Andres H. Neuhaus

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.

Persistent dysfunctional frontal lobe activation in former smokers

ObjectiveChronic smoking and nicotine exposure are accompanied by impaired cognitive task performance, modulated cerebral activity in brain imaging studies, and neuritic damage in experimental animals. The profile of the described dysfunctions matches frontal lobe circuits which also play a role in reward processing and reinforcement behavior. However, it is largely unknown if cerebral dysfunctions are reversible or persist during long term abstinence.Materials and methodsCortical activation during auditory target processing (oddball task, P300 component) was recorded with 32-channel EEG in 247 healthy subjects consisting of 84 smokers, 53 former smokers (mean time of abstinence 11.9 years), and 110 never smokers.ResultsBoth current smokers and former smokers exhibited significantly diminished P300 amplitudes (Cz, Pz) relative to never smokers. Neuroelectric source analysis (low resolution brain electromagnetic tomography) revealed a hypoactivation of the anterior cingulate, orbitofrontal, and prefrontal cortex in smokers compared to never smokers. A similar profile of hypoactivation was observed in former smokers.ConclusionFor the first time, evidence is provided that dysfunctional activation of frontal lobe networks in smokers is also present in long term abstainers.

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.

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.

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.

Electrophysiological and neuropsychological analysis of a delirious state: The role of the anterior cingulate gyrus

Functional neuroimaging studies in humans have provided evidence that a frontal network including the anterior cingulate cortex (ACC) plays an important role in attention and awareness. Disturbed attention and awareness are core symptoms of delirium, but imaging studies of attentional dysfunctions in delirium are lacking. However, an increase of slow electroencephalographic (EEG) activity (delta, theta) is a consistent biological finding in delirium. The question whether this slow activity is related to a disturbance in the frontal attentional network has not yet been addressed. The delirium after electroconvulsive therapy (ECT) has been investigated using 32-channel resting EEG before and shortly after ECT in 12 patients with major depressive disorder. During delirium compared with baseline studies, substantial increases of delta and theta power and a decrease of alpha power were observed. The decrease of theta activity at the Fz electrode position in the following 24 h was significantly related to the recovery of awareness and performance of free recall. Source analysis with Low Resolution Electromagnetic Tomography (LORETA) indicated that the main generators of the theta excess during delirium were significantly localized in the anterior cingulate cortex, and additionally in right fronto-temporal brain areas. The results support the concept that a disturbance of attention and awareness during delirium is related to a dysfunction of an attentional network involving the ACC. However, the localization of the theta excess may reflect some motor dysfunctions as well. This dysfunction of the ACC was shown for the first time in patients during a delirious state and may represent an important pathophysiological aspect of delirium.

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.

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.

Test-retest reliability of Attention Network Test measures in schizophrenia.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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.