Biologically relevant subgroups within the schizophrenia syndrome

In the present thesis, we aimed to explore the existence of biological subgroups within schizophrenia patients by using data from structural and functional brain connectivity as well as a genetic information. It includes five articles with sample sizes from 27 to 121 schizophrenia patients and 27 to 144 healthy controls. All patients were diagnosed according to DSM-IV or V criteria and their symptoms were scored using the Positive and Negative Syndrome Scale (PANSS). Structural connectivity was assessed in two different ways. Firstly, using structural magnetic resonance imaging (MRI) we extracted measures of cortical curvature. Secondly, diffusion magnetic resonance imaging (dMRI) was used to obtain values of streamline count and fractional anisotropy in white matter tracts connecting a priori selected regions. Functional connectivity was calculated using electroencephalography (EEG) recordings during the performance of an auditive odd-ball task, in which participants were instructed to respond to infrequent targets while ignoring other stimuli. Then, small-worldness (SWn) index, which quantifies the efficiency of the global electrical network, was calculated at two temporal windows: before and after the target stimulus onset (baseline/pre-stimulus and response window, respectively). We focused our study on the SWn difference between pre-stimulus and response windows as a measure of modulation efficiency.Esta tesis incluye datos procedentes de varias técnicas que estudian los procesos biológicos cerebrales, analizando su relación con la esquizofrenia y las posibles alteraciones biológicas en este trastorno. En otras palabras, mediante un análisis de las alteraciones cerebrales y genéticas en pacientes con esquizofrenia y en comparación con la población sana, se planteó definir patrones de alteración de la conectividad estructural y funcional independientemente del diagnóstico clínico inicial. Para ello, se partió del estudio anatómico del cerebro utilizando imágenes de resonancia magnética (RM) que cuantifican las regiones cerebrales y la integridad de las conexiones estructurales. La idea inicial era la identificación de grupos de pacientes con distintas alteraciones, para lo que se estudió la relación entre medidas corticales y de conectividad estructural y se analizó esa conectividad estructural en los pacientes. Posteriormente, se evaluó la relación entre variantes genéticas relacionadas con un aumento del riesgo de la esquizofrenia e implicadas en funciones relevantes con las alteraciones de las conexiones cerebrales funcionales. Y, por último, se estudió la capacidad de estas variantes genéticas para identificar subgrupos de pacientes con distintas anomalías de la conectividad funcional.Departamento de Pediatría e Inmunología, Obstetricia y Ginecología, Nutrición y Bromatología, Psiquiatría e Historia de la CienciaDoctorado en Investigación Biomédic

Early neglect associated to prefrontal structural disconnectivity in schizophrenia

[ES] Negligencia y descuido temprano asociado a la desconexión estructural prefrontal en la esquizofrenia

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

[EN]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

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

Producción CientíficaObjective. 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 especially 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 an accuracy of 89.87% and area under ROC of 0.9510. 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 binary stepwise logistic regression procedure selected features from both KLD and RP, supporting the idea that these measures can be complementary.This research project was supported in part by the projects TEC2014-53196-R of ‘Ministerio de Economía y Competitividad’ and FEDER; the project VA037U16 from the “Consejería de Educación de la Junta de Castilla y León”, the “Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III)” under projects FIS PI11/02203 and PI15/00299; and the “Gerencia Regional de Salud de Castilla y León” under projects GRS 932/A/14 and GRS 1134/A/15. P. Núñez was in receipt of a ‘Promoción de empleo joven e implantación de la Garantía Juvenil en I+D+i’ grant from ‘Ministerio de Economía y Competitividad’ and the University of Valladolid, A. Bachiller and J. Gomez-Pilar were in receipt of a PIF-UVA grant from the University of Valladolid. A. Lubeiro has a predoctoral scholarship from the “Junta de Castilla y León” and European Social Fund

Analysis of Functional Connectivity during an Auditory Oddball Task in Schizophrenia

Producción CientíficaThe aim of this study was to evaluate neural coupling patterns in schizophrenia (SCH) patients and healthy controls during an auditory oddball task. Two measures of functional connectivity were applied to 28 SCH patients and 51 healthy controls to characterize electroencephalographic (EEG) activity. Specifically, magnitude squared coherence (MSC) and the imaginary part of coherency (ICOH) were computed for five frequency bands: theta, alpha, beta-1, beta-2 and gamma. The results showed a statistically significant modulation increase in MSC and ICOH for controls with respect to SCH in the theta band, and a decrease in ICOH for the beta-2 band. Furthermore, controls showed more significant changes from the baseline and active task windows than SCH patients. Our findings suggest that SCH patients show coupling abnormalities during an auditory oddball task compared to healthy controls.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

Novel Measure of the Weigh Distribution Balance on the Brain Network: Graph Complexity Applied to Schizophrenia

Producción CientíficaThe aim of this study was to assess brain complexity dynamics in schizophrenia (SCH) patients during an auditory oddball task. For that task, we applied a novel graph measure based on the balance of the node weighs distribution. Previous studies applied complexity parameters that were strongly dependent on network topology. This fact could bias the results besides being necessary correction techniques as surrogating process. In the present study, we applied a novel graph complexity measure from the information theory: Shannon Graph Complexity (SGC). Complexity patterns form electroencephalographic recordings of 20 healthy controls and 20 SCH patients during an auditory oddball task were analyzed. Results showed a significantly more pronounced decrease of SGC for controls than for SCH patients during the cognitive task. These findings suggest an important change in the brain configuration towards more balanced networks, mainly in the connections related to long-range interactions. Since these changes are significantly more pronounced in controls, it implies a deficit in the neural network reorganization in SCH patients. In addition, SGC showed a suitable discrimination ability using a leave-one-out cross-validation: 0.725 accuracy and 0.752 area under receiver operating characteristics curve. The novel complexity measure proposed in this study demonstrated to be independent of network topology and, therefore, it complements traditional graph measures to characterize brain networks.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

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

Producción CientíficaThe 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.This research project was supported in part by “Ministerio de Economía y Competitividad” and FEDER under project TEC2014-53196-R, by ‘European Commission’ (POCTEP 0378_AD_EEGWA_2_P), by ‘Consejería de Educación de la Junta de Castilla y León’ (VA037U16), by “Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III)” under projects FIS PI11/02203 and PI15/00299, and by “Gerencia Regional de Salud de Castilla y León” under projects GRS 932/A/14 and GRS 1134/A/15. A. Lubeiro was in receipt of a grant from the Consejería de Educación (Junta de Castilla y León). J. Gomez-Pilar was in receipt of a grant from University of Valladolid

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.This work was supported by the Instituto Carlos III (PI11/02708, PI11/02203 and PI15/00299) and the Gerencia Regional de Salud de Castilla y León (GRS 1134/A/15 and GRS 1263/A/16) grants; the ‘MINECO and FEDER (TEC2014-53196-R), ‘Consejería de Educación de la Junta de Castilla y León’ (VA037U16); and predoctoral fellowships to A. Lubeiro (‘Consejería de Educación Junta de Castilla y León’) and to J. Gomez-Pilar (University of Valladolid)

Analysis of the Non-stationarity of Neural Activity during an Auditory Oddball Task in Schizophrenia

Producción CientíficaThe 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.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

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

Producción CientíficaObjective: To assess using graph-theory properties of both structural and functional networks in schizophrenia patients, as well as the possible prediction of the latter based on the former. Abnormal structural and functional network parameters have been found in schizophrenia, but the dependence of functional network properties on structural alterations has not been described yet in this syndrome. Experimental design: We applied averaged path-length (PL), clustering coefficient (CLC) and density (D) measurements to structural data derived from diffusion magnetic resonance and functional data derived from electroencephalography in 39 schizophrenia patients and 79 controls. Functional data were collected for the global and theta frequency bands with subjects performing an odd-ball task, both prior to stimulus delivery and at the corresponding processing window. Connectivity matrices were constructed respectively from (i) tractography and registered cortical segmentations (structural) and (ii) phase-locking values (functional). Principal observations: In both groups, we observed a significant EEG task-related modulation (change between pre-stimulus and response windows) in the global and theta bands. Patients showed larger structural PL and pre-stimulus density in the global and theta bands, and lower PL task-related modulation in the theta band. Structural network values predicted pre-stimulus global band values in controls and global band task-related modulation in patients. Abnormal functional values found in patients (pre-stimulus 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. Conclusions: 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.This research project was supported in part by grants from Instituto de Salud Carlos III under project PI15/00299, “Gerencia Regional de Salud de Castilla y León” under projects GRS 1263/A/16 and GRS 1485/A/17, and “Ministerio de Economía y Competitividad” and FEDER under grants TEC2014-53196-R and TEC2013-44194-P; by ‘European Commission’ and FEDER under project 'Análisis y correlación entre el genoma completo y la actividad cerebral para la ayuda en el diagnóstico de la enfermedad de Alzheimer' ('Cooperation Programme Interreg V-A Spain-Portugal POCTEP 2014-2020'), and by ‘Consejería de Educación de la Junta de Castilla y León’ and FEDER under project VA037U16. J. Gomez-Pilar was in receipt of a grant from University of Valladolid and A. Lubeiro was in receipt of a grant from Consejería de Educación de la Junta de Castilla y León