Neuro-cardiac-guided transcranial magnetic stimulation: Unveiling the modulatory effects of low-frequency and high-frequency stimulation on heart rate.

Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of researchers have turned their attention towards optimizing TMS site localization. Since the influence of TMS in reducing heart rate (HR) offers insights into its regulatory impact on the autonomic nervous system, a novel approach, called neurocardiac-guided TMS (NCG-TMS), has been proposed to pinpoint the brain region eliciting the maximal individual reduction in HR as a personalized optimal stimulation target. The present study intends to systematically explore the effects of stimulation frequency, left and right hemispheres, stimulation positions, and individual differences on HR modulation using the NCG-TMS method. In experiment 1, low-frequency TMS was administered to 30 subjects, and it was found that low-frequency NCG-TMS significantly downregulated HR, with more significant effects in the right hemisphere than in the left hemisphere and the prefrontal cortex than in other brain areas. In experiment 2, high-frequency NCG-TMS stimulation was administered to 30 subjects, showing that high-frequency NCG-TMS also downregulated HR and had the greatest modulatory effect in the right prefrontal region. Simultaneously, both experiments revealed sizeable individual variability in the optimal stimulation site, which in turn validated the feasibility of the NCG-TMS method. In conclusion, the present experiments independently replicated the effect of NCG-TMS, provided an effect of high-/low-frequency TMS stimulation to downregulate HR, and identified a right lateralization of the HR modulation effect.

Assessment of left ventricular structure and function in preeclampsia subtypes by multimodal echocardiography.

AIM: To explore left ventricular structural/functional abnormalities in preeclampsia patients by using multimodal echocardiography and to analyze the cardiac impact in preeclampsia subtypes. METHODS: A total of 103 individuals, including 64 preeclampsia patients and 39 healthy pregnant women were recruited for this study from 2019 to 2021. There were 34 patients with preeclampsia with severe features (SPE) patients and 30 with preeclampsia with nonsevere features (NSPE), including 9 with early-onset NSPE (EO-NSPE) patients, 27 early-onset SPE (EO-SPE) patients, 21 later-onset NSPE (LO-NSPE), and 7 with later-onset SPE (LO-SPE). All patients underwent multimodal echocardiography before treatment, including two-dimensional, Doppler, and speckle-tracking echocardiography, to evaluate left ventricular structure/function. Analysis of variance was used to determine statistical significance across groups. RESULTS: EO-SPE patients showed decreased left ventricular ejection fractions, peak longitudinal systolic strain at apical four-chambers, peak circumferential, and radial systolic strain at the apical and mitral annular plane systolic excursion (MAPSE), and increased mitral regurgitation compared to other preeclampsia patients. Compared to LO-NSPE and EO-SPE patients, LO-SPE patients showed increased left ventricular mass indexed to height2.7 and early diastolic left ventricular diastolic filling/mitral annular velocity, and decreased MAPSE and early/late diastolic mitral annular velocity. CONCLUSION: EO-SPE patients were characterized by left ventricular injury and systolic function reduced. LO-SPE patients were characterized by left ventricular hypertrophy and reduced diastolic function. Multimodal echocardiography can detect myocardial injury in PE patients at an early stage.

Combined effect of transcutaneous auricular vagus nerve stimulation and 0.1 Hz slow-paced breathing on working memory.

Background: Previous research has found that transcutaneous auricular vagus nerve stimulation (taVNS) can improve working memory (WM) performance. It has also been shown that 0.1 Hz slow-paced breathing (SPB, i.e., breathing at a rate of approximately 6 breaths/min) can significantly influence physical state and cognitive function via changes in autonomic afferent activity. In the present study, we investigated the synergistic effects of taVNS and SPB on WM performance. Methods: A total of 96 healthy people participated in this within-subjects experiment involving four conditions, namely taVNS, SPB, combined taVNS with SPB (taVNS + SPB), and sham. Each participant underwent each intervention for 30 min and WM was compared pre- and post-intervention using the spatial and digit n-back tasks in a random order four times. Permutation-based analysis of variance was used to assess the interaction between time and intervention. Results: For the spatial 3-back task, a significant interaction between time and intervention was found for the accuracy rate of matching trials (mACC, p = 0.03). Post hoc analysis suggested that both taVNS and taVNS + SPB improved WM performance, however, no significant difference was found in the SPB or sham groups. Conclusion: This study has replicated the effects of taVNS on WM performance reported in previous studies. However, the synergistic effects of combined taVNS and SPB warrant further research.

Rbm24 regulates inner-ear-specific alternative splicing and is essential for maintaining auditory and motor coordination.

Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.

Transcutaneous Auricular Vagus Nerve Stimulation Improves Spatial Working Memory in Healthy Young Adults.

Working memory (WM) is one of the core components of higher cognitive functions. There exists debate regarding the extent to which current techniques can enhance human WM capacity. Here, we examined the WM modulation effects of a previously less studied technique, transcutaneous auricular vagus nerve stimulation (taVNS). In experiment 1, a within-subject study, we aimed to investigate whether and which stimulation protocols of taVNS can modulate spatial WM performance in healthy adults. Forty-eight participants performed baseline spatial n-back tasks (1, 3-back) and then received online taVNS, offline taVNS, or sham stimulation before or during (online group) the posttest of spatial n-back tasks in random order. Results showed that offline taVNS could significantly increase hits in spatial 3-back task, whereas no effect was found in online taVNS or sham group. No significant taVNS effects were found on correct rejections or reaction time of accurate trials (aRT) in both online and offline protocols. To replicate the results found in experiment 1 and further investigate the generalization effect of offline taVNS, we carried out experiment 2. Sixty participants were recruited and received offline taVNS or offline earlobe stimulation in random order between baseline and posttests of behavioral tests (spatial/digit 3-back tasks). Results replicated the findings; offline taVNS could improve hits but not correct rejections or aRT in spatial WM performance, which were found in experiment 1. However, there were no significant stimulation effects on digit 3-back task. Overall, the findings suggest that offline taVNS has potential on modulating WM performance.

Rbm24 modulates adult skeletal muscle regeneration via regulation of alternative splicing.

Rationale: The adult skeletal muscle can self-repair efficiently following mechanical or pathological damage due to its remarkable regenerative capacity. However, regulatory mechanisms underlying muscle regeneration are complicated and have not been fully elucidated. Alternative splicing (AS) is a major mechanism responsible for post-transcriptional regulation. Many aberrant AS events have been identified in patients with muscular dystrophy which is accompanied by abnormal muscle regeneration. However, little is known about the correlation between AS and muscle regeneration. It has been reported that RNA binding motif protein 24 (Rbm24), a tissue-specific splicing factor, is involved in embryo myogenesis while the role of Rbm24 in adult myogenesis (also called muscle regeneration) is poorly understood. Methods: To investigate the role of Rbm24 in adult skeletal muscle, we generated Rbm24 conditional knockout mice and satellite cell-specific knockout mice. Furthermore, a cardiotoxin (CTX)-induced injury model was utilized to assess the effects of Rbm24 on skeletal muscle regeneration. Genome-wide RNA-Seq was performed to identify the changes in AS following loss of Rbm24. Results: Rbm24 knockout mice displayed abnormal regeneration 4 months after tamoxifen treatment. Using RNA-Seq, we found that Rbm24 regulated a complex network of AS events involved in multiple biological processes, including myogenesis, muscle regeneration and muscle hypertrophy. Moreover, using a CTX-induced injury model, we showed that loss of Rbm24 in skeletal muscle resulted in myogenic fusion and differentiation defects and significantly delayed muscle regeneration. Furthermore, satellite cell-specific Rbm24 knockout mice recapitulated the defects in regeneration seen in the global Rbm24 knockout mice. Importantly, we demonstrated that Rbm24 regulated AS of Mef2d, Naca, Rock2 and Lrrfip1 which are essential for myogenic differentiation and muscle regeneration. Conclusions: The present study demonstrated that Rbm24 regulates dynamic changes in AS and is essential for adult skeletal muscle regeneration.

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy.

RNA splicing contributes to a broad spectrum of post-transcriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.