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.

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.

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.

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.

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.

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 P_FWE < 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 P_FWE = 0.001) and the N-back task (cluster size = 73 voxels, cluster level P_FWE = 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 P_FWE = 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.

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.

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<0.001 for RT differences and P=0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P=0.009), the AY condition of the DPX (P<0.001), and the Stroop conflict effect (P=0.003 for RT differences and P=0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in five measures for the patients (1-back, P=0.025; BX, P=0.017; AY, P<0.001; ANT conflict effect (RT differences), P=0.005; Stroop conflict effect (RT differences), P=0.019) and three measures for the controls ( for the 2-back task, P=0.042; for the ANT conlict effect (RT differences), P=0.013; for the ANT conflict effect (RT ratios), P=0.028). Then, with a separate sample of 78 healthy controls, we examined the association between rs3782206 and brain activation patterns during the N-back task and the Stroop task. Whole brain analyses found that the risk allele carriers showed reduced activation at the right inferior frontal gyrus (IFG) during both tasks. Finally, we examined functional connectivity seeded from the right IFG to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex under three conditions (the N-back task, the Stroop task, and the resting state). Results showed reduced connectivity with the DLPFC for the risk allele carriers mainly in the Stroop task and the resting state. Taken together, results of this study strongly suggested a link between NOS1 gene polymorphism at rs3782206 and cognitive functions and their neural underpinnings at the IFG. These results have important implications for our understanding of the neural mechanism underlying the association between NOS1 gene polymorphism and schizophrenia.

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.

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.