Effects of ZNF804A on auditory P300 response in schizophrenia.
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ABSTRACT:
SUBMITTER: O'Donoghue T
PROVIDER: S-EPMC3905225 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
Publications
Effects of ZNF804A on auditory P300 response in schizophrenia.
O'Donoghue T T Morris D W DW Fahey C C Da Costa A A Moore S S Cummings E E Leicht G G Karch S S Hoerold D D Tropea D D Foxe J J JJ Gill M M Corvin A A Donohoe G G
Translational psychiatry 20140114
The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked ...[more]
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Project description:Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment.
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Project description:The uncompetitive low-affinity NMDA receptor antagonist, memantine, acutely increases electrophysiological measures of auditory information processing in both healthy subjects (HS) and patients with schizophrenia. Memantine effects on functional measures of auditory discrimination performance and learning are not known; conceivably, beneficial effects on these measures might suggest a role for memantine in augmenting the cognitive and functional impact of auditory targeted cognitive training (TCT). Here, carefully characterized HS (n = 20) and schizophrenia patients (n = 22) were tested in measures of auditory discrimination performance (words-in-noise (WIN), quick speech-in-noise (QuickSIN), gaps-in-noise) and auditory frequency modulation learning (a component of TCT) on 2 days about a week apart, after ingesting either placebo or 20 mg memantine po, in a double-blind, within-subject cross-over random order design. Memantine modestly enhanced functional measures of auditory discrimination in both schizophrenia patients (WIN) and HS (WIN and QuickSIN), as well as auditory frequency modulation learning in schizophrenia patients. These findings converge with a growing literature showing that memantine can enhance a range of metrics of auditory function. These properties could contribute to the apparent benefits of memantine as an adjunctive treatment in schizophrenia, and suggest that memantine might augment learning and potentially clinical gains from auditory-based TCT.
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Project description:Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 in the gene ZNF804A encoding zinc finger protein 804A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of PubMed database identified 25 case-control studies with available genotype frequencies of rs1344706 for the meta-analysis, involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations (P=0.028, OR=1.138, 95% CI: 1.014-1.278; P=0.004 for heterogeneity) and Asian populations (P=0.008, OR=1.092, 95% CI: 1.023-1.165; P=0.001 for heterogeneity), but not in other populations (P=0.286, OR=1.209, 95% CI: 0.853-1.714, P=0.120 for heterogeneity). Egger's test (P>0.05) and Begg's test (P>0.05) are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.
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Project description:Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.
| S-EPMC3984519 | biostudies-literature
Project description:BACKGROUND:Individuals with schizophrenia have heterogeneous impairments of the auditory processing system that likely mediate differences in the cognitive gains induced by auditory training (AT). Mismatch negativity (MMN) is an event-related potential component reflecting auditory echoic memory, and its amplitude reduction in schizophrenia has been linked to cognitive deficits. Therefore, MMN may predict response to AT and identify individuals with schizophrenia who have the most to gain from AT. Furthermore, to the extent that AT strengthens auditory deviance processing, MMN may also serve as a readout of the underlying changes in the auditory system induced by AT. METHODS:Fifty-six individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of AT or Computer Games (CG). Cognitive assessments and EEG recordings during a multi-deviant MMN paradigm were obtained before and after AT and CG. Changes in these measures were compared between the treatment groups. Baseline and trait-like MMN data were evaluated as predictors of treatment response. MMN data collected with the same paradigm from a sample of Healthy Controls (HC; n = 105) were compared to baseline MMN data from the ESZ group. RESULTS:Compared to HC, ESZ individuals showed significant MMN reductions at baseline (p = .003). Reduced Double-Deviant MMN was associated with greater general cognitive impairment in ESZ individuals (p = .020). Neither ESZ intervention group showed significant change in MMN. We found high correlations in all MMN deviant types (rs = .59-.68, all ps < .001) between baseline and post-intervention amplitudes irrespective of treatment group, suggesting trait-like stability of the MMN signal. Greater deficits in trait-like Double-Deviant MMN predicted greater cognitive improvements in the AT group (p = .02), but not in the CG group. CONCLUSIONS:In this sample of ESZ individuals, AT had no effect on auditory deviance processing as assessed by MMN. In ESZ individuals, baseline MMN was significantly reduced relative to HCs, and associated with global cognitive impairment. MMN did not show changes after AT and exhibited trait-like stability. Greater deficits in the trait aspects of Double-Deviant MMN predicted greater gains in global cognition in response to AT, suggesting that MMN may identify individuals who stand to gain the most from AT. TRIAL REGISTRATION:NCT00694889. Registered 1 August 2007.
| S-EPMC5568850 | biostudies-literature