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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.

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, Five consecutive days iTBS over the left parietal cortex has increased contralateral delay activity, a neural indicator of working memory capacity. The effects of iTBS were limited within the stimulated left hemisphere.

Transcranial magnetic stimulation efficacy is largely dependent upon coil position and orientation. A good method for describing coil placement is required for both computational optimization (planning) and actual placement (implementation). In coordinate dependent parameter-spaces (CDPs), three-dimensional coordinates are used to represent coil position and three orthogonal unit vectors are used to represent coil orientation. A CDP can precisely describe arbitrary coil placement; therefore it offers great advantage in computational optimization which checks through all possible placements. However, a neuronavigation system is usually required to accurately implement the optimized CDP parameters on a participant’s head. Routine clinical practice, on the other hand, often uses the International 10-20 system to describe coil placement. Although the 10-20 system can only perform modeling and placement at limited scalp landmarks, it allows the synthesis of different individuals’ targeting effects to find group-optimal parameters; it also allows manual placement, which is important for commonly-seen use cases without individual MRI scans and navigation devices. This study proposes a new scalp geometry based parameter-space (SGP), integrating the advantages of CDP and 10-20 methods. Our SGP 1) can quantitatively specify all possible conventional coil positions and orientations on an individual’s scalp, which is important for electrical modeling and optimization, 2) maintains inter-individual correspondence, which is important for synthesizing TMS effects from different individuals and studies. 3) enables fast and simple manual implementation. Demonstration experiments were conducted to illustrate the application of an SGP-based framework for both individual and group-based optimization. A measurement experiment was performed to evaluate speed, precision and reliability of SGP-based manual implementation; results show it surpasses previous manual placement methods.

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.

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.

One of the main goals of the new generation of antipsychotics is to improve cognitive functions of schizophrenia patients, which makes it necessary to identify genes related to not only schizophrenia but also its cognitive impairments. Starting with 58 trans-ancestry risk variants found in a genome-wide association study of Chinese schizophrenia patients, we conducted two studies with four samples to systematically examine these variants’ potential roles in working memory. Study 1 was a behavioral study (Sample I included 510 healthy volunteers who completed the n-back, dot-pattern expectancy [DPX], delayed match-to-sample [DMS], and spatial span tasks; Sample II included 819 healthy volunteers and 893 schizophrenia patients who completed the n-back and DPX tasks). Study 2 was an fMRI study (Sample III included 163 healthy volunteers and 52 schizophrenia patients, who were scanned with fMRI during an n-back task; and Sample IV included 89 healthy volunteers, who were scanned during a spatial span task). Sample I identified rs11210892 as the only SNP that was associated with performance on multiple tasks (n-back, DPX, and DMS) after Bonferroni correction. Sample II replicated this association on the n-back task and the DPX task. FMRI data showed that the risk allele “G” of rs11210892 was associated with an increased activation within the right dorsolateral prefrontal cortex (Sample III) and the bilateral striatum (Sample IV). We conclude that rs11210892 is significantly associated with working memory and its neural underpinnings, so the genes near this SNP might be potential gene targets for treating cognitive impairment associated with schizophrenia.

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.

Highlights • The working memory training strengthened the right DLPFC-left HF functional coupling. • Rs1344706 was associated with the right DLPFC-left HF functional coupling at pretest. • Rs1344706 impacted the plasticity of the right DLPFC-left HF functional coupling., 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.

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

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

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 adaptive spatial span training decreased brain activation in the prefrontal and parietal cortex. The COMT Val158Met polymorphism modulated the left frontal plasticity induced by training.

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.

Visual perceptual learning has been shown to be highly specific to the retinotopic location and attributes of the trained stimulus. Recent psychophysical studies suggest that these specificities, which have been associated with early retinotopic visual cortex, may in fact not be inherent in perceptual learning and could be related to higher-order brain functions. Here we provide direct electrophysiological evidence in support of this proposition. In a series of event-related potential (ERP) experiments, we recorded high-density electroencephalography (EEG) from human adults over the course of learning in a texture discrimination task (TDT). The results consistently showed that the earliest C1 component (68-84ms), known to reflect V1 activity driven by feedforward inputs, was not modulated by learning regardless of whether the behavioral improvement is location specific or not. In contrast, two later posterior ERP components (posterior P1 and P160-350) over the occipital cortex and one anterior ERP component (anterior P160-350) over the prefrontal cortex were progressively modified day by day. Moreover, the change of the anterior component was closely correlated with improved behavioral performance on a daily basis. Consistent with recent psychophysical and imaging observations, our results indicate that perceptual learning can mainly involve changes in higher-level visual cortex as well as in the neural networks responsible for cognitive functions such as attention and decision making.

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, Highlights • This study was the first to report the effect of ZNF804A rs1344706 on the property of the whole-brain network. • We found a significant interaction of rs1344706 genotype × diagnosis on the functional connectivity of the PCU.

Nitric oxide (NO), a gaseous neurotransmitter, has been implicated in the pathogenesis of schizophrenia. Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the nitric oxide synthase 1 (NOS1), have been found to convey a risk for schizophrenia. This study examined the role of NOS1 gene polymorphisms in cognitive functions and related neural mechanism. First, with a sample of 580 schizophrenia patients and 720 healthy controls, we found that rs3782206 genotype had main effects on the 1-back task (P=0.005), the 2-back task (P=0.049), the AY condition of the dot-pattern expectancy (DPX) task (P=0.001), and the conflict effect of the attention network (ANT) test (P

Objective The aims of this study were to investigate the effects of low-frequency repetitive transcranial magnetic stimulation on patients with visual spatial neglect and to explore the potential mechanisms of visual spatial neglect. Methods A total of 14 patients with prior stroke and visual spatial neglect were divided into a control group and a treatment group. The treatment group was exposed to low-frequency, repetitive transcranial magnetic stimulation for 2 weeks, twice a day, for 15 min per session. Stimuli were delivered at 0.5 Hz to the left posterior parietal cortex (i.e. position P3 according to 10-20 electroencephalogram co-ordinate systems). All patients performed a battery of tasks, including line bisection and line cancellation tests, 2 weeks before treatment, at the beginning, at the end, and 2 weeks after treatment. Results Following low-frequency repetitive transcranial magnetic stimulation, the performance of the patients in the treatment group improved significantly. The behaviour assessment data changed with time; at time-points 2 and 3 the comparison test showed a significant difference in line cancellation and line bisection results (p = 0.003 and p = 0.027, respectively). Conclusion This study indicates that low-frequency repetitive transcranial magnetic stimulation of the unimpaired hemisphere might improve visual spatial neglect after stroke and points to the need for further studies. The results support the theory of inter-hemispheric competition in the attentional network.