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The complex etiology of neurodegenerative disease has prompted studies on multiple mechanisms including genetic predisposition, brain biochemistry, immunological responses, and microbial insult. In particular, Lyme disease is often associated with neurocognitive impairment with variable manifestations between patients. We sought to develop methods to reliably detect Borrelia burgdorferi , the spirochete bacteria responsible for Lyme disease, in autopsy specimens of patients with a history of neurocognitive disease. In this report, we describe the use of multiple molecular detection techniques for this pathogen and its application to a case study of a Lyme disease patient. The patient had a history of Lyme disease, was treated with antibiotics, and years later developed chronic symptoms including dementia. The patient's pathology and clinical case description was consistent with Lewy body dementia. B. burgdorferi was identified by PCR in several CNS tissues and by immunofluorescent staining in the spinal cord. These studies offer proof of the principle that persistent infection with the Lyme disease spirochete may have lingering consequences on the CNS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gadila, Rosoklija, Dwork, Fallon and Embers.)

Background: Although it is the general consensus that sarcoidosis patients who present with sarcoidosis-related symptoms have a worse outcome than patients whose disease is detected incidentally without symptoms, this premise has not been rigorously examined., Methods: Consecutive patients followed longitudinally at one US university sarcoidosis clinic were questioned concerning the onset and description of sarcoidosis-related symptoms at disease presentation. The patients were classified into those with no sarcoidosis-related symptoms at presentation (NSP group) and those with symptoms at presentation (SP group). The following outcomes were examined in the NSP and SP groups: most recent spirometry, organ involvement, need for sarcoidosis therapy, most recent health related quality of life (HRQOL) as measured by the Sarcoidosis Assessment Tool (SAT), most recent chest imaging Scadding stage results., Results: 660 sarcoidosis patients were analyzed, with 175 in the NSP group and 485 in the SP group. Compared to the NSP group, the SP group had a more frequent requirement for any sarcoidosis treatment, corticosteroid treatment, and non-corticosteroid treatment at some time and within the most recent year of follow up (at least 50% more than the NP group with strong statistical differences with p values all 0.01 or less). In addition, the SP group had significantly more organ involvement (p < 0.001) and several worse SAT domains (p < 0.022) than the NP group. There were no differences between the groups in terms of final spirometry or development of Scadding stage 4 chest radiographs. These findings held even after adjusting for age, sex, race, and time between presentation and the most recent follow-up visit using a multivariable logistic regression framework., Conclusions: In our sarcoidosis cohort, compared to the absence of symptoms at presentation, the presence of symptoms was associated with a greater need for treatment, more organ involvement, and worse HRQOL., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical gray matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco., Results: In this study, we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (assayed via Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed the false discovery correction (FDR ≤ 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions of GNA15 and SDHAP3 of smoking-exposed fetuses. Interestingly, the developmental up-regulation of SDHAP3 mRNA was delayed in smoking-exposed fetuses. Interaction analysis between gestational age and smoking exposure identified significant DMRs annotated to SYCE3 , C21orf56 / LSS, SPAG1 and RNU12 / POLDIP3 that passed FDR. Furthermore, utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We also show through in vitro experiments that nicotine impedes the differentiation of neurons independent of cell death., Conclusions: We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine.

Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles. Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation. Synopsis: Autophagosome biogenesis is impaired in Rett syndrome, a complex neurodevelopmental disorder caused by loss of function mutations in MECP2. Autophagy enhancement restores defects in neurons lacking Mecp2, suggesting a possible contribution of this pathway in the pathogenesis of Rett. LC3B-II lipidation, which is essential for autophagosome biogenesis, is defective in Mecp2 KO cells, probably due to the reduced availability of phosphatidylethanolamine (PE). The natural disaccharide and autophagy inducer trehalose restores the amount of PE and improves dendritic complexity and synaptic ultrastructure in Mecp2 KO neurons. In vivo administration of trehalose ameliorates exploratory and locomotor skills of Mecp2 KO male mice. Autophagosome biogenesis is impaired in Rett syndrome, a complex neurodevelopmental disorder caused by loss of function mutations in MECP2. Autophagy enhancement restores defects in neurons lacking Mecp2, suggesting a possible contribution of this pathway in the pathogenesis of Rett. [ABSTRACT FROM AUTHOR]

The microcircuitry within superficial layers of the dorsolateral prefrontal cortex (DLPFC), composed of excitatory pyramidal neurons and inhibitory GABAergic interneurons, has been suggested as the neural substrate of working memory performance. In schizophrenia, working memory impairments are thought to result from alterations of microcircuitry within the DLPFC. GABAergic interneurons, in particular, are crucially involved in synchronizing neural activity at gamma frequency, the power of which increases with working memory load. Alterations of GABAergic interneurons, particularly parvalbumin (PV) and somatostatin (SST) subtypes, are frequently observed in schizophrenia. Abnormalities of GABAergic neurotransmission, such as deficiencies in the 67 kDA isoform of GABA synthesis enzyme (GAD67), vesicular GABA transporter (vGAT), and GABA reuptake transporter 1 (GAT1) in presynaptic boutons, as well as postsynaptic alterations in GABAA receptor subunits further contribute to impaired inhibition. This review explores GABAergic abnormalities of the postmortem DLPFC in schizophrenia, with a focus on the roles of interneuron subtypes involved in cognition, and GABAergic neurotransmission within presynaptic boutons and postsynaptic alterations. Where available, comparisons between schizophrenia and affective disorders that share cognitive pathology such as bipolar disorder and major depressive disorder will be made. Challenges in directly measuring GABA levels are addressed, emphasizing the need for innovative techniques. Understanding GABAergic abnormalities and their implications for neural circuit dysfunction in schizophrenia is crucial for developing targeted therapies. [ABSTRACT FROM AUTHOR]

Background Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N -methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells. Methods Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays. Results We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration. Conclusions In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R , S)-ketamine. [ABSTRACT FROM AUTHOR]

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer's disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors. [ABSTRACT FROM AUTHOR]

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mechanisms underlying brain arterial remodeling are uncertain. We tested the hypothesis that arterial size and location are important determinants of arterial characteristics. We collected large and penetrating brain arteries from cadavers with and without HIV. Morphometric characterization was obtained from digital images using color-based thresholding. The association of arterial size and location with lumen diameter, media and adventitia area, media proportion, a wall thickness, wall-to-lumen ratio and stenosis was obtained with multilevel mixed models and a P value ≤ 0.05 was considered significant. We included 336 brains, in which 2279 large arteries and 1488 penetrating arteries were identified. We found that arterial size was significantly associated with all arterial characteristics studied of large and penetrating arteries with exception of arterial stenosis in large arteries. After adjusting for size, an independent association was found between lumen diameters, media and adventitia thickness with artery locations. Arterial stenosis was also associated with artery location in both large and penetrating arteries. In summary, significant effects of size and/or location were found in arterial characteristics typically used to define arterial remodeling. Brain arterial remodeling characteristics differ across arterial sizes and location, and these differences should be controlled for in future studies of brain arterial remodeling.

DNA methylation is essential in brain function and behavior; therefore, understanding the role of DNA methylation in brain-based disorders begins with the study of DNA methylation profiles in normal brain. Determining the patterns and scale of methylation conservation and alteration in an evolutionary context enables the design of focused but effective methylation studies of disease states. We applied an enzymatic-based approach, Methylation Mapping Analysis by Paired-end Sequencing (Methyl-MAPS), which utilizes second-generation sequencing technology to provide an unbiased representation of genome-wide DNA methylation profiles of human and mouse brains. In this large-scale study, we assayed CpG methylation in cerebral cortex of neurologically and psychiatrically normal human postmortem specimens, as well as mouse forebrain specimens. Cross-species human-mouse DNA methylation conservation analysis shows that DNA methylation is not correlated with sequence conservation. Instead, greater DNA methylation conservation is correlated with increasing CpG density. In addition to CpG density, these data show that genomic context is a critical factor in DNA methylation conservation and alteration signatures throughout mammalian brain evolution. We identify key genomic features that can be targeted for identification of epigenetic loci that may be developmentally and evolutionarily conserved and wherein aberrations in DNA methylation patterns can confer risk for disease.

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels., Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation., Conclusion: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Background: Emerging evidence suggests that DNA methylation plays an expansive role in the central nervous system (CNS). Large-scale whole genome DNA methylation profiling of the normal human brain offers tremendous potential in understanding the role of DNA methylation in brain development and function., Methodology/significant Findings: Using methylation-sensitive SNP chip analysis (MSNP), we performed whole genome DNA methylation profiling of the prefrontal, occipital, and temporal regions of cerebral cortex, as well as cerebellum. These data provide an unbiased representation of CpG sites comprising 377,509 CpG dinucleotides within both the genic and intergenic euchromatic region of the genome. Our large-scale genome DNA methylation profiling reveals that the prefrontal, occipital, and temporal regions of the cerebral cortex compared to cerebellum have markedly different DNA methylation signatures, with the cerebral cortex being hypermethylated and cerebellum being hypomethylated. Such differences were observed in distinct genomic regions, including genes involved in CNS function. The MSNP data were validated for a subset of these genes, by performing bisulfite cloning and sequencing and confirming that prefrontal, occipital, and temporal cortices are significantly more methylated as compared to the cerebellum., Conclusions: These findings are consistent with known developmental differences in nucleosome repeat lengths in cerebral and cerebellar cortices, with cerebrum exhibiting shorter repeat lengths than cerebellum. Our observed differences in DNA methylation profiles in these regions underscores the potential role of DNA methylation in chromatin structure and organization in CNS, reflecting functional specialization within cortical regions.

Abnormalities of cerebral white matter, oligodendrocytes, and myelin have been observed in schizophrenia with in-vivo imaging and post-mortem biochemistry. White-matter abnormalities are also frequently associated with cognitive impairment in both healthy and diseased individuals, and cognitive dysfunction is an important component of schizophrenia. While many studies have documented these associations, only a handful have examined the role of white matter in cognitive function in schizophrenia. In this paper, we explore what is known about white-matter deficits in relation to schizophrenia, cognitive deficits, or both together, in order to generate a theoretical model for the role that compromise of white matter might play in producing cognitive impairment in schizophrenia.

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.

Background: A large body of research has identified the positive effects of physical activity on children with autism spectrum disorders (ASD). However, the specific benefits of different types of sports on executive functioning in children with ASD remain unclear. The aim of this study was to further analyze the effects of different sports on executive functioning in children with ASD using reticulated meta-analysis and to establish their effectiveness ranking. Methods: This study conducted a comprehensive online search in Web of Science, PubMed, Cochrane, Embase, and CNKI databases. It included randomized controlled trials and quasi-experimental studies, and synthesized the data using a Bayesian framework. Results: Several relevant studies were included. The results showed that physical activity significantly improved all three dimensions of executive functioning (inhibitory control, cognitive flexibility, and working memory) in children with ASD. The improvement in cognitive flexibility and inhibitory control both reached a medium effect size. However, the improvement in inhibitory control was better than that in cognitive flexibility, while the improvement in working memory did not reach the level of a medium effect. Mini Basketball was effective in improving inhibitory control and cognitive flexibility, but not working memory. Ping Pong was more effective in cognitive flexibility and working memory, but weaker in inhibitory control. Fixed Bicycle was less effective in all three dimensions. Among other interventions, Learning Bicycles, Animal-assisted therapy, and Exergaming performed better in cognitive flexibility. SPARK, Neiyang Gong, and Martial Arts were also effective in improving inhibitory control. However, SPARK and Fixed Bicycle were not significant in improving working memory. Conclusion: Physical activity as an intervention can significantly improve the executive function of children with ASD. The intervention effects of different sports on different dimensions of executive function vary. Mini Basketball was outstanding in improving inhibitory control and cognitive flexibility. Ping Pong was effective in improving cognitive flexibility and working memory. Fixed Bicycle was not effective in any dimension. [ABSTRACT FROM AUTHOR]

Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA. [ABSTRACT FROM AUTHOR]

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental condition that is associated with atypical brain network organization, with prior work suggesting differential connectivity alterations with respect to functional connection length. Here, we tested whether functional connectopathy in ASD specifically relates to disruptions in long- relative to short-range functional connections. Our approach combined functional connectomics with geodesic distance mapping, and we studied associations to macroscale networks, microarchitectural patterns, as well as socio-demographic and clinical phenotypes. Methods: We studied 211 males from three sites of the ABIDE-I dataset comprising 103 participants with an ASD diagnosis (mean ± SD age = 20.8 ± 8.1 years) and 108 neurotypical controls (NT, 19.2 ± 7.2 years). For each participant, we computed cortex-wide connectivity distance (CD) measures by combining geodesic distance mapping with resting-state functional connectivity profiling. We compared CD between ASD and NT participants using surface-based linear models, and studied associations with age, symptom severity, and intelligence scores. We contextualized CD alterations relative to canonical networks and explored spatial associations with functional and microstructural cortical gradients as well as cytoarchitectonic cortical types. Results: Compared to NT, ASD participants presented with widespread reductions in CD, generally indicating shorter average connection length and thus suggesting reduced long-range connectivity but increased short-range connections. Peak reductions were localized in transmodal systems (i.e., heteromodal and paralimbic regions in the prefrontal, temporal, and parietal and temporo-parieto-occipital cortex), and effect sizes correlated with the sensory-transmodal gradient of brain function. ASD-related CD reductions appeared consistent across inter-individual differences in age and symptom severity, and we observed a positive correlation of CD to IQ scores. Limitations: Despite rigorous harmonization across the three different acquisition sites, heterogeneity in autism poses a potential limitation to the generalizability of our results. Additionally, we focussed male participants, warranting future studies in more balanced cohorts. Conclusions: Our study showed reductions in CD as a relatively stable imaging phenotype of ASD that preferentially impacted paralimbic and heteromodal association systems. CD reductions in ASD corroborate previous reports of ASD-related imbalance between short-range overconnectivity and long-range underconnectivity. [ABSTRACT FROM AUTHOR]

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopment disease characterized by impaired social and cognitive abilities. Despite its prevalence, reliable biomarkers for identifying individuals with ASD are lacking. Recent studies have suggested that alterations in the functional connectivity of the brain in ASD patients could serve as potential indicators. However, previous research focused on static functional-connectivity analysis, neglecting temporal dynamics and spatial interactions. To address this gap, our study integrated dynamic functional connectivity, local graph-theory indicators, and a feature-selection and ranking approach to identify biomarkers for ASD diagnosis. Methods: The demographic information, as well as resting and sleeping electroencephalography (EEG) data, were collected from 20 ASD patients and 25 controls. EEG data were pre-processed and segmented into five sub-bands (Delta, Theta, Alpha-1, Alpha-2, and Beta). Functional-connection matrices were created by calculating coherence, and static-node-strength indicators were determined for each channel. A sliding-window approach, with varying widths and moving steps, was used to scan the EEG series; dynamic local graph-theory indicators were computed, including mean, standard deviation, median, inter-quartile range, kurtosis, and skewness of the node strength. This resulted in 95 features (5 sub-bands × 19 channels) for each indicator. A support-vector-machine recurrence-feature-elimination method was used to identify the most discriminative feature subset. Results: The dynamic graph-theory indicators with a 3-s window width and 50% moving step achieved the highest classification performance, with an average accuracy of 95.2%. Notably, mean, median, and inter-quartile-range indicators in this condition reached 100% accuracy, with the least number of selected features. The distribution of selected features showed a preference for the frontal region and the Beta sub-band. Conclusions: A window width of 3 s and a 50% moving step emerged as optimal parameters for dynamic graph-theory analysis. Anomalies in dynamic local graph-theory indicators in the frontal lobe and Beta sub-band may serve as valuable biomarkers for diagnosing autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Grapheme-color synesthesia is a normal and healthy variation of human perception. It is characterized by the association of letters or numbers with color perceptions. The etiology of synesthesia is not yet fully understood. Theories include hyperconnectivity in the brain, cross-activation of adjacent or functionally proximate sensory areas of the brain, or various models of lack of inhibitory function in the brain. The growth factor brain-derived neurotrophic (BDNF) plays an important role in the development of neurons, neuronal pathways, and synapses, as well as in the protection of existing neurons in both the central and peripheral nervous systems. ELISA methods were used to compare BDNF serum concentrations between healthy test subjects with and without grapheme-color synesthesia to establish a connection between concentration and the occurrence of synesthesia. The results showed that grapheme-color synesthetes had an increased BDNF serum level compared to the matched control group. Increased levels of BDNF can enhance the brain's ability to adapt to changing environmental conditions, injuries, or experiences, resulting in positive effects. It is discussed whether the integration of sensory information is associated with or results from increased neuroplasticity. The parallels between neurodegeneration and brain regeneration lead to the conclusion that synesthesia, in the sense of an advanced state of consciousness, is in some cases a more differentiated development of the brain rather than a relic of early childhood. [ABSTRACT FROM AUTHOR]

This document is a compilation of various scientific articles related to the neurovascular unit (NVU) and its role in mental health disorders such as depression. The articles discuss the structural and functional damage to the NVU in diabetes-related depression, the use of selective serotonin reuptake inhibitors in depression treatment, and the association between chronic stress and depression. Other topics covered include the expression of glutamine and glutamate transporter proteins in NVU cells, the concept of the NVU, and the higher blood-brain barrier permeability in patients with major depressive disorder. The document provides a comprehensive overview of the current research on the NVU and its implications for depression. [Extracted from the article]

Background: Although males excel at motor tasks requiring strength, females exhibit greater motor learning flexibility. Cognitive flexibility is associated with low baseline mushroom spine densities achieved by pruning which can be triggered by α4βδ GABAA receptors (GABARs); defective synaptic pruning impairs this process. Methods: We investigated sex differences in adolescent pruning of mushroom spine pruning of layer 5 pyramidal cells of primary motor cortex (L5M1), a site essential for motor learning, using microscopic evaluation of Golgi stained sections. We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4βδ GABARs). We then compared performance of groups with different post-pubertal mushroom spine densities on motor learning (constant speed) and learning flexibility (accelerating speed following constant speed) rotarod tasks. Results: Mushroom spines in proximal L5M1 of female mice decreased >60% from PND35 (puberty onset) to PND56 (Pubertal: 2.23 ± 0.21 spines/10 μm; post-pubertal: 0.81 ± 0.14 spines/10 μm, P < 0.001); male mushroom spine density was unchanged. This was due to greater α4βδ GABAR expression in the female (P < 0.0001) because α4 -/- mice did not exhibit mushroom spine pruning. Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility. Conclusions: These results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice. [ABSTRACT FROM AUTHOR]

The corpus callosum--the largest commissural fiber system connecting the two cerebral hemispheres--is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons. [ABSTRACT FROM AUTHOR]

Objective: We utilized bibliometric and data visualization techniques to discern the primary research domains and emerging frontiers in the field of adult hippocampal neurogenesis (AHN). Methods: We systematically searched the Web of Science database for AHNrelated articles published between 2004 and 2023. The retrieved articles were filtered based on publication types (articles and reviews) and language (English). We employed CiteSpace, VOSviewer, and the online bibliometric platform (bibliometric.com) to visualize and analyze the collected data. Results: In total, 1,590 AHN-related publications were discovered, exhibiting a steady increase in yearly publications over time. The United States emerged as the leading contributor in AHN research in terms of both publication quantity and national influence. Among all research institutions in the field of AHN, the University of California System exhibited the highest impact. Kempermann, Gerd was the most active author. The publications of the top three active authors primarily focused on the functions of AHN, and reversing hippocampal damage and cognitive impairment by improving AHN. An analysis of reference co-citation clustering revealed 8 distinct research clusters, and the notable ones included "adult hippocampal neurogenesis," "neurogenesis," "hippocampus," "dentate gyrus," "neural stem cell," and "depression." Additionally, a burst keyword detection indicated that 'anxiety' is a current research hotspot in the field of AHN. Conclusion: This in-depth bibliographic assessment of AHN offers a deeper insight into the present research hotspots in the field. The association between AHN and cognitive diseases, such as Alzheimer's disease (AD) and anxiety, has emerged as a prominent research hotspot. [ABSTRACT FROM AUTHOR]

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.

Background: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Methods and results: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls. Conclusion: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming. [ABSTRACT FROM AUTHOR]

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders. [ABSTRACT FROM AUTHOR]

Background: To investigate whether the intraoperative superb microvascular imaging(SMI) technique helps evaluate lesion boundaries compared with conventional grayscale ultrasound in brain tumor surgery and to explore factors that may be associated with complete radiographic resection. Methods: This study enrolled 57 consecutive brain tumor patients undergoing surgery. During the operation, B-mode and SMI ultrasound evaluated the boundaries of brain tumors. MRI before and within 48h after surgery was used as the gold standard to evaluate gross-total resection(GTR). The ultrasound findings and GTR results were analyzed to determine the imaging factors related to GTR. Results: A total of 57 patients were enrolled in the study, including 32 males and 25 females, with an average age of 53.4 ± 14.1 years old(range 19 ~ 80). According to the assessment criteria of MRI, before and within 48 h after the operation, 37(63.9%) cases were classified as GTR, and 20(35.1%) cases were classified as GTR. In comparing tumor interface definition between B-mode and SMI mode, SMI improved HGG boundary recognition in 5 cases(P = 0.033). The results showed that the tumor size ≥ 5 cm and unclear ultrasonic boundary were independent risk factors for nGTR (OR>1, P<0.05). Conclusions: As an innovative intraoperative doppler technique in neurosurgery, SMI can effectively demarcate the tumor's boundary and help achieve GTR as much as possible. [ABSTRACT FROM AUTHOR]

Robotically assisted proteomics provides insights into the regulation of multiple proteins achieving excellent spatial resolution. However, developing an effective method for spatially resolved quantitative proteomics of formalin fixed paraffin embedded tissue (FFPE) in an accessible and economical manner remains challenging. We introduce non-robotic In-insert FFPE proteomics approach, combining glass insert FFPE tissue processing with spatial quantitative data-independent mass spectrometry (DIA). In-insert approach identifies 450 proteins from a 5 µm thick breast FFPE tissue voxel with 50 µm lateral dimensions covering several tens of cells. Furthermore, In-insert approach associated a keratin series and moesin (MOES) with prolactin-induced protein (PIP) indicating their prolactin and/or estrogen regulation. Our data suggest that PIP is a spatial biomarker for hormonally triggered cytoskeletal remodeling, potentially useful for screening hormonally affected hotspots in breast tissue. In-insert proteomics represents an alternative FFPE processing method, requiring minimal laboratory equipment and skills to generate spatial proteotype repositories from FFPE tissue. In-insert protocol offers cost-effective, versatile, and low loss spatial quantitative proteomic analysis of FFPE tissue, identifying prolactin-induced protein as a hormonal cytoskeleton reorganization spatial biomarker in mammary tissue. [ABSTRACT FROM AUTHOR]

Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study aimed to identify and synthesize evidence of the relationship between glial dysfunction and suicidal behavior to understand the neurobiology of suicide. As of 26 January 2024, 46 articles that met the inclusion criteria were identified by searching PubMed and ISI Web of Science. Most postmortem studies, including 30 brain regions, have determined no density or number of total Nissl-glial cell changes in suicidal patients with major psychiatric disorders. There were 17 astrocytic, 14 microglial, and 9 oligodendroglial studies using specific markers of each glial cell and further on their specific gene expression. Those studies suggest that astrocytic and oligodendroglial cells lost but activated microglia in suicides with affective disorder, bipolar disorders, major depression disorders, or schizophrenia in comparison with non-suicided patients and non-psychiatric controls. Although the data from previous studies remain complex and cannot fully explain the effects of glial cell dysfunction related to suicidal behaviors, they provide risk directions potentially leading to suicide prevention. [ABSTRACT FROM AUTHOR]

Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression. [ABSTRACT FROM AUTHOR]

Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an association between neurological complications in long COVID (sometimes referred to as 'post-acute sequelae of COVID-19') and α-synucleinopathies, but its underlying mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory responses. We also identified that S1 directly affects aggregation of α-synuclein in dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and mitochondrial ROS, and they provide pathological insights, as well as a foundation for the clinical management of α-synucleinopathies and the onset of neurological symptoms after the COVID-19 outbreak. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development. [ABSTRACT FROM AUTHOR]

Introduction: The cause of Developmental Coordination Disorder (DCD) is unknown, but neuroimaging evidence suggests that DCD may be related to altered brain development. Children with DCD show less structural and functional connectivity compared to typically developing (TD) children, but few studies have examined cortical volume in children with DCD. The purpose of this study was to investigate cortical grey matter volume using voxel-based morphometry (VBM) in children with DCD compared to TD children. Methods: This cross-sectional study was part of a larger randomized-controlled trial (ClinicalTrials.gov ID: NCT02597751) that involved various MRI scans of children with/without DCD. This paper focuses on the anatomical scans, performing VBM of cortical grey matter volume in 30 children with DCD and 12 TD children. Preprocessing and VBM data analysis were conducted using the Computational Anatomy Tool Box-12 and a study-specific brain template. Differences between DCD and TD groups were assessed using a one-way ANOVA, controlling for total intracranial volume. Regression analyses examined if motor and/or attentional difficulties predicted grey matter volume. We used threshold-free cluster enhancement (5,000 permutations) and set an alpha level of 0.05. Due to the small sample size, we did not correct for multiple comparisons. Results: Compared to the TD group, children with DCD had significantly greater grey matter in the left superior frontal gyrus. Lower motor scores (meaning greater impairment) were related to greater grey matter volume in left superior frontal gyrus, frontal pole, and right middle frontal gyrus. Greater grey matter volume was also significantly correlated with higher scores on the Conners 3 ADHD Index in the left superior frontal gyrus, superior parietal lobe, and precuneus. These results indicate that greater grey matter volume in these regions is associated with poorer motor and attentional skills. Discussion: Greater grey matter volume in the left superior frontal gyrus in children with DCD may be a result of delayed or absent healthy cortical thinning, potentially due to altered synaptic pruning as seen in other neurodevelopmental disorders. These findings provide further support for the hypothesis that DCD is related to altered brain development. [ABSTRACT FROM AUTHOR]

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Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms. [ABSTRACT FROM AUTHOR]

In previous studies, we showed that fibroblast growth factor receptors (FGFRs) contribute to inflammatory mediator output from primary rhesus microglia in response to live Borrelia burgdorferi. We also demonstrated that non-viable B. burgdorferi can be as pathogenic as live bacteria, if not more so, in both CNS and PNS tissues. In this study we assessed the effect of live and non-viable B. burgdorferi in inducing FGFR expression from rhesus frontal cortex (FC) and dorsal root ganglion (DRG) tissue explants as well as their neuronal/astrocyte localization. Specific FGFR inhibitors were also tested for their ability to attenuate inflammatory output and apoptosis in response to either live or non-viable organisms. Results show that in the FC, FGFR2 was the most abundantly expressed receptor followed by FGFR3 and FGFR1. Non-viable B. burgdorferi significantly upregulated FGFR3 more often than live bacteria, while the latter had a similar effect on FGFR1, although both treatments did affect the expressions of both receptors. FGFR2 was the least modulated in the FC tissues by the two treatments. FGFR1 expression was more prevalent in astrocytes while FGFR2 and FGFR3 showed higher expression in neurons. In the DRG, all three receptor expressions were also seen, but could not be distinguished from medium controls by immunofluorescence. Inhibition of FGFR1 by PD166866 downregulated both inflammation and apoptosis in both FC and DRG in response to either treatment in all the tissues tested. Inhibition of FGFR1-3 by AZD4547 similarly downregulated both inflammation and apoptosis in both FC and DRG in response to live bacteria, while with sonicated remnants, this effect was seen in one of the two FC tissues and 2 of 3 DRG tissues tested. CCL2 and IL-6 were the most downregulated mediators in the FC, while in the DRG it was CXCL8 and IL-6 in response to FGFR inhibition. Downregulation of at least two of these three mediators was observed to downregulate apoptosis levels in general. We show here that FGFR inhibition can be an effective anti-inflammatory treatment in antibiotic refractive neurological Lyme. Alternatively, two biologics may be needed to effectively curb neuroinflammation and pathology in the CNS and PNS. [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence-powered interventions have emerged as promising tools to support autistic individuals. However, more research must examine how teachers and educators perceive and experience these AI systems when implemented. Objectives: The first objective was to investigate informants' perceptions and experiences of AI-empowered interventions for children with autism. Mainly, it explores the informants' perceived benefits and challenges of using AI-empowered interventions and their recommendations for avoiding the perceived challenges. Methodology: A qualitative phenomenological approach was used. Twenty educators and parents with experience implementing AI interventions for autism were recruited through purposive sampling. Semi-structured and focus group interviews conducted, transcribed verbatim, and analyzed using thematic analysis. Findings: The analysis identified four major themes: perceived benefits of AI interventions, implementation challenges, needed support, and recommendations for improvement. Benefits included increased engagement and personalized learning. Challenges included technology issues, training needs, and data privacy concerns. Conclusions: AI-powered interventions show potential to improve autism support, but significant challenges must be addressed to ensure effective implementation from an educator's perspective. The benefits of personalized learning and student engagement demonstrate the potential value of these technologies. However, with adequate training, technical support, and measures to ensure data privacy, many educators will likely find integrating AI systems into their daily practices easier. Implications: To realize the full benefits of AI for autism, developers must work closely with educators to understand their needs, optimize implementation, and build trust through transparent privacy policies and procedures. With proper support, AI interventions can transform how autistic individuals are educated by tailoring instruction to each student's unique profile and needs. [ABSTRACT FROM AUTHOR]