TY  - JOUR
A1  - Chen, Hao
A1  - Belanger, Matthew J.
A1  - Garbusow, Maria
A1  - Kuitunen-Paul, Soeren
A1  - Huys, Quentin J. M.
A1  - Heinz, Andreas
A1  - Rapp, Michael Armin
A1  - Smolka, Michael N.
T1  - Susceptibility to interference between Pavlovian and instrumental control predisposes risky alcohol use developmental trajectory from ages 18 to 24
JF  - Addiction biology
N2  - Pavlovian cues can influence ongoing instrumental behaviour via Pavlovian-to-instrumental transfer (PIT) processes. While appetitive Pavlovian cues tend to promote instrumental approach, they are detrimental when avoidance behaviour is required, and vice versa for aversive cues. We recently reported that susceptibility to interference between Pavlovian and instrumental control assessed via a PIT task was associated with risky alcohol use at age 18. We now investigated whether such susceptibility also predicts drinking trajectories until age 24, based on AUDIT (Alcohol Use Disorders Identification Test) consumption and binge drinking (gramme alcohol/drinking occasion) scores. The interference PIT effect, assessed at ages 18 and 21 during fMRI, was characterized by increased error rates (ER) and enhanced neural responses in the ventral striatum (VS), the lateral and dorsomedial prefrontal cortices (dmPFC) during conflict, that is, when an instrumental approach was required in the presence of an aversive Pavlovian cue or vice versa. We found that a stronger VS response during conflict at age 18 was associated with a higher starting point of both drinking trajectories but predicted a decrease in binge drinking. At age 21, high ER and enhanced neural responses in the dmPFC were associated with increasing AUDIT-C scores over the next 3 years until age 24. Overall, susceptibility to interference between Pavlovian and instrumental control might be viewed as a predisposing mechanism towards hazardous alcohol use during young adulthood, and the identified high-risk group may profit from targeted interventions.
KW  - interference control
KW  - Pavlovian-to-instrumental transfer
KW  - risky drinking
Y1  - 2023
U6  - https://doi.org/10.1111/adb.13263
SN  - 1355-6215
SN  - 1369-1600
VL  - 28
IS  - 2
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Chen, Hao
A1  - Nebe, Stephan
A1  - Mojtahedzadeh, Negin
A1  - Kuitunen-Paul, Soren
A1  - Garbusow, Maria
A1  - Schad, Daniel
A1  - Rapp, Michael Armin
A1  - Huys, Quentin J. M.
A1  - Heinz, Andreas
A1  - Smolka, Michael N.
T1  - Susceptibility to interference between Pavlovian and instrumental control is associated with early hazardous alcohol use
T2  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe
N2  - Pavlovian-to-instrumental transfer (PIT) tasks examine the influence of Pavlovian stimuli on ongoing instrumental behaviour. Previous studies reported associations between a strong PIT effect, high-risk drinking and alcohol use disorder. This study investigated whether susceptibility to interference between Pavlovian and instrumental control is linked to risky alcohol use in a community sample of 18-year-old male adults. Participants (N = 191) were instructed to 'collect good shells' and 'leave bad shells' during the presentation of appetitive (monetary reward), aversive (monetary loss) or neutral Pavlovian stimuli. We compared instrumental error rates (ER) and functional magnetic resonance imaging (fMRI) brain responses between the congruent and incongruent conditions, as well as among high-risk and low-risk drinking groups. On average, individuals showed a substantial PIT effect, that is, increased ER when Pavlovian cues and instrumental stimuli were in conflict compared with congruent trials. Neural PIT correlates were found in the ventral striatum and the dorsomedial and lateral prefrontal cortices (lPFC). Importantly, high-risk drinking was associated with a stronger behavioural PIT effect, a decreased lPFC response and an increased neural response in the ventral striatum on the trend level. Moreover, high-risk drinkers showed weaker connectivity from the ventral striatum to the lPFC during incongruent trials. Our study links interference during PIT to drinking behaviour in healthy, young adults. High-risk drinkers showed higher susceptibility to Pavlovian cues, especially when they conflicted with instrumental behaviour, indicating lower interference control abilities. Increased activity in the ventral striatum (bottom-up), decreased lPFC response (top-down), and their altered interplay may contribute to poor interference control in the high-risk drinkers.
T3  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 855 
KW  - high‐risk drinking
KW  - interference control
KW  - Pavlovian‐to‐instrumental transfer
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-569609
SN  - 1866-8364
IS  - 4
ER  - 
TY  - JOUR
A1  - Chen, Hao
A1  - Nebe, Stephan
A1  - Mojtahedzadeh, Negin
A1  - Kuitunen-Paul, Soren
A1  - Garbusow, Maria
A1  - Schad, Daniel
A1  - Rapp, Michael Armin
A1  - Huys, Quentin J. M.
A1  - Heinz, Andreas
A1  - Smolka, Michael N.
T1  - Susceptibility to interference between Pavlovian and instrumental control is associated with early hazardous alcohol use
JF  - Addiction biology
N2  - Pavlovian-to-instrumental transfer (PIT) tasks examine the influence of Pavlovian stimuli on ongoing instrumental behaviour. Previous studies reported associations between a strong PIT effect, high-risk drinking and alcohol use disorder. This study investigated whether susceptibility to interference between Pavlovian and instrumental control is linked to risky alcohol use in a community sample of 18-year-old male adults. Participants (N = 191) were instructed to 'collect good shells' and 'leave bad shells' during the presentation of appetitive (monetary reward), aversive (monetary loss) or neutral Pavlovian stimuli. We compared instrumental error rates (ER) and functional magnetic resonance imaging (fMRI) brain responses between the congruent and incongruent conditions, as well as among high-risk and low-risk drinking groups. On average, individuals showed a substantial PIT effect, that is, increased ER when Pavlovian cues and instrumental stimuli were in conflict compared with congruent trials. Neural PIT correlates were found in the ventral striatum and the dorsomedial and lateral prefrontal cortices (lPFC). Importantly, high-risk drinking was associated with a stronger behavioural PIT effect, a decreased lPFC response and an increased neural response in the ventral striatum on the trend level. Moreover, high-risk drinkers showed weaker connectivity from the ventral striatum to the lPFC during incongruent trials. Our study links interference during PIT to drinking behaviour in healthy, young adults. High-risk drinkers showed higher susceptibility to Pavlovian cues, especially when they conflicted with instrumental behaviour, indicating lower interference control abilities. Increased activity in the ventral striatum (bottom-up), decreased lPFC response (top-down), and their altered interplay may contribute to poor interference control in the high-risk drinkers.
KW  - high‐risk drinking
KW  - interference control
KW  - Pavlovian‐to‐instrumental transfer
Y1  - 2020
U6  - https://doi.org/10.1111/adb.12983
SN  - 1355-6215
SN  - 1369-1600
VL  - 26
IS  - 4
SP  - 1
EP  - 14
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Deserno, Lorenz
A1  - Beck, Anne
A1  - Huys, Quentin J. M.
A1  - Lorenz, Robert C.
A1  - Buchert, Ralph
A1  - Buchholz, Hans-Georg
A1  - Plotkin, Michail
A1  - Kumakara, Yoshitaka
A1  - Cumming, Paul
A1  - Heinze, Hans-Jochen
A1  - Grace, Anthony A.
A1  - Rapp, Michael Armin
A1  - Schlagenhauf, Florian
A1  - Heinz, Andreas
T1  - Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum
JF  - European journal of neuroscience
N2  - Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non-drug-related stimuli towards drug-related stimuli. Such hijacked' dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N=27). All participants also underwent 6-[F-18]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs nor striatal dopamine synthesis capacity differed between groups. However, ventral striatal coding of RPEs correlated inversely with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between dopamine synthesis capacity and RPE coding depended on the amount of chronic, habitual alcohol intake. Despite the relatively small sample size, a power analysis supports the reported results. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence in proportion to long-term alcohol intake of patients. Alcohol intake may perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake.
KW  - alcohol addiction
KW  - dopamine
KW  - fMRI
KW  - PET
KW  - prediction error
Y1  - 2015
U6  - https://doi.org/10.1111/ejn.12802
SN  - 0953-816X
SN  - 1460-9568
VL  - 41
IS  - 4
SP  - 477
EP  - 486
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Friedel, Eva
A1  - Schlagenhauf, Florian
A1  - Beck, Anne
A1  - Dolan, Raymond J.
A1  - Huys, Quentin J. M.
A1  - Rapp, Michael Armin
A1  - Heinz, Andreas
T1  - The effects of life stress and neural learning signals on fluid intelligence
T2  - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe
N2  - Fluid intelligence (fluid IQ), defined as the capacity for rapid problem solving and behavioral adaptation, is known to be modulated by learning and experience. Both stressful life events (SLES) and neural correlates of learning [specifically, a key mediator of adaptive learning in the brain, namely the ventral striatal representation of prediction errors (PE)] have been shown to be associated with individual differences in fluid IQ. Here, we examine the interaction between adaptive learning signals (using a well-characterized probabilistic reversal learning task in combination with fMRI) and SLES on fluid IQ measures. We find that the correlation between ventral striatal BOLD PE and fluid IQ, which we have previously reported, is quantitatively modulated by the amount of reported SLES. Thus, after experiencing adversity, basic neuronal learning signatures appear to align more closely with a general measure of flexible learning (fluid IQ), a finding complementing studies on the effects of acute stress on learning. The results suggest that an understanding of the neurobiological correlates of trait variables like fluid IQ needs to take socioemotional influences such as chronic stress into account.
T3  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 621 
KW  - reinforcement learning
KW  - prediction error signal
KW  - ventral striatum
KW  - stress
KW  - intelligence
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-435140
SN  - 1866-8372
IS  - 621
SP  - 35
EP  - 43
ER  - 
TY  - JOUR
A1  - Friedel, Eva
A1  - Schlagenhauf, Florian
A1  - Beck, Anne
A1  - Dolan, Raymond J.
A1  - Huys, Quentin J. M.
A1  - Rapp, Michael Armin
A1  - Heinz, Andreas
T1  - The effects of life stress and neural learning signals on fluid intelligence
JF  - European archives of psychiatry and clinical neuroscience : official organ of the German Society for Biological Psychiatry
N2  - Fluid intelligence (fluid IQ), defined as the capacity for rapid problem solving and behavioral adaptation, is known to be modulated by learning and experience. Both stressful life events (SLES) and neural correlates of learning [specifically, a key mediator of adaptive learning in the brain, namely the ventral striatal representation of prediction errors (PE)] have been shown to be associated with individual differences in fluid IQ. Here, we examine the interaction between adaptive learning signals (using a well-characterized probabilistic reversal learning task in combination with fMRI) and SLES on fluid IQ measures. We find that the correlation between ventral striatal BOLD PE and fluid IQ, which we have previously reported, is quantitatively modulated by the amount of reported SLES. Thus, after experiencing adversity, basic neuronal learning signatures appear to align more closely with a general measure of flexible learning (fluid IQ), a finding complementing studies on the effects of acute stress on learning. The results suggest that an understanding of the neurobiological correlates of trait variables like fluid IQ needs to take socioemotional influences such as chronic stress into account.
KW  - Reinforcement learning
KW  - Prediction error signal
KW  - Ventral striatum
KW  - Stress
KW  - Intelligence
Y1  - 2015
U6  - https://doi.org/10.1007/s00406-014-0519-3
SN  - 0940-1334
SN  - 1433-8491
VL  - 265
IS  - 1
SP  - 35
EP  - 43
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - GEN
A1  - Garbusow, Maria
A1  - Nebe, Stephan
A1  - Sommer, Christian
A1  - Kuitunen-Paul, Sören
A1  - Sebold, Miriam Hannah
A1  - Schad, Daniel
A1  - Friedel, Eva
A1  - Veer, Ilya M.
A1  - Wittchen, Hans-Ulrich
A1  - Rapp, Michael Armin
A1  - Ripke, Stephan
A1  - Walter, Henrik
A1  - Huys, Quentin J. M.
A1  - Schlagenhauf, Florian
A1  - Smolka, Michael N.
A1  - Heinz, Andreas
T1  - Pavlovian-To-Instrumental Transfer and Alcohol Consumption in Young Male Social Drinkers
BT  - Behavioral, Neural and Polygenic Correlates
T2  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe
N2  - In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
T3  - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 841 
KW  - Pavlovian-to-instrumental transfer
KW  - amygdala
KW  - alcohol
KW  - polygenic risk
KW  - high risk drinkers
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473280
SN  - 1866-8364
IS  - 841
ER  - 
TY  - JOUR
A1  - Garbusow, Maria
A1  - Nebe, Stephan
A1  - Sommer, Christian
A1  - Kuitunen-Paul, Sören
A1  - Sebold, Miriam Hannah
A1  - Schad, Daniel
A1  - Friedel, Eva
A1  - Veer, Ilya M.
A1  - Wittchen, Hans-Ulrich
A1  - Rapp, Michael Armin
A1  - Ripke, Stephan
A1  - Walter, Henrik
A1  - Huys, Quentin J. M.
A1  - Schlagenhauf, Florian
A1  - Smolka, Michael N.
A1  - Heinz, Andreas
T1  - Pavlovian-To-Instrumental Transfer and Alcohol Consumption in Young Male Social Drinkers
BT  - Behavioral, Neural and Polygenic Correlates
JF  - Journal of Clinical Medicine
N2  - In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
KW  - Pavlovian-to-instrumental transfer
KW  - amygdala
KW  - alcohol
KW  - polygenic risk
KW  - high risk drinkers
Y1  - 2019
U6  - https://doi.org/10.3390/jcm8081188
SN  - 2077-0383
VL  - 8
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Garbusow, Maria
A1  - Schad, Daniel
A1  - Sebold, Miriam Hannah
A1  - Friedel, Eva
A1  - Bernhardt, Nadine
A1  - Koch, Stefan P.
A1  - Steinacher, Bruno
A1  - Kathmann, Norbert
A1  - Geurts, Dirk E. M.
A1  - Sommer, Christian
A1  - Mueller, Dirk K.
A1  - Nebe, Stephan
A1  - Paul, Soeren
A1  - Wittchen, Hans-Ulrich
A1  - Zimmermann, Ulrich S.
A1  - Walter, Henrik
A1  - Smolka, Michael N.
A1  - Sterzer, Philipp
A1  - Rapp, Michael Armin
A1  - Huys, Quentin J. M.
A1  - Schlagenhauf, Florian
A1  - Heinz, Andreas
T1  - Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence
JF  - Addiction biology
N2  - In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n=31 detoxified patients diagnosed with alcohol dependence and n=24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.
KW  - human Pavlovian-to-instrumental transfer
KW  - nucleus accumbens
KW  - relapse in alcohol use disorder
Y1  - 2016
U6  - https://doi.org/10.1111/adb.12243
SN  - 1355-6215
SN  - 1369-1600
VL  - 21
SP  - 719
EP  - 731
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Garbusow, Maria
A1  - Schad, Daniel
A1  - Sommer, Christian
A1  - Juenger, Elisabeth
A1  - Sebold, Miriam Hannah
A1  - Friedel, Eva
A1  - Wendt, Jean
A1  - Kathmann, Norbert
A1  - Schlagenhauf, Florian
A1  - Zimmermann, Ulrich S.
A1  - Heinz, Andreas
A1  - Huys, Quentin J. M.
A1  - Rapp, Michael Armin
T1  - Pavlovian-to-instrumental transfer in alcohol dependence: a pilot study
JF  - Neuropsychobiology : international journal of experimental and clinical research in biological psychiatry, pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography
N2  - Background: Pavlovian processes are thought to play an important role in the development, maintenance and relapse of alcohol dependence, possibly by influencing and usurping ongoing thought and behavior. The influence of pavlovian stimuli on ongoing behavior is paradigmatically measured by pavlovian-to-instrumental transfer (PIT) tasks. These involve multiple stages and are complex. Whether increased PIT is involved in human alcohol dependence is uncertain. We therefore aimed to establish and validate a modified PIT paradigm that would be robust, consistent and tolerated by healthy controls as well as by patients suffering from alcohol dependence, and to explore whether alcohol dependence is associated with enhanced PIT. Methods: Thirty-two recently detoxified alcohol-dependent patients and 32 age- and gender-matched healthy controls performed a PIT task with instrumental go/no-go approach behaviors. The task involved both pavlovian stimuli associated with monetary rewards and losses, and images of drinks. Results: Both patients and healthy controls showed a robust and temporally stable PIT effect. Strengths of PIT effects to drug-related and monetary conditioned stimuli were highly correlated. Patients more frequently showed a PIT effect, and the effect was stronger in response to aversively conditioned CSs (conditioned suppression), but there was no group difference in response to appetitive CSs. Conclusion: The implementation of PIT has favorably robust properties in chronic alcohol-dependent patients and in healthy controls. It shows internal consistency between monetary and drug-related cues. The findings support an association of alcohol dependence with an increased propensity towards PIT.
KW  - Pavlovian-to-instrumental transfer
KW  - Alcohol dependence
KW  - Human
Y1  - 2014
U6  - https://doi.org/10.1159/000363507
SN  - 0302-282X
SN  - 1423-0224
VL  - 70
IS  - 2
SP  - 111
EP  - 121
PB  - Karger
CY  - Basel
ER  -