Visual P3 amplitude modulation deficit in schizophrenia is independent of duration of illness.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Single-subject classification of schizophrenia by event-related potentials during selective attention.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Dissection of early bottom-up and top-down deficits during visual attention in schizophrenia.

OBJECTIVE: To characterize the interplay of bottom-up and top-down processing deficits of the early visual ERP component N1 in schizophrenia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SIGNIFICANCE: Visual top-down disturbances in schizophrenia appear to be confounded by visual bottom-up deficits.

Evidence of specificity of a visual P3 amplitude modulation deficit in schizophrenia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample.

BACKGROUND: 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. AIM: 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). PATIENTS & METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Event-related potentials associated with Attention Network Test.

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.

Attention Network Test reveals alerting network dysfunction in multiple sclerosis.

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.

Attention network test (ANT) reveals gender-specific alterations of executive function in schizophrenia.

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.

Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects.

Cerebral dopamine homeostasis has been implicated in a wide range of cognitive processes and is of great pathophysiological importance in schizophrenia. A novel approach to study cognitive effects of dopamine is to deplete its cerebral levels with branched chain amino acids (BCAAs) that acutely lower dopamine precursor amino acid availability. Here, we studied the effects of acute dopamine depletion on early and late attentive cortical processing. Auditory event-related potential (ERP) components N2 and P3 were investigated using high-density electroencephalography in 22 healthy male subjects after receiving BCAAs or placebo in a randomized, double-blind, placebo-controlled crossover design. Total free serum prolactin was also determined as a surrogate marker of cerebral dopamine depletion. Acute dopamine depletion increased free plasma prolactin and significantly reduced prefrontal ERP components N2 and P3. Subcomponent analysis of N2 revealed a significant attenuation of early attentive N2b over prefrontal scalp sites. As a proof of concept, these results strongly suggest that BCAAs are acting on basic information processing. Dopaminergic neurotransmission seems to be involved in auditory top-down processing as indexed by prefrontal N2 and P3 reductions during dopamine depletion. In healthy subjects, intact early cortical top-down processing can be acutely dysregulated by ingestion of BCAAs. We discuss the potential impact of these findings on schizophrenia research.

Spatiotemporal mapping of sex differences during attentional processing.

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.

Clozapine-induced agranulocytosis and its genetic determinants.

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.

Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.

INTRODUCTION: The genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance. METHODS: We analyzed block structure and association patterns of an approximately 173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance. RESULTS: We identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers. CONCLUSIONS: We report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus.

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Selective anterior cingulate cortex deficit during conflict solution in schizophrenia: an event-related potential study.

BACKGROUND: Schizophrenia research has gained a new focus on identification and further characterization of neurocognitive deficits in the search for behavioural endophenotypes of this disorder. The objective of this study was to explore differential cortical processing during executive control in schizophrenia as assessed with the attention network test (ANT). METHODS: Sixteen schizophrenic patients and sixteen healthy controls matched for gender, age, education, and nicotine consumption were tested with the ANT while recording 29-channel-electroencephalogram (EEG). Visual event-related potentials (ERP) N200 and P300 were topographically analyzed and cortical mapping using low resolution brain electromagnetic tomography (LORETA) was applied to localize neuroelectric generators of ERP. RESULTS: Behaviourally, significant differences between schizophrenic patients and controls were found only for the conflict condition (p<0.05) and for conflict adjusted by mean reaction time (p<0.01). Examining ERP of control subjects, N200 failed to show robust flanker congruency effects. P300 amplitude was reduced at Pz (p<0.05) and P300 latency was increased at Cz (p<0.005) for the conflict condition. Schizophrenic patients differed significantly in P300 latency at Cz during late conflict processing (p<0.005). Source analysis revealed a deficit in anterior cingulate cortex (p<0.05). CONCLUSION: Our results are in line with previous reports about dysfunctional ACC activation in schizophrenia and argue in favour of a selective deficit of cortical conflict resolution. It is further proposed that dysfunctional ACC activation during executive processing may be a neurophysiologic endophenotype candidate of schizophrenia.

[New strategies in schizophrenia: impact of endophentotypes]. / Neue Ansätze in der Schizophrenieforschung: Die Bedeutung von neuropsychologischen Endophänotypen und deren möglicher Nutzen.

Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and genetic underpinnings of this disabling disease still remain unclear. Reasonable explanations for current problems in identifying candidate genes for schizophrenia are the complexity of its genetic background as well as the heterogeneity of the clinical appearance of this disease. For a higher efficiency in genetic investigations, a new approach came up which defines clinically distinct traits much more precisely: the so called endophenotype concept. Schizophrenic patients suffer from marked cognitive deficits. These deficits are closely related to the neurobiological basis of the disease, exhibit a high negative impact on clinical outcome, and may serve as endophenotypes for genetic studies. Identification of neurocognitive endopenotypes is usually performed in terms of a combination of neuropsychological tests and neurophysiological measurements. Thus, future genetic investigations as well as psychosocial and psychopharmacological therapy strategies will focus on the severity and potential therapeutic modification of cognitive deficits in order to improve psychosocial reintegration of schizophrenic patients in the long-term.