Auditory P3a and P3b neural generators in schizophrenia: An adaptive sLORETA P300 localization approach
Introduction
Alterations in cognitive processing in schizophrenia (Sz) have long been assessed using electroencephalographic (EEG) recordings (Roach and Mathalon, 2008). In particular, it is usual to obtain the event-related potentials (ERP) as the average of EEG epochs time-locked to repeated external stimulus or events. Reduced P300 amplitude during an auditory oddball paradigm is one of the most consistent findings in schizophrenia (Sz) (Bramon et al., 2004); however, the neural bases of this amplitude reduction are incompletely understood. In this regard, the analyses focused on the localization of neural generators can contribute to elucidate possible sources of altered information processing in Sz (Mulert et al., 2004).
The oddball paradigm is a common experimental design used in ERP analyses to obtain the P300 wave. The 3-stimulus variant of the auditory-oddball paradigm is characterized by infrequent-distractor stimuli interspersed randomly into a sequence of frequent-standard and rare-target. This paradigm allows the examination of cognitive processing as response to both relevant and irrelevant stimuli (Polich, 2007). The resulting P300 wave includes two components: the P3a, evoked by distractor stimuli for which no subject-response is expected; and the P3b, elicited by target stimuli for which the subject is instructed to respond. The neural processing as a response to auditory distractor tones has been related to bottom-up attentional mechanisms; hence, P3a may be generated whether sufficient attentional focus is engaged. In contrast, P3b seems to be related to conscious top-down target processing, likely contributing to processing the stimulus information and performing cognitive response (Polich, 2007, Strobel et al., 2008). In previous reports, we found a blunted ERP modulation in Sz as response to both target (Bachiller et al., 2014) and distractor (Bachiller et al., 2015b) tones during an oddball paradigm. Thus, the analysis of the differences in neural pattern generators between Sz patients and healthy controls becomes an interesting research topic to clarify the neural substrate of reduced P300 amplitude in Sz.
Source imaging techniques may help to detect neural generators that contribute to the scalp recorded ERPs, resulting in an acceptable compromise between spatial and temporal resolutions. The inverse solution (i.e. the computation of 3-D intracerebral images of electric neuronal activity based on scalp-recorded EEG) would provide useful information on the time course and localization of brain functions (Pascual-Marqui, 2002). There is no unique solution to the inverse problem; nevertheless, the low-resolution brain electromagnetic tomography (LORETA) is one of the most reliable methods for localizing ERP electrical activity and it is associated with relatively low error rates (Pascual-Marqui, 2002, Jung et al., 2012). LORETA has been widely used for source localization in psychiatric disorders, such as Sz or depression (Kawasaki et al., 2004, Mientus et al., 2002). Moreover, auditory P3a and P3b source localization has been previously addressed in healthy controls using LORETA and functional magnetic resonance imaging (fMRI). P3a generators are localized in anterior cingulate, frontal area and parietal cortices (Polich, 2007, Strobel et al., 2008, Volpe et al., 2007), whereas P3b sources include a more distributed network, involving superior and medial temporal, posterior parietal, hippocampal, cingulate and frontal structures (Polich, 2007, Strobel et al., 2008, Volpe et al., 2007, Wronka et al., 2012).
It is noteworthy that the previous LORETA findings are influenced by one important technical shortcoming: although ERP analyses show a considerable inter-subject variability of P300 latency (Campanella et al., 1999), LORETA source imaging studies commonly used a large fixed post-stimulus window of interest (WOI), like [250 500] ms (Higuchi et al., 2008, Kawasaki et al., 2007, Sumiyoshi et al., 2006), [280 450] ms (Wang et al., 2003, Wang et al., 2010), [240 420] ms (Pae et al., 2003), [227 383] ms (Volpe et al., 2007), or [400 700] ms (Wronka et al., 2012).
In this study we proposed a new LORETA approach based on P300 wave (‘P300 latency adaptive WOI’) to properly localize P300 brain-source generators in each subject. To the best of our knowledge, this is the first study that analyzes the sources of both P3a and P3b in Sz using LORETA. Hence, this research is aimed at: (i) analyzing the performance of the adaptive WOI method in comparison to conventional fixed WOI analysis; and (ii) applying the adaptive WOI method to analyze the differences of auditory P3a and P3b underlying cortical sources between Sz patients and healthy controls.
Section snippets
Subjects
Thirty-one patients with paranoid Sz (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSM-IV-TR, criteria) and 38 healthy controls were recruited. Sz group was composed by 20 chronic stably treated patients, 7 fist-episode patients and 4 patients who had dropped their medications for a period longer than 6 months. Chronic patients were previously treated with atypical antipsychotics. First-episode patients have not been received previous antipsychotic treatment, except for
Results
Table 1 presents the grand-average ERP amplitude and latency values, as well as the adaptive WOI length and the corresponding aWOI limits for each group. Statistically significant differences between groups (Kruskal–Wallis test, p < 0.05) were only obtained for P3a (p = 0.0007) and P3b (p = 0.0036) amplitudes. Although a large P300 latency and an adaptive WOI variability across subjects have been observed (Fig. 1), non-statistical differences between groups were obtained.
Based on the observation of
Discussion
The aim of the present study was to provide further insights into the neural correlates of target (P3b) and distractor (P3a) processing in Sz. A 3-tone auditory-oddball paradigm was used to characterize P3b and P3a brain sources and to compare them between Sz patients and controls.
Firstly, regarding the validity of the proposed P300 latency adaptive WOI algorithm, our research shows how the selection of the WOI influences the sLORETA findings. A wide fixed WOI has been commonly used to solve
Role of the funding source
The project FIS PI1102303 from the ‘Fondo de Investigaciones Sanitarias’ (‘Instituto de Salud Carlos III’, ISCIII) and the projects GRS 613/A/11 and GRS 932/A/14 from the ‘Gerencia Regional de Salud de Castilla y León’ supported the collection of data. The PIF-UVA grant from University of Valladolid provides the employment of A. Bachiller.
Contributors
Alejandro Bachiller designed the study, analyzed the data, interpreted the results and drafted the manuscript. Sergio Romero, Joan F. Alonso and Miguel A. Mañanas participated in the analysis of data and the interpretation of the results. Vicente Molina took part in the diagnosis of subjects, the collection of data and the interpretation of the results. Jesús Poza and Roberto Hornero designed the study, analyzed the data and interpreted the results. All authors read and approved the final
Acknowledgments
This study was supported by the ‘Ministerio de Economía y Competitividad’ and FEDER (projects TEC2014-53196-R, DPI2011-22680 and DPI2014-59049-R), the ‘Consejería de Educación de la Junta de Castilla y León’ (VA059U13), the ‘Fondo de Investigaciones Sanitarias’ (‘Instituto de Salud Carlos III’, ISCIII) (FIS PI1102303) and the ‘Gerencia Regional de Salud de Castilla y León’ (GRS 613/A/11; GRS 932/A/14) grants to V. Molina. CIBER-BBN is an initiative of the ISCIII. Finally, A. Bachiller was in
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