A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A).

The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back: 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AA/AG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

Background: The synchronized activity of distributed neural assemblies ­ reflected in the electroencephalogram (EEG) ­ underpins mental function. In schizophrenia, modulation deficits of EEG spectral content during a P300 task have been replicated. The effects of treatment, chronicity and specificity in these deficits and their possible relationship with anatomic connectivity remain to be explored. Methods: We assessed spectral entropy modulation of the EEG during a P300 task in 79 patients with schizophrenia (of those, 31 werein their first episode), 29 patients with bipolar disorder and 48 healthy controls. Spectral entropy values summarize EEG characteristics by quantifying the irregularity of spectral content. In a subsample, we calculated the network architecture of structural connectivity using diffusion tensor imaging and graph-theory parameters. Results: We found significant spectral entropy modulation deficits with task performance in patients with chronic or first-episode schizophrenia and in patients with bipolar disorder, without significant pre-stimulus spectral entropy differences. The deficits were unrelated to treatment doses, and spectral entropy modulation did not differ between patients taking or not taking antipsychotics, lithium, benzodiazepines or antidepressants. Structural connectivity values were unrelated to spectral entropy modulation. In patients with schizophrenia, spectral entropy modulation was inversely related to negative symptoms and directly related to verbal memory. Limitations: All patients were taking medication. Patients with bipolar disorder were euthymic and chronic. The cross-sectional nature of this study prevented a more thorough analysis of state versus trait criteria for spectral entropy changes. Conclusion: Spectral entropy modulation with task performance is decreased in patients with schizophrenia and bipolar disorder. This deficit was not an effect of psychopharmacological treatment or structural connectivity and might reflect a deficit in the synchronization of the neural assemblies that underlie cognitive activity.

Analysis of KCNH2 and CACNA1C schizophrenia risk genes on EEG functional network modulation during an auditory odd-ball task.

A deficit in task-related functional connectivity modulation from electroencephalogram (EEG) has been described in schizophrenia. The use of measures of neuronal connectivity as an intermediate phenotype may allow identifying genetic factors involved in these deficits, and therefore, establishing underlying pathophysiological mechanisms. Genes involved in neuronal excitability and previously associated with the risk for schizophrenia may be adequate candidates in relation to functional connectivity alterations in schizophrenia. The objective was to study the association of two genes of voltage-gated ion channels (CACNA1C and KCNH2) with the functional modulation of the cortical networks measured with EEG and graph-theory parameter during a cognitive task, both in individuals with schizophrenia and healthy controls. Both CACNA1C (rs1006737) and KCNH2 (rs3800779) were genotyped in 101 controls and 50 schizophrenia patients. Small-world index (SW) was calculated from EEG recorded during an odd-ball task in two different temporal windows (pre-stimulus and response). Modulation was defined as the difference in SW between both windows. Genetic, group and their interaction effects on SW in the pre-stimulus window and in modulation were evaluated using ANOVA. The CACNA1C genotype was not associated with SW properties. KCNH2 was significantly associated with SW modulation. Healthy subjects showed a positive SW modulation irrespective of the KCNH2 genotype, whereas within patients allele-related differences were observed. Patients carrying the KCNH2 risk allele (A) presented a negative SW modulation and non-carriers showed SW modulation similar to the healthy subjects. Our data suggest that KCNH2 genotype contributes to the efficient modulation of brain electrophysiological activity during a cognitive task in schizophrenia patients.

Topography of activation deficits in schizophrenia during P300 task related to cognition and structural connectivity.

BACKGROUND: The study of cerebral underpinnings of schizophrenia may benefit from the high temporal resolution of electromagnetic techniques, but its spatial resolution is low. However, source imaging approaches such as low-resolution brain electromagnetic tomography (LORETA) allow for an acceptable compromise between spatial and temporal resolutions. METHODS: We combined LORETA with 32 channels and 3-Tesla diffusion magnetic resonance (Dmr) to study cerebral dysfunction in 38 schizophrenia patients (17 first episodes, FE), compared to 53 healthy controls. The EEG was acquired with subjects performing an odd-ball task. Analyses included an adaptive window of interest to take into account the interindividual variability of P300 latency. We compared source activation patters to distractor (P3a) and target (P3b) tones within- and between-groups. RESULTS: Patients showed a reduced activation in anterior cingulate and lateral and medial prefrontal cortices, as well as inferior/orbital frontal regions. This was also found in the FE patients alone. The activation was directly related to IQ in the patients and controls and to working memory performance in controls. Symptoms were unrelated to source activation. Fractional anisotropy in the tracts connecting lateral prefrontal and anterior cingulate regions predicted source activation in these regions in the patients. CONCLUSIONS: These results replicate the source activation deficit found in a previous study with smaller sample size and a lower number of sensors and suggest an association between structural connectivity deficits and functional alterations.

Relations between structural and EEG-based graph metrics in healthy controls and schizophrenia patients.

Our aim was to assess structural and functional networks in schizophrenia patients; and the possible prediction of the latter based on the former. The possible dependence of functional network properties on structural alterations has not been analyzed in schizophrenia. We applied averaged path-length (PL), clustering coefficient, and density (D) measurements to data from diffusion magnetic resonance and electroencephalography in 39 schizophrenia patients and 79 controls. Functional data were collected for the global and theta frequency bands during an odd-ball task, prior to stimulus delivery and at the corresponding processing window. Connectivity matrices were constructed from tractography and registered cortical segmentations (structural) and phase-locking values (functional). Both groups showed a significant electroencephalographic task-related modulation (change between prestimulus and response windows) in the global and theta bands. Patients showed larger structural PL and prestimulus density in the global and theta bands, and lower PL task-related modulation in the theta band. Structural network values predicted prestimulus global band values in controls and global band task-related modulation in patients. Abnormal functional values found in patients (prestimulus density in the global and theta bands and task-related modulation in the theta band) were not predicted by structural data in this group. Structural and functional network abnormalities respectively predicted cognitive performance and positive symptoms in patients. Taken together, the alterations in the structural and functional theta networks in the patients and the lack of significant relations between these alterations, suggest that these types of network abnormalities exist in different groups of schizophrenia patients.

Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study.

We aimed to profile a broad panel of inflammatory markers in patients with schizophrenia and healthy controls. Additionally, we performed a meta-analysis of chemokine alterations that have not been subjected to quantitative synthesis so far. We recruited 78 patients with schizophrenia and 78 healthy controls, and measured inflammatory markers using the Luminex technology. After adjustment for multiple testing, we found elevated levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, interferon-γ, eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor with two B subunits (PDGF-BB), macrophage inflammatory protein (MIP)-1α, MIP-1ß, vascular endothelial growth factor A (VEGF-A) and RANTES in multiple-episode schizophrenia (MES) patients. These differences, except for the difference in eotaxin-1 levels, appeared to be significant after co-varying for the dosage of antipsychotics. There were no significant differences in the levels of immune markers between first-episode schizophrenia (FES) patients and controls. Our meta-analysis revealed elevated levels of MCP-1 in first-episode psychosis (FEP) patients and MES individuals. Other chemokine alterations (elevated levels of IL-8, eotaxin-1 and MIP-1ß) were present only in MES patients. Our results indicate that dysregulation of immune response in schizophrenia develops with illness progression or appears as a long-term medication effect. Chemokine alterations are another example of aberrant immune response in schizophrenia patients. Elevated levels of MCP-1 might represent trait markers since these alterations were found in FEP and MES patients. Other chemokine alterations might be the markers of disease progression or might represent medication effects.

Variation at NRG1 genotype related to modulation of small-world properties of the functional cortical network.

Functional brain networks possess significant small-world (SW) properties. Genetic variation relevant to both inhibitory and excitatory transmission may contribute to modulate these properties. In healthy controls, genotypic variation in Neuregulin 1 (NRG1) related to the risk of psychosis (risk alleles) would contribute to functional SW modulation of the cortical network. Electroencephalographic activity during an odd-ball task was recorded in 144 healthy controls. Then, small-worldness (SWn) was calculated in five frequency bands (i.e., theta, alpha, beta1, beta2 and gamma) for baseline (from -300 to the stimulus onset) and response (150-450 ms post-target stimulus) windows. The SWn modulation was defined as the difference in SWn between both windows. Association between SWn modulation and carrying the risk allele for three single nucleotide polymorphisms (SNP) of NRG1 (i.e., rs6468119, rs6994992 and rs7005606) was assessed. A significant association between three SNPs of NRG1 and the SWn modulation was found, specifically: NRG1 rs6468119 in alpha and beta1 bands; NRG1 rs6994992 in theta band; and NRG1 rs7005606 in theta and beta1 bands. Genetic variation at NRG1 may influence functional brain connectivity through the modulation of SWn properties of the cortical network.

Noise power associated with decreased task-induced variability of brain electrical activity in schizophrenia.

In schizophrenia, both increased baseline metabolic and electroencephalographic (EEG) activities as well as decreased task-related modulation of neural dynamics have been reported. Noise power (NP) can measure the background EEG activity during task performance, and Shannon entropy (SE) is useful for quantifying the global modulation of EEG activity with a high temporal resolution. In this study, we have assessed the possible relationship between increased NP in theta and gamma bands and decreased SE modulation in 24 patients with schizophrenia and 26 controls over the parietal and central regions during a P300 task. SE modulation was calculated as the change from baseline to the active epoch (i.e., 150-550 ms following the target stimulus onset). Patients with schizophrenia displayed statistically significant higher NP values and lower SE modulation than healthy controls. We found a significant association between gamma NP and SE in all of the participants. Specifically, a NP increase in the gamma band was followed by a decrease in SE change. These results support the notion that an excess of gamma activity, unlocked to the task being performed, is accompanied by a decreased modulation of EEG activity in schizophrenia.

Elevated midline-parietal gamma band noise power in schizophrenia but not in bipolar patients.

Gamma oscillations are key in coordinating brain activity and seem to be altered in schizophrenia. In previous work, we studied the spatial distribution of a noise power measure (scalp-recorded electroencephalographic activity unlocked to stimuli) and found higher magnitudes in the gamma band related to symptoms and cognition in schizophrenia. In the current study, we sought to replicate those findings and to study its specificity for schizophrenia in a completely independent sample. A principal component analysis (PCA) was used to determine the factorial structure of gamma noise power acquired with an electroencephalographic recording during an odd-ball P300 paradigm in the 250- to 550-ms window in 70 patients with schizophrenia (16 patients with first episode), 45 bipolar patients and 65 healthy controls. Clinical and cognitive correlates of the resulting factors were also assessed. Three factors arose from the PCA. The first displayed a midline-parietal distribution (roughly corresponding to the default mode network), the second was centro-temporal and the third anterior-frontal. Schizophrenia but not bipolar patients showed higher gamma noise power loadings in the first factor in comparison with controls. Scores for this factor were significantly and directly associated with positive and total symptoms in patients and inversely associated with global cognition in all participants. The results of this study replicate those of our previous publication and suggest an elevated midline-parietal gamma noise power specific to schizophrenia. The gamma noise power measure seems to be a useful tool for studying background oscillatory activity during performance of cognitive tasks.

Decreased entropy modulation of EEG response to novelty and relevance in schizophrenia during a P300 task.

The analysis of the interaction between novelty and relevance may be of interest to test the aberrant salience hypothesis of schizophrenia (SCH). In comparison with other neuroimaging techniques, such as functional magnetic resonance imaging, electroencephalography (EEG) provides high temporal resolution. Therefore, EEG is useful to analyze transient dynamics in neural activity, even in the range of milliseconds. In this study, EEG activity from 31 patients with SCH and 38 controls was analyzed using Shannon spectral entropy (SE) and median frequency (MF). The aim of the study was to quantify differences between distractor (i.e., novelty) and target (i.e., novelty and relevance) tones in an auditory oddball paradigm. Healthy controls displayed a larger SE decrease in response to target stimulus than in response to distractor tones. SE decrease was accompanied by a significant and widespread reduction of MF (i.e., a significant slowing of EEG activity). In comparison with controls, patients showed a significant reduction of changes in SE in response to both target and distractor tones. These differences were also observed in patients that only received a minimal treatment prior to EEG recording. Furthermore, significant changes in SE were inversely correlated to positive and total symptoms severity for SCH patients. Our findings support the notion that SCH is associated with a reduced response to both novelty and relevance during an auditory P300 task.

New insights of the role of the KCNH2 gene in schizophrenia: An fMRI case-control study.

The KCNH2 gene, encoding for a subunit of a voltage-gated potassium channel, has been identified as a key element of neuronal excitability and a promising novel therapeutic target for schizophrenia (SZ). Nonetheless, evidence highlighting the role of KCNH2 on cognitive and brain activity phenotypes comes mainly from studies based on healthy controls (HC). Therefore, we aimed to study the role of KCNH2 on the brain functional differences between patients with SZ and HC. The fMRI sample comprised 78 HC and 79 patients with SZ (matched for age, sex and premorbid IQ). We studied the effect of the polymorphism KCNH2-rs3800779 on attention and working memory-related brain activity, evaluated through the N-back task, in regions with detected diagnostic differences (regression model, controlled for age, sex and premorbid IQ, FEAT-FSL). We report a significant diagnosis x KCNH2 interaction on brain activity (1-back vs baseline contrast) at the medial superior prefrontal cortex (Zmax=3.55, p = 0.00861). In this region, patients with SZ carrying the risk genotype (AA) show a deactivation failure, while HC depict the opposite pattern towards deactivation. The brain region with significant diagnosis x KCNH2 interaction has been previously associated with SZ. The results of this study, in which the role of KCNH2 on fMRI response is analysed for the first time in patients, suggest that KCNH2 variability contributes to inefficient brain activity modulation during the N-back task in affected subjects. These data may pave the way to further understand how KCNH2 genetic variability is related to the pathophysiological mechanisms underlying schizophrenia.

Identificacion of MRI-based psychosis subtypes: Replication and refinement.

The identification of the cerebral substrates of psychoses such as schizophrenia and bipolar disorder is likely hampered by its biological heterogeneity, which may contribute to the low replication of results in the field. In this study we aimed to replicate in a completely new sample and supplement the results of a previous study with additional data on this topic. In the aforementioned study we identified a schizophrenia cluster characterized by high mean cortical curvature and low cortical thickness, subcortical hypometabolism and progressive negative symptoms. Here, we have used magnetic resonance images from 61 schizophrenia and 28 bipolar patients, as well as 51 healthy controls and a cluster analysis to search for possible subgroups primarily characterized by cerebral structural data. Diffusion tensor imaging (fractional anisotropy, FA), cognition, clinical data and electroencephalographic (EEG) modulation during a P300 task were used to validate the possible clusters. Two clusters of patients were identified. The first cluster (29 schizophrenia and 18 bipolar patients) showed decreased cortical thickness and area values, as well as lower subcortical volumes and higher cortical curvature in some regions, as compared to the second cluster. This first cluster also showed decreased FA in frontal lobe connections and worse cognitive performance. Although this cluster also showed longer illness duration, there were first episode patients in both clusters and treatment doses and types were not different between clusters. Both clusters of patients showed decreased EEG task-related modulation. In conclusion, our data give additional support to a distinct biologically based cluster encompassing schizophrenia and bipolar disorder patients with cortical and subcortical alterations, hampered cortical connectivity and lower cognitive performance.

Social cognition in psychosis: Predictors and effects of META-cognitive training.

Social cognition deficits are found in schizophrenia and bipolar disorder, but its neural underpinnings are poorly understood. Given the complexity of psychological functions underlying this kind of cognition, we hypothesized that alterations in global structural connectivity could contribute to those deficits. To test this hypothesis, we studied a group of schizophrenia and bipolar patients with connectomics based on diffusion magnetic resonance imaging and assessments of general and social cognition. The latter was assessed using the Mayer, Salovey and Caruso Emotional Intelligence Test (MSCEIT) for emotional intelligence and the Spanish Group for Schizophrenia Treatment Optimization (Grupo Español para la OPtimización del Tratamiento de la Esquizofrenia, GEOPTE) test for behavioral aspects of social cognition. Graph theory applied to fractional anisotropy for the connections among cortical regions was used to obtain the small-world (SW) index of the structural connectivity network. In addition, we assessed the possibility of predicting the response of social cognition deficits to Meta-cognitive Training based on their possible underpinnings in a subgroup of patients. Patients showed lower scores in emotional intelligence and behavioral social cognition. MSCEIT scores were associated with SW index and working memory, and GEOPTE scores were related to verbal memory. Improvement in social cognition after Meta-cognitive Training was associated with lower scores of the social cognition in the baseline, according to the GEOPTE scale. Our findings support structural connectivity as one of the factors underlying emotional intelligence in schizophrenia, and the use of Meta-cognitive Training to improve social cognition in patients with larger deficits.

Structural connectivity in schizophrenia and bipolar disorder: Effects of chronicity and antipsychotic treatment.

Previous studies based on graph theory parameters applied to diffusion tensor imaging support an alteration of the global properties of structural connectivity network in schizophrenia. However, the specificity of this alteration and its possible relation with chronicity and treatment have received small attention. We have assessed small-world (SW) and connectivity strength indexes of the structural network built using fractional anisotropy values of the white matter tracts connecting 84 cortical and subcortical regions in 25 chronic and 18 first episode (FE) schizophrenia and 24 bipolar patients and 28 healthy controls. Chronic schizophrenia and bipolar patients showed significantly smaller SW and connectivity strength indexes in comparison with controls and FE patients. SW reduction was driven by increased averaged path-length (PL) values. Illness duration but not treatment doses were negatively associated with connectivity strength, SW and PL in patients. Bipolar patients exposed to antipsychotics did not differ in SW or connectivity strength from bipolar patients without such an exposure. Executive functions and social cognition were related to SW index in the schizophrenia group. Our results support a role for chronicity but not treatment in structural network alterations in major psychoses, which may not differ between schizophrenia and bipolar disorder, and may hamper cognition.

Vascular endothelial growth factor in patients with schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Accumulating evidence indicates that schizophrenia might be accompanied by abnormal vascularization. Vascular endothelial growth factor (VEGF) is one of key molecules involved in the development of vessels with vasodilatory activities. OBJECTIVES: We aimed to perform a systematic review and meta-analysis of studies investigating serum or plasma levels of VEGF in patients with schizophrenia and first-episode psychosis (FEP). METHODS: Electronic databases were searched from their inception until 18th Apr 2018. Meta-analysis was performed using random-effects models with Hedges' g as the effect size estimate. Quality assessment was performed using the Newcastle-Ottawa Scale. RESULTS: We included 15 eligible studies, representing 982 patients and 791 healthy controls. Main analysis revealed no significant differences in VEGF levels between patients and controls (g = 0.10, 95%CI = -0.24-0.45, p = .553). Subgroup analysis demonstrated unaltered levels of VEGF in FEP patients (g = 0.03, 95%CI = -0.53-0.59, p = .911), including antipsychotic-naïve individuals (g = 0.34, 95%CI = -0.07-0.74, p = .103). However, the levels of VEGF were significantly higher in medicated multiple-episode schizophrenia (MES) patients (g = 0.45, 95%CI = 0.03-0.87, p = .036) compared to controls. Heterogeneity across studies was significant in the majority of analyses, except for the analysis of antipsychotic-naïve FEP patients. Tests of asymmetry were insignificant, indicating a lack of publication bias. LIMITATIONS: Main limitations of our meta-analysis include inability to address medication effects exhaustively and relatively low number of studies in subgroup analyses. CONCLUSIONS: Our results indicate elevated levels of VEGF in MES patients that are unaltered in FEP individuals. Longitudinal studies are required to disentangle whether elevated levels of VEGF in MES patients reflect illness progression, comorbid physical health impairments or appear due to medication effects.

Quantification of Graph Complexity Based on the Edge Weight Distribution Balance: Application to Brain Networks.

The aim of this study was to introduce a novel global measure of graph complexity: Shannon graph complexity (SGC). This measure was specifically developed for weighted graphs, but it can also be applied to binary graphs. The proposed complexity measure was designed to capture the interplay between two properties of a system: the 'information' (calculated by means of Shannon entropy) and the 'order' of the system (estimated by means of a disequilibrium measure). SGC is based on the concept that complex graphs should maintain an equilibrium between the aforementioned two properties, which can be measured by means of the edge weight distribution. In this study, SGC was assessed using four synthetic graph datasets and a real dataset, formed by electroencephalographic (EEG) recordings from controls and schizophrenia patients. SGC was compared with graph density (GD), a classical measure used to evaluate graph complexity. Our results showed that SGC is invariant with respect to GD and independent of node degree distribution. Furthermore, its variation with graph size [Formula: see text] is close to zero for [Formula: see text]. Results from the real dataset showed an increment in the weight distribution balance during the cognitive processing for both controls and schizophrenia patients, although these changes are more relevant for controls. Our findings revealed that SGC does not need a comparison with null-hypothesis networks constructed by a surrogate process. In addition, SGC results on the real dataset suggest that schizophrenia is associated with a deficit in the brain dynamic reorganization related to secondary pathways of the brain network.

Parkinsonism is associated to fronto-caudate disconnectivity and cognition in schizophrenia.

The present work studies the possible relation of parkinsonism and fronto-caudate dysconnectivity, as well as its relation to cognition in schizophrenia patients. We assessed parkinsonism using Simpson-Angus scale and prefronto-caudate connectivity using diffusion magnetic resonance in 22 schizophrenia patients (11 first-episodes) and 14 healthy controls. Fractional anisotropy was calculated for the white matter tracts directly linking rostral middle prefrontal (RMPF) and superior medial prefrontal (SMPF) regions with caudate nucleus. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia Scale (BACS). Total parkinsonism scores were negatively related to fractional anisotropy in the right SMPF-caudate tract in patients, which was also found in the first-episode patients alone, but not in controls. Parkinsonism was also inversely associated in patients to performance in social cognition, verbal memory, working memory and performance speed tests. In conclusion, our data support the involvement of fronto-striatal dysconnectivity in parkinsonism in schizophrenia.

Altered predictive capability of the brain network EEG model in schizophrenia during cognition.

The study of the mechanisms involved in cognition is of paramount importance for the understanding of the neurobiological substrates in psychiatric disorders. Hence, this research is aimed at exploring the brain network dynamics during a cognitive task. Specifically, we analyze the predictive capability of the pre-stimulus theta activity to ascertain the functional brain dynamics during cognition in both healthy and schizophrenia subjects. Firstly, EEG recordings were acquired during a three-tone oddball task from fifty-one healthy subjects and thirty-five schizophrenia patients. Secondly, phase-based coupling measures were used to generate the time-varying functional network for each subject. Finally, pre-stimulus network connections were iteratively modified according to different models of network reorganization. This adjustment was applied by minimizing the prediction error through recurrent iterations, following the predictive coding approach. Both controls and schizophrenia patients follow a reinforcement of the secondary neural pathways (i.e., pathways between cortical brain regions weakly connected during pre-stimulus) for most of the subjects, though the ratio of controls that exhibited this behavior was statistically significant higher than for patients. These findings suggest that schizophrenia is associated with an impaired ability to modify brain network configuration during cognition. Furthermore, we provide direct evidence that the changes in phase-based brain network parameters from pre-stimulus to cognitive response in the theta band are closely related to the performance in important cognitive domains. Our findings not only contribute to the understanding of healthy brain dynamics, but also shed light on the altered predictive neuronal substrates in schizophrenia.

Deficit of entropy modulation of the EEG in schizophrenia associated to cognitive performance and symptoms. A replication study.

Spectral entropy (SE) is a measurement from information theory field that provides an estimation of EEG regularity and may be useful as a summary of its spectral properties. Previous studies using small samples reported a deficit of EEG entropy modulation in schizophrenia during cognitive activity. The present study is aimed at replicating this finding in a larger sample, to explore its cognitive and clinical correlates and to discard antipsychotic treatment as the main source of that deficit. We included 64 schizophrenia patients (21 first episodes, FE) and 65 healthy controls. We computed SE during performance of an odd-ball paradigm, at the windows prior (-300 to 0ms) and following (150 to 450ms) stimulus presentation. Modulation of SE was defined as the difference between post- and pre-stimulus windows. In comparison to controls, patients showed a deficit of SE modulation over frontal and central regions, also shown by FE patients. Baseline SE did not differ between patients and controls. Modulation deficit was directly associated with cognitive deficits and negative symptoms, and inversely with positive symptoms. SE modulation was not related to antipsychotic doses. Patients also showed a smaller change of median frequency (i.e., smaller slowing of oscillatory activity) of the EEG from pre- to post-stimulus windows. These results support that a deficit of fast modulation contributes to cognitive deficits and symptoms in schizophrenia patients.

Deficits of entropy modulation in schizophrenia are predicted by functional connectivity strength in the theta band and structural clustering.

Spectral entropy (SE) allows comparing task-related modulation of electroencephalogram (EEG) between patients and controls, i.e. spectral changes of the EEG associated to task performance. A SE modulation deficit has been replicated in different schizophrenia samples. To investigate the underpinnings of SE modulation deficits in schizophrenia, we applied graph-theory to EEG recordings during a P300 task and fractional anisotropy (FA) data from diffusion tensor imaging in 48 patients (23 first episodes) and 87 healthy controls. Functional connectivity was assessed from phase-locking values among sensors in the theta band, and structural connectivity was based on FA values for the tracts connecting pairs of regions. From those data, averaged clustering coefficient (CLC), characteristic path-length (PL) and connectivity strength (CS, also known as density) were calculated for both functional and structural networks. The corresponding functional modulation values were calculated as the difference in SE and CLC, PL and CS between the pre-stimulus and response windows during the task. The results revealed a higher functional CS in the pre-stimulus window in patients, predictive of smaller modulation of SE in this group. The amount of increase in theta CS from pre-stimulus to response related to SE modulation in patients and controls. Structural CLC was associated with SE modulation in the patients. SE modulation was predictive of negative symptoms, whereas CLC and PL modulation was associated with cognitive performance in the patients. These results support that a hyperactive functional connectivity and/or structural connective deficits in the patients hamper the dynamical modulation of connectivity underlying cognition.