Mandarin-Speaking Amusics' Online Recognition of Tone and Intonation.

PURPOSE: Congenital amusia is a neurogenetic disorder of musical pitch processing. Its linguistic consequences have been examined separately for speech intonations and lexical tones. However, in a tonal language such as Chinese, the processing of intonations and lexical tones interacts with each other during online speech perception. Whether and how the musical pitch disorder might affect linguistic pitch processing during online speech perception remains unknown. METHOD: We investigated this question with intonation (question vs. statement) and lexical tone (rising Tone 2 vs. falling Tone 4) identification tasks using the same set of sentences, comparing behavioral and event-related potential measurements between Mandarin-speaking amusics and matched controls. We specifically focused on the amusics without behavioral lexical tone deficits (the majority, i.e., pure amusics). RESULTS: Results showed that, despite relative to normal performance when tested in word lexical tone test, pure amusics demonstrated inferior recognition than controls during sentence tone and intonation identification. Compared to controls, pure amusics had larger N400 amplitudes in question stimuli during tone task and smaller P600 amplitudes in intonation task. CONCLUSION: These data indicate that musical pitch disorder affects both tone and intonation processing during sentence processing even for pure amusics, whose lexical tone processing was intact when tested with words.

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.

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.

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.

Behavioral and neural rhythm sensitivities predict phonological awareness and word reading development in Chinese.

The present study examined both the development of behavioral and electrophysiological rhythm processing and their contribution to phonological awareness and word reading in Chinese. We followed a sample of 47 Mandarin-speaking Chinese children from age 9 (Grade 3) to age 11 (Grade 5). Results showed first a significant improvement over time in behavioral beat perception and in P3as for small beat changes. Second, behavioral and neural beat sensitivities at age 9 predicted phonological awareness (phoneme deletion and tone identification) at age 11 and its development over the two-year span of the study. Neural beat sensitivities at age 9 also explained unique variance in reading accuracy (but not reading fluency) at age 11 and its two-year development. Taken together, these findings suggest that rhythm and Chinese reading-related skills are intricately related. Neural rhythm sensitivities could serve as predictive biomarkers for the development of phonological awareness and reading in Chinese school-age children.

The cerebellum and cognition: further evidence for its role in language control.

The cognitive function of the human cerebellum could be characterized as enigmatic. However, researchers have attempted to detail the comprehensive role of the cerebellum in several cognitive processes in recent years. Here, using functional magnetic resonance imaging (fMRI) and transcranial direct current stimulation (tDCS), we revealed different functions of bilateral cerebellar lobules in bilingual language production. Specifically, brain activation showed the bilateral posterolateral cerebellum was associated with bilingual language control, and an effective connectivity analysis built brain networks for the interaction between the cerebellum and the cerebral cortex. Furthermore, anodal tDCS over the right cerebellum significantly optimizes language control performance in bilinguals. Together, these results reveal a precise asymmetrical functional distribution of the cerebellum in bilingual language production, suggesting that the right cerebellum is more involved in language control. In contrast, its left counterpart undertakes a computational role in cognitive control function by connecting with more prefrontal, parietal, subcortical brain areas.

The neurovascular couplings between electrophysiological and hemodynamic activities in anticipatory selective attention.

Selective attention is thought to involve target enhancement and distractor inhibition processes. Here, we recorded simultaneous electroencephalographic (EEG) and functional near-infrared spectroscopy (fNIRS) data from human adults when they were pre-cued by the visual field of coming target, distractor, or both of them. From the EEG data, we found alpha power relatively decreased contralaterally to the to-be-attended target, as reflected by the positive-going alpha modulation index. Late alpha power relatively increased contralaterally to the to-be-suppressed distractor, as reflected by the negative-going alpha modulation index. From the fNIRS data, we found enhancements of hemodynamic activity over the contralateral hemisphere in response to both the target and the distractor anticipation but within nonoverlapping posterior brain regions. More importantly, we described the specific neurovascular modulation between alpha power and oxygenated hemoglobin signal, which showed a positive coupling effect during target anticipation and a negative coupling effect during distractor anticipation. Such flexible neurovascular couplings between EEG oscillation and hemodynamic activity seem to play an essential role in the final behavioral outcomes. These results provide unique neurovascular evidence for the dissociation of the mechanisms of target enhancement and distractor inhibition. Individual behavioral differences can be related to individual differences in neurovascular coupling.

Intermittent theta burst stimulation over the parietal cortex has a significant neural effect on working memory.

The crucial role of the parietal cortex in working memory (WM) storage has been identified by fMRI studies. However, it remains unknown whether repeated parietal intermittent theta-burst stimulation (iTBS) can improve WM. In this within-subject randomized controlled study, under the guidance of fMRI-identified parietal activation in the left hemisphere, 22 healthy adults received real and sham iTBS sessions (five consecutive days, 600 pulses per day for each session) with an interval of 9 months between the two sessions. Electroencephalography signals of each subject before and after both iTBS sessions were collected during a change detection task. Changes in contralateral delay activity (CDA) and K-score were then calculated to reflect neural and behavioral WM improvement. Repeated-measures ANOVA suggested that real iTBS increased CDA more than the sham one (p = .011 for iTBS effect). Further analysis showed that this effect was more significant in the left hemisphere than in the right hemisphere (p = .029 for the hemisphere-by-iTBS interaction effect). Pearson correlation analyses showed significant correlations for two conditions between CDA changes in the left hemisphere and K score changes (ps <.05). In terms of the behavioral results, significant K score changes after real iTBS were observed for two conditions, but a repeated-measures ANOVA showed a nonsignificant main effect of iTBS (p = .826). These results indicate that the current iTBS protocol is a promising way to improve WM capability based on the neural indicator (CDA) but further optimization is needed to produce a behavioral effect.

The development of brain rhythms at rest and its impact on vocabulary acquisition.

A long-standing question in developmental science is how the neurodevelopment of the brain influences cognitive functions. Here, we examined the developmental change of resting EEG power and its links to vocabulary acquisition in school-age children. We further explored what mechanisms may mediate the relation between brain rhythm maturation and vocabulary knowledge. Eyes-opened resting-state EEG data were recorded from 53 typically-developing Chinese children every 2 years between the ages of 7 and 11. Our results showed first that delta, theta, and gamma power decreased over time, whereas alpha and beta power increased over time. Second, after controlling for general cognitive abilities, age, home literacy environment, and phonological skills, theta decreases explained 6.9% and 14.4% of unique variance in expressive vocabulary at ages 9 and 11, respectively. We also found that beta increase from age 7 to 9 significantly predicted receptive vocabulary at age 11. Finally, theta decrease predicted expressive vocabulary through the effects of phoneme deletion at age 9 and tone discrimination at age 11. These results substantiate the important role of brain oscillations at rest, especially theta rhythm, in language development. The developmental change of brain rhythms could serve as sensitive biomarkers for vocabulary development in school-age children, which would be of great value in identifying children at risk of language impairment.

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.

Visual Working Memory Guides Spatial Attention: Evidence from alpha oscillations and sustained potentials.

Selective attention can facilitate performance by filtering irrelevant information and temporary maintaining limited information to accomplish the current task. However, the neural substrate how attentional selection can be guided by visual working memory (vWM) is not clear. Here, we recorded electrophysiological signals during vWM retention and investigated the relationship between objects held in memorial templates and the subsequent attentional selection during visual search. We observed that sustained posterior contralateral delay activity (CDA) was present and scaled with lateral vWM loads during the whole period of vWM retention, but that it was absent when objects were bilaterally held in vWM. Surprisingly, a strikingly similar pattern emerged for modulations in the averaged posterior alpha (8-12 Hz) power during the late period but not during the early period of retention. More importantly, it was the alpha modulation, but not the CDA, that strongly predicted the subsequent biomarker of attentional selection (the memorial template-induced N2pc) during visual search. We further observed the N2pc amplitudes decreased with increasing memory loads and predicted the same gradation of the final behavioral accuracy in visual search. All these results suggested that the subsequent memorial template-induced N2pc is response to the level of top-down attentional guiding effect caused by vWM. Our results provide neurophysiological evidence that keeping multiple templates in working memory simultaneously weakens the guiding effect to the following attentional selection.

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.

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).

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.

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.

Polymorphism in schizophrenia risk gene MIR137 is associated with the posterior cingulate Cortex's activation and functional and structural connectivity in healthy controls.

MIR137 gene has been repeatedly reported as a schizophrenia risk gene in genome-wide association studies (GWAS). A polymorphism (rs1625579) at the MIR137 gene has been associated with both neural activation and behavioral performance during a working memory task. This study examined MIR137's associations with task-related (N-back working memory) fMRI, resting state fMRI, and diffusion tensor images (DTI) data in 177 healthy adults. We found less deactivation of the PCC in risk allele homozygotes (TT) as compared to the GT heterozygotes (cluster size = 630 voxels, cluster level PFWE < 0.001) during the N-back task, which replicated previous findings. Using the identified cluster within the PCC as the seed, we further found decreased functional connectivity between the PCC and the anterior cingulate cortex and its adjacent medial prefrontal cortex (ACC/MPFC) in risk allele homozygotes during both resting state (cluster size = 427 voxels, cluster level PFWE = 0.001) and the N-back task (cluster size = 73 voxels, cluster level PFWE = 0.05). Finally, an analysis of our DTI data showed decreased white matter integrity of the posterior cingulum in risk allele homozygotes (cluster size = 214 voxels, cluster level PFWE = 0.03). Taken together, rs1625579 seems to play an important role in both functional and structural connectivity between the PCC and the ACC/MPFC, which may serve as the brain mechanisms for the link between rs1625579 and schizophrenia.

Attentional selection and suppression in children and adults.

The fundamental role of covert spatial attention is to enhance the processing of attended items while simultaneously ignoring irrelevant items. However, relatively little is known about how brain electrophysiological activities associated with target selection and distractor suppression are involved as they develop and become fully functional. The current study aimed to identify the neurophysiological bases of the development of covert spatial attention, focusing on electroencephalographic (EEG) markers of attentional selection (N2pc) and suppression (PD ). EEG data were collected from healthy young adults and typically developing children (9-15 years old) as they searched for a shape singleton target in either the absence or the presence of a salient-but-irrelevant color singleton distractor. The ERP results showed that a lateral shape target elicited a smaller N2pc in children compared with adults regardless of whether a distractor was present or not. Moreover, the target-elicited N2pc was always followed by a similar positivity in both age groups. Counterintuitively, a lateral salient-but-irrelevant distractor elicited a large PD in children with low behavioral accuracy, whereas high-accuracy children exhibited a small and "adult-like" PD . More importantly, we found no evidence for a correlation between the target-elicited N2pc and the distractor-elicited PD in either age group. Our results provide neurophysiological evidence for the developmental differences between target selection and distractor suppression. Compared with adults, 9-15-year-old children deploy insufficient attentional selection resources to targets but use "adult-like" or even more attentional suppression resources to resist irrelevant distractors. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=NhWapx0d75I.

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.