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ABSTRACT: Several studies employed the repetition suppression paradigm to investigate the face-specific N170 component of the event-related potential (ERP), but yielded highly inconsistent results. Varying inter-stimulus intervals (ISIs) may account for inconsistencies between studies. This study aimed at exploring the time course of repetition suppression by systematically investigating the association between ISI and ERP adaptation. Fourteen healthy subjects were investigated with a passive face recognition paradigm using paired stimuli. Stimuli were presented for 500 ms and ISIs parametrically varied between 400 and 2,000 ms. N170 was constructed to investigate adaptation effects on the level of perceptual face processing. We found evidence for an asymptotic decay of repetition suppression over time with significant N170 adaptation effects only after the shortest ISI. Our results robustly demonstrate that N170 adaptation in a paired stimulus protocol critically depends on short ISIs, thereby explaining inconsistencies observed in previous studies. For future social cognition studies using neuronal adaptation to face stimuli, the current results provide a well defined ISI associated with a large N170 adaptation effect.
International journal of psychophysiology: official journal of the International Organization of Psychophysiology 12/2012; · 3.05 Impact Factor
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ABSTRACT: Smoking prevalence is highly elevated in schizophrenia compared to the general population and to other psychiatric populations. Evidence suggests that smoking may lead to improvements of schizophrenia-associated attention deficits; however, large-scale studies on this important issue are scarce. We examined whether sustained, selective, and executive attention processes are differentially modulated by long-term nicotine consumption in 104 schizophrenia patients and 104 carefully matched healthy controls. A significant interaction of 'smoking status' × 'diagnostic group' was obtained for the domain of selective attention. Smoking was significantly associated with a detrimental conflict effect in controls, while the opposite effect was revealed for schizophrenia patients. Likewise, a positive correlation between a cumulative measure of nicotine consumption and conflict effect in controls and a negative correlation in patients were found. These results provide evidence for specific directional effects of smoking on conflict processing that critically dissociate with diagnosis. The data supports the self-medication hypothesis of smoking in schizophrenia and suggests selective attention as a specific cognitive domain targeted by nicotine consumption. A potential mechanistic model explaining these findings is discussed.
Neuropharmacology 03/2012; 62(4):1897-902. · 4.81 Impact Factor
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JAMA The Journal of the American Medical Association 02/2012; 307(8):783; author reply 783-4. · 30.03 Impact Factor
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ABSTRACT: The Attention Network Test (ANT) is a well established behavioral measure in neuropsychological research to assess three different facets of selective attention, i.e., alerting, orienting, and conflict processing. Although the ANT has been applied in healthy individuals and various clinical populations, data on retest reliability are scarce in healthy samples and lacking for clinical populations. The objective of the present study was a longitudinal assessment of relevant ANT network measures in healthy controls and schizophrenic patients.
Forty-five schizophrenic patients and 55 healthy controls were tested with ANT in a test-retest design with an average interval of 7.4 months between test sessions. Test-retest reliability was analyzed with Pearson and Intra-class correlations.
Healthy controls revealed moderate to high test-retest correlations for mean reaction time, mean accuracy, conflict effect, and conflict error rates. In schizophrenic patients, moderate test-retest correlations for mean reaction time, orienting effect, and conflict effect were found. The analysis of error rates in schizophrenic patients revealed very low test-retest correlations.
The current study provides converging statistical evidence that the conflict effect and mean reaction time of ANT yield acceptable test-retest reliabilities in healthy controls and, investigated longitudinally for the first time, also in schizophrenia. Obtained differences of alerting and orienting effects in schizophrenia case-control studies should be considered more carefully. The analysis of error rates revealed heterogeneous results and therefore is not recommended for case control studies in schizophrenia.
Biological Psychiatry 12/2011; 133(1-3):218-22. · 8.28 Impact Factor
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ABSTRACT: Schizophrenia has been associated with deficits in functional brain lateralization. According to some authors, the reduction of asymmetry could even promote this psychosis. At the same time, schizophrenia is accompanied by a high prevalence of nicotine dependency compared to any other population. This association is very interesting, because sex-dependent effects of smoking in auditory language asymmetries have been reported recently, and the verbal domain is also one major focus in cognitive deficit studies of schizophrenia. Thus, the altered laterality pattern in schizophrenia could, at least in part, result from secondary artefacts due to smoking rather than being a pure cause of the disease itself. To test this hypothesis, the present study examined auditory language lateralization in 67 schizophrenia patients and in 72 healthy controls in a phonemic and an emotional dichotic listening task. Our findings replicate previous research, in that smoking reduces language lateralization in men in phonemic dichotic listening. In addition, we show that smoking also reduces laterality in women in the emotional dichotic listening task. Thus, smoking alters phonemic and emotional language asymmetries differentially for men and women, with a stronger effect for men in the left hemisphere phonemic task, and a stronger effect for women in the right hemisphere emotional task. Together, these findings point towards an effect of smoking which is possibly independent of sex and hemisphere. Importantly, by testing equal numbers of smoking and non-smoking patients and controls, we found no schizophrenia-associated asymmetry effect. Possible neurobiological mechanisms with which smoking may alter auditory microcircuits and thereby diminish left-right differences are discussed.
Brain and Cognition 07/2011; 76(2):300-9. · 3.17 Impact Factor
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Maria C Athanasiou, Michael Dettling,
Ingolf Cascorbi,
Igor Mosyagin,
Benjamin A Salisbury,
Kerri A Pierz,
Wei Zou,
Heidi Whalen,
Anil K Malhotra,
Todd Lencz,
Stanton L Gerson,
John M Kane,
Carol R Reed
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ABSTRACT: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA).
Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls).
Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not.
A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine.
The Journal of Clinical Psychiatry 04/2011; 72(4):458-63. · 5.80 Impact Factor
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ABSTRACT: Executive dysfunction has repeatedly been proposed as a robust and promising substrate of analytical approaches in the research of neurocognitive markers of schizophrenia. Here, we present a mixed model- and data-driven classification approach by applying a task that targets executive dysfunction in schizophrenia and by investigating relevant event-related potential (ERP) features with machine learning classifiers.
Forty schizophrenic patients and forty matched healthy controls completed the Attention Network Test while an electroencephalogram was recorded. Target-locked N1 and P3 ERP components were constructed and submitted to different classification analyses without a priori hypotheses. Standardized source localization was applied to estimate neural sources of N1 and P3 deficits in schizophrenia.
We obtained a classification accuracy of 79% using only very few ERP components. Central P3 components following compatible and incompatible trials and right parietal N1 latencies averaged across targets and were sufficient for classification. P3 deficits were associated with anterior cingulate cortex dysfunction, while right posterior current density deficits were observed in schizophrenia during the N1 time frame.
The data exemplarily show how automated inference may be applied to classify a pathological state in single subjects without prior knowledge of their diagnoses. While classification accuracy may be optimized by application of other executive paradigms, this approach illustrates the potential of machine learning algorithms for the identification of biomarkers that are independent of clinical assessments. Conversely, data suggest a pathophysiological mechanism that includes early visual and late executive deficits during response inhibition in schizophrenia.
NeuroImage 03/2011; 55(2):514-21. · 5.89 Impact Factor
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ABSTRACT: In the search for markers of schizophrenia, functional deficits during inhibition have been a major focus. In previous studies, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients during inhibition in the Attention Network Test (ANT). The objective of the present study was to explore whether this deficit exhibits properties of a trait or state marker of schizophrenia.
Eighteen recent onset inpatients and eighteen chronic schizophrenic outpatients as well as 36 healthy controls, including a young adult and an old adult group to match recent onset and chronic illness groups for age and sex, were included. Participants were tested with ANT while 32-channel electroencephalogram was recorded and visual P3 amplitudes were analyzed. Amplitude modulation was defined as the variation of P3 amplitude at Pz as a function of ANT flanker conditions.
There were no significant behavioral between-group differences in terms of alerting, orienting, and inhibition. Mean visual P3 was significantly lower in schizophrenic patients than in healthy controls. Parietal P3 amplitude was significantly less modulated in both recent onset (-0.035) and chronic schizophrenic patients (-0.081) compared with young (-0.588; p<0.05) and older healthy controls, respectively (-0.556; p<0.05). No correlations were obtained between P3 modulation and clinical or demographic variables.
The results provide evidence that the observed deficit of visual P3 amplitude modulation is independent of duration of illness and age and may contain properties of a trait marker of schizophrenia.
Biological Psychiatry 03/2011; 130(1-3):210-5. · 8.28 Impact Factor
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ABSTRACT: To characterize the interplay of bottom-up and top-down processing deficits of the early visual ERP component N1 in schizophrenia.
Thirty-three schizophrenic patients and 61 healthy controls underwent a visual selective attention paradigm while 32-channel electroencephalogram was recorded. Visual N1 responses were calculated and source localization was applied.
Significant reductions of the cue N1 as well as the target N1 components were found in schizophrenia patients. Linear regression slopes for the cue N1 and for the cue-locked target N1 indicated significantly reduced early bottom-up and top-down modulation in patients relative to controls. Source analyses indicated that bottom-up as well as top-down N1 deficits in schizophrenia are associated with partially overlapping current density deficits in posterior cortex areas. Differential functional deficits were observed in right parietal lobe during bottom-up processing and in anterior cingulate cortex during top-down attention.
The results provide evidence for both early visual bottom-up and top-down deficits in schizophrenia and illustrate how disturbances in these processing streams converge on the visual N1 amplitude.
Visual top-down disturbances in schizophrenia appear to be confounded by visual bottom-up deficits.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 01/2011; 122(1):90-8. · 3.12 Impact Factor
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ABSTRACT: In a previous study, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients compared with healthy controls during inhibition in the Attention Network Test (ANT). The objective of the present study was to replicate this finding and to explore whether this cortical processing deficit is specific to schizophrenia.
Sixteen schizophrenic patients, sixteen depressive patients, and sixteen healthy controls matched for age, sex, and education were included. Participants were tested with the ANT, a test of selective attention that provides behavioral estimates for alerting, orienting, and inhibition. 32-Channel electroencephalogram was recorded and visual P3 amplitudes were topographically analyzed and compared between groups.
There were no significant behavioral between-group differences in terms of mean reaction time, accuracy, and ANT effects alerting, orienting, and inhibition. Absolute visual P3 amplitude was not reduced in schizophrenia or depression. P3 amplitude modulation was defined as P3 amplitude at Pz as a function of ANT flanker conditions. We found a parietal P3 amplitude modulation deficit in schizophrenic patients (-.015) that was absent in both healthy controls (-.705; p = .002) and depressive patients (-1.022; p = .001).
The results provide evidence that a deficit of visual P3 amplitude modulation distinguishes schizophrenia from healthy and disease controls and provides greater discriminative power than absolute visual P3 amplitude.
Biological Psychiatry 12/2010; 124(1-3):119-26. · 8.28 Impact Factor
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ABSTRACT: Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy.
We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP).
We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests.
We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs.
The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism.
Pharmacogenomics 06/2010; 11(6):773-80. · 3.97 Impact Factor
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ABSTRACT: Selective visual attention is thought to be comprised of distinct neuronal networks that serve different attentional functions. The Attention Network Test (ANT) has been introduced to allow for assessment of alerting, orienting, and response inhibition. Information on associated measures of neural processing during ANT is still scarce. We topographically analyzed top-down ANT effects on visual event-related potential morphology in 44 healthy participants. Significant reaction time effects were obtained for all attention networks. Posterior cue-locked target N1 amplitude was significantly increased during both alerting and orienting. P3 amplitude was significantly modulated at frontal and parietal leads as a function of inhibition. Our data suggests that attentional mechanisms of alerting and orienting are employed simultaneously at early stages of the visual processing stream to amplify perceptual discrimination and load onto the same ERP component. Fronto-parietal modulations of P3 amplitude seem to mirror both response inhibition and visual target detection and may be interesting markers for further studies.
International journal of psychophysiology: official journal of the International Organization of Psychophysiology 02/2010; 76(2):72-9. · 3.05 Impact Factor
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Carsten Urbanek,
Nicholetta Weinges-Evers,
Judith Bellmann-Strobl,
Markus Bock,
Jan Dörr,
Eric Hahn,
Andres H Neuhaus,
Carolin Opgen-Rhein,
Thi Minh Tam Ta,
Katja Herges,
Caspar F Pfueller,
Helena Radbruch,
Klaus D Wernecke,
Stephanie Ohlraun,
Frauke Zipp, Michael Dettling,
Friedemann Paul
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ABSTRACT: Attention is one of the cognitive domains typically affected in multiple sclerosis. The Attention Network Test was developed to measure the function of the three distinct attentional networks, alerting, orienting, and executive control. The Attention Network Test has been performed in various neuropsychiatric conditions, but not in multiple sclerosis. Our objective was to investigate functions of attentional networks in multiple sclerosis by means of the Attention Network Test. Patients with relapsing-remitting multiple sclerosis (n = 57) and healthy controls (n = 57) matched for age, sex, and education performed the Attention Network Test. Significant differences between patients and controls were detected in the alerting network (p = 0.003), in contrast to the orienting (p = 0.696) and the conflict (p = 0.114) network of visual attention. Mean reaction time in the Attention Network Test was significantly longer in multiple sclerosis patients than in controls (p = 0.032), Multiple sclerosis patients benefited less from alerting cues for conflict resolution compared with healthy controls. The Attention Network Test revealed specific alterations of the attention network in multiple sclerosis patients which were not explained by an overall cognitive slowing.
Multiple Sclerosis 12/2009; 16(1):93-9. · 4.26 Impact Factor
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ABSTRACT: The Attention Network Test (ANT) provides measures for three different components of visual attention: executive control (=conflict inhibition), orienting, and alerting. There is reasonable evidence that alterations of attention-mainly in the executive/conflict domain-are associated with susceptibility to psychiatric illness. Specific impairments may be a characteristic for a medical condition such as schizophrenia and thus shift our understanding from a neuropsychological endophenotype to a more precise genetic understanding of this disorder. Study subjects comprised 35 schizophrenic patients and 35 healthy controls (13 female and 22 male in both groups). The ANT was administered to all participants and rated individual responses for the three factors (alerting, orienting, and conflict) and their respective ratios relative to mean reaction times. With regard to gender differences, group comparisons were performed for schizophrenic patients vs. healthy controls. Significant differences between patients and controls could be detected for mean reaction time (639 vs. 538 ms) and for conflict ratio (0.158 vs. 0.191). The latter difference mainly resulted from gender-specific variances of the conflict network in opposite directions. The executive function as represented by the conflict network of visual attention of the ANT is affected in schizophrenia. We have detected hitherto unreported gender-specific differences between healthy controls and schizophrenic patients. Especially as regards the conflict network, the ANT offers a promising methodology to detect a neuropsychological endophenotype of schizophrenia.
Psychiatry Research 08/2009; 168(2):102-9. · 2.52 Impact Factor
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The Lancet 05/2009; 373(9671):1249; author reply 1249-50. · 38.28 Impact Factor
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ABSTRACT: Functional neuroimaging studies have increasingly aimed at approximating neural substrates of human cognitive sex differences elicited by visuospatial challenge. It has been suggested that females and males use different behaviorally relevant neurocognitive strategies. In females, greater right prefrontal cortex activation has been found in several studies. The spatiotemporal dynamics of neural events associated with these sex differences is still unclear. We studied 22 female and 22 male participants matched for age, education, and nicotine with 29-channel-electroencephalogram recorded under a visual selective attention paradigm, the Attention Network Test. Visual event-related potentials (ERP) were topographically analyzed and neuroelectric sources were estimated. In absence of behavioral differences, ERP analysis revealed a novel frontal-occipital second peak of visual N100 that was significantly increased in females relative to males. Further, in females exclusively, a corresponding central ERP component at around 220 ms was found; here, a strong correlation between stimulus salience and sex difference of the central ERP component amplitude was observed. Subsequent source analysis revealed increased cortical current densities in right rostral prefrontal (BA 10) and occipital cortex (BA 19) in female subjects. This is the first study to report on a tripartite association between sex differences in ERPs, visual stimulus salience, and right prefrontal cortex activation during attentional processing.
Human Brain Mapping 02/2009; 30(9):2997-3008. · 5.88 Impact Factor
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JAMA The Journal of the American Medical Association 11/2008; 300(15):1757; author reply 1758-9. · 30.03 Impact Factor
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ABSTRACT: Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in schizophrenic patients. Although this adverse reaction has been well known for almost 30 years, only few genetically based determinants can be identified to date. Furthermore, owing to rare occurrence, specific clinical course and complexity of pathomechanisms of antipsychotic-induced agranulocytosis, only a few of the findings met the criteria of replication. The most promising susceptibility genes for CiA include genes involved in the human leukocyte antigen system and in specific metabolizing enzyme systems. However, complex idiosyncratic drug reactions such as CiA are considered to be determined by multiple, possibly interacting genetic variations, rather than by a single causative variant.
Pharmacogenomics 09/2008; 9(8):1101-11. · 3.97 Impact Factor
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New England Journal of Medicine 03/2008; 358(6):645; author reply 646. · 53.30 Impact Factor
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ABSTRACT: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT.
We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT.
Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention.
Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance.
Schizophrenia Bulletin 02/2008; 34(6):1231-9. · 8.80 Impact Factor
