The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Nicotine enhances an auditory Event-Related Potential component which is inversely related to habituation

Nicotine is a psychoactive substance that is commonly consumed in the context of music. However, the reason why music and nicotine are coconsumed is uncertain. One possibility is that nicotine affects cognitive processes relevant to aspects of music appreciation in a beneficial way. Here we investigated this possibility using Event-Related Potentials (ERPs). Participants underwent a simple decision-making task (to maintain attentional focus), responses to which were signaled by auditory stimuli. Unlike most previous research looking at the effects of nicotine on auditory processing, we used tones of different pitch, a fundamental element of music. In addition, unlike most other studies, we tested non-smoking subjects to avoid withdrawal-related complications. We found that nicotine (4.0 mg, administered as gum) increased P2 amplitude in the frontal region. Since a decrease in P2 amplitude and latency is related to habituation processes, and an enhanced ability to disengage from irrelevant stimuli, our findings suggest that nicotine may cause a reduction in habituation, resulting in non-smokers being less able to adapt to repeated stimuli. A corollary of that decrease in adaptation may be that nicotine extends the temporal window during which a listener is able and willing to engage with a piece of music

Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance

Emotion-Related Visual Mismatch Responses in Schizophrenia: Impairments and Correlations with Emotion Recognition.

BACKGROUND AND OBJECTIVES:Mismatch negativity (MMN) is an event-related potential (ERP) measure of preattentional sensory processing. While deficits in the auditory MMN are robust electrophysiological findings in schizophrenia, little is known about visual mismatch response and its association with social cognitive functions such as emotion recognition in schizophrenia. Our aim was to study the potential deficit in the visual mismatch response to unexpected facial emotions in schizophrenia and its association with emotion recognition impairments, and to localize the sources of the mismatch signals. EXPERIMENTAL DESIGN:The sample comprised 24 patients with schizophrenia and 24 healthy control subjects. Controls were matched individually to patients by gender, age, and education. ERPs were recorded using a high-density 128-channel BioSemi amplifier. Mismatch responses to happy and fearful faces were determined in 2 time windows over six regions of interest (ROIs). Emotion recognition performance and its association with the mismatch response were also investigated. PRINCIPAL OBSERVATIONS:Mismatch signals to both emotional conditions were significantly attenuated in patients compared to controls in central and temporal ROIs. Controls recognized emotions significantly better than patients. The association between overall emotion recognition performance and mismatch response to the happy condition was significant in the 250-360 ms time window in the central ROI. The estimated sources of the mismatch responses for both emotional conditions were localized in frontal regions, where patients showed significantly lower activity. CONCLUSIONS:Impaired generation of mismatch signals indicate insufficient automatic processing of emotions in patients with schizophrenia, which correlates strongly with decreased emotion recognition

Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis

Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis

RATIONALE: Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-D-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model). OBJECTIVES: The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design. MATERIALS AND METHODS: Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation. RESULTS: Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN. CONCLUSIONS: The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis

Differentiation of Schizophrenia Patients from Healthy Subjects by Mismatch Negativity and Neuropsychological Tests

BACKGROUND: Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects. METHODOLOGY/PRINCIPAL FINDINGS: 120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%). CONCLUSIONS/SIGNIFICANCE: MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility

Incidence and trends of blastomycosis-associated hospitalizations in the United States

We used the State Inpatient Databases from the United States Agency for Healthcare Research and Quality to provide state-specific age-adjusted blastomycosis-associated hospitalization incidence throughout the entire United States. Among the 46 states studied, states within the Mississippi and Ohio River valleys had the highest age-adjusted hospitalization incidence. Specifically, Wisconsin had the highest age-adjusted hospitalization incidence (2.9 hospitalizations per 100,000 person-years). Trends were studied in the five highest hospitalization incidence states. From 2000 to 2011, blastomycosis-associated hospitalizations increased significantly in Illinois and Kentucky with an average annual increase of 4.4% and 8.4%, respectively. Trends varied significantly by state. Overall, 64% of blastomycosis-associated hospitalizations were among men and the median age at hospitalization was 53 years. This analysis provides a complete epidemiologic description of blastomycosis-associated hospitalizations throughout the endemic area in the United States

Solulin reduces infarct volume and regulates gene-expression in transient middle cerebral artery occlusion in rats

<p>Abstract</p> <p>Background</p> <p>Thrombolysis after acute ischemic stroke has only proven to be beneficial in a subset of patients. The soluble recombinant analogue of human thrombomodulin, Solulin, was studied in an <it>in vivo </it>rat model of acute ischemic stroke.</p> <p>Methods</p> <p>Male SD rats were subjected to 2 hrs of transient middle cerebral artery occlusion (tMCAO). Rats treated with Solulin intravenously shortly before reperfusion were compared to rats receiving normal saline i.v. with respect to infarct volumes, neurological deficits and mortality. Gene expression of IL-6, IL-1β, TNF-α, MMP-9, CD11B and GFAP were semiquantitatively analyzed by rtPCR of the penumbra.</p> <p>Results</p> <p>24 hrs after reperfusion, rats were neurologically tested, euthanized and infarct volumes determined. Solulin significantly reduced mean total (p = 0.001), cortical (p = 0.002), and basal ganglia (p = 0.036) infarct volumes. Hippocampal infarct volumes (p = 0.191) were not significantly affected. Solulin significantly downregulated the expression of IL-1β (79%; p < 0.001), TNF-α (59%; p = 0.001), IL-6 (47%; p = 0.04), and CD11B (49%; p = 0.001) in the infarcted cortex compared to controls.</p> <p>Conclusions</p> <p>Solulin reduced mean total, cortical and basal ganglia infarct volumes and regulated a subset of cytokines and proteases after tMCAO suggesting the potency of this compound for therapeutic interventions.</p