Alba Lubeiro

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

Abstract 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.

Alterations in prefrontal connectivity in schizophrenia assessed using diffusion magnetic resonance imaging

Background: Spatial and biological characteristics of structural frontal disconnectivity in schizophrenia remain incompletely understood. Simultaneous streamline count (SC) and fractional anisotropy (FA) analyses may yield relevant complementary information to this end. Methods: Using 3T diffusion magnetic resonance imaging both SC and FA were calculated for the tracts linking lateral and medial subregions of prefrontal cortex (PFC) to cingulate, hippocampus, caudate and thalamus in 27 schizophrenia patients (14 first‐episodes) and 27 controls. Relationships of these parameters with cognition, symptoms, treatment doses and illness duration were assessed where significant between‐groups differences were detected. Results: Patients showed lower SC and FA in the tracts linking lateral and medial PFC to thalamus (likely corresponding to anterior thalamic peduncle) and lower FA in those linking PFC to caudate (likely through internal capsule), right caudal anterior cingulate and left hippocampus (likely corresponding to hippocampal‐prefrontal pathway). Moreover, patients showed greater SC values for the tracts linking medial PFC and left caudal anterior cingulate. SC and FA values for the tracts linking PFC and caudal anterior cingulate were positively related to motor speed, executive function, problem solving and completed categories in WCST. FA for the tract linking right lateral PFC and caudate was directly related to positive symptoms and FA for the tract linking left medial PFC and left thalamus was inversely related to negative symptoms. Treatment doses were not associated with SC or FA values in any tract. Illness duration was negatively associated with SC and FA in the tracts linking PFC and subcortical areas. Conclusions: Widespread alterations in frontal structural connectivity of PFC can be found in schizophrenia, and are related to cognition, symptoms and illness duration. HighlightsWe assessed fractional anisotropy and streamline counts for the tracts linking prefrontal cortex with relevant regions.Lower fractional anisotropy were found in schizophrenia patients in most of these anatomical connections.Streamline counts were lower in the patients for the right prefrontal cortico‐thalamic tract.These alterations were related with cognition and symptoms.FA and SC were inversely associated to illness duration, but not to treatment doses.

Identification of two clusters within schizophrenia with different structural, functional and clinical characteristics.

BACKGROUND Several biologically distinct subgroups may coexist within schizophrenia, which may hamper the necessary replicability to translate research findings into clinical practice. METHODS Cortical thickness, curvature and area values and subcortical volumes of 203 subjects (121 schizophrenia patients, out of which 64 were first episodes), 60 healthy controls and 22 bipolar patients were used to identify clusters using principal components and canonical discriminant analyses. Regional glucose metabolism using positron emission tomography, P300 event related potential, baseline clinical data and percentage of improvement with treatment were used to validate possible clusters based on MRI data. RESULTS All the controls, the bipolar patients and most of the schizophrenia patients were grouped in a cluster (cluster A). A group of 24 schizophrenia patients (12 first episodes), characterized by large intrinsic curvature values, was identified (cluster B). These patients, but not those in cluster A, showed reduced thalamic and cingulate glucose metabolism in comparison to controls, as well as a worsening of negative symptoms at follow-up. Patients in cluster A showed a significant putaminal metabolic increase, which was not observed for those in cluster B. P300 amplitude was reduced in patients of both clusters, in comparison to controls. CONCLUSIONS Results of this study support the existence of a biologically distinct group within the schizophrenia syndrome, characterized by increased cortical curvature values, reduced thalamic and cingulate metabolism, lack of the expected increased putaminal metabolism with antipsychotics and persistent negative symptoms.

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-1β, 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-1β) 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.

Functional EEG network analysis in schizophrenia: Evidence of larger segregation and deficit of modulation

Objective: Higher mental functions depend on global cerebral functional coordination. Our aim was to study fast modulation of functional networks in schizophrenia that has not been previously assessed. Methods: Graph‐theory was used to analyze the electroencephalographic (EEG) activity during an odd‐ball task in 57 schizophrenia patients (18 first episode patients, FEPs) and 59 healthy controls. Clustering coefficient (CLC), characteristic path length (PL) and small‐worldness (SW) were computed at baseline ([−300 0] ms prior to stimulus delivery) and response ([150 450] ms post‐stimulus) windows. Clinical and cognitive assessments were performed. Results: CLC, PL and SW showed a significant modulation between baseline and response in controls but not in patients. Patients obtained higher CLC and SW at baseline, lower CLC and higher PL at response, and diminished modulation of CLC and SW as compared to controls. In patients, CLC and SW modulation were inversely associated to cognitive performance in executive tasks and directly associated to working memory. Similar patterns were observed in FEPs. CLC and SW during the baseline were inversely associated to their respective modulation magnitudes. Conclusions: Our results are coherent with a hyper‐segregated network at baseline (higher CLC) and a decreased modulation of the functional connectivity during cognition in schizophrenia. HighlightsA deficit in fast modulation of functional network properties during an odd‐ball task was found in schizophrenia patientsThis deficit was also found in first‐episode patientsThere was a significant association between network modulation deficits and cognition in the patients

Exploring non-stationarity patterns in schizophrenia: neural reorganization abnormalities in the alpha band

OBJECTIVE The aim of this paper was to characterize brain non-stationarity during an auditory oddball task in schizophrenia (SCH). The level of non-stationarity was measured in the baseline and response windows of relevant tones in SCH patients and healthy controls. APPROACH Event-related potentials were recorded from 28 SCH patients and 51 controls. Non-stationarity was estimated in the conventional electroencephalography frequency bands by means of Kullback-Leibler divergence (KLD). Relative power (RP) was also computed to assess a possible complementarity with KLD. MAIN RESULTS Results showed a widespread statistically significant increase in the level of non-stationarity from baseline to response in all frequency bands for both groups. Statistically significant differences in non-stationarity were found between SCH patients and controls in beta-2 and in the alpha band. SCH patients showed more non-stationarity in the left parieto-occipital region during the baseline window in the beta-2 band. A leave-one-out cross validation classification study with feature selection based on binary stepwise logistic regression to discriminate between SCH patients and controls provided a positive predictive value of 72.73% and negative predictive value of 78.95%. SIGNIFICANCE KLD can characterize transient neural reorganization during an attentional task in response to novelty and relevance. Our findings suggest anomalous reorganization of neural dynamics in SCH during an oddball task. The abnormal frequency-dependent modulation found in SCH patients during relevant tones is in agreement with the hypothesis of aberrant salience detection in SCH. The increase in non-stationarity in the alpha band during the active task supports the notion that this band is involved in top-down processing. The baseline differences in the beta-2 band suggest that hyperactivation of the default mode network during attention tasks may be related to SCH symptoms. Furthermore, the classification improved when features from both KLD and RP were used, supporting the idea that these measures can be complementary.

Modulation of brain network parameters associated with subclinical psychotic symptoms

OBJECTIVE Static deficits in small-world properties of brain networks have been described in clinical psychosis, but task-related modulation of network properties has been scarcely studied. Our aim was to assess the modulation of those properties and its association with subclinical psychosis and cognition in the general population. METHOD Closeness centrality and small-worldness were compared between pre-stimulus baseline and response windows of an odd-ball task in 200 healthy individuals. The correlation between modulation of network parameters and clinical (scores in the Community Assessment of Psychological Experiences) and cognitive measures (performance in the dimensions included in the Brief Assessment of Cognition in Schizophrenia battery) was analyzed, as well as between these measures and the corresponding network parameters during baseline and response windows during task performance. RESULTS In the theta band, closeness centrality decreased and small-worldness increased in the response window. Centrality and small-worldness modulation were, respectively, directly and inversely associated with subclinical symptoms. CONCLUSIONS A widespread modulation of network properties in theta band was observed, with a transient increase of small-worldness during the response window, compatible with a transiently more integrated cortical activity associated to cognition. This supports the relevance of electroencephalography to study of normal and altered cognition and its substrates. A relative deficit in the ability to reorganize brain networks may contribute to subclinical psychotic symptoms.

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.

Analysis of the non-stationarity of neural activity during an auditory oddball task in schizophrenia

The aim of this study was to characterize brain dynamics during an auditory oddball task. For this purpose, a measure of the non-stationarity of a given time-frequency representation (TFR) was applied to electroencephalographic (EEG) signals. EEG activity was acquired from 20 schizophrenic (SCH) patients and 20 healthy controls while they underwent a three-stimulus auditory oddball task. The Degree of Stationarity (DS), a measure of the non-stationarity of the TFR, was computed using the continuous wavelet transform. DS was calculated for both the baseline [-300 0] ms and active task [150 550] ms windows of a P300 auditory oddball task. Results showed a statistically significant increase (p<;0.05) in non-stationarity for controls during the cognitive task in the central region, while less widespread statistically significant differences were obtained for SCH patients, especially in the beta-2 and gamma bands. Our findings support the relevance of DS as a means to study cerebral processing in SCH. Furthermore, the lack of statistically significant changes in DS for SCH patients suggests an abnormal reorganization of neural dynamics during an oddball task.

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.