Humans need social closeness to prosper. There is evidence that empathy can induce social closeness. However, it remains unclear how empathy-related social closeness is formed and how stable it is as time passes. We applied an acquisition-extinction paradigm combined with computational modeling and fMRI, to investigate the formation and stability of empathy-related social closeness. Female participants observed painful stimulation of another person with high probability (acquisition) and low probability (extinction) and rated their closeness to that person. The results of two independent studies showed increased social closeness in the acquisition block that resisted extinction in the extinction block. Providing insights into underlying mechanisms, reinforcement learning modeling revealed that the formation of social closeness is based on a learning signal (prediction error) generated from observing another\'s pain, whereas maintaining social closeness is based on a learning signal generated from observing another\'s pain relief. The results of a reciprocity control study indicate that this feedback recalibration is specific to learning of empathy-related social closeness. On the neural level, the recalibration of the feedback signal was associated with neural responses in anterior insula and adjacent inferior frontal gyrus and the bilateral superior temporal sulcus/temporoparietal junction. Together, these findings show that empathy-related social closeness generated in bad times, that is, empathy with the misfortune of another person, transfers to good times and thus may form one important basis for stable social relationships.

UNASSIGNED: Renewal of extinguished responses is associated with higher activity in specific extinction-relevant brain regions, i.e., hippocampus (HC), inferior frontal gyrus (IFG), and ventromedial PFC (vmPFC). HC is involved in processing of context information, while IFG and vmPFC use such context information for selecting and deciding among competing response options. However, it is as yet unknown to what extent trials with changed versus unchanged outcome, or extinction trials that evoke renewal (i.e., extinction context differs from acquisition and test context: ABA trials) and trials that do not (i.e., same context in all phases: AAA trials) are represented differentially in extinction-relevant brain regions.
UNASSIGNED: In this study, we applied representational similarity analysis (RSA) to determine differences in neural representations of these trial types and their relationship to extinction error rates and renewal level.
UNASSIGNED: Overall, individuals with renewal (REN) and those without (NoREN) did not differ significantly in their discrimination levels between ABA and AAA extinction trials, with the exception of right posterior HC, where REN exhibited more pronounced context-related discrimination. In addition, higher dissimilarity of representations in bilateral posterior HC, as well as in several IFG regions, during extinction learning was linked to lower ABA renewal rates. Both REN and NoREN benefitted from prediction error feedback from ABA extinction errors for context- and outcome-related discrimination of trials in IFG, vmPFC, and HC, but only the NoREN group also benefitted from error feedback from AAA extinction errors.
UNASSIGNED: Thus, while in both groups the presence of a novel context supported formation of distinct representations, only in NoREN the expectancy violation of the surprising change of outcome alone had a similar effect. In addition, only in NoREN context-related discrimination was linked to error feedback in vmPFC. In summary, the findings show that context- and outcome-related discrimination of trials in HC, vmPFC, and IFG is linked to extinction learning errors, regardless of renewal propensity, and at the same time point towards differential context processing strategies in REN and NoREN. Moreover, better discrimination of context-related trials during extinction learning promotes less renewal during extinction recall, suggesting that renewal may be related to suboptimal context-related trial discrimination.

UNASSIGNED: Magnesium (Mg) is an essential nutrient for the maintenance of vital physiological functions. Magnesium deficiency is associated with diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS); however, conclusions have been inconsistent, and there is a particular lack of evidence regarding this association in Chinese population older than 45 years. This study aimed to assess the association between plasma magnesium and the risk of MetS and its components, the dose-response relationship, and the threshold effect relationship in a Chinese population involving older than 45 years.
UNASSIGNED: A total of 2,101 individuals were randomly selected from the China Nutrition and Health Surveillance (CNHS) (2015-2017) by considering monitoring points. We used the joint statement of the International Diabetes Federation (IDF) in 2009 to define participants with MetS. The plasma magnesium was tested by inductively coupled plasma mass spectrometry (ICP-MS). The logistic regression and restricted cubic spline (RCS) models were used to analyze the association and dose-response relationship between plasma Mg and MetS and its components.
UNASSIGNED: Compared with the lowest quintile (Q1) for plasma Mg, the odds ratios (ORs) and 95% confidence intervals (95% CI) for MetS, impaired fasting glucose (IFG), hypertension, and triglyceride (TG) elevation at the highest quintile (Q5) were 0.419 (0.301, 0.583), 0.303 (0.221, 0.415), 0.446 (0.322, 0.618), and 0.526 (0.384, 0.720), respectively, with all p < 0.05. However, in the components of decreased high-density lipoprotein cholesterol (HDL-C) and central obesity, no trend toward lowering with higher plasma magnesium was observed (p = 0.717, p = 0.865). These associations were not altered by further adjustment for potential confounding variables, including age, gender, education, nationality, area, residence, body mass index (BMI), and heart rate. The RCS analysis showed that, when plasma magnesium was lower than 0.85 mmol/L, the curve was leveled off, and then, the curve showed a decreasing trend with the increase in plasma magnesium.
UNASSIGNED: Therefore, plasma Mg was negatively associated with MetS and its components (including IFG, hypertension, and elevated TG) in people older than 45 years. In addition, plasma Mg greater than or equal to 0.85 mmol/L, which is higher than the commonly used threshold of 0.75 mmol/L, may be protective against MetS and its components (including elevated FPG, elevated blood pressure, and elevated TG). More prospective studies, such as randomized controlled trials, are necessary to confirm the effective impact of Mg on MetS and its components. Plasma Mg levels in the MetS population older than 45 years require attention.

Reading, naming, and repetition are classical neuropsychological tasks widely used in the clinic and psycholinguistic research. While reading and repetition can be accomplished by following a direct or an indirect route, pictures can be named only by means of semantic mediation. By means of fMRI multivariate pattern analysis, we evaluated whether this well-established fundamental difference at the cognitive level is associated at the brain level with a difference in the degree to which semantic representations are activated during these tasks. Semantic similarity between words was estimated based on a word association model. Twenty subjects participated in an event-related fMRI study where the three tasks were presented in pseudo-random order. Linear discriminant analysis of fMRI patterns identified a set of regions that allow to discriminate between words at a high level of word-specificity across tasks. Representational similarity analysis was used to determine whether semantic similarity was represented in these regions and whether this depended on the task performed. The similarity between neural patterns of the left Brodmann area 45 (BA45) and of the superior portion of the left supramarginal gyrus correlated with the similarity in meaning between entities during picture naming. In both regions, no significant effects were seen for repetition or reading. The semantic similarity effect during picture naming was significantly larger than the similarity effect during the two other tasks. In contrast, several regions including left anterior superior temporal gyrus and left ventral BA44/frontal operculum, among others, coded for semantic similarity in a task-independent manner. These findings provide new evidence for the dynamic, task-dependent nature of semantic representations in the left BA45 and a more task-independent nature of the representational activation in the lateral temporal cortex and ventral BA44/frontal operculum.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with altered emotion processing and modulation in specific brain regions, i.e., the amygdala, insula, and medial prefrontal and anterior cingulate cortices. Functional alterations in these regions, recorded shortly after trauma exposure, may predict changes in PTSD symptoms.
METHODS: Survivors (N = 104) of a traumatic event, predominantly a motor vehicle accident, were included. Functional magnetic resonance imaging was used to assess brain activation 1, 6, and 14 months after trauma exposure (T1, T2, and T3, respectively). Participants performed the Shifted-attention Emotional Appraisal Task, which probes 3 affective processes: implicit emotional processing (of emotional faces), emotion modulation by attention shifting (away from these faces), and emotion modulation by appraisal (of the participants\' own emotional response to these faces). We defined regions of interest based on task-related activations, extracted beta weights from these regions of interest, and submitted them to a series of analyses to examine relationships between neural activation and PTSD severity over the 3 time points.
RESULTS: At T1, a regression model containing activations in the left dorsolateral prefrontal cortex, bilateral inferior frontal gyrus (IFG), and medial prefrontal cortex during emotion modulation by appraisal significantly predicted change in PTSD symptoms. More specifically, greater right IFG activation at T1 was associated with greater reduction in symptom severity (T1-T3). Exploratory analysis also found that activation of the right IFG increased from T1 to T3.
CONCLUSIONS: The results suggest that greater early posttrauma activation during emotion appraisal in the right IFG, a region previously linked to cognitive control in PTSD, predicts recovery from PTSD symptoms.

fMRI language mapping studies report right-hemispheric contribution to language in healthy individuals. However, it remains unclear whether these right-hemispheric patterns of activity are critical for language, which is highly relevant for clinical preoperative language mapping. The available findings are controversial. In this study, we first measured individual patterns of language lateralization with an fMRI language localizer in healthy participants with different handedness (N = 31). Then, the same participants received rTMS over the individual coordinates of peak fMRI-based activation in the left and right inferior frontal gyri. During rTMS, participants performed a picture naming task. It included both objects and actions to test whether naming of nouns and verbs would be equally modulated by rTMS. Stimulation of the left inferior frontal gyrus resulted in accuracy facilitation of verb production regardless of individual language lateralization. No modulation of object naming was found at any stimulation site in terms of accuracy nor reaction time. This study causally confirmed the critical contribution of the left, but not the right hemisphere to verb production regardless of the language lateralization patterns observed with fMRI. Also, the results stress that action rather than object naming is the task of choice for mapping language in the frontal lobe.

BACKGROUND: Lipid accumulation product (LAP) is considered to be a new convenient useful indicator to assess the visceral fat. Therefore, we aimed to evaluate the risk factors of impaired fasting glucose (IFG) and diabetes, and explore the possible interacting influences of LAP with other factors on the risk of IFG and diabetes among Chinese normotension adults.
METHODS: A multistage stratified cluster sampling method was conducted to select urban residents in Bengbu, China. For each eligible participant, data on questionnaire survey, anthropometric measurements and laboratory tests were obtained. The effects of body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR) and LAP for predicting IFG and diabetes were performed by multiple logistic regressions and receiver operating characteristic (ROC) analyses. The interaction effects were evaluated by relative excess risk of interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI).
RESULTS: Six thousand, four hundred sixty-seven normotension subjects (2695 men and 3772 women) were enrolled in our study, the prevalence of IFG and diabetes were 9.37% and 14.33%, respectively. When assessed using ROC curve analysis, LAP exhibited higher diagnostic accuracy for identifying IFG and diabetes than BMI, the area under the AUC curve was 0.650 (95% CI: 0.637 to 0.662). After adjustment for age, sex, educational level and other confounding factors, multivariate logistic regression analyses indicated that subjects with the fourth quartile of LAP were more likely to develop IFG (adjusted OR: 2.735, 95% CI: 1.794-4.170) and diabetes (adjusted OR: 1.815, 95% CI: 1.297-2.541) than those with the first quartile. A significant interaction between LAP and family history of diabetes was observed in participants (RERI = 1.538, 95%CI: 0.167 to 3.612; AP = 0.375, 95%CI: 0.118 to 0.631; SI = 1.980, 95%CI: 1.206 to 3.251). However, a significant interaction between LAP and abdominal obesity was indicated by the value of RERI (1.492, 95%CI: 0.087 to 3.723) and AP (0.413, 95%CI: 0.014 to 0.756), but not the value of SI (1.824, 95%CI: 0.873 to 3.526).
CONCLUSIONS: Our results demonstrated that there might be synergistic effect between LAP and family history of diabetes on the risk of IFG and diabetes.

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are high-risk factors of diabetes development and may be caused by defective insulin secretion in pancreatic beta-cells. Glucose-stimulated insulin secretion is mediated by voltage-gated Ca2+ (CaV) channels in which the gamma-4 subunit (CaVγ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of CaVγ4 in controlling glucose homeostasis by employing the CaVγ4-/- mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that CaVγ4-/- mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated insulin secretion is blunted in CaVγ4-/- mouse islets. Remarkably, CaVγ4 deletion results in reduced expression of the transcription factor essential for beta-cell maturation, MafA, on both mRNA and protein levels in islets from human donors and CaVγ4-/- mice, as well as in INS-1 832/13 cells. Moreover, we prove that CaMKII is responsible for mediating this regulatory pathway linked between CaVγ4 and MafA, which is further confirmed by human islet RNA-seq data. We demonstrate that CaVγ4 is a key player in preserving normal blood glucose homeostasis, which sheds light on CaVγ4 as a novel target for the treatment of prediabetes through correcting the impaired metabolic status.

BACKGROUND: Alzheimer\'s disease (AD) is associated with abnormal tau and amyloid-β accumulation in the brain, leading to neurofibrillary tangles, neuropil threads and extracellular amyloid-β plaques. Treatment is limited to symptom management, a disease-modifying therapy is not available. To advance search of therapy approaches, there is a continued need to identify targets for disease intervention both by confirming existing hypotheses and generating new hypotheses.
METHODS: We conducted a mRNA-seq study to identify genes associated with AD in post-mortem brain samples from the superior temporal gyrus (STG, n ​= ​76), and inferior frontal gyrus (IFG, n ​= ​65) brain regions. Differentially expressed genes (DEGs) were identified correcting for gender and surrogate variables to capture hidden variation not accounted for by pre-planned covariates. The results from this study were compared with the transcriptome studies from the Accelerated Medicine Partnership - Alzheimer\'s Disease (AMP-AD) initiative. Over-representation and gene set enrichment analysis (GSEA) was used to identify disease-associated pathways. Protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) analyses were carried out and co-expressed gene modules and their hub genes were identified and associated with additional phenotypic traits of interest.
RESULTS: Several hundred mRNAs were differentially expressed between AD cases and cognitively normal controls in the STG, while no and few transcripts met the same criteria (adjusted p less than 0.05 and fold change greater than 1.2) in the IFG. The findings were consistent at the gene set level with two out of three cohorts from AMP-AD. PPI analysis suggested that the DEGs were enriched in protein-protein interactions than expected by random chance. Over-representation and GSEA analysis suggested genes playing roles in neuroinflammation, amyloid-β, autophagy and trafficking being important for the AD disease process. At the gene level, 10 genes from the STG that were consistently differentially expressed in this study and in the MSBB study (one of the three cohorts within the AMP-AD initiative) were enriched in microglial genes (TREM2, C3AR1, ITGAX, OLR1, CD74, and HLA-DRA), but also included genes with a broader cell type expression pattern such as CDK2AP1. Among the DEGs with supporting evidence from an independent study, CDK2AP1 (most abundantly expressed in astrocyte) was the transcript with strongest association with antemortem cognitive measure (last Mini-Mental State Examination score) and neurofibril tangle burden but also associated with amyloid plaque burden, while OLR1 was the transcript with strongest association with amyloid plaque burden. GSEA and over-representation analyses revealed gene sets related to immune processes including neutrophil degranulation, interleukin 10 signaling, and interferon gamma signaling, complement and coagulation cascades, phosphatidylinositol signaling system, phagosome and neurotransmitter receptors and postsynaptic signal transmission were enriched from this study and replicated in an independent study.
CONCLUSIONS: This study identified differential gene sets, common with two out of three AMP-AD cohorts (ROSMAP and MSBB) and highlights microglia and astrocyte as the key cell-types with DGEs associated with AD clinical diagnosis, and/or antemortem cognitive measure as well as neuropathological indices. Future meta-analysis and causal inferential analysis will be helpful in pinpointing the most relevant pathways and genes to intervene.

According to the theory of embodied simulation, mirror neurons (MN) in our brain\'s motor system are the neuronal basis of all social-cognitive processes. The assumption of such a mirroring process in humans could be supported by results showing that within one person the same region is involved in different social cognition tasks. We conducted an fMRI-study with 75 healthy participants who completed three tasks: imitation, empathy, and theory of mind. We analyzed the data using group conjunction analyses and individual shared voxel counts. Across tasks, across and within participants, we find common activation in inferior frontal gyrus, inferior parietal cortex, fusiform gyrus, posterior superior temporal sulcus, and amygdala. Our results provide evidence for a shared neural basis for different social-cognitive processes, indicating that interpersonal understanding might occur by embodied simulation.