Neural correlates of impaired cognitive flexibility in schizophrenia: An ERP study using the cued task-switching paradigm

Neural correlates of impaired cognitive flexibility in schizophrenia: An ERP study using the cued task-switching paradigm | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neural correlates of impaired cognitive flexibility in schizophrenia: An ERP study using the cued task-switching paradigm Qian Mei, Lin Zhang, Zheng Fan, Ziqi Huang, Limin Chen, Xiaohong Liu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7649864/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2025 Read the published version in BMC Psychiatry → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Patients with schizophrenia (SCZ) have impaired cognitive flexibility; however, the neuroelectrophysiological mechanism underlying this impairment remains unclear. The cued task-switching paradigm (CTSP) is used to measure cognitive flexibility. The aim of this study is to investigate the neuroelectrophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia using event-related potential (ERP) technology with CTSP. Methods: Our sample included 39 patients with schizophrenia and 46 healthy controls (HCs). All participants underwent ERP recording while performing the CTSP. Error rates (ERs), reaction times (RTs), and the switching costs of ERs and RTs were used for the analysis of behavioral data. Time-domain analysis was used for the analysis of ERP data. Results: Patients with schizophrenia had higher ERs and longer RTs. ERP data analysis revealed that compared with HCs, patients with schizophrenia exhibited greater P3 amplitudes and longer latencies, as well as smaller difference wave amplitudes, during CTSP. Conclusion: Patients with schizophrenia showed impaired cognitive flexibility and neural correlates of these impairments, as reflected by an abnormal ERP P3. These findings provide valuable insights into the understanding of the neural mechanisms underlying impaired cognitive flexibility and may guide targeted interventions in patients with schizophrenia. Event-related potential cued task-switching paradigm schizophrenia cognitive flexibility switch cost Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1. Introduction Schizophrenia (SCZ) is a serious mental illness with a complex etiology and high incidence[ 1 ]. Cognitive impairments are considered core features of schizophrenia and are present in various domains[ 2 , 3 ]. Cognitive flexibility, a critical component of executive functions, refers to the ability to adapt cognitive processing strategies to face new conditions, switch between tasks, and update priorities in response to changing environments[ 4 , 5 ]. In patients with schizophrenia, impairments in cognitive flexibility are pronounced[ 6 , 7 , 5 , 8 ]. Patients show marked difficulties in task switching, which involves the ability to shift attention between tasks that have different cognitive demands. Reduced cognitive flexibility in patients with schizophrenia also hampers the ability to handle new or unexpected situations and affects the ability to monitor and correct errors. These patients may not effectively recognize when an error has been made or may struggle to implement corrective actions, further exacerbating difficulties in task performance. Recently, functional MRI (fMRI) studies have shown that patients with schizophrenia consistently exhibit reduced activation in the dorsolateral prefrontal cortex (DLPFC) during tasks requiring cognitive set-shifting[ 9 , 10 ], and volumetric analyses of structural MRI have revealed reduced gray matter in the PFC and the anterior cingulate cortex (ACC)[ 6 , 11 ]. Diffusion tensor imaging (DTI) studies typically report decreased fractional anisotropy in the frontal lobes[ 12 ], indicating impaired white matter connectivity, which could underpin the deficits in efficient information processing required for flexible cognition. Positron emission tomography (PET) imaging has revealed that dopaminergic and serotonergic dysfunction, particularly in the prefrontal cortex (PFC) and striatum, is linked to cognitive flexibility deficits in patients with schizophrenia[ 13 ]. Event-related potentials (ERPs) provide critical insights into the neural dynamics associated with impaired cognitive flexibility in patients with schizophrenia[ 14 ]. P3, as one of the main components of ERPs, is a positive wave with a peak at approximately 300 milliseconds (ms) to 600 ms. P3 is evoked by some psychological experimental paradigms, such as the oddball paradigm, Stroop task and Flanker task. Each psychological experimental paradigm reflects the response to cognitive processing. For example, the P3 evoked by the oddball paradigm is related to the ability to pay attention to resource allocation[ 15 ], whereas the P3 evoked by the Stroop task is suitable for measuring cognitive load in precisely timed tasks[ 16 ], and the P3 evoked by the Flanker task is related to the ability to exert inhibitory control[ 17 ]. In schizophrenia, P300 (P3a and P3b), which is evoked by the oddball paradigm, is associated with reduced amplitudes and delayed latencies, indicating impairments in both the attentional shift necessary for adapting to new tasks and the cognitive updating required for effective task management[ 18 , 19 ]. Patients with schizophrenia often exhibit altered N2 (N2b) amplitudes. N2, which is a negative wave that peaks at approximately 200 ms to 350 ms after the target stimuli, and is evoked by Go/No-go and Flanker tasks, suggests difficulties in conflict detection and the initial stages of adjusting behavior when confronted with conflicting information[ 20 ]. The application of the oddball paradigm in eliciting ERPs to measure cognitive flexibility features a limitation that must be acknowledged. The oddball paradigm primarily assesses the neural response to deviance and may not directly measure the complex multifaceted nature of cognitive flexibility. Cognitive flexibility involves not only the detection of novelty but also the ability to adapt and switch between different thoughts and actions in response to changing environments. Thus, the paradigm’s focus on stimulus-driven processes such as the P3 component, primarily reflecting attentional allocation and the processing of unexpected events, might provide a narrow view of cognitive flexibility. The use of the Go/No-go paradigm to elicit ERPs for measuring cognitive flexibility features also presents a notable limitation. The task is designed to assess inhibitory control rather than the broader spectrum of cognitive flexibility. It measures an individual’s ability to suppress an already initiated response, which is just one component of the multifaceted construct of cognitive flexibility. The cued task-switching paradigm (CTSP) is specifically designed to assess task-switching capabilities, a core component of cognitive flexibility[ 21 , 22 ]. The application of this paradigm in eliciting ERPs for measuring cognitive flexibility offers an advantage that is pivotal in understanding this complex cognitive construct[ 23 ]. The advantage of using the cued task-switching paradigm is its direct relevance to cognitive flexibility. From a neurophysiological perspective, the cued task-switching paradigm is beneficial because it reliably elicits specific ERP components known to be associated with task switching[ 24 ]. Previous studies in healthy populations have shown that N2 amplitude is greater during switch trials than during repeat trials[ 25 ] and that P3 amplitude is greater during switch trials[ 22 ]. Additionally, a task-switching cost is evident in slower reaction times and reduced accuracy during switch trials than during repeat trials[ 26 ]. Previous studies in patients with depression revealed increased N2 amplitude, reduced P3 amplitude, increased latency, and increased task-switching cost during the cued-switch task[ 27 , 28 ]. No studies on the ERP characteristics of cognitive flexibility with CTSP in patients with schizophrenia have been reported. Further investigations of the ERP characteristics of cognitive flexibility in patients with schizophrenia would be helpful in understanding the neural process of cognitive flexibility. Moreover, insights into the neural mechanisms underlying these deficits could provide novel targets for pharmacological and neuromodulatory treatments. In the present study, the participants included patients with schizophrenia and normal controls, and the measurements of ERPs during the CTSP were used to investigate the neural process of cognitive flexibility. The purpose of the present study was to investigate the ERP characteristics of cognitive flexibility and further explore the neural mechanism of the cognitive processing of abnormal cognitive flexibility in patients with schizophrenia. 2. Materials and Methods 2.1 Participants The participants included patients with schizophrenia and HCs. The inclusion criteria for the SCZ group were as follows: (1) the diagnostic criteria for schizophrenia in the American Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5); (2) age range from 18 to 65 years; (3) no use of any medication that affects cognitive function in the past 2 weeks (such as benzodiazepines and anticholinergics); (4) no history of electroconvulsive Therapy (ECT) or modified ECT in the past 12 months; (5) no comorbidity diagnosis of other psychiatric disorders according to the DSM-5 criteria, such as depression, anxiety, or substance abuse; (6) no physical/neurological illnesses or traumatic brain injury; and (7) informed consent of the guardian and cooperator. The inclusion criteria for the HC group were (1) no diagnosis of any psychiatric disorder according to the DSM-5 criteria; (2) no physical/neurological illnesses or traumatic brain injury; (3) no family history of any mental disorders; and (4) age ranging from 18 to 65 years. Patients with schizophrenia were selected from the affiliated Mental Health Center of Jiangnan University, China and HCs were residents of Wuxi city, Jiangsu Province, China. In this study, G*Power software (latest ver. 3.1.9.7; Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) was used to estimate the sample size. In the F tests, α = 0.05 was statistically significant, and a minimum requirement of 29 subjects per group met the sample size requirement. A total of 39 patients with schizophrenia and 46 HCs were included in this study. For patients with schizophrenia, the dose of antipsychotic medication was calculated on the basis of chlorpromazine equivalence[ 29 ]. The participants or their guardians and family members were informed of the purpose and procedure of the study before the experiment, and written informed consent was provided. This study was conducted from January 1, 2025, to March 15, 2025, with the approval of the Human Research Ethics Committee of the Affiliated Mental Health Center of Jiangnan University, China (WXMHCIRB2025LLky016). The study was carried out in accordance with the guidelines outlined in the Declaration of Helsinki. Participants were told about their tasks, and all signed informed consent forms prior to their participation. Each participant was compensated 300.00 Chinese yuan. 2.2 Clinical Assessments All patients with schizophrenia were evaluated by an attending psychiatrist and an associate chief psychiatrist. Psychopathology was assessed using the Positive and Negative Symptom Scale (PANSS). The PANSS positive scores for the 7 items ranged from 7 to 49 points, the PANSS negative scores for the 7 items ranged from 7 to 49 points, and the PANSS general scores for the 16 items ranged from 16 to 112 points. The total PANSS score was the sum of the scores of the 30 items. The more severe symptoms are, the higher the total PANSS score. Participants’ cognitive flexibility was assessed using the CTSP. The Annett handedness scale was used to rate the participants’ handedness[ 30 ]. The Annett handedness scale has twelve actions to elicit hand preference. Six primary actions can be performed with a single hand, and six nonprimary actions can be performed with both hands, with one hand doing the main part of the action[ 31 ]. 2.3 Stimuli and Experimental Paradigm 2.3.1 Stimuli Cognitive flexibility was measured using the cued task-switching paradigm, with a total of 40 pictures of the stimuli, which were divided into four categories, i.e., living, nonliving, larger than a shoebox, and smaller than a shoebox, with 10 pictures of each category. Each participant selected eight of the pictures, two from each of the four types. Each picture was randomly bordered with blue or red borders. The CTSP stimuli are presented in Fig. 1 . 2.3.2 Procedure of the cued task-switching paradigm The CTSP had 8 blocks of 32 trials, and participants made judgments based on whether the picture stimuli had a blue or red border and pressed the corresponding button. The blue border need to determine whether the picture is living or nonliving (F: living; V: non-living), and the red border needs to determine whether the picture is larger or smaller than the shoebox (J: larger than the shoebox; N: Smaller than a shoebox)[ 32 ]. The picture stimulus was presented for 3000 ms, and the subject was asked to respond to the task within 3000 ms. The feedback (correct or wrong) appeared for 500 ms when the button was pressed, and the intertrial interval (ITI) was 1500 ms. There were 8 exercises before the start of the formal trial, and the correct rate could be reached 6 or more times before the participants entered the formal stage to ensure that the subjects were familiar with the rules. There was a rest period after each block to avoid fatigue. The flowchart of the CTSP is shown in Fig. 2 . In this paradigm, switching costs can provide more exact results of cognitive flexibility. Switching costs were calculated as the absolute value of response times (RTs) or error rates (ERs) of switching trials for CTSP minus response times (RTs) or error rates (ERs) of repeat trials for CTSP. Smaller switching costs indicate that the switching process is easier or that participants have greater cognitive flexibility. Conversely, the higher the switching costs are, the lower the level of cognitive flexibility[ 33 ]. 2.3.3 Electrophysiological Recording and Preprocessing A BioSemi Active Two system was used to continuously record electroencephalograms (EEG) at a digitized rate of 500 Hertz (Hz). A custom BrainCap (EasyCap, Herrsching, Germany) containing 64 Ag/AgCl ring electrodes was used for EEG recording according to the international 10/20 system. A vertical electrooculogram (VEOG) was obtained from electrodes placed 1–2 cm below the right eye. We kept the impedances of all electrodes below 5 kilohms (kΩ). The horizontal EOG was derived from the electrode located beside each eye. As soon as the participants stated that they understood the instructions and were ready to start, the continuous EEG was recorded. The EEG signal was preamplified to increase the signal-to-noise ratio on the electrodes. The raw EEG data were processed using a reference offline to the average of the left and right mastoids, whereas continuous signals were filtered at 0.01 Hz for high-pass signals and 30 Hz for low-pass signals during offline signal analysis. The EEG was epoched from − 200 ms to 1000 ms before and after the stimulus marker, and the baseline was corrected using the mean from − 200 ms to 0 ms. Epochs were rejected if their absolute amplitudes exceeded 70 µV, and those of the same condition were averaged at the individual level. In addition, both electric eye artifact elimination and data correction were carried out by the independent component analysis (ICA) statistical procedure. In accordance with the grand average waveform, the P3 component was used for analysis. Moreover, three regions of interest (ROI) (frontal region: F3, F4, Fz; central region: C3, C4, Cz; and parietal region: P3, P4, Pz) were selected for further analysis. The selection of the time window of the P3 component was based on previously reported literature and grand-averaged ERP [ 34 ]. For the P3 component, the indicators of interest were the peak amplitudes for each condition in 350–600 ms time window. We measured the peak amplitude and latency of the P3 component and then averaged the amplitudes and latencies for each of the ROIs. Owing to the difference in waves (switch trials minus repeat trials) of P3 components reflecting switching costs, we also averaged the difference in P3 wave amplitudes and latencies for the ROIs to examine the switching ability of the decision-making process in the CSTP[ 28 ]. 2.4 Statistical Analysis Social science statistical software 22.0 (SPSS 22.0, IBM Corp., Armonk, NY, USA) was used for statistical analysis of the data. The mean age (years), years of schooling (years), duration of disease (months), and age of onset of patients with schizophrenia were compared with those of the HCs by the independent sample t -test. Handedness and the sex ratio were compared by the Pearson chi-square test. 2 group (SCZ vs. HC) ◊2 trial type (repeat vs. switch). Repeated measurements analysis of variance (ANOVA) was used to compare the RTs and ERs of the cued task-switching paradigm for each group (SCZ vs. HC). The mean amplitudes and latencies of ERP components were compared by three-factor repeated measure ANOVA. The difference waves (switch task minus repeat task) of the P3 component were also calculated and analyzed by 2 group (SCZ vs. HC) ×3 ROI (frontal vs. central vs. parietal) repeated-measures ANOVA. 3. Results 3.1 Demographic characteristics of the participants As shown in Table 1 , there were no significant differences in mean age, mean years of schooling, duration of disease, or handedness between the SCZ group and the HC group. Thirty-nine patients were treated with antipsychotics: six with risperidone (mean dosage 4.0 ± 1.3 mg/day), ten with olanzapine (mean dosage 12.75 ± 2.15 mg/day), seven with quetiapine (mean dosage 500.0 ± 100.65 mg/day), six with aripiprazole (mean dosage 15.0 ± 9.37 mg/day), seven with amisulpride (mean dosage 250.50 ± 26.25 mg/day), and three with paliperidone (mean dosage 7.50 ± 2.20 mg/day). For SCZ patients, the mean chlorpromazine-equivalent dosage was 250.50 ± 10.66 mg/day, as calculated according to a previous report [ 29 ]. Table 1 Demographic characteristics and clinical data (Mean (SD)). Variables SCZ (n = 39) HC (n = 46) Test statistic Age (years) 37.3 (9.7) 34.4 (8.7) t = -1.509, p = 0.135 Sex (M/F) 28/11 26/20 χ ² = 2.125, p = 0.145 Handedness (R/M/L) 12/13/14 15/16/15 χ ² = 0.866, p = 0.352 Education (years) 12.2 (2.8) 13.9 (2.6) t = 2.387, p = 0.06 Age at onset (years) 24.7 (8.5) - - Duration of illness (moths) 136 (11.4) - - PANSS Positive scores 17.2 (4.2) - - PANSS Negative scores 20.63 (5.89) - - PANSS General scores 35.1 (3.8) - - PANSS Total scores 72.4 (3.2) - - Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group; SD, standard deviation; R, right; M, mixed; L, left; PANSS, Positive and Negative Syndrome Scale. 3.2 Analysis of behavioral data The behavioral data of the SCZ and HC groups are shown in Table 2 . The RTs and ERs of the two groups in the repeat trial, switch trial and switching cost are shown in Fig. 3 . Table 2 Behavioral data for the CTSP in SCZ and HC group (Mean (SD)). Variables SCZ (n = 39) HC (n = 46) Repeat trail Switch trail Repeat trail Switch trail RTs (ms) 1374.9(33.14) 1580.7(360.7) 1230.6(230.5) 1288.4(331.6) ERs 0.146 (0.139) 0.175 (0.168) 0.054 (0.044) 0.050 (0.046) RTs_SC (ms) 205.8 (245.8) 57.9 (93.3) ERs_SC 0.030 (0.095) -0.005 (0.006) Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group; RTs, reaction times; ERs, error rates; RTs_SC, switching cost of reaction times; ERs_SC, switching cost of error rates. Using RTs as the dependent variable, repeated-measures ANOVA of the 2 groups (SCZ vs. HC) ◊2 trial type (repeat vs. switch) revealed that the main effect of the group on RTs was significant ( F (1, 83) = 13.017, p = 0.001, η 2 = 0.136), and the SCZ group had higher RTs than the HC group did. The main effect of the trial type was significant ( F (1, 83) = 45.285, p = 0.000, η 2 = 0.353). The interaction effect of trial type ◊group was significant ( F (1, 83) = 14.249, p = 0.000, η 2 = 0.147), and a simple effects test revealed that the RTs of the two trial types of the two groups were significant and that both groups had longer RTs to switch trials than to repeat trials. Using the ER as the dependent variable, repeated-measures ANOVA of the 2 groups (SCZ vs. HC) ◊2 trial type (repeat vs. switch) revealed that the main effect of the group at the ER was significant ( F (1, 83) = 23.045, p = 0.000, η 2 = 0.217), and the SCZ group had greater ER than the HC group did. The main effect of trial type was not significant ( F (1, 83) = 2.617, p = 0.109, η 2 = 0.031). The interaction effect of trial type × group was significant ( F (1, 83) = 4.882; p = 0.030; η 2 = 0.056), and simple effects test revealed that the two trial types of the two groups for the ERs were significant; both groups had higher ER values for switching trials than for repeat trials. The switching costs of RTs and ERs for the two groups were analyzed using an independent sample t test. There were significant differences between the two groups for the switching costs of RTs and ERs ( t = 3.775, 2.210; p = 0.000, 0.030), and the switching costs of RTs and ERs in the SCZ group were greater than those in the HC group. Compared with the HC group, the SCZ group had a higher switching cost. 3.3 Analysis of ERP data To ensure the quality of the data, we rejected bad epochs caused by inevitable artifacts (e.g., violent muscle shocks, unavoidable signal interference and poorly conditioned electrodes) that the tool for preprocessing could not remove. Consequently, the number of trials in the repeat and switch trials differed. The number of trials [mean standard deviation (SD)] entered into the statistics in the repeat and switch conditions were 118.18 (10.64) and 131.00 (27.86) for the SCZ group and 119.48 (14.31) and 125.18 (18.86) for the HC group, respectively. In accordance with previous studies[ 28 , 35 , 36 ] and the ERP total mean topographic map of this study, frontal location (F3, Fz, and F4), central location (C3, Cz, and C4), and parietal location (P3, Pz, and P4) were selected to analyze P3 (350–600 ms) amplitudes. The grand averaged ERPs of the brain regions are shown in Fig. 4 , and the ERP total mean topographic map is shown in Fig. 5 . For P3 amplitudes, the main effect in the ROI was significant ( F (2, 166) = 22.799, p = 0.000, η 2 = 0.215). Post hoc analysis (Bonferroni correction) revealed that the ROI was significant ( F (2, 82) = 14.297, p = 0.000, η 2 = 0.259) and that the P3 amplitudes at the frontal location were lower than those at the central and parietal locations. There was also a significant main effect of group ( F (1, 83) = 8.609; p = 0.004; η 2 = 0.094), and the P3 amplitude was greater in the SCZ group than in the HC group. In addition, the interaction between group and trial type was significant ( F (1, 83) = 10.633, p = 0.002, η 2 = 0.114); a simple effects test showed that the switch trials and repeat trials were significant in the HC group ( F (1, 83) = 12.345, p = 0.001, η 2 = 0.129), and compared with switch trials, the repeat trials had significant larger amplitudes. However, there was no significant difference in the SCZ group between the repeat and switch trials. Simple effects test also revealed that the SCZ group and HC group were significantly different in the two trial types. With respect to P3 latency, there were significant main effects of group, ROI and trial type (all p < 0.05). Post hoc analysis (Bonferroni correction) of the ROI revealed significant differences. Compared with the HC group, the SCZ group had significantly longer latencies. Moreover, the P3 latencies of the repeat trials were longer than those of the switch trials, and those at the frontal location were longer than those at the central and parietal locations were. The P3 difference waves (switch trial minus repeat trial) were also analyzed at different ROIs in the two groups. The grand-averaged P3 difference waveforms are shown in Fig. 6 , and the topographic map of the grand-averaged P3 difference waveforms is shown in Fig. 7 . The group difference in the P3 difference wave amplitude was significant ( F (1, 83) = 10.633; p = 0.002; η 2 = 0.114), and the absolute P3 difference wave amplitude in the SCZ group was smaller than that in the HC group. There was no significant difference in P3 wave latency between the two groups. 3.3 Analysis of exploratory correlations between variables We conducted a correlation analysis between the PANSS and ERP data, the PANSS and behavioral data, and the ERP and behavioral data, and performed false discovery rate (FDR) correction on the results after the correlation analyses. Significant correlation among the variables are shown in Table 3 and A bar chart to visualize pairwise correlations in Fig. 8 . In the SCZ group, there was no significant correlation between the PANSS and ERP data or between the PANSS and behavior data; however, there was a significant positive correlation between the ERs of repeat trials and the P3 latencies of repeats in the central location ( r = 0.45, p = 0.009). In the HC group, there was a significant negative correlation between RTs of repeat trials and P3 amplitudes of repeats in the central location ( r = -0.42, p = 0.017), and the RTs of repeat trials were negatively correlated with P3 amplitudes of repeats in the parietal location ( r = -0.39, p = 0.02). Table 3 Significant correlation among the variables. Variables Correlation FDR p-value SCZ (C-R-L/ERs-R) 0.45 0.008 HC (C-R-A/RTs-R) -0.42 0.017 HC (P-R-A/RTs-R) -0.39 0.002 Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group; SCZ (C-R-L/ERs-R), P3 latencies of repeat trials in central location compare with error rates of repeat trials in SCZ; HC (C-R-A/RTs-R), P3 amplitudes of repeat trials in central location compare with reaction times of repeat in HC; HC (P-R-A/RTs-R), P3 amplitudes of repeat trials in parietal location compare with reaction times of repeat in HC; FDR, False Discovery Rate. 4. Discussion This study investigated the ERP characteristics of cognitive flexibility with the cued task-switching paradigm in patients with schizophrenia and is the first study to elucidate the neuroelectrophysiological mechanisms of dysfunctions in cognitive flexibility in patients with schizophrenia. Furthermore, this study revealed that compared with HCs, patients with SCZ had longer RTs, higher ERs and higher switching costs during CTSP. Consistent with the findings of previous studies[ 6 , 7 , 5 , 8 ], these behavioral findings indicated that patients with SCZ presented dysfunctions in cognitive flexibility. Compared with other cognitive assessment methods, such as the oddball paradigm and the Go/No-go paradigm, the CTSP offers distinct advantages in measuring cognitive flexibility. This advantage stems primarily from the CTSP’s ability to directly evaluate the efficiency and mechanisms underlying an individual’s capacity to switch between cognitive tasks, reflecting higher-order executive functions. In contrast, the oddball paradigm primarily measures the ability to process novel or target stimuli amid repetitive, nontarget stimuli. Similarly, the Go/No-go paradigm is designed to assess inhibitory control, requiring participants to perform an action in response to certain stimuli (Go) and withhold the response in the presence of others (No-go). Therefore, CTSP is superior in its ability to directly and comprehensively assess cognitive flexibility[ 18 , 19 , 5 ]. A previous study on major depressive disorder (MDD) revealed that compared with HCs, patients with MDD had similar switching costs of RTs and ERs while they performed the emotional task switching paradigm (ETSP) and nonemotional task switching paradigm (N-ETSP)[ 28 ]; however, in our study, compared with HCs, patients with SCZ had greater switching costs of RTs and ERs, which suggests different neuroelectrophysiological mechanisms for patients with SCZ and patients with MDD in terms of dysfunction of cognitive flexibility. In this study, the ERP data revealed that patients with SCZ had larger P3 amplitudes and lower difference wave amplitudes in P3 when they performed CTSP. The larger P3 amplitudes in the SCZ patients are inconsistent with those reported in previous ERP studies[ 37 , 38 ]. There might be two reasons for this. First, in previous studies, the oddball paradigm was used to measure cognitive flexibility, and the P3 amplitudes evoked by the oddball paradigm were smaller[ 39 , 40 ]. In our study, the CSTP paradigm was used to examine cognitive flexibility. Owing to the greater credibility of the CTSP in assessing cognitive flexibility, this experimental paradigm exhibits distinct characteristics in ERP P3 responses compared with those observed in the oddball paradigm. Second, many studies have confirmed that larger P3 amplitudes indicate that participants have to pay more cognitive and attentional resources to regulate cognitive flexibility[ 41 – 44 ]. In our study, the switching costs of the patients with SCZ were greater than those of the HCs, which confirms that patients with SCZ need to pay more cognitive resources to complete the CSTP with larger P3 amplitudes. In addition, this study revealed that in the SCZ group, the P3 amplitudes of the switch trial were greater and the latencies were longer than those of the repeat trial, which was inconsistent with the findings of the previous CSTP in healthy people[ 45 , 46 ]. These studies on HCs contribute to a better understanding of baseline cognitive flexibility, providing a reference point for comparisons with clinical populations where these mechanisms may be impaired, such as in patients with schizophrenia or other neurocognitive disorders. Our results suggest that there are abnormalities in cognitive flexibility function in patients with SCZ. On the other hand, our study revealed that the difference in waves of P3 amplitudes in patients with SCZ was smaller, which was inconsistent with recent research showing that P3 difference in wave amplitudes was similar between patients with MDD and HCs. Our findings suggest that the ability to flexibly switch and make decisions may be poorer in patients with schizophrenia than in patients with MDD and HCs in CTSP[ 28 ]. Moreover, our study revealed that compared with the central and parietal regions, the frontal region has the smallest P3 amplitudes and the longest P3 latencies in both HCs and patients with SCZ, which is consistent with the findings of a previous study of P3 abnormalities in patients with SCZ[ 47 ]. Owing to the different neuroelectrophysiological mechanisms between patients with SCZ and HCs, this study revealed that the larger P3 amplitudes in the CTSP in patients with SCZ than in HCs indicate lower cognitive flexibility. Therefore, these findings indicate that the frontal region has less impairment of cognitive flexibility than the central and parietal regions do. In this study, the PANSS score was not correlated with ERP or behavioral data, which might suggest that abnormal ERP components and behavioral characteristics might be trait biomarkers rather than state biomarkers in patients with schizophrenia. In the HC group, the P3 amplitudes of the repeat trials in the central location and parietal location were negatively correlated with the RTs of the repeat, which might suggest that the speed of neural information transmission in the HCs was accelerated and that the decision output was shortened. However, in the SCZ group, the ERs of repeat trials was positively correlated with the P3 latencies of repeats in the central location. This finding might suggest that the slowdown of the processing speed of patients with SCZ is closely related to the processing accuracy. In summary, this study presented important neuroelectrophysiological evidence of impaired cognitive flexibility in patients with SCZ. These results suggest that P3 may be an important neuroelectrophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia. Previous studies have shown that P3 neurofeedback training can improve social attention, thereby improving cognitive flexibility function[ 48 ]; this study may provide a theoretical basis for the cognitive flexibility of patients with in terms of neurofeedback training. 5. Limitations This study had several limitations. First, the cross-sectional design limits our ability to capture dynamic changes in cognitive flexibility over time, and future longitudinal studies are needed to track the evolution of cognitive flexibility in patients with SCZ over the course of the disease. Second, owing to the small sample size this was a preliminary study, and the results need to be replicated using large samples with the same parameters. Third, owing to the low spatial resolution of EEG, future studies should combine high-spatial-resolution fMRI to further clarify the neurophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia. 6. Conclusion Patients with schizophrenia showed impaired cognitive flexibility and neural correlates of these impairments, as reflected by the abnormal ERP P3. These findings provide valuable insights into the understanding of the neural mechanisms underlying impaired cognitive flexibility and may guide targeted interventions in patients with schizophrenia. Declarations Funding Wuxi Municipal Health Commission Major Project (No. Z202107 to Zhenhe Zhou) and Wuxi Taihu Talent Project (No. WXTTP 2021 to Zhenhe Zhou). Acknowledgements We are grateful for the support by Wuxi Municipal Health Commission Major Project (No. Z202107 to Zhenhe Zhou) and Wuxi Taihu Talent Project (No. WXTTP 2021 to Zhenhe Zhou) and the contributions of all the participants. Clinical trial number Not applicable Ethics approval and consent to participate This study was approved by the Ethics Committee of affiliated Mental Health Center of Jiangnan University (WXMHCIRB2025LLky016). All participants provided written informed consent. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Salahuddin NH, Schütz A, Pitschel-Walz G, Mayer SF, Chaimani A, Siafis S, et al. Psychological and psychosocial interventions for treatment-resistant schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry 2024;11:545–53. https://doi.org/10.1016/S2215-0366(24)00136-6. Hearne LJ, Mill RD, Keane BP, Repovš G, Anticevic A, Cole MW. Activity flow underlying abnormalities in brain activations and cognition in schizophrenia. 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Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood. Nat Rev Neurosci 2017;18:335–46. https://doi.org/10.1038/nrn.2017.45. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 23 Oct, 2025 Reviews received at journal 21 Oct, 2025 Reviews received at journal 20 Oct, 2025 Reviewers agreed at journal 02 Oct, 2025 Reviewers agreed at journal 30 Sep, 2025 Reviewers invited by journal 30 Sep, 2025 Editor invited by journal 25 Sep, 2025 Editor assigned by journal 22 Sep, 2025 Submission checks completed at journal 22 Sep, 2025 First submitted to journal 18 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7649864","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":528227055,"identity":"8090a793-aa59-4600-8747-023df3dca631","order_by":0,"name":"Qian Mei","email":"","orcid":"","institution":"Department of Psychiatry, Wuxi Mental Health Center, Wannan Medical College Graduate Training Unit","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Mei","suffix":""},{"id":528227056,"identity":"2481e25d-2ca0-4efa-9a6b-f507ac5576be","order_by":1,"name":"Lin 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02:13:40","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15037,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/9ccd337286110dc91ac5872e.png"},{"id":93539153,"identity":"04e1ede0-642a-43db-84d7-5e1965971045","added_by":"auto","created_at":"2025-10-15 02:13:40","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37089,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/f617572c26b52cdc04026393.png"},{"id":93539150,"identity":"3ac4579c-c3e7-4d54-a96a-ba803adec8ef","added_by":"auto","created_at":"2025-10-15 02:13:40","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11280,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/6220e569940543ab02bfdc67.png"},{"id":93539161,"identity":"6e18c520-63fc-494a-a249-39c34fe1b62c","added_by":"auto","created_at":"2025-10-15 02:13:40","extension":"xml","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":144652,"visible":true,"origin":"","legend":"","description":"","filename":"f2046914c7c54fd6a934ff484504de931structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/8be28cd50f29e9e3440db459.xml"},{"id":93539160,"identity":"2980d6c7-2821-44f6-93a5-73f1fa680ace","added_by":"auto","created_at":"2025-10-15 02:13:40","extension":"html","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":159697,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/af88c60591bd040759b7b9f7.html"},{"id":93539127,"identity":"c2068895-119d-4033-83eb-e581fe601ec7","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39415,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of the cued task-switching paradigm.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/1f5fb71076e8fabd1c1246f6.png"},{"id":93539125,"identity":"f740edc3-33c1-42b9-8e3a-665e1c79d4e0","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52977,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the cued task-switching paradigm.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/f470970e101d9524b87fd930.png"},{"id":93539892,"identity":"16ff6cd4-d64b-4d07-b116-4224640bc0fa","added_by":"auto","created_at":"2025-10-15 02:21:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19576,"visible":true,"origin":"","legend":"\u003cp\u003eThe reaction times and error rates of the two groups in the repeat trial, switch trial and switch cost respectively. Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group; RTs, reaction times; ERs, error rate; RTs_SC, switching cost of reaction times; ERs_SC, switching cost of error rates.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/29a42dd7907dc30ec532305e.png"},{"id":93539133,"identity":"2dbd6308-ed18-45c4-b2c9-c99354652fa3","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97639,"visible":true,"origin":"","legend":"\u003cp\u003eGrand-averaged ERPs waveforms are shown for P3 with different trial types (repeat, switch) in SCZ group and HC group at ROIs (frontal brain areas (F3, Fz, F4), central brain areas (C3, Cz, C4), and parietal brain areas (P3, Pz, P4)) during CTSP. The P3 time window ranged from 350 to 600 ms. Abbreviations: SCZ_Switch, the switch trials in schizophrenia patients; SCZ_Repeat, the repeat trials in schizophrenia patients; HC_Switch, the switch trials in healthy controls; HC_Repeat, the repeat trials in healthy controls.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/d0a5146d3f73f533b757be35.png"},{"id":93539136,"identity":"4152cda2-a9f3-4746-8a05-750e4236993e","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":164022,"visible":true,"origin":"","legend":"\u003cp\u003eERP total mean topographic map. Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/eef9539e13f0bcaef59aca4d.png"},{"id":93539143,"identity":"3e739865-a987-4501-9810-d656d8fab773","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":32142,"visible":true,"origin":"","legend":"\u003cp\u003eGrand-averaged ERPs waveforms are shown for P3 difference waves in SCZ group and HC group during the CTSP. F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, were selected and grand averaged.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/b297dc99a65d9c373e2488b8.png"},{"id":93539134,"identity":"18aa5387-13b0-4bd0-b6aa-f9a814ffb95b","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":99209,"visible":true,"origin":"","legend":"\u003cp\u003eDifference wave topographic maps are shown for P3 difference waves in SCZ group and HC group during CTSP. Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/3efc14bee0a783a299adb027.png"},{"id":93539130,"identity":"3369bcfb-2fd2-4afb-a382-a34056f03af3","added_by":"auto","created_at":"2025-10-15 02:13:39","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":25871,"visible":true,"origin":"","legend":"\u003cp\u003eA bar chart to visualize pairwise correlations. Abbreviations: Abbreviations: SCZ, schizophrenia patient group; HC, healthy control group; SCZ (C-R-L/ERs-R), P3 latencies of repeat trials in central location compare with error rates of repeat trials in SCZ; HC (C-R-A/RTs-R), P3 amplitudes of repeat trials in central location compare with reaction times of repeat in HC; HC (P-R-A/RTs-R), P3 amplitudes of repeat trials in parietal location compare with reaction times of repeat in HC; FDR, False Discovery Rate. **\u0026lt;0.01, *\u0026lt;0.05.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/d25ba962ca7ecfcb0ae22aa7.png"},{"id":97724822,"identity":"628d0b5b-99b9-48dd-b4cf-7b66c1c5f89f","added_by":"auto","created_at":"2025-12-08 16:13:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1343994,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7649864/v1/af23b15e-3506-4230-a2c4-b1d911f423d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neural correlates of impaired cognitive flexibility in schizophrenia: An ERP study using the cued task-switching paradigm","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSchizophrenia (SCZ) is a serious mental illness with a complex etiology and high incidence[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cognitive impairments are considered core features of schizophrenia and are present in various domains[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Cognitive flexibility, a critical component of executive functions, refers to the ability to adapt cognitive processing strategies to face new conditions, switch between tasks, and update priorities in response to changing environments[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In patients with schizophrenia, impairments in cognitive flexibility are pronounced[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Patients show marked difficulties in task switching, which involves the ability to shift attention between tasks that have different cognitive demands. Reduced cognitive flexibility in patients with schizophrenia also hampers the ability to handle new or unexpected situations and affects the ability to monitor and correct errors. These patients may not effectively recognize when an error has been made or may struggle to implement corrective actions, further exacerbating difficulties in task performance. Recently, functional MRI (fMRI) studies have shown that patients with schizophrenia consistently exhibit reduced activation in the dorsolateral prefrontal cortex (DLPFC) during tasks requiring cognitive set-shifting[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and volumetric analyses of structural MRI have revealed reduced gray matter in the PFC and the anterior cingulate cortex (ACC)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Diffusion tensor imaging (DTI) studies typically report decreased fractional anisotropy in the frontal lobes[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], indicating impaired white matter connectivity, which could underpin the deficits in efficient information processing required for flexible cognition. Positron emission tomography (PET) imaging has revealed that dopaminergic and serotonergic dysfunction, particularly in the prefrontal cortex (PFC) and striatum, is linked to cognitive flexibility deficits in patients with schizophrenia[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEvent-related potentials (ERPs) provide critical insights into the neural dynamics associated with impaired cognitive flexibility in patients with schizophrenia[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. P3, as one of the main components of ERPs, is a positive wave with a peak at approximately 300 milliseconds (ms) to 600 ms. P3 is evoked by some psychological experimental paradigms, such as the oddball paradigm, Stroop task and Flanker task. Each psychological experimental paradigm reflects the response to cognitive processing. For example, the P3 evoked by the oddball paradigm is related to the ability to pay attention to resource allocation[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], whereas the P3 evoked by the Stroop task is suitable for measuring cognitive load in precisely timed tasks[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and the P3 evoked by the Flanker task is related to the ability to exert inhibitory control[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In schizophrenia, P300 (P3a and P3b), which is evoked by the oddball paradigm, is associated with reduced amplitudes and delayed latencies, indicating impairments in both the attentional shift necessary for adapting to new tasks and the cognitive updating required for effective task management[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Patients with schizophrenia often exhibit altered N2 (N2b) amplitudes. N2, which is a negative wave that peaks at approximately 200 ms to 350 ms after the target stimuli, and is evoked by Go/No-go and Flanker tasks, suggests difficulties in conflict detection and the initial stages of adjusting behavior when confronted with conflicting information[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe application of the oddball paradigm in eliciting ERPs to measure cognitive flexibility features a limitation that must be acknowledged. The oddball paradigm primarily assesses the neural response to deviance and may not directly measure the complex multifaceted nature of cognitive flexibility. Cognitive flexibility involves not only the detection of novelty but also the ability to adapt and switch between different thoughts and actions in response to changing environments. Thus, the paradigm\u0026rsquo;s focus on stimulus-driven processes such as the P3 component, primarily reflecting attentional allocation and the processing of unexpected events, might provide a narrow view of cognitive flexibility. The use of the Go/No-go paradigm to elicit ERPs for measuring cognitive flexibility features also presents a notable limitation. The task is designed to assess inhibitory control rather than the broader spectrum of cognitive flexibility. It measures an individual\u0026rsquo;s ability to suppress an already initiated response, which is just one component of the multifaceted construct of cognitive flexibility.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe cued task-switching paradigm (CTSP) is specifically designed to assess task-switching capabilities, a core component of cognitive flexibility[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The application of this paradigm in eliciting ERPs for measuring cognitive flexibility offers an advantage that is pivotal in understanding this complex cognitive construct[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The advantage of using the cued task-switching paradigm is its direct relevance to cognitive flexibility. From a neurophysiological perspective, the cued task-switching paradigm is beneficial because it reliably elicits specific ERP components known to be associated with task switching[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Previous studies in healthy populations have shown that N2 amplitude is greater during switch trials than during repeat trials[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and that P3 amplitude is greater during switch trials[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Additionally, a task-switching cost is evident in slower reaction times and reduced accuracy during switch trials than during repeat trials[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Previous studies in patients with depression revealed increased N2 amplitude, reduced P3 amplitude, increased latency, and increased task-switching cost during the cued-switch task[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNo studies on the ERP characteristics of cognitive flexibility with CTSP in patients with schizophrenia have been reported. Further investigations of the ERP characteristics of cognitive flexibility in patients with schizophrenia would be helpful in understanding the neural process of cognitive flexibility. Moreover, insights into the neural mechanisms underlying these deficits could provide novel targets for pharmacological and neuromodulatory treatments.\u003c/p\u003e\u003cp\u003eIn the present study, the participants included patients with schizophrenia and normal controls, and the measurements of ERPs during the CTSP were used to investigate the neural process of cognitive flexibility. The purpose of the present study was to investigate the ERP characteristics of cognitive flexibility and further explore the neural mechanism of the cognitive processing of abnormal cognitive flexibility in patients with schizophrenia.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Participants\u003c/h2\u003e\u003cp\u003eThe participants included patients with schizophrenia and HCs. The inclusion criteria for the SCZ group were as follows: (1) the diagnostic criteria for schizophrenia in the American Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5); (2) age range from 18 to 65 years; (3) no use of any medication that affects cognitive function in the past 2 weeks (such as benzodiazepines and anticholinergics); (4) no history of electroconvulsive Therapy (ECT) or modified ECT in the past 12 months; (5) no comorbidity diagnosis of other psychiatric disorders according to the DSM-5 criteria, such as depression, anxiety, or substance abuse; (6) no physical/neurological illnesses or traumatic brain injury; and (7) informed consent of the guardian and cooperator. The inclusion criteria for the HC group were (1) no diagnosis of any psychiatric disorder according to the DSM-5 criteria; (2) no physical/neurological illnesses or traumatic brain injury; (3) no family history of any mental disorders; and (4) age ranging from 18 to 65 years.\u003c/p\u003e\u003cp\u003ePatients with schizophrenia were selected from the affiliated Mental Health Center of Jiangnan University, China and HCs were residents of Wuxi city, Jiangsu Province, China.\u003c/p\u003e\u003cp\u003eIn this study, G*Power software (latest ver. 3.1.9.7; Heinrich-Heine-Universit\u0026auml;t D\u0026uuml;sseldorf, D\u0026uuml;sseldorf, Germany) was used to estimate the sample size. In the \u003cem\u003eF\u003c/em\u003e tests, \u003cem\u003eα\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05 was statistically significant, and a minimum requirement of 29 subjects per group met the sample size requirement. A total of 39 patients with schizophrenia and 46 HCs were included in this study. For patients with schizophrenia, the dose of antipsychotic medication was calculated on the basis of chlorpromazine equivalence[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The participants or their guardians and family members were informed of the purpose and procedure of the study before the experiment, and written informed consent was provided.\u003c/p\u003e\u003cp\u003e This study was conducted from January 1, 2025, to March 15, 2025, with the approval of the Human Research Ethics Committee of the Affiliated Mental Health Center of Jiangnan University, China (WXMHCIRB2025LLky016). The study was carried out in accordance with the guidelines outlined in the Declaration of Helsinki. Participants were told about their tasks, and all signed informed consent forms prior to their participation. Each participant was compensated 300.00 Chinese yuan.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Clinical Assessments\u003c/h2\u003e\u003cp\u003eAll patients with schizophrenia were evaluated by an attending psychiatrist and an associate chief psychiatrist. Psychopathology was assessed using the Positive and Negative Symptom Scale (PANSS). The PANSS positive scores for the 7 items ranged from 7 to 49 points, the PANSS negative scores for the 7 items ranged from 7 to 49 points, and the PANSS general scores for the 16 items ranged from 16 to 112 points. The total PANSS score was the sum of the scores of the 30 items. The more severe symptoms are, the higher the total PANSS score. Participants\u0026rsquo; cognitive flexibility was assessed using the CTSP. The Annett handedness scale was used to rate the participants\u0026rsquo; handedness[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The Annett handedness scale has twelve actions to elicit hand preference. Six primary actions can be performed with a single hand, and six nonprimary actions can be performed with both hands, with one hand doing the main part of the action[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Stimuli and Experimental Paradigm\u003c/h2\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.3.1 Stimuli\u003c/h2\u003e\u003cp\u003eCognitive flexibility was measured using the cued task-switching paradigm, with a total of 40 pictures of the stimuli, which were divided into four categories, i.e., living, nonliving, larger than a shoebox, and smaller than a shoebox, with 10 pictures of each category. Each participant selected eight of the pictures, two from each of the four types. Each picture was randomly bordered with blue or red borders. The CTSP stimuli are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.3.2 Procedure of the cued task-switching paradigm\u003c/h2\u003e\u003cp\u003eThe CTSP had 8 blocks of 32 trials, and participants made judgments based on whether the picture stimuli had a blue or red border and pressed the corresponding button. The blue border need to determine whether the picture is living or nonliving (F: living; V: non-living), and the red border needs to determine whether the picture is larger or smaller than the shoebox (J: larger than the shoebox; N: Smaller than a shoebox)[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The picture stimulus was presented for 3000 ms, and the subject was asked to respond to the task within 3000 ms. The feedback (correct or wrong) appeared for 500 ms when the button was pressed, and the intertrial interval (ITI) was 1500 ms. There were 8 exercises before the start of the formal trial, and the correct rate could be reached 6 or more times before the participants entered the formal stage to ensure that the subjects were familiar with the rules. There was a rest period after each block to avoid fatigue. The flowchart of the CTSP is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In this paradigm, switching costs can provide more exact results of cognitive flexibility. Switching costs were calculated as the absolute value of response times (RTs) or error rates (ERs) of switching trials for CTSP minus response times (RTs) or error rates (ERs) of repeat trials for CTSP. Smaller switching costs indicate that the switching process is easier or that participants have greater cognitive flexibility. Conversely, the higher the switching costs are, the lower the level of cognitive flexibility[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.3.3 Electrophysiological Recording and Preprocessing\u003c/h2\u003e\u003cp\u003eA BioSemi Active Two system was used to continuously record electroencephalograms (EEG) at a digitized rate of 500 Hertz (Hz). A custom BrainCap (EasyCap, Herrsching, Germany) containing 64 Ag/AgCl ring electrodes was used for EEG recording according to the international 10/20 system. A vertical electrooculogram (VEOG) was obtained from electrodes placed 1\u0026ndash;2 cm below the right eye. We kept the impedances of all electrodes below 5 kilohms (kΩ). The horizontal EOG was derived from the electrode located beside each eye. As soon as the participants stated that they understood the instructions and were ready to start, the continuous EEG was recorded. The EEG signal was preamplified to increase the signal-to-noise ratio on the electrodes. The raw EEG data were processed using a reference offline to the average of the left and right mastoids, whereas continuous signals were filtered at 0.01 Hz for high-pass signals and 30 Hz for low-pass signals during offline signal analysis. The EEG was epoched from \u0026minus;\u0026thinsp;200 ms to 1000 ms before and after the stimulus marker, and the baseline was corrected using the mean from \u0026minus;\u0026thinsp;200 ms to 0 ms. Epochs were rejected if their absolute amplitudes exceeded 70 \u0026micro;V, and those of the same condition were averaged at the individual level. In addition, both electric eye artifact elimination and data correction were carried out by the independent component analysis (ICA) statistical procedure. In accordance with the grand average waveform, the P3 component was used for analysis. Moreover, three regions of interest (ROI) (frontal region: F3, F4, Fz; central region: C3, C4, Cz; and parietal region: P3, P4, Pz) were selected for further analysis. The selection of the time window of the P3 component was based on previously reported literature and grand-averaged ERP [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. For the P3 component, the indicators of interest were the peak amplitudes for each condition in 350\u0026ndash;600 ms time window. We measured the peak amplitude and latency of the P3 component and then averaged the amplitudes and latencies for each of the ROIs. Owing to the difference in waves (switch trials minus repeat trials) of P3 components reflecting switching costs, we also averaged the difference in P3 wave amplitudes and latencies for the ROIs to examine the switching ability of the decision-making process in the CSTP[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e\u003cp\u003eSocial science statistical software 22.0 (SPSS 22.0, IBM Corp., Armonk, NY, USA) was used for statistical analysis of the data. The mean age (years), years of schooling (years), duration of disease (months), and age of onset of patients with schizophrenia were compared with those of the HCs by the independent sample \u003cem\u003et\u003c/em\u003e-test. Handedness and the sex ratio were compared by the Pearson chi-square test. 2 group (SCZ vs. HC) \u0026loz;2 trial type (repeat vs. switch). Repeated measurements analysis of variance (ANOVA) was used to compare the RTs and ERs of the cued task-switching paradigm for each group (SCZ vs. HC). The mean amplitudes and latencies of ERP components were compared by three-factor repeated measure ANOVA. The difference waves (switch task minus repeat task) of the P3 component were also calculated and analyzed by 2 group (SCZ vs. HC) \u0026times;3 ROI (frontal vs. central vs. parietal) repeated-measures ANOVA.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Demographic characteristics of the participants\u003c/h2\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, there were no significant differences in mean age, mean years of schooling, duration of disease, or handedness between the SCZ group and the HC group. Thirty-nine patients were treated with antipsychotics: six with risperidone (mean dosage 4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 mg/day), ten with olanzapine (mean dosage 12.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.15 mg/day), seven with quetiapine (mean dosage 500.0\u0026thinsp;\u0026plusmn;\u0026thinsp;100.65 mg/day), six with aripiprazole (mean dosage 15.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.37 mg/day), seven with amisulpride (mean dosage 250.50\u0026thinsp;\u0026plusmn;\u0026thinsp;26.25 mg/day), and three with paliperidone (mean dosage 7.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20 mg/day). For SCZ patients, the mean chlorpromazine-equivalent dosage was 250.50\u0026thinsp;\u0026plusmn;\u0026thinsp;10.66 mg/day, as calculated according to a previous report [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic characteristics and clinical data (Mean (SD)).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSCZ (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHC (n\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTest statistic\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.3 (9.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.4 (8.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003et\u003c/em\u003e = -1.509, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.135\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (M/F)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28/11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eχ\u003c/em\u003e\u0026sup2; = 2.125, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.145\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHandedness (R/M/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12/13/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15/16/15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eχ\u003c/em\u003e\u0026sup2; = 0.866, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.352\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEducation (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.2 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.9 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.387, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at onset (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.7 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of illness (moths)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e136 (11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePANSS Positive scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.2 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePANSS Negative scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.63 (5.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePANSS General scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.1 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePANSS Total scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.4 (3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: SCZ, schizophrenia patient group; HC, healthy control group; SD, standard deviation; R, right; M, mixed; L, left; PANSS, Positive and Negative Syndrome Scale.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Analysis of behavioral data\u003c/h2\u003e\u003cp\u003eThe behavioral data of the SCZ and HC groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The RTs and ERs of the two groups in the repeat trial, switch trial and switching cost are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBehavioral data for the CTSP in SCZ and HC group (Mean (SD)).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSCZ (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eHC (n\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRepeat trail\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSwitch trail\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRepeat trail\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSwitch trail\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRTs (ms)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1374.9(33.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1580.7(360.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1230.6(230.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1288.4(331.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eERs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.146 (0.139)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.175 (0.168)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.054 (0.044)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.050 (0.046)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRTs_SC (ms)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e205.8 (245.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e57.9 (93.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eERs_SC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e0.030 (0.095)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-0.005 (0.006)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: SCZ, schizophrenia patient group; HC, healthy control group; RTs, reaction times; ERs, error rates; RTs_SC, switching cost of reaction times; ERs_SC, switching cost of error rates.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eUsing RTs as the dependent variable, repeated-measures ANOVA of the 2 groups (SCZ vs. HC) \u0026loz;2 trial type (repeat vs. switch) revealed that the main effect of the group on RTs was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;13.017, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.136), and the SCZ group had higher RTs than the HC group did. The main effect of the trial type was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45.285, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.353). The interaction effect of trial type \u0026loz;group was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;14.249, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.147), and a simple effects test revealed that the RTs of the two trial types of the two groups were significant and that both groups had longer RTs to switch trials than to repeat trials.\u003c/p\u003e\u003cp\u003eUsing the ER as the dependent variable, repeated-measures ANOVA of the 2 groups (SCZ vs. HC) \u0026loz;2 trial type (repeat vs. switch) revealed that the main effect of the group at the ER was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;23.045, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.217), and the SCZ group had greater ER than the HC group did. The main effect of trial type was not significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.617, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.109, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.031). The interaction effect of trial type \u0026times; group was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.882; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030; \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.056), and simple effects test revealed that the two trial types of the two groups for the ERs were significant; both groups had higher ER values for switching trials than for repeat trials.\u003c/p\u003e\u003cp\u003eThe switching costs of RTs and ERs for the two groups were analyzed using an independent sample \u003cem\u003et\u003c/em\u003e test. There were significant differences between the two groups for the switching costs of RTs and ERs (\u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.775, 2.210; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, 0.030), and the switching costs of RTs and ERs in the SCZ group were greater than those in the HC group. Compared with the HC group, the SCZ group had a higher switching cost.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Analysis of ERP data\u003c/h2\u003e\u003cp\u003eTo ensure the quality of the data, we rejected bad epochs caused by inevitable artifacts (e.g., violent muscle shocks, unavoidable signal interference and poorly conditioned electrodes) that the tool for preprocessing could not remove. Consequently, the number of trials in the repeat and switch trials differed. The number of trials [mean standard deviation (SD)] entered into the statistics in the repeat and switch conditions were 118.18 (10.64) and 131.00 (27.86) for the SCZ group and 119.48 (14.31) and 125.18 (18.86) for the HC group, respectively.\u003c/p\u003e\u003cp\u003eIn accordance with previous studies[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] and the ERP total mean topographic map of this study, frontal location (F3, Fz, and F4), central location (C3, Cz, and C4), and parietal location (P3, Pz, and P4) were selected to analyze P3 (350\u0026ndash;600 ms) amplitudes. The grand averaged ERPs of the brain regions are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, and the ERP total mean topographic map is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. For P3 amplitudes, the main effect in the ROI was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(2, 166)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;22.799, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.215). Post hoc analysis (Bonferroni correction) revealed that the ROI was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(2, 82)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;14.297, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.259) and that the P3 amplitudes at the frontal location were lower than those at the central and parietal locations. There was also a significant main effect of group (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;8.609; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.094), and the P3 amplitude was greater in the SCZ group than in the HC group. In addition, the interaction between group and trial type was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;10.633, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.114); a simple effects test showed that the switch trials and repeat trials were significant in the HC group (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12.345, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.129), and compared with switch trials, the repeat trials had significant larger amplitudes. However, there was no significant difference in the SCZ group between the repeat and switch trials. Simple effects test also revealed that the SCZ group and HC group were significantly different in the two trial types. With respect to P3 latency, there were significant main effects of group, ROI and trial type (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Post hoc analysis (Bonferroni correction) of the ROI revealed significant differences. Compared with the HC group, the SCZ group had significantly longer latencies. Moreover, the P3 latencies of the repeat trials were longer than those of the switch trials, and those at the frontal location were longer than those at the central and parietal locations were.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe P3 difference waves (switch trial minus repeat trial) were also analyzed at different ROIs in the two groups. The grand-averaged P3 difference waveforms are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, and the topographic map of the grand-averaged P3 difference waveforms is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. The group difference in the P3 difference wave amplitude was significant (\u003cem\u003eF\u003c/em\u003e \u003csub\u003e\u003cem\u003e(1, 83)\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;10.633; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.114), and the absolute P3 difference wave amplitude in the SCZ group was smaller than that in the HC group. There was no significant difference in P3 wave latency between the two groups.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Analysis of exploratory correlations between variables\u003c/h2\u003e\u003cp\u003eWe conducted a correlation analysis between the PANSS and ERP data, the PANSS and behavioral data, and the ERP and behavioral data, and performed false discovery rate (FDR) correction on the results after the correlation analyses. Significant correlation among the variables are shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and A bar chart to visualize pairwise correlations in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e. In the SCZ group, there was no significant correlation between the PANSS and ERP data or between the PANSS and behavior data; however, there was a significant positive correlation between the ERs of repeat trials and the P3 latencies of repeats in the central location (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.45, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). In the HC group, there was a significant negative correlation between RTs of repeat trials and P3 amplitudes of repeats in the central location (\u003cem\u003er\u003c/em\u003e = -0.42, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017), and the RTs of repeat trials were negatively correlated with P3 amplitudes of repeats in the parietal location (\u003cem\u003er\u003c/em\u003e = -0.39, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSignificant correlation among the variables.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCorrelation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFDR p-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSCZ (C-R-L/ERs-R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHC (C-R-A/RTs-R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHC (P-R-A/RTs-R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: SCZ, schizophrenia patient group; HC, healthy control group; SCZ (C-R-L/ERs-R), P3 latencies of repeat trials in central location compare with error rates of repeat trials in SCZ; HC (C-R-A/RTs-R), P3 amplitudes of repeat trials in central location compare with reaction times of repeat in HC; HC (P-R-A/RTs-R), P3 amplitudes of repeat trials in parietal location compare with reaction times of repeat in HC; FDR, False Discovery Rate.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study investigated the ERP characteristics of cognitive flexibility with the cued task-switching paradigm in patients with schizophrenia and is the first study to elucidate the neuroelectrophysiological mechanisms of dysfunctions in cognitive flexibility in patients with schizophrenia. Furthermore, this study revealed that compared with HCs, patients with SCZ had longer RTs, higher ERs and higher switching costs during CTSP. Consistent with the findings of previous studies[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], these behavioral findings indicated that patients with SCZ presented dysfunctions in cognitive flexibility.\u003c/p\u003e\u003cp\u003eCompared with other cognitive assessment methods, such as the oddball paradigm and the Go/No-go paradigm, the CTSP offers distinct advantages in measuring cognitive flexibility. This advantage stems primarily from the CTSP\u0026rsquo;s ability to directly evaluate the efficiency and mechanisms underlying an individual\u0026rsquo;s capacity to switch between cognitive tasks, reflecting higher-order executive functions. In contrast, the oddball paradigm primarily measures the ability to process novel or target stimuli amid repetitive, nontarget stimuli. Similarly, the Go/No-go paradigm is designed to assess inhibitory control, requiring participants to perform an action in response to certain stimuli (Go) and withhold the response in the presence of others (No-go). Therefore, CTSP is superior in its ability to directly and comprehensively assess cognitive flexibility[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA previous study on major depressive disorder (MDD) revealed that compared with HCs, patients with MDD had similar switching costs of RTs and ERs while they performed the emotional task switching paradigm (ETSP) and nonemotional task switching paradigm (N-ETSP)[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]; however, in our study, compared with HCs, patients with SCZ had greater switching costs of RTs and ERs, which suggests different neuroelectrophysiological mechanisms for patients with SCZ and patients with MDD in terms of dysfunction of cognitive flexibility.\u003c/p\u003e\u003cp\u003eIn this study, the ERP data revealed that patients with SCZ had larger P3 amplitudes and lower difference wave amplitudes in P3 when they performed CTSP. The larger P3 amplitudes in the SCZ patients are inconsistent with those reported in previous ERP studies[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. There might be two reasons for this. First, in previous studies, the oddball paradigm was used to measure cognitive flexibility, and the P3 amplitudes evoked by the oddball paradigm were smaller[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In our study, the CSTP paradigm was used to examine cognitive flexibility. Owing to the greater credibility of the CTSP in assessing cognitive flexibility, this experimental paradigm exhibits distinct characteristics in ERP P3 responses compared with those observed in the oddball paradigm. Second, many studies have confirmed that larger P3 amplitudes indicate that participants have to pay more cognitive and attentional resources to regulate cognitive flexibility[\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In our study, the switching costs of the patients with SCZ were greater than those of the HCs, which confirms that patients with SCZ need to pay more cognitive resources to complete the CSTP with larger P3 amplitudes.\u003c/p\u003e\u003cp\u003eIn addition, this study revealed that in the SCZ group, the P3 amplitudes of the switch trial were greater and the latencies were longer than those of the repeat trial, which was inconsistent with the findings of the previous CSTP in healthy people[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. These studies on HCs contribute to a better understanding of baseline cognitive flexibility, providing a reference point for comparisons with clinical populations where these mechanisms may be impaired, such as in patients with schizophrenia or other neurocognitive disorders. Our results suggest that there are abnormalities in cognitive flexibility function in patients with SCZ. On the other hand, our study revealed that the difference in waves of P3 amplitudes in patients with SCZ was smaller, which was inconsistent with recent research showing that P3 difference in wave amplitudes was similar between patients with MDD and HCs. Our findings suggest that the ability to flexibly switch and make decisions may be poorer in patients with schizophrenia than in patients with MDD and HCs in CTSP[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMoreover, our study revealed that compared with the central and parietal regions, the frontal region has the smallest P3 amplitudes and the longest P3 latencies in both HCs and patients with SCZ, which is consistent with the findings of a previous study of P3 abnormalities in patients with SCZ[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Owing to the different neuroelectrophysiological mechanisms between patients with SCZ and HCs, this study revealed that the larger P3 amplitudes in the CTSP in patients with SCZ than in HCs indicate lower cognitive flexibility. Therefore, these findings indicate that the frontal region has less impairment of cognitive flexibility than the central and parietal regions do.\u003c/p\u003e\u003cp\u003eIn this study, the PANSS score was not correlated with ERP or behavioral data, which might suggest that abnormal ERP components and behavioral characteristics might be trait biomarkers rather than state biomarkers in patients with schizophrenia. In the HC group, the P3 amplitudes of the repeat trials in the central location and parietal location were negatively correlated with the RTs of the repeat, which might suggest that the speed of neural information transmission in the HCs was accelerated and that the decision output was shortened. However, in the SCZ group, the ERs of repeat trials was positively correlated with the P3 latencies of repeats in the central location. This finding might suggest that the slowdown of the processing speed of patients with SCZ is closely related to the processing accuracy.\u003c/p\u003e\u003cp\u003eIn summary, this study presented important neuroelectrophysiological evidence of impaired cognitive flexibility in patients with SCZ. These results suggest that P3 may be an important neuroelectrophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia. Previous studies have shown that P3 neurofeedback training can improve social attention, thereby improving cognitive flexibility function[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]; this study may provide a theoretical basis for the cognitive flexibility of patients with in terms of neurofeedback training.\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eThis study had several limitations. First, the cross-sectional design limits our ability to capture dynamic changes in cognitive flexibility over time, and future longitudinal studies are needed to track the evolution of cognitive flexibility in patients with SCZ over the course of the disease. Second, owing to the small sample size this was a preliminary study, and the results need to be replicated using large samples with the same parameters. Third, owing to the low spatial resolution of EEG, future studies should combine high-spatial-resolution fMRI to further clarify the neurophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003ePatients with schizophrenia showed impaired cognitive flexibility and neural correlates of these impairments, as reflected by the abnormal ERP P3. These findings provide valuable insights into the understanding of the neural mechanisms underlying impaired cognitive flexibility and may guide targeted interventions in patients with schizophrenia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWuxi Municipal Health Commission Major Project (No. Z202107 to Zhenhe Zhou) and Wuxi Taihu Talent Project (No. WXTTP 2021 to Zhenhe Zhou).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful for the support by Wuxi Municipal Health Commission Major Project (No. Z202107 to Zhenhe Zhou) and Wuxi Taihu Talent Project (No. WXTTP 2021 to Zhenhe Zhou) and the contributions of all the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of affiliated Mental Health Center of Jiangnan University (WXMHCIRB2025LLky016). All participants provided written informed consent. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSalahuddin NH, Sch\u0026uuml;tz A, Pitschel-Walz G, Mayer SF, Chaimani A, Siafis S, et al. Psychological and psychosocial interventions for treatment-resistant schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry 2024;11:545\u0026ndash;53. https://doi.org/10.1016/S2215-0366(24)00136-6.\u003c/li\u003e\n\u003cli\u003eHearne LJ, Mill RD, Keane BP, Repov\u0026scaron; G, Anticevic A, Cole MW. 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Biological Psychiatry: Cognitive Neuroscience and Neuroimaging 2023;8:162\u0026ndash;70. https://doi.org/10.1016/j.bpsc.2021.12.012.\u003c/li\u003e\n\u003cli\u003eYuan J, Zhang Y, Zhao Y, Gao K, Tan S, Zhang D. The Emotion-Regulation Benefits of Implicit Reappraisal in Clinical Depression: Behavioral and Electrophysiological Evidence. Neurosci Bull 2023;39:973\u0026ndash;83. https://doi.org/10.1007/s12264-022-00973-z.\u003c/li\u003e\n\u003cli\u003eWu J, Chen Y, Li Z, Li F. Cognitive control is modulated by hierarchical complexity of task switching: An event-related potential study. Behav Brain Res 2022;434:114025. https://doi.org/10.1016/j.bbr.2022.114025.\u003c/li\u003e\n\u003cli\u003ePetruo VA, M\u0026uuml;ckschel M, Beste C. On the role of the prefrontal cortex in fatigue effects on cognitive flexibility - a system neurophysiological approach. Sci Rep 2018;8:6395. https://doi.org/10.1038/s41598-018-24834-w.\u003c/li\u003e\n\u003cli\u003eDevrim-\u0026Uuml;\u0026ccedil;ok M, Keskin-Ergen HY, \u0026Uuml;\u0026ccedil;ok A. Visual P3 abnormalities in patients with first-episode schizophrenia, unaffected siblings of schizophrenia patients and individuals at ultra-high risk for psychosis. Prog Neuropsychopharmacol Biol Psychiatry 2023;122:110678. https://doi.org/10.1016/j.pnpbp.2022.110678.\u003c/li\u003e\n\u003cli\u003eAnacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility \u0026mdash; linking memory and mood. Nat Rev Neurosci 2017;18:335\u0026ndash;46. https://doi.org/10.1038/nrn.2017.45.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Event-related potential, cued task-switching paradigm, schizophrenia, cognitive flexibility, switch cost","lastPublishedDoi":"10.21203/rs.3.rs-7649864/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7649864/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePatients with schizophrenia (SCZ) have impaired cognitive flexibility; however, the neuroelectrophysiological mechanism underlying this impairment remains unclear. The cued task-switching paradigm (CTSP) is used to measure cognitive flexibility. The aim of this study is to investigate the neuroelectrophysiological mechanism of impaired cognitive flexibility in patients with schizophrenia using event-related potential (ERP) technology with CTSP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eOur sample included 39 patients with schizophrenia and 46 healthy controls (HCs). All participants underwent ERP recording while performing the CTSP. Error rates (ERs), reaction times (RTs), and the switching costs of ERs and RTs were used for the analysis of behavioral data. Time-domain analysis was used for the analysis of ERP data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003ePatients with schizophrenia had higher ERs and longer RTs. ERP data analysis revealed that compared with HCs, patients with schizophrenia exhibited greater P3 amplitudes and longer latencies, as well as smaller difference wave amplitudes, during CTSP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Patients with schizophrenia showed impaired cognitive flexibility and neural correlates of these impairments, as reflected by an abnormal ERP P3. These findings provide valuable insights into the understanding of the neural mechanisms underlying impaired cognitive flexibility and may guide targeted interventions in patients with schizophrenia.\u003c/p\u003e","manuscriptTitle":"Neural correlates of impaired cognitive flexibility in schizophrenia: An ERP study using the cued task-switching paradigm","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 02:13:34","doi":"10.21203/rs.3.rs-7649864/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-23T18:13:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-22T00:18:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-20T10:05:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"213050673041824410061999001620694543077","date":"2025-10-02T05:13:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3450049559099159216571667578964658078","date":"2025-09-30T06:21:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-30T04:34:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-25T14:02:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-22T06:54:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-22T06:51:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-09-18T12:48:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"784a4787-2b21-4841-8cd2-933c14cf99e8","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:11:27+00:00","versionOfRecord":{"articleIdentity":"rs-7649864","link":"https://doi.org/10.1186/s12888-025-07660-z","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-12-02 15:57:56","publishedOnDateReadable":"December 2nd, 2025"},"versionCreatedAt":"2025-10-15 02:13:34","video":"","vorDoi":"10.1186/s12888-025-07660-z","vorDoiUrl":"https://doi.org/10.1186/s12888-025-07660-z","workflowStages":[]},"version":"v1","identity":"rs-7649864","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7649864","identity":"rs-7649864","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}