DataSheet_1_Personalized connectivity-based network targeting model of transcranial magnetic stimulation for treatment of psychiatric disorders: computational feasibility and reproducibility.docx

Repetitive transcranial magnetic stimulation (rTMS) holds promise for treating psychiatric disorders; however, the variability in treatment efficacy among individuals underscores the need for further improvement. Growing evidence has shown that TMS induces a broad network modulatory effect, and its effectiveness may rely on accurate modulation of the pathological network specific to each disorder. Therefore, determining the optimal TMS coil setting that will engage the functional pathway delivering the stimulation is crucial. Compared to group-averaged functional connectivity (FC), individual FC provides specific information about a person’s brain functional architecture, offering the potential for more accurate network targeting for personalized TMS. However, the low signal-to-noise ratio (SNR) of FC poses a challenge when utilizing individual resting-state FC. To overcome this challenge, the proposed solutions include increasing the scan duration and employing the cluster method to enhance the stability of FC. This study aimed to evaluate the stability of a personalized FC-based network targeting model in individuals with major depressive disorder or schizophrenia with auditory verbal hallucinations. Using resting-state functional magnetic resonance imaging data from the Human Connectome Project, we assessed the model’s stability. We employed longer scan durations and cluster methodologies to improve the precision in identifying optimal individual sites. Our findings demonstrate that a scan duration of 28 minutes and the utilization of the cluster method achieved stable identification of individual sites, as evidenced by the intraindividual distance falling below the ~1cm spatial resolution of TMS. The current model provides a feasible approach to obtaining stable personalized TMS targets from the scalp, offering a more accurate method of TMS targeting in clinical applications.</p

Table_2_Weighted gene co-expression network analysis identifies dysregulated B-cell receptor signaling pathway and novel genes in pulmonary arterial hypertension.XLSX

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.</p

Data_Sheet_1_Weighted gene co-expression network analysis identifies dysregulated B-cell receptor signaling pathway and novel genes in pulmonary arterial hypertension.PDF

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.</p

Table_1_Weighted gene co-expression network analysis identifies dysregulated B-cell receptor signaling pathway and novel genes in pulmonary arterial hypertension.XLSX

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.</p

Time course of Mn²⁺ transport through the habenulomesencephalic pathway.

<p>(A) Anatomical MR image illustrating the site of unilateral infusion of MnCl₂ into the dorsal diencephalon. The injection site, which appears as a black circle on the right side of the image, encompassed the entire habenula and a portion of the mediodorsal nucleus of the thalamus. An overlay adapted from the atlas of Paxinos and Watson [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127773#pone.0127773.ref032" target="_blank">32</a>] is positioned on the left side of the image for orientation. Abbreviations: Hip-hippocampus; Hab—habeunla; MD—mediodorsal nucleus of the thalamus; ic—internal capsule; 3V – 3^<b>rd</b> ventricle. (B) Corresponding T1 weighted images showing the distribution of Mn^<b>2+</b>hyperintensityat the injection site 2.5 hours (B1) and 9 hours (B2) after infusion. (C-D) Representative coronal sections of the caudal midbrain at 0, 2, 4, and 6 hours (1–4, respectively) after the start of the imaging study in a sham control (C) and MnCl₂-injected rat (D). Note the time-dependent increase in MR signal intensity in the IPN beginning 3.25 hours following the start of MnCl₂ injection into the Hb (cf. region below black arrowhead in image D₄). MRI images presented in A,B and D were obtained from the same rat. (E) Summary of the changes in longitudinal relaxation rate (ordinate) within the IPN as a function of the time (in hours) after MnCl₂ injection in the Hb (abscissa). Each point represents the arithmetic mean ± SEM of 8–11 animals. Asterisks denote a significant difference from sham injection controls.</p

Data_Sheet_2_Weighted gene co-expression network analysis identifies dysregulated B-cell receptor signaling pathway and novel genes in pulmonary arterial hypertension.PDF

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.</p

Table_3_Weighted gene co-expression network analysis identifies dysregulated B-cell receptor signaling pathway and novel genes in pulmonary arterial hypertension.xlsx

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.</p

Electrophysiological characteristics of spontaneously active habenula neurons following MnCl₂ injection.

<p>All values represent the mean ± SEM. There were no significant correlations with time from injection (all p-values > 0.05).</p><p>* Spike width was measured at half-amplitude (peak-to-peak).</p><p>Electrophysiological characteristics of spontaneously active habenula neurons following MnCl₂ injection.</p

AMPA enhances Mn²⁺ uptake into Hb projection neurons in part through a TTX-insensitive mechanism.

<p>Changes in longitudinal relaxation rate in the IPN expressed as a function of time after the start of Mn^<b>2+</b> injection into the Hb. * P < 0.05 vs. Mn^<b>2+</b> only; # p< 0.05 vs. Mn^<b>2+</b> + AMPA.</p

Concomitant blockade of voltage-activated Na⁺ and Ca²⁺ channels prevents AMPA-induced enhancement of Mn²⁺ accumulation in the IPN.

<p>Changes in longitudinal relaxation rate in the IPN expressed as a function of time after the start of Mn^<b>2+</b> injection into the Hb. * P < 0.05 vs. Mn^<b>2+</b> only.</p