The VNTR of the AS3MT gene is associated with brain activations during a memory span task and their training-induced plasticity.

BACKGROUND: The Arsenic (+3 oxidation state) methyltransferase (AS3MT) gene has been identified as a top risk gene for schizophrenia in several large-scale genome-wide association studies. A variable number tandem repeat (VNTR) of this gene is the most significant expression quantitative trait locus, but its role in brain activity in vivo is still unknown. METHODS: We first performed a functional magnetic resonance imaging (fMRI) scan of 101 healthy subjects during a memory span task, trained all subjects on an adaptive memory span task for 1 month, and finally performed another fMRI scan after the training. After excluding subjects with excessive head movements for one or more scanning sessions, data from 93 subjects were included in the final analyses. RESULTS: The VNTR was significantly associated with both baseline brain activation and training-induced changes in multiple regions including the prefrontal cortex and the anterior and posterior cingulate cortex. Additionally, it was associated with baseline brain activation in the striatum and the parietal cortex. All these results were corrected based on the family-wise error rate method across the whole brain at the peak level. CONCLUSIONS: This study sheds light on the role of AS3MT gene variants in neural plasticity related to memory span training.

Isolation of state-dependent monoclonal antibodies against the 12-transmembrane domain glucose transporter 4 using virus-like particles.

The insulin-responsive 12-transmembrane transporter GLUT4 changes conformation between an inward-open state and an outward-open state to actively facilitate cellular glucose uptake. Because of the difficulties of generating conformational mAbs against complex and highly conserved membrane proteins, no reliable tools exist to measure GLUT4 at the cell surface, follow its trafficking, or detect the conformational state of the protein. Here we report the isolation and characterization of conformational mAbs that recognize the extracellular and intracellular domains of GLUT4, including mAbs that are specific for the inward-open and outward-open states of GLUT4. mAbs against GLUT4 were generated using virus-like particles to present this complex membrane protein in its native conformation and using a divergent host species (chicken) for immunization to overcome immune tolerance. As a result, the isolated mAbs recognize conformational epitopes on native GLUT4 in cells, with apparent affinities as high as 1 pM and with specificity for GLUT4 across the human membrane proteome. Epitope mapping using shotgun mutagenesis alanine scanning across the 509 amino acids of GLUT4 identified the binding epitopes for mAbs specific for the states of GLUT4 and allowed the comprehensive identification of the residues that functionally control the GLUT4 inward-open and outward-open states. The mAbs identified here will be valuable molecular tools for monitoring GLUT4 structure, function, and trafficking, for differentiating GLUT4 conformational states, and for the development of novel therapeutics for the treatment of diabetes.

ERP evidence for the effect of working memory span training on working memory maintenance: A randomized controlled trial.

There is a lot of debate in the literature with regards to whether the effects of working memory span training generalize to working memory tasks that are different from the trained task, however, there is little evidence to date supporting this idea. The present randomized controlled trial included 80 undergraduate students who were randomly assigned to either the experimental group (N = 40) or the control group (N = 40) in order to receive a working memory span intervention for 20 sessions over the course of 4 weeks. Brain electrophysiological signals during a dot pattern expectancy (DPX) task and a change detection task were recorded both before and after the intervention. The amplitudes of characteristic event-related potential (ERP) components reflecting working memory maintenance capability during the delay period of both tasks (i.e., the contingent negative variation or CNV, derived from the DPX task, and the contralateral delay activity or CDA, derived from the change detection task) were used as the primary outcome measures. Our data indicated that the intervention resulted in specific changes in both, the CNV and the CDA, suggesting that working memory span training generalized to working memory maintenance processes as observed in working memory tasks that were different from the trained task. We conclude that working memory span training might serve as a useful tool to improve working memory maintenance capability. Trial Registration: Chinese Clinical Trial Registry (chiCTR-INR-17011728).

Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex.

Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N-back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N-back task. These findings helped to elucidate the role of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp 37:2398-2406, 2016. © 2016 Wiley Periodicals, Inc.

The ANK3 gene and facial affect processing: An ERP study.

ANK3 is one of the most promising candidate genes for bipolar disorder (BD). A polymorphism (rs10994336) within the ANK3 gene has been associated with BD in at least three genome-wide association studies of BD [McGuffin et al., 2003; Kieseppä, 2004; Edvardsen et al., 2008]. Because facial affect processing is disrupted in patients with BD, the current study aimed to explore whether the BD risk alleles are associated with the N170, an early event-related potential (ERP) component related to facial affect processing. We collected data from two independent samples of healthy individuals (Ns = 83 and 82, respectively) to test the association between rs10994336 and an early event-related potential (ERP) component (N170) that is sensitive to facial affect processing. Repeated-measures analysis of covariance in both samples consistently revealed significant main effects of rs10994336 genotype (Sample I: F (1, 72) = 7.24, P = 0.009; Sample II: F (1, 69) = 11.81, P = 0.001), but no significant interaction of genotype × electrodes (Ps > 0.05) or genotype × emotional conditions (Ps > 0.05). These results suggested that rs10994336 was linked to early ERP component reflecting facial structural encoding during facial affect processing. These results shed new light on the brain mechanism of this risk SNP and associated disorders such as BD. © 2016 Wiley Periodicals, Inc.

Mediation effects of positive and negative affect on the relationship between emotional intelligence and life satisfaction in rural school teachers.

Few studies have investigated the ways in which the specific facets of trait emotional intelligence (EI), positive affect (PA), and negative affect (NA) influence individuals' general life satisfaction, especially in teachers. This study explored the effects of three facets of trait EI [appraisal and expression of emotions (AEE), utilization of emotion (UE), and regulation of emotions (RE)] and two typical affects (PA and NA) on teachers' general life satisfaction. The participants were 577 Chinese rural school teachers (ages 18-49 years) who completed three questionnaires-the Schutte Self-Report Emotional Intelligence Test, Positive and Negative Affective scale, and Satisfaction with Life Scale. After validating the scales, a structural equation modeling analysis showed that trait EI, PA, and NA had a significant and positive effect on teachers' general life satisfaction. PA played a partial mediating role between trait EI and life satisfaction. Furthermore, this study found that PA significantly and positively mediated the relationship between AEE, UE, RE, and life satisfaction. These results suggest that teachers with higher EI are more likely to have positive emotions, thereby enhancing their general life satisfaction, and that understanding the role of one's own and others' emotions and increasing positive emotions may be the key to improving teachers' general life satisfaction. Future implications and the study limitations are discussed.

Effects of forward and backward span trainings on working memory: Evidence from a randomized controlled trial.

Both forward and backward working memory span tasks have been used in cognitive training, but no study has been conducted to test whether the two types of trainings are equally effective. Based on data from a randomized controlled trial, this study (N = 60 healthy college students) tested the effects of backward span training, forward span training, and no intervention. Event-related potential (ERP) signals were recorded at the pre-, mid-, and post-tests while the subjects were performing a distractor version of the change detection task, which included three conditions (2 targets and 0 distractor [2T0D]; 4 targets and 0 distractor [4T0D]; and 2 targets and 2 distractors [2T2D]). Behavioral data were collected from two additional tasks: a multi-object version of the change detection task, and a suppress task. Compared to no intervention, both forward and backward span trainings led to significantly greater improvement in working memory maintenance, based on indices from both behavioral (Kmax) and ERP data (CDA_2T0D and CDA_4T0D). Backward span training also improved interference control based on the ERP data (CDA_filtering efficiency) to a greater extent than did forward span training and no intervention, but the three groups did not differ in terms of behavioral indices of interference control. These results have potential implications for optimizing the current cognitive training on working memory.

Hypoxia-induced acidosis uncouples the STIM-Orai calcium signaling complex.

The endoplasmic reticulum Ca(2+)-sensing STIM proteins mediate Ca(2+) entry signals by coupling to activate plasma membrane Orai channels. We reveal that STIM-Orai coupling is rapidly blocked by hypoxia and the ensuing decrease in cytosolic pH. In smooth muscle cells or HEK293 cells coexpressing STIM1 and Orai1, acute hypoxic conditions rapidly blocked store-operated Ca(2+) entry and the Orai1-mediated Ca(2+) release-activated Ca(2+) current (I(CRAC)). Hypoxia-induced blockade of Ca(2+) entry and I(CRAC) was reversed by NH(4)(+)-induced cytosolic alkalinization. Hypoxia and acidification both blocked I(CRAC) induced by the short STIM1 Orai-activating region. Although hypoxia induced STIM1 translocation into junctions, it did not dissociate the STIM1-Orai1 complex. However, both hypoxia and cytosolic acidosis rapidly decreased Förster resonance energy transfer (FRET) between STIM1-YFP and Orai1-CFP. Thus, although hypoxia promotes STIM1 junctional accumulation, the ensuing acidification functionally uncouples the STIM1-Orai1 complex providing an important mechanism protecting cells from Ca(2+) overload under hypoxic stress conditions.

STIM protein coupling in the activation of Orai channels.

STIM proteins are sensors of endoplasmic reticulum (ER) luminal Ca(2+) changes and rapidly translocate into near plasma membrane (PM) junctions to activate Ca(2+) entry through the Orai family of highly Ca(2+)-selective "store-operated" channels (SOCs). Dissecting the STIM-Orai coupling process is restricted by the abstruse nature of the ER-PM junctional domain. To overcome this problem, we studied coupling by using STIM chimera and cytoplasmic C-terminal domains of STIM1 and STIM2 (S1ct and S2ct) and identifying a fundamental action of the powerful SOC modifier, 2-aminoethoxydiphenyl borate (2-APB), the mechanism of which has eluded recent scrutiny. We reveal that 2-APB induces profound, rapid, and direct interactions between S1ct or S2ct and Orai1, effecting full Ca(2+) release-activated Ca(2+) (CRAC) current activation. The short 235-505 S1ct coiled-coil region was sufficient for functional Orai1 coupling. YFP-tagged S1ct or S2ct fragments cleared from the cytosol seconds after 2-APB addition, binding avidly to Orai1-CFP with a rapid increase in FRET and transiently increasing CRAC current 200-fold above basal levels. Functional S1ct-Orai1 coupling occurred in STIM1/STIM2(-/-) DT40 chicken B cells, indicating ct fragments operate independently of native STIM proteins. The 2-APB-induced S1ct-Orai1 and S2-ct-Orai1 complexes undergo rapid reorganization into discrete colocalized PM clusters, which remain stable for >100 s, well beyond CRAC activation and subsequent deactivation. In addition to defining 2-APB's action, the locked STIMct-Orai complex provides a potentially useful probe to structurally examine coupling.

Evidence for the contribution of HCN1 gene polymorphism (rs1501357) to working memory at both behavioral and neural levels in schizophrenia patients and healthy controls.

Gene HCN1 polymorphism (rs1501357) has been proposed to be one of the candidate risk genes for schizophrenia in the second report of the Psychiatric Genomics Consortium-Schizophrenia Workgroup. Although animal studies repeatedly showed a role of this gene in working memory, its contribution to working memory in human samples, especially in schizophrenia patients, is still unknown. To explore the association between rs1501357 and working memory at both behavioral (Study 1) and neural (Study 2) levels, the current study involved two independent samples. Study 1 included 876 schizophrenia patients and 842 healthy controls, all of whom were assessed on a 2-back task, a dot pattern expectancy task (DPX), and a digit span task. Study 2 included 56 schizophrenia patients and 155 healthy controls, all of whom performed a 2-back task during functional magnetic resonance imaging (fMRI) scanning. In both studies, we consistently found significant genotype-by-diagnosis interaction effects. For Study 1, the interaction effects were significant for the three tasks. Patients carrying the risk allele performed worse than noncarriers, while healthy controls showed the opposite pattern. For Study 2, the interaction effects were observed at the parietal cortex and the medial frontal cortex. Patients carrying the risk allele showed increased activation at right parietal cortex and increased deactivation at the medial frontal cortex, while healthy controls showed the opposite pattern. These results suggest that the contributions of rs1501357 to working memory capability vary in different populations (i.e., schizophrenia patients vs. healthy controls), which expands our understanding of the functional impact of the HCN1 gene. Future studies should examine its associations with other cognitive functions.

Effect of schizophrenia risk gene polymorphisms on cognitive and neural plasticity.

A recent Chinese genome-wide association study found evidence for 58 out of the 128 schizophrenia-associated variants previously discovered in Western samples by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). However, the functional impact of these trans-ancestry genome-wide single-nucleotide polymorphisms (SNPs) is not clear. In the current study, we examined the roles of trans-ancestry SNPs in cognitive and neural plasticity. We first performed a behavioral study of 547 healthy volunteers, who received month-long working memory training, and working memory capability assessment both before and after the training. A separate sample of 101 subjects received the same training and received fMRI scans during a working memory task, both before and after the training. The behavioral study found a significant association between the polygenic risk score (PRS) and behavioral plasticity, with higher schizophrenia risk scores being linked to less plasticity. At the SNP level, rs36068923 showed a significant signal, with the risk allele being associated with less plasticity. The fMRI study further found that the PRS and rs36068923 polymorphism were associated with training-induced changes in striatal activation, with higher PRS and the risk allele of rs36068923 being linked to less brain plasticity. In sum, this study found that a high genetic risk for schizophrenia was associated with less plasticity at both behavioral and neural levels. These results provide new insights into the neural and cognitive mechanisms linking genes to schizophrenia.

STIM and Orai: dynamic intermembrane coupling to control cellular calcium signals.

Ca(2+) signals controlling a vast array of cell functions involve both Ca(2+) store release and external Ca(2+) entry. These two events are coordinated through a dynamic intermembrane coupling between two distinct membrane proteins, STIM and Orai. STIM proteins are endoplasmic reticulum (ER) luminal Ca(2+) sensors that undergo a profound redistribution into discrete junctional ER domains closely juxtaposed with the plasma membrane (PM). Orai proteins are PM Ca(2+) channels that migrate and become tethered by STIM within the ER-PM junctions, where they mediate exceedingly selective Ca(2+) entry. We describe a new understanding of the nature of the proteins and how they function to mediate this remarkable intermembrane signaling process controlling Ca(2+) signals.

Effect of ZNF804A gene polymorphism (rs1344706) on the plasticity of the functional coupling between the right dorsolateral prefrontal cortex and the contralateral hippocampal formation.

ZNF804A has now been recognized as a schizophrenia risk gene by multiple genome-wide association studies with its intronic polymorphism rs1344706 being reported as the first genome-wide significant risk variant for schizophrenia. Although the functional impact of this gene is still unknown, rs1344706's contribution to the functional coupling between the right dorsolateral prefrontal cortex (DLPFC) and the contralateral hippocampal formation (HF) has been reported by several studies. The current study tested whether the right DLPFC-left HF functional coupling showed plasticity during cognitive training (Study I) and whether rs1344706 affected the plasticity (Study II). In Study I, we conducted a randomized controlled trial with 30 subjects receiving 20 sessions of adaptive training on a memory span task (the training group) and 30 subjects practicing on a non-adaptive easy version of the same memory span task for 20 sessions (the control group). All subjects were scanned using fMRI before and after the training. Analyses of resting-state and task-state fMRI data consistently showed that the adaptive memory span training significantly strengthened the right DLPFC-left HF functional coupling. In Study II, we conducted a genetic association study with 101 subjects (combining the data from the training group in Study I with those from an additional subsequent sample of 71 subjects who received the same training and fMRI scans). Results showed that rs1344706 was significantly associated with training-induced changes in functional coupling. Subjects carrying the non-risk allele (C) of rs1344706 showed greater training-induced plasticity than the risk allele (A) homozygotes. These findings expanded our current understanding of the functional impact of the schizophrenia risk variant of ZNF804A gene and suggested that the ZNF804A gene could be used as a prospective target for future antipsychotic drugs and clinical research.

Evidence for the contribution of COMT gene Val158/108Met polymorphism (rs4680) to working memory training-related prefrontal plasticity.

BACKGROUND: Genetic factors have been suggested to affect the efficacy of working memory training. However, few studies have attempted to identify the relevant genes. METHODS: In this study, we first performed a randomized controlled trial (RCT) to identify brain regions that were specifically affected by working memory training. Sixty undergraduate students were randomly assigned to either the adaptive training group (N = 30) or the active control group (N = 30). Both groups were trained for 20 sessions during 4 weeks and received fMRI scans before and after the training. Afterward, we combined the data from the 30 participants in the RCT study who received adaptive training with data from 71 additional participants who also received the same adaptive training but were not part of the RCT study (total N = 101) to test the contribution of the COMT Val158/108Met polymorphism to the interindividual difference in the training effect within the identified brain regions. RESULTS: In the RCT study, we found that the adaptive training significantly decreased brain activation in the left prefrontal cortex (TFCE-FWE corrected p = .030). In the genetic study, we found that compared with the Val allele homozygotes, the Met allele carriers' brain activation decreased more after the training at the left prefrontal cortex (TFCE-FWE corrected p = .025). CONCLUSIONS: This study provided evidence for the neural effect of a visual-spatial span training and suggested that genetic factors such as the COMT Val158/108Met polymorphism may have to be considered in future studies of such training.

The effects of CACNA1C gene polymorphism on prefrontal cortex in both schizophrenia patients and healthy controls.

CACNA1C gene polymorphism rs2007044 has been reported to be associated with schizophrenia, but its underlying brain mechanism is not clear. First, we conducted an exploratory functional magnetic resonance imaging (fMRI) study using an N-BACK task and a Stroop task in 194 subjects (55 schizophrenia patients and 139 healthy controls). Our whole brain analysis found that the risk allele was associated with reduced activation of the left inferior frontal gyrus (IFG) during the Stroop task (cluster size = 390 voxels, P < 0.05 TFCE-FWE corrected; peak MNI coordinates: x = -57, y = -6, z = 30). We also conducted a functional near-infrared spectroscopy (fNIRS) study using the same Stroop task in an independent sample of 126 healthy controls to validate the fMRI finding. Our repeated-measures ANCOVA on the six channels (20, 27, 33, 34, 40 and 46) within the left IFG also found significant result. The polymorphism rs2007044 showed significant effect on the oxy-Hb data (F = 5.072, P = 0.026) and showed significant interaction effect with channels on the deoxy-Hb data (F = 2.841, P = 0.015). Taken together, results of this study suggested that rs2007044 could affect the activation of the left IFG, which was a possible brain mechanism underlying the association between CACNA1C gene polymorphism and schizophrenia.

Network functional connectivity analysis in individuals at ultrahigh risk for psychosis and patients with schizophrenia.

Schizophrenia is a severe mental disorder, and the onset of which is preceded by a stage of ultrahigh risk (UHR) for developing psychosis. Therefore, analyzing individuals with UHR is essential for identifying predictive biomarkers for the onset of schizophrenia. The current study aimed to identify such biomarkers based on a voxelwise whole-brain functional degree centrality (FDC) analysis. Conjunction analysis showed that, compared with healthy controls, both UHR subjects and patients with schizophrenia showed significantly increased FDC at the medial prefrontal cortex (MPFC) and significantly decreased FDC at the right fusiform gyrus (FG). The subsequent partial correlation analysis showed significant correlations between the disorganization symptoms and FDCs at the MPFC and the right FG for both UHR subjects and patients with schizophrenia. These findings suggest that FDC within the MPFC and the right FG could be candidate biomarkers for the onset of schizophrenia.

Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle.

Ca2+ entry signals are crucial in the control of smooth muscle contraction. Smooth muscle cells are unusual in containing plasma membrane (PM) Ca2+ entry channels that respond to voltage changes, receptor activation and Ca2+ store depletion. Activation of these channel subtypes is highly coordinated. The TRPC6 channel, widely expressed in most smooth muscle cell types, is largely non-selective to cations and is activated by diacylglycerol arising from receptor-induced phosholipase C activation. Receptor activation results largely in Na+ ion movement through TRPC6 channels, depolarization and subsequent activation of voltage-dependent L-type Ca2+ channels. The TRPC6 channels also appear to be activated by mechanical stretch, resulting again in depolarization and L-type Ca2+ channel activation. Such a coupling may be crucial in mediating the myogenic tone response in vascular smooth muscle. The emptying of stores mediated by inositol 1,4,5-trisphosphate receptors triggers the endoplasmic reticulum (ER) Ca2+ sensing protein stromal-interacting molecule (STIM) 1 to translocate into defined ER-PM junctional areas in which coupling occurs to Orai proteins, which serve as highly Ca2+-selective low-conductance Ca2+ entry channels. These ER-PM junctional domains may serve as crucial sites of interaction and integration between the function of store-operated, receptor-operated and voltage-operated Ca2+ channels. The STIM, Orai and TRPC channels represent highly promising new pharmacological targets through which such control may be induced.

Enhancing antibody patent protection using epitope mapping information.

As the $100B therapeutic monoclonal antibody (mAb) market continues to grow, developers of therapeutic mAbs increasingly face the need to strengthen patent protection of their products and enforce their patents in courts. In view of changes in the patent law landscape, patent applications are strategically using information on the precise binding sites of their mAbs, i.e., the epitopes, to support patent novelty, non-obviousness, subject matter, and a tightened written description requirement for broad genus antibody claims. Epitope data can also allow freedom-to-operate for second-generation mAbs by differentiation from patented first-generation mAbs. Numerous high profile court cases, including Amgen v. Sanofi over rival mAbs that block PCSK9 activity, have been centered on epitope mapping claims, highlighting the importance of epitopes in determining broad mAb patent rights. Based on these cases, epitope mapping claims must describe a sufficiently large number of mAbs that share an epitope, and each epitope must be described at amino acid resolution. Here, we review current best practices for the use of epitope information to overcome the increasing challenges of patenting mAbs, and how the quality, conformation, and resolution of epitope residue data can influence the breadth and strength of mAb patents.

Effect of rs1344706 in the ZNF804A gene on the brain network.

ZNF804A rs1344706 (A/C) was the first SNP that reached genome-wide significance for schizophrenia. Recent studies have linked rs1344706 to functional connectivity among specific brain regions. However, no study thus far has examined the role of this SNP in the entire functional connectome. In this study, we used degree centrality to test the role of rs1344706 in the whole-brain voxel-wise functional connectome during the resting state. 52 schizophrenia patients and 128 healthy controls were included in the final analysis. In our whole-brain analysis, we found a significant interaction effect of genotype × diagnosis at the precuneus (PCU) (cluster size = 52 voxels, peak voxel MNI coordinates: x = 9, y = - 69, z = 63, F = 32.57, FWE corrected P < 0.001). When we subdivided the degree centrality network according to anatomical distance, the whole-brain analysis also found a significant interaction effect of genotype × diagnosis at the PCU with the same peak in the short-range degree centrality network (cluster size = 72 voxels, F = 37.29, FWE corrected P < 0.001). No significant result was found in the long-range degree centrality network. Our results elucidated the contribution of rs1344706 to functional connectivity within the brain network, and may have important implications for our understanding of this risk gene's role in functional dysconnectivity in schizophrenia.

The contribution of the contingent negative variation (CNV) to goal maintenance.

The dot pattern expectancy (DPX) task has been strongly recommended as a measure of goal maintenance, which is impaired in schizophrenia patients. The current event-related potential (ERP) study was designed mainly to identify the ERP component that could represent the goal maintenance process of the DPX task as indexed by the error rate of the BX vs. AY (EBX-AY). We focused our analysis on the cue-phased contingent negative variation (CNV) and found a significant association between the EBX-AY and the amplitude of the difference wave of cue B vs. cue A (CNVB-A) (for CP3, ß=-0.262, P=0.001; for CPZ, ß=-0.184, P=0.025; for CP4, ß=-0.201, P=0.015). Lower EBX-AY (better goal maintenance) was correlated with larger CNVB-A. Further analysis found a significant association between the error rate of AY condition (EAY) and the amplitude of CNVA (for CP3, ß=-0.180, P=0.029; for CPZ, ß=-0.184, P=0.024; for CP4, ß=-0.208, P=0.011) and a significant association between the error rate of BX condition (EBX) and the amplitude of CNVB-A (for CP3, ß=-0.198, P=0.016; for CPZ, ß=-0.165, P=0.043; for CP4, ß=-0.151, P=0.066), but not the amplitude of the CNVB (all P>0.05). All these results together suggested that the cue-phased CNV could be used to represent the goal maintenance process. Future research needs to verify these results with schizophrenia patients.