delayed in the PKU patients relative to the control group. The mean magnitude of k3S in the striatum of the PKU patients (0.0052+/-0.0004 min(-1)) was significantly lower than in the control group (0.0088+/-0.0009 min(-1)) (P<0.001). There was no significant correlation between individual serum Phe levels and k3S. The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe. Assuming this competition to be spatially uniform, the relationship between striatum and cerebellum time-activity curves additionally suggests inhibition of DOPA efflux, possibly also due to competition from Phe. The linear graphical analysis shows reduced k3S in striatum, indicating reduced DOPA decarboxylase activity.Journal of Cerebral Blood Flow & Metabolism 04/2008; 28(4):824-31. · 5.01 Impact Factor -
Article: Tiagabine does not attenuate alcohol-induced activation of the human reward system.
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ABSTRACT: The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting gamma-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [(18)F]-fluoro-deoxyglucose positron emission tomography (PET). Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the mu-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.Psychopharmacologia 06/2007; 191(4):975-83. · 4.08 Impact Factor -
Article: Decreased dopamine D2/D3-receptor binding in temporal lobe epilepsy: an [18F]fallypride PET study.
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ABSTRACT: Although animal data are suggestive, evidence for an alteration of the extrastriatal dopaminergic system in human focal epilepsy is missing. To quantify D2/D3-receptor density, we studied seven patients with temporal lobe epilepsy (TLE) and nine age-matched controls with positron emission tomography (PET) by using the high-affinity dopamine D2/D3-receptor ligand [18F]Fallypride ([18F]FP) suitable for imaging extrastriatal binding. TLE was defined by interictal and ictal video-EEG, magnetic resonance imaging (MRI), and [18F]fluorodeoxyglucose ([18F]FDG)-PET and was due to hippocampal sclerosis (HS), based on histology in all patients. Primary analysis was based on regions of interest (ROIs) defined on individual MRIs. For each patient, binding potential (BP) was calculated by using the simplified reference tissue model, and the epileptogenic was compared with the unaffected hemisphere in each ROI. To confirm the results, an additional voxel-based group analysis was performed by using statistical parametric mapping. Compared with controls, [18F]FP BP was significantly decreased in the epileptogenic temporal lobe in all patients. On ROI analysis, this reduction was evident in areas surrounding the seizure-onset zone at the pole (-34.2%) and lateral aspects (-32.9%) of the temporal lobe. Although the hippocampus [18F]FDG uptake (-8.1%) and hippocampal MR volume (-35.1%) were significantly reduced, no significant decrease of [18F]FP BP was found. Reduction of [18F]FP BP did not correlate with hippocampal atrophy. D2/D3-receptor binding is reduced at the pole and in lateral aspects of the epileptogenic temporal lobe in patients with mesial TLE and HS. This area might correspond to "the irritative zone," indicating that D2/D3 receptors might play a specific role in the pathophysiology of mesial TLE.Epilepsia 09/2006; 47(8):1392-6. · 3.96 Impact Factor -
Article: The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.
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ABSTRACT: Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.Neuropsychopharmacology 05/2006; 31(5):1027-35. · 7.99 Impact Factor -
Article: Parametric mapping of binding in human brain of D2 receptor ligands of different affinities.
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ABSTRACT: (11)C-Raclopride has been widely used for PET studies of dopamine D(2/3) receptors in human brain. The long half-life of (18)F may impart advantages to the novel moderate-affinity benzamide (18)F-desmethoxyfallypride and its high-affinity congener (18)F-fallypride for competition studies and for detection of extrastriatal binding. However, the in vivo kinetics of these compounds and the quantification approaches for parametric mapping of their specific bindings have not been systematically compared. Dynamic emission recordings of the 3 tracers were obtained in groups of healthy subjects. A conventional model, graphical analysis using metabolite-corrected arterial inputs, and models with reference tissue inputs were used to calculate voxelwise parametric maps of the equilibrium distribution volume (V(d)) and the binding potential (BP) of the 3 radioligands in brain. To test for bias, voxelwise kinetic results were compared with those obtained by volume-of-interest (VOI) analysis. The V(d) and BP estimates obtained by VOI analysis did not differ from the mean of voxelwise estimates in the same striatal volumes. In striatum, the mean (18)F-desmethoxyfallypride BP ranged from 1.9 to 2.5, whereas the mean (11)C-raclopride BP ranged from 3 to 4, depending on the method used for calculation. In contrast, the mean BP of (18)F-fallypride ranged from 16 to 27 in striatum and could also be readily quantified in the thalamus. Reference tissue methods for the voxelwise calculation of binding parameters are suitable for parametric mapping of the 3 dopamine D(2/3) receptor ligands.Journal of Nuclear Medicine 07/2005; 46(6):964-72. · 6.38 Impact Factor -
Article: Acute alcohol effects on neuronal and attentional processing: striatal reward system and inhibitory sensory interactions under acute ethanol challenge.
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ABSTRACT: The acute influence of ethanol on cerebral activity induces complex psycho-physiological effects that are considerably more pronounced during acute ethanol influx than during maximal blood alcohol concentration (elimination phase). Despite the psychiatric and forensic relevance of these different ethanol effects, the underlying neuronal mechanisms are still unclear. In total, 20 male healthy volunteers were investigated each with three different experimental conditions in a randomized order using an intravenous ethanol challenge (40 g bolus infusion): during influx phase, elimination phase, and under placebo condition. During and after the ethanol (or placebo) infusion, neuropsychological testing of divided attention for visual and auditory stimuli was performed with subsequent 18-FDG PET acquisition. The PET data were analysed using SPM99. Ethanol influx and elimination phase showed focal activations in the bilateral striatum and frontal cortex and deactivations in the occipital cortex. The comparison of influx phase vs elimination phase revealed activations in the anterior cingulate and right prefrontal cortex, relevant deactivations were found in the left superior temporal cortex including Wernicke's area. Neuropsychological testing showed an attentional impairment under ethanol influx compared to ethanol elimination and placebo with an inverse correlation of the attentional performance for auditory stimuli to occipital activity and for visual stimuli to the left temporal (including auditory) cortex. Acute ethanol administration in healthy volunteers stimulates those striatal regions that are considered to have a particular relevance for alcohol craving ('reward system'). Modality specific reciprocal inhibition of sensory cortex activity seems to be relevant for attentional performance during acute alcohol impact.Neuropsychopharmacology 09/2004; 29(8):1527-37. · 7.99 Impact Factor
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- Psychiatry Research (2)
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Institutions
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2005–2010
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Johannes Gutenberg-Universität Mainz
- Institute for Nuclear Chemistry
Mainz, Rhineland-Palatinate, Germany
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