A bibliometric analysis of global research status and trends in neuromodulation techniques in the treatment of autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease which has risen to become the main cause of childhood disability, placing a heavy burden on families and society. To date, the treatment of patients with ASD remains a complicated problem, for which neuromodulation techniques are a promising solution. This study analyzed the global research situation of neuromodulation techniques in the treatment of ASD from 1992 to 2022, aiming to explore the global research status and frontier trends in this field. METHODS: The Web of Science (WoS) was searched for literature related to neuromodulation techniques for ASD from 1992 to October 2022. A knowledge atlas to analyze collaboration among countries, institutions, authors, publishing journals, reference co-citation patterns, keyword co-occurrence, keyword clustering, and burst keywords was constructed using Rstudio software, CiteSpace, and VOSviewer. RESULTS: In total, 392 publications related to the treatment of ASD using neuromodulation techniques were included. Despite some fluctuations, the number of publications in this field has shown a growing trend in recent years. The United States and Deakin University are the leading country and institution in this field, respectively. The greatest contributing authors are Peter G Enticott, Manuel F Casanova, and Paul B Fitzgerald et al. The most prolific and cited journal is Brain Stimulation and the most commonly co-cited journal is The Journal of Autism and Developmental Disorders. The most frequently cited article was that of Simone Rossi (Safety, ethical considerations, and application guidelines for the use of transverse magnetic stimulation in clinical practice and research, 2009). "Obsessive-compulsive disorder," "transcranial direct current stimulation," "working memory," "double blind" and "adolescent" were identified as hotspots and frontier trends of neuromodulation techniques in the treatment of ASD. CONCLUSION: The application of neuromodulation techniques for ASD has attracted the attention of researchers worldwide. Restoring the social ability and improving the comorbid symptoms in autistic children and adults have always been the focus of research. Neuromodulation techniques have demonstrated significant advantages and effects on these issues. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are new therapeutic methods introduced in recent years, and are also directions for further exploration.

Altered anterior insula-superior frontal gyrus functional connectivity is correlated with cognitive impairment following total sleep deprivation.

Sleep deprivation is an important cause of cognitive impairment, and anterior insular subregions are core brain regions linked to cognitive function. However, the relationship between anterior insular subregions functional connectivity (FC) and the cognitive impairment that occurs following total sleep deprivation (TSD) remains unknown. As such, this study was designed to evaluate how such anterior insular subregions FC alterations are linked with impaired cognitive activity after TSD. This study recruited 20 healthy volunteers who underwent two rounds of resting-state functional magnetic resonance imaging (rs-fMRI), with one being conducted while in a state of rested wakefulness (RW) and the other being conducted following 24 h of TSD. These rs-fMRI data were then used to conduct seed-based FC analyses for the bilateral anterior insular subregions, including the dorsal anterior insula (dAI) and the ventral anterior insula (vAI). The Psychomotor Vigilance Test (PVT) was used to gauge cognitive performance, and associations between altered FC in these anterior insular subregions and PVT performance following TSD were measured using Pearson correlation analyses. Significant changes in the FC of these bilateral insular subregions were observed following 24 h of TSD relative to the RW state. Significantly enhanced FC was evident between the left dAI and right superior frontal gyrus (SFG), right dAI and bilateral SFG and right putamen, and right vAI and left medial SFG. Moreover, the observed enhancement of FC between the left vAI and right SFG functional connectivity was positively correlated with worse PVT performance. These data suggest that altered FC in the anterior insular subregions represents a prominent neuroimaging biomarker associated with cognitive impairment following TSD.

Alterations of RNAs in the insula related to cocaine-induced condition place preference in adolescent mice.

Cocaine as a highly addictive psychostimulant can cause changes in the body at the cellular and molecular levels over a long period of time. It reminds us that cocaine may have a potential role in post-transcriptional regulation, but the alteration of insula-expression profile in adolescent cocaine use disorder (CUD) has not been reported. To reveal the mechanisms underlying the post-transcriptional regulation of cocaine, we investigate the transcriptome in the insula of cocaine-induced mice based on high-throughput strand-specific RNA sequencing. We analyzed the alterations of messenger RNA (mRNA) expression profile in the insula of cocaine-induced condition place preference (CPP) mice and then correlated it with microRNAs to reveal their involvement in the formation of cocaine-induced CPP. In this study, a total of 27786 genes were identified, 5750 new genes (novel expressed transcripts of unannotated in the reference genome) were discovered, among which 1,205 were annotated functionally. A total of 198 differentially expressed genes (DEG) that functioned in synaptic transmission, cholinergic, developmental process, neurotransmitter metabolic process, drug catabolism, cellular response to drug, MAP kinase activity, ceramidase activity, and drug resistance were significantly enriched. Further analysis showed that 26045 mRNAs formed 45,208 network-relationship pairs with 1770 microRNAs. In the current study, our work was the first to reveal that alterations of RNAs in the insula, as a core brain region of the neural circuits of interoception, were involved in the process of cocaine-induced CPP of adolescent mice. These findings enrich the biology and expand the molecular regulatory network related to adolescence CUD. They provided the possibility that some DEGs may be used as novel biomarkers for the diagnosis or evaluation of substance use disorder, and also provided clues for elucidating the neurobiological mechanism of substance use disorder.

Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model.

BACKGROUND: Until now, the treatment of patients with autism spectrum disorder (ASD) remain a difficult problem. The insula is involved in empathy and sensorimotor integration, which are often impaired in individuals with ASD. Deep brain stimulation, modulating neuronal activity in specific brain circuits, has recently been considered as a promising intervention for neuropsychiatric disorders. Valproic acid (VPA) is a potential teratogenic agent, and prenatal exposure can cause autism-like symptoms including repetitive behaviors and defective sociability. Herein, we investigated the effects of continuous high-frequency deep brain stimulation in the anterior insula of rats exposed to VPA and explored cognitive functions, behavior, and molecular proteins connected to autism spectrum disorder. METHODS: VPA-exposed offspring were bilaterally implanted with electrodes in the anterior insula (Day 0) with a recovery period of 1 week. (Day 0-7). High-frequency deep brain stimulation was applied from days 11 to 29. Three behavioral tests, including three-chamber social interaction test, were performed on days 7, 13, 18, 25 and 36, and several rats were used for analysis of immediate early genes and proteomic after deep brain stimulation intervention. Meanwhile, animals were subjected to a 20 day spatial learning and cognitive rigidity test using IntelliCage on day 11. RESULTS: Deep brain stimulation improved the sociability and social novelty preference at day 18 prior to those at day 13, and the improvement has reached the upper limit compared to day 25. As for repetitive/stereotypic-like behavior, self- grooming time were reduced at day 18 and reached the upper limit, and the numbers of burried marbles were reduced at day 13 prior to those at day 18 and day 25. The improvements of sociability and social novelty preference were persistent after the stimulation had ceased. Spatial learning ability and cognitive rigidity were unaffected. We identified 35 proteins in the anterior insula, some of which were intimately linked to autism, and their expression levels were reversed upon administration of deep brain stimulation. CONCLUSIONS: Autism-like behavior was ameliorated and autism-related proteins were reversed in the insula by deep brain stimulation intervention, these findings reveal that the insula may be a potential target for DBS in the treatment of autism, which provide a theoretical basis for its clinical application., although future studies are still warranted.

Apigenin exhibits anti-inflammatory effects in LPS-stimulated BV2 microglia through activating GSK3ß/Nrf2 signaling pathway.

Objective: Apigenin is a natural flavonoid compound extracted from Matricaria chamomilla. We evaluated the anti-inflammatory effects of apigenin in this study using the Lipopolysaccharide (LPS)-stimulated BV2 microglia.Methods: BV2 cells were treated with apigenin for 1 h and then treated with LPS. The inflammatory cytokine productions were tested by qRT-PCR and ELISA. The expression of GSK3ß, Nrf2, and NF-κB signaling pathways were measured by western blot analysis.Results: Apigenin significantly attenuated LPS-induced TNF-α, IL-1ß, and IL-6 production. Apigenin suppressed LPS-induced NF-κB activation. Furthermore, GSK3ß, Nrf2, and HO-1 were concentration-dependently increased by apigenin. The suppression of apigenin on LPS-induced inflammatory response and NF-κB activation were prevented when Nrf2 was knocked out or by GSK3ß inhibitor.Conclusions: Collectively, apigenin suppressed LPS-induced microglia activation via activating GSK3ß/Nrf2 signaling pathway.

Knowledge Atlas of the Co-Occurrence of Epilepsy and Autism: A Bibliometric Analysis and Visualization Using VOSviewer and CiteSpace.

Objective: This study aimed to analyze research on epilepsy in autism and autism in epilepsy using VOSviewer and CiteSpace to identify research hotspots and future directions. Methods: We searched the Web of Science Core Collection (WoSCC) for relevant studies about epilepsy in autism and autism in epilepsy published from inception to 31 May 2022. VOSviewer and CiteSpace were used to analyze the authors, institutions, countries, publishing journals, reference co-citation patterns, keyword co-occurrence, keyword clustering, keywords with citation bursts, and other aspects to construct a knowledge atlas. Results: A total of 473 publications related to epilepsy/autism were retrieved. The number of publications about epilepsy/ASD has generally increased over time, with some fluctuations. The USA (202 papers) and University of California-Los Angeles (15 papers) were the leading country and institution, respectively, in this field. Frye, Richard E. was the most published author (9 papers). Notably, collaboration between institutions, countries, and authors does not appear to be active. Hot topics and research frontiers include intellectual disability and exploring the mechanism of epilepsy/ASD from a genetics perspective. Conclusion: This analysis identified the most influential publications, authors, journals, institutions, and countries in the field of epilepsy/ASD research. Using co-occurrence and evolution analyses, the status of the field was identified and future trends were predicted.

Is the insula linked to sleep? A systematic review and narrative synthesis.

Background: Sleep is critical to human beings in a surprisingly diverse set of ways, and there is, thus, continual investigation into the mechanisms of sleep. Although current studies have confirmed that multiple brain regions are involved in the regulation of both sleep and wakefulness, the association between certain important brain regions such as the insula and sleep is still unclear. Objective: The purpose of this study was to systematically review studies on the insula and sleep and to discuss the relationship between the insula and sleep. Methods: We searched the PubMed and Web of Science Core Collection (WoSCC) for articles on sleep and the insula. The time span was from inception to June 30, 2022. The search results were then narratively summarized. Results: A total of 939 studies were identified in the PubMed and WoSCC of which 115 studies were finally included in the narrative synthesis. These 115 studies can be roughly divided into 41 studies on insomnia, 39 on sleep deprivation, 33 on sleep-related experiments examining the insula, and 2 studies using basic experiments. Conclusion: The combined findings of many sleep-related studies have confirmed a close link between the insula and sleep loss, including insomnia, sleep deprivation, sleep-related disorders, and more. Although these results do not directly confirm that the insula is involved in sleep, a overall analysis of the results indicates that the insula may be a potential key brain region involved in sleep.

Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson's disease rats.

Background: Parkinson's disease (PD) is a common movement disorder disease. Left vagus nerve stimulation (LVNS) is a potential treatment option for PD. Compared with the left vagus nerve, the right vagus nerve is more closely connected with the midbrain dopaminergic neurons, which are the lesion locations of PD. However, whether right vagus nerve stimulation (RVNS) has a therapeutic effect on PD has not yet been studied. Therefore, in this study, we studied the therapeutic effect and underlying mechanism of RVNS using a PD rat model. Methods: To establish the PD rat model, 8-week-old male Sprague-Dawley rats were intraperitoneally injected with rotenone for 21 days. The cuff electrodes were implanted into the right cervical vagal carotid sheaths of the rats. The right vagus nerve was continuously stimulated for 14 days using a radio stimulation system. Behavioral tests were performed before and after stimulation. Finally, tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and α-synuclein in the midbrain, including the substantia nigra (SN) and ventral tegmental area (VTA), were detected by immunofluorescence. Results: A markedly lower distance traveled and rearing number was observed in the rotenone, rotenone + sham, and rotenone + RVNS groups compared to the vehicle group. After the stimulation days, the distance traveled and rearing number were both higher in the rotenone + RVNS group compared to the rotenone and rotenone + sham groups (P<0.01, P<0.0001). A remarkable increase in distance traveled and rearing number was observed in the rotenone + RVNS group after stimulation. TH expression in the vehicle group was significantly up-regulated than the other groups. RVNS markedly up-regulated TH expression level. A significantly higher expression of α-synuclein was observed in the rotenone, rotenone + sham, and rotenone + RVNS groups compared to the vehicle group. The expression of α-synuclein was lower in the rotenone + RVNS group compared to the rotenone and rotenone + sham groups. A markedly higher VMAT2 expression was observed in the vehicle group compared to other groups. RVNS significantly up-regulated VMAT2 expression. Conclusions: The improved motor behavior and neuroprotective effects on the midbrain dopaminergic neurons in the PD rat model suggest that RVNS could be used as a potential treatment for PD.

Effectiveness of antiseizure medications therapy in preventing seizures in brain injury patients: A network meta-analysis.

Purpose: To explore the effectiveness of different anti-seizure medications in preventing early and late post-traumatic epilepsy (PTE). The efficacy, treatment-related side-effects, and mortality of the different treatments were compared using a ranking model to identify the optimal treatment. Methods: A comprehensive literature search was performed using Pubmed, Medline, Embase, and Cochrane library databases. All relevant published articles up to 10 March 2022 were evaluated. The quality of the extracted data was assessed using either the Cochrane risk of bias tool or the Newcastle-Ottawa scale. The primary outcome measures were early or late post-traumatic seizures. The secondary outcome measures were mortality, treatment-related adverse effects, length of hospital stay, and length of stay within the intensive care unit (ICU). Results: A total of seven randomized controlled trials and 18 non-randomized controlled trials were included in this network meta-analysis. The trials included six interventions: Phenytoin (PHT)+phenobarbital (PB), levetiracetam (LEV), PHT, PHT-LEV, lacosamide (LCM), and valproate (VPA). All interventions except VPA significantly reduced the rate of early PTE in TBI patients compared with the placebo. Seven studies reported the impact of four treatments (PHT + PB, LEV, PHT, VPA) on late seizures and showed a significant reduction in the incidence of late seizures in patients with TBI compared with placebo. The impact of PHT, LEV, and VPA on mortality was reported in nine studies. PHT had no impact on mortality, but patients treated with both LEV and VPA had higher mortality than those treated with placebo. The treatment-related adverse effects of LEV, PHT, and LCM were reported in five studies. LEV and PHT had higher treatment-related adverse effects incidence than placebo, while LCM had no effect on treatment related-adverse effects. Conclusion: LEV and PHT prevented early and late PTE. PHT also reduced the mortality rate in patients with TBI. Both LEV and PHT had higher treatment-related adverse effects compared with placebo. However, LEV had a slightly lower incidence of treatment-related adverse effects when compared with PHT. Compared with PHT, LEV did not reduce the length of hospital stay but shortened the length of ICU stays. Therefore, based on the findings of this meta-analysis, we speculate that LEV is the best treatment option for TBI patients. However, further high-quality randomized controlled trials are required to confirm these findings.

Effect of drug therapy on nerve repair of moderate-severe traumatic brain injury: A network meta-analysis.

Objective: This network meta-analysis aimed to explore the effect of different drugs on mortality and neurological improvement in patients with traumatic brain injury (TBI), and to clarify which drug might be used as a more promising intervention for treating such patients by ranking. Methods: We conducted a comprehensive search from PubMed, Medline, Embase, and Cochrane Library databases from the establishment of the database to 31 January 2022. Data were extracted from the included studies, and the quality was assessed using the Cochrane risk-of-bias tool. The primary outcome measure was mortality in patients with TBI. The secondary outcome measures were the proportion of favorable outcomes and the occurrence of drug treatment-related side effects in patients with TBI in each drug treatment group. Statistical analyses were performed using Stata v16.0 and RevMan v5.3.0. Results: We included 30 randomized controlled trials that included 13 interventions (TXA, EPO, progesterone, progesterone + vitamin D, atorvastatin, beta-blocker therapy, Bradycor, Enoxaparin, Tracoprodi, dexanabinol, selenium, simvastatin, and placebo). The analysis revealed that these drugs significantly reduced mortality in patients with TBI and increased the proportion of patients with favorable outcomes after TBI compared with placebo. In terms of mortality after drug treatment, the order from the lowest to the highest was progesterone + vitamin D, beta-blocker therapy, EPO, simvastatin, Enoxaparin, Bradycor, Tracoprodi, selenium, atorvastatin, TXA, progesterone, dexanabinol, and placebo. In terms of the proportion of patients with favorable outcomes after drug treatment, the order from the highest to the lowest was as follows: Enoxaparin, progesterone + vitamin D, atorvastatin, simvastatin, Bradycor, EPO, beta-blocker therapy, progesterone, Tracoprodi, TXA, selenium, dexanabinol, and placebo. In addition, based on the classification of Glasgow Outcome Scale (GOS) scores after each drug treatment, this study also analyzed the three aspects of good recovery, moderate disability, and severe disability. It involved 10 interventions and revealed that compared with placebo treatment, a higher proportion of patients had a good recovery and moderate disability after treatment with progesterone + vitamin D, Bradycor, EPO, and progesterone. Meanwhile, the proportion of patients with a severe disability after treatment with progesterone + vitamin D and Bradycor was also low. Conclusion: The analysis of this study revealed that in patients with TBI, TXA, EPO, progesterone, progesterone + vitamin D, atorvastatin, beta-blocker therapy, Bradycor, Enoxaparin, Tracoprodi, dexanabinol, selenium, and simvastatin all reduced mortality and increased the proportion of patients with favorable outcomes in such patients compared with placebo. Among these, the progesterone + vitamin D had not only a higher proportion of patients with good recovery and moderate disability but also a lower proportion of patients with severe disability and mortality. However, whether this intervention can be used for clinical promotion still needs further exploration.

Decreased cognitive function of ALG13KO female mice may be related to the decreased plasticity of hippocampal neurons.

Asparagine-linked glycosylation 13 (ALG13) is an X-linked gene that encodes a protein involved in the glycosylation of the N-terminus. ALG13 deficiency leads to ALG13-congenital disorders of glycosylation (ALG13-CDG), usually in females presenting with mental retardation and epilepsy. Cognitive function is an important function of the hippocampus, and forms the basis for learning, memory and social abilities. However, researchers have not yet investigated the effect of ALG13 on hippocampal cognitive function. In this study, the exploration, learning, memory and social abilities of ALG13 knockout (KO) female mice were decreased in behavioral experiments. Golgi staining demonstrated a decrease in the complexity of hippocampal neurons. Western blot and immunofluorescence staining of the synaptic plasticity factors postsynaptic density protein 95 (PSD95) and synaptophysin (SYP) displayed varying degrees of decline. In other words, the KO of ALG13 may have reduced the expression of PSD95 and SYP in the hippocampus of female mice. Moreover, it may have lowered the synaptic plasticity in various areas of the hippocampus, thus resulting in decreased dendrite length, complexity, and dendrite spine density, which affected the hippocampal function and reduced the cognitive function in female mice.