Multimodal Investigation Research Articles

The STAR collaborative nonsuicidal self-injury study: methods and sample description of the face-to-face sample

BackgroundNonsuicidal self-injury (NSSI) is highly prevalent in adolescents and young adults worldwide. It is linked to a broad variety of mental disorders and an increased suicide risk. Despite its high prevalence, research on the underlying mechanisms and on potential risk and resilience factors for maintaining or quitting NSSI remains scarce. This manuscript presents an overview of the “Self-injury: Treatment-Assessment-Recovery” (STAR) collaboration, which aimed to address these gaps.MethodsWe investigated the natural course of NSSI as well as its social, psychological, and neurobiological predictors (observational study; OS). OS data collection occurred at four timepoints (baseline [T0], 4 [post, T1], 12 [follow-up (FU), T2], and 18 [FU, T3] months after baseline) for the NSSI group, which was compared to a healthy control (HC) group at T0 only. Online self-report was used at all timepoints, while semi-structured interviews (face-to-face (f2f)) were conducted at T0 and T3. At T0 only, we conducted ecological momentary assessment and neurobiological investigations. Here, we present the general methodology and sample characteristics of the completed OS including the f2f subprojects, while other subprojects are not within the scope of this paper.Sample descriptionThe OS sample consists of 343 participants at T0 (180 NSSI, 163 HC). Mean age in the NSSI group (T0) was 18.1 years (SD = 2.09, range: 15–25), gender-related data is available for 166: 156 = female, 7 = male, 3 = transgender, 10 = not disclosed). In the HC group, mean age (T0) was 19.1 years (SD = 2.35, range: 15–25) (142 = female, 21 = male). At T1, 128 (71.11%) of the NSSI participants completed the questionnaires, at T2 125 (69.44%) and at T3 104 (57.78%). In the fMRI subproject, 126 adolescents participated (NSSI = 66, HC = 60, 100% female; mean age (T0): NSSI = 18.10 years, SD = 2.21; HC = 19.08, SD = 2.36).ConclusionUnderstanding predictors is of utmost importance for adequate diagnosis and intervention for NSSI. Our OS applied a multimodal investigation of social, psychological, and neurobiological parameters and is the largest sample of adolescents with NSSI to date including follow-up assessments. As health care providers require specific knowledge to develop new treatments, we believe that our in-depth assessments can potentially enhance care for youths engaging in NSSI.

Multimodal investigation of dynamic brain network alterations in autism spectrum disorder: Linking connectivity dynamics to symptoms and developmental trajectories

BackgroundAutism spectrum disorder (ASD) has been associated with disrupted brain connectivity, yet a comprehensive understanding of the dynamic neural underpinnings remains lacking. This study employed concurrent electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) techniques to investigate dynamic functional connectivity (dFC) patterns and neurovascular characteristics in children with ASD. We also explored associations between neurovascular characteristics and the developmental trajectory of adaptive behavior in individuals with ASD. MethodsResting-state EEG and fNIRS data were simultaneously recorded from 58 ASD and 63 TD children. We implemented a k-means clustering approach to extract the dFC states for each modality. In addition, a multimodal covariance network (MCN) was constructed from the EEG and fNIRS dFC features to capture the neurovascular characteristics linked to ASD. ResultsEEG analyses revealed atypical properties of dFC states in the beta and gamma bands in children with ASD compared to TD children. For fNIRS, the ASD group exhibited atypical properties of dFC states such as duration and transitions relative to the TD group. The MCN analysis revealed significantly suppressed functional covariance between right superior temporal and left Broca's areas, alongside enhanced right dorsolateral prefrontal-left Broca covariance in ASD. Notably, we found that early neurovascular characteristics can predict the developmental progress of adaptive functioning in ASD. ConclusionThe multimodal investigation revealed distinct dFC patterns and neurovascular characteristics associated with ASD, elucidating potential neural mechanisms underlying core symptoms and their developmental trajectories. Our study highlights that integrating complementary neuroimaging modalities may aid in unraveling the complex neurobiology of ASD.

The role of mood in shaping reactions to smoking cessation messages among adults who smoke: a multimodal investigation

IntroductionMood-tailored communications may help increase the effectiveness of smoking cessation messaging interventions. We used both self-report and psychophysiological measures to test the impact of mood on responses to cessation messages in adults who smoke.MethodsIn a two-part (crowdsourcing and psychophysiological studies) study, the impact of 30 smoking cessation messages comprised of five themes (i.e., financial, health, quality-of-life, challenges in quitting, motivation to quit) were tested. In a crowdsourcing study, participants (N = 600) were randomly placed into one of three mood induction tasks (i.e., positive, negative, neutral), and then viewed the smoking cessation messages. After each message, they were asked to self-report their motivation to quit, message receptivity, and the perceived relevance of the messages. In an in-lab, psychophysiological study, participants (N = 42) completed the same tasks as the crowdsourcing participants but were monitored for heart rate, skin conductance, and eye-tracking while viewing the cessation messages. Using a multi-attribute decision-making model (MADM) using outcomes from both studies, messages were ranked for each mood state.ResultsThe top messages for participants in the positive mood condition included the challenges in quitting, financial costs/rewards, and motivations to quit themes. The top messages for participants assigned to the negative mood condition included the challenges in quitting, quality-of-life, and financial costs/rewards themes. For participants in the neutral mood condition, messages in the challenges in quitting and quality of life themes performed best.ConclusionsVariations in the preferences of messages and themes by mood condition suggest that mood-tailored communication may increase the effectiveness of smoking cessation messages.

Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy.

Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism.

The spectrum of systemic sclerosis-associated pulmonary hypertension: Insights from the ASPIRE registry

There are limited data assessing the spectrum of systemic sclerosis-associated pulmonary hypertension (PH). Data for 912 systemic sclerosis patients assessed between 2000and 2020 were retrieved from the Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre (ASPIRE) registry and classified based on 2022 European Society of Cardiology/European Respiratory Society(ESC/ERS) guidelines and multimodality investigations. Reduction in pulmonary vascular resistance (PVR) diagnostic threshold to >2WU resulted in a 19% increase in precapillary PH diagnoses. Patients with PVR ≤2WU had superior survival to PVR >2-3WU which was similar to PVR >3-4WU. Survival in pulmonary arterial hypertension (PAH) was superior to PH associated with lung disease. However, patients with mild parenchymal disease on CT had similar characteristics and outcomes to patients without lung disease. Combined pre- and postcapillary PH had significantly poorer survival than isolated postcapillary PH. Patients with mean pulmonary arterial wedge pressure (PAWP) 13-15mmHg had similar haemodynamics and left atrial volumes to those with PAWP>15mmHg. Unclassified-PH had more frequently dilated left atria and higher PAWP than PAH. Although Unclassified-PH had a similar survival to No-PH, 36% were subsequently diagnosed with PAH or PH associated with left heart disease. The presence of 2-3 radiological signs of pulmonary veno-occlusive disease was noted in 7% of PAH patients and was associated with worse survival. Improvement in incremental shuttle walking distance of ≥30m following initiation of PAH therapy was associated with superior survival. PAH patients diagnosed after 2011 had greater use of combination therapy and superior survival. A number of systemic sclerosis PH phenotypes can be recognized and characterized using haemodynamics, lung function and multimodality imaging.

Intrinsic functional and structural network organization in the macaque insula

Abstract In recent decades, in vivo magnetic resonance imaging (MRI) studies have provided previously inaccessible insights into the structure and function of healthy and pathological human brains in the laboratory and the clinic. However, the correlational nature of this work and relatively low resolution mean that ground truth neuroanatomical studies and causal manipulations of neural circuitry must still occur in animal models offering greater tractability and higher resolution, rendering a scale and species gap in translation. Here, we bridge this gap with a detailed, multimodal investigation of the macaque insula in vivo. Using both functional and diffusion MRI—tools available for use in humans—we demonstrate a neural architecture in the macaque insula with clear correspondence to prior in vivo MRI findings in humans and postmortem cytoarchitectural and tract-tracing studies in monkeys. Results converged across analysis methods and imaging modalities, supporting the translational potential of the macaque model.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

A Multimodal Investigation: Epistemological Implications from Video Art

A Multimodal Investigation: Epistemological Implications from Video Art

Children and adolescents with primary headaches exhibit altered sensory profiles – a multi-modal investigation

BackgroundPediatric headache is an increasing medical problem that has adverse effects on children’s quality of life, academic performance, and social functioning. Children with primary headaches exhibit enhanced sensory sensitivity compared to their healthy peers. However, comprehensive investigations including multimodal sensory sensitivity assessment are lacking. This study aimed to compare sensory sensitivity of children with primary headaches with their healthy peers across multiple sensory domains.MethodsThe study included 172 participants aged 6 to 17 years (M = 13.09, SD = 3.02 years; 120 girls). Of these 80 participants were patients with migraine, 23 were patients with tension-type headache, and 69 were healthy controls. The following sensory measures were obtained: Mechanical Detection Threshold (MDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), detection and pain threshold for Transcutaneous Electrical Nerve Stimulation (TENS), olfactory and intranasal trigeminal detection threshold, and odor identification ability. Sensory sensitivity was compared between groups with a series of Kruskal-Wallis tests. Binomial regression models were used to compare the relative utility of sensory sensitivity measures in classifying participants into patients and healthy controls, as well as into patients with migraine and tension-type headache.ResultsPatients with migraine had lower MPT measured at the forearm than patients with tension-type headaches and healthy controls. MPS was higher in patients with migraine than in healthy controls. All patients with headaches had lower detection threshold of TENS and higher olfactory sensitivity. Healthy controls showed increased intranasal trigeminal sensitivity. Scores in MPS, TENS, and olfactory and trigeminal thresholds were significantly predicting presence of primary headaches. Additionally, scores in MPT, olfactory and trigeminal threshold were positive predictors of type of headache.ConclusionsChildren with primary headaches exhibit different sensory profiles than healthy controls. The obtained results suggest presence of increased overall, multimodal sensitivity in children with primary headaches, what may negatively impact daily functioning and contribute to further pain chronification.Trial registrationThe study was registered in the German Registry of Clinical Trials (DRKS) DRKS00021062.

The relation between stress-induced dopamine release in the ventromedial prefrontal cortex, fronto-striatal functional connectivity, and negative urgency: A multimodal investigation using [18F]Fallypride PET, MRI and experience sampling

Negative urgency (NU), or the tendency to act rashly when stress of negative affect is high, could be the result of an insufficient control of the ventromedial prefrontal cortex (vmPFC) over the striatum, through an impaired dopamine (DA) transmission. Therefore, we investigated in vivo human stress-induced DA release in the vmPFC, its relation with fronto-striatal functional connectivity (FC), and NU in daily life. In total, 12 female healthy participants performed a simultaneous [18 F]fallypride PET and fMRI scan during which stress was induced. Regions displaying stress-induced DA release were identified and used to investigate stress-induced changes in fronto-striatal FC. Additionally, participants enrolled in an experience sampling study, reporting on daily life stress and rash actions over a 12-month-long period. Mixed models explored whether stress-induced DA release and FC moderated NU in daily life. Stress led to a lower FC between the vmPFC and dorsal striatum, but a higher FC between the vmPFC and contralateral ventral striatum. Participants with a higher FC between the vmPFC and dorsal striatum displayed more NU in daily life. A higher stress-induced DA release in the vmPFC was related to a higher stress-induced change in FC between the vmPFC and striatum. Participants with a higher DA release in the vmPFC displayed more NU in daily life. In conclusion, stress could differentially impact fronto-striatal FC whereby the connectivity with the dorsal striatum is especially important for NU in daily life. This could be mediated by a higher, but not a lower, stress-induced DA release in the vmPFC.

IMG-10. IMAGING SUBTYPES OF PEDIATRIC LOW-GRADE GLIOMA ARE ASSOCIATED WITH DISTINCT MOLECULAR CHARACTERISTICS

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) have diverse molecular subtypes with distinct prognoses, necessitating personalized treatments. We aimed to determine whether radiomic features of pLGGs co-segregate with molecular subtypes, establishing a proof-of-concept that distinct molecular aberrations could manifest in differentiable imaging features. METHODS Leveraging radiomic, genomic, and transcriptomic data from 201 pLGG patients from the Children’s Brain Tumor Network (CBTN), we identified imaging-based pLGG subtypes through their radiophenotypes. This involved investigating the association of imaging subtypes with 2021 WHO pLGG classifications and profiling transcriptional characteristics distinguishing pLGG clusters. We used principal component analysis and K-Means clustering on 881 radiomic features and incorporated clinical variables (age, sex, tumor location), and derived three imaging subtypes. RESULTS BRAF V600E mutations were mainly found in subtype 3, while BRAF::KIAA1549 fusion in subtype 1. To ascertain transcriptome pathways most closely associated with imaging-based subtypes, we applied a supervised machine learning model with elastic net logistic regression using a one-versus-rest strategy for each imaging cluster, considering the top 100 most variable pathways, identified through gene set enrichment and gene co-expression network analyses, molecular subtype, tumor location, age, sex, and race. The predictive accuracy (area under the receiver operating characteristic curve) of the model was 0.86 | 0.72 for imaging subtype 1, 0.93 | 0.71 for subtype 2, and 0.91 | 0.64 for subtype 3 in the training | testing sets. Notably, each imaging subtype exhibited distinct molecular mechanisms; subtype 1 showed up-regulation of oxidative phosphorylation, PDGFRB, and interleukin 4, 10, and 13 signaling, while subtype 3 was linked to histone acetylation and DNA methylation pathways, relating to BRAF V600E pLGGs. CONCLUSIONS Our radiogenomics study suggests that intrinsic molecular characteristics of tumors drive distinct imaging subgroups of pLGG, providing a basis for future multi-modal investigations that may better define progression and targetability of the disease.

Understanding Structural Brain Alterations in Anorexia Nervosa: A Multimodal Investigation of Morphometry, Magnetic Resonance Spectroscopy and Blood-Based Biomarkers

Understanding Structural Brain Alterations in Anorexia Nervosa: A Multimodal Investigation of Morphometry, Magnetic Resonance Spectroscopy and Blood-Based Biomarkers

183. A Multimodal Investigation of the Antidepressant Mechanisms of rTMS: Glutamatergic Metabolism Influences Changes in Functional Connectivity

183. A Multimodal Investigation of the Antidepressant Mechanisms of rTMS: Glutamatergic Metabolism Influences Changes in Functional Connectivity

Complex drivers of geomorphic response and habitat formation revealed in multiyear monitoring of Cosumnes River experimental floodplain reconnection

In this study, we examine a novel levee breach experiment that reconnected a floodplain along the Cosumnes River, California to determine the decadal impact of removing 250 meters of levee and assess the recruitment of large wood. This is the latest study in an ongoing series of investigations 40 years in the making along the largest river on the western slope of the Sierra Nevada without a major dam. We present the findings of this multi-modal investigation here by first measuring the geomorphic alteration of the floodplain surface to quantify the depletion and accretion of sediment across the excavated site. We then identify and quantify the deposition of large wood. Results indicate initiation of anastomosing channel formation and distinct areas of large wood recruitment supporting a naturally evolving lateral levee. Accretion resulted in more than 25,000 m3 of sediment deposition within the original excavation site, the development of multiple sand splays, and natural recruitment of native riparian tree species. We conclude by discussing implications following other approaches to floodplain restoration as a Nature-based Solution. In episodic flow regimes, like in California’s Mediterranean-montane hydroclimatic regime, restoring lateral hydrologic connectivity facilitates ecosystem function. Large flood pulse events drive sediment dynamics and geomorphic heterogeneity while enriching biodiversity through biogeochemical fluxes and habitat creation on reconnected floodplains that store floodwaters and reduce peak discharge. These findings support the importance of long-term monitoring efforts of floodplain restoration.

Time Resolved Cryo‐Correlative Light and Electron Microscopy

AbstractComplex materials exhibit fascinating features especially in situations far from equilibrium. Thus, methods for investigating structural dynamics with sub‐second time resolution are becoming a question of interest at varying spatial scales. With novel microscopy techniques steadily improving, the temporal and spatial limits of multiple imaging methods are investigated with an emphasis on the important role of correlative imaging and cryo‐fixation. A deep‐dive is taken into cryo‐correlative light and electron microscopy (CLEM) as a starting point for multimodal investigations of ultrastructural dynamics at high spatiotemporal resolution. The focus is on highlighting the different microscopy methods that capture the following key aspects: 1) samples are as close to native state as possible 2) dynamic process information is captured, 3) high structural resolution is enabled. Additionally, the size of samples that can be imaged under these conditions is looked at and approaches not only focusing on single molecules, but larger structures are highlighted.

Vocal tasks-based EEG and speech signal analysis in children with neurodevelopmental disorders: a multimodal investigation

Vocal tasks-based EEG and speech signal analysis in children with neurodevelopmental disorders: a multimodal investigation

Study protocol for identifying resting brain functional connectivity markers of response to continuous Theta Burst Stimulation and cathodal transcranial Direct Current Stimulation in patients with schizophrenia with persistent auditory hallucinations

Background Schizophrenia is one of the most burdensome psychiatric disorders. Novel neuromodulatory techniques including cathodal transcranial direct current stimulation (c-tDCS) and continuous theta burst stimulation (cTBS) using repetitive transcranial magnetic stimulation (rTMS) are increasingly being used in alleviating the auditory verbal hallucinations that are persisting despite adequate antipsychotic treatment. Brain connectivity modulation by stimulating the left temporoparietal junction is thought to mediate these effects. The differential neurobiological mechanisms and efficacy of these two neuromodulation techniques are not known. We are unaware of any systematic studies that can guide clinicians in choosing between the two techniques. This protocol describes a parallel-arm, double-blind, randomized cross-over study to identify resting brain functional connectivity markers of response to cTBS and c-tDCS persistent auditory hallucinations to improve the efficacy of interventions. Methods Two hundred and ten consenting patients with schizophrenia with persistent auditory hallucinations will be randomly assigned to receive 15 days (30 sessions) of c-tDCS+sham-TBS or sham-tDCS+cTBS over the left temporoparietal region at three study centres. After a gap of 2-4 weeks, non-responders to the intervention will cross-over to the other arm. Clinical assessments, neurocognitive assessments, and multimodal investigations (magnetic resonance imaging, electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphisms) will be conducted at baseline and repeated after the end of both phases of the trial. A differential pre-treatment resting brain functional connectivity signal will identify responders to cTBS or c-tDCS. Registration Clinical Trial Registry of India (CTRI/2021/05/033783) registered on 25/05/2021.

Remodeling the tumor-immune microenvironment by anti-CTLA4 blockade enhanced subsequent anti-PD-1 efficacy in advanced nasopharyngeal carcinoma

Sequential immunotherapy has shown certain advantages in malignancy. Here, we aim to evaluate the efficacy of sequential anti-CTLA-4 and anti-PD-1 treatment for recurrent or metastatic nasopharyngeal carcinoma patients (R/M NPC). We retrospectively analysis 2 phase I trial of ipilimumab and camrelizumab in Chinese R/M NPC patients. These patients were initially treated with ipilimumab, a CTLA4 blockade, followed by anti-PD-1 treatment. We observed a durable tumor remission in these patients (mPFS: 12.3 months; mDoR: 20.9 months). Multimodal investigations of biopsy samples disclosed remodeling of tumor-immune microenvironment triggered by ipilimumab. In responders, we found increased tumoral PD-L1/PD-L2 expression and T-cell infiltration after ipilimumab treatment, accompanied by reduced stroma and malignant cell components. In contrast, non-responders exhibited increased B-cell infiltration and increased peripheral CD19 + B cells, suggesting a defective transition from memory B cells to plasma cells. This study proposes that sequential therapy can potentially enhance treatment efficacy in chemotherapy-resistant NPC patients and provides insights into how preexisting anti-CTLA4 blockade can influence subsequent anti-PD-1 efficacy by remodeling the TME. Additionally, our results highlight the need for therapeutic strategies targeting naïve/memory B cells.

Are hemodynamics responsible for inflammatory changes in venous vessel walls? A quantitative study of wall-enhancing intracranial arteriovenous malformation draining veins.

Signal enhancement of vascular walls on vessel wall MRI might be a biomarker for inflammation. It has been theorized that contrast enhancement on vessel wall imaging (VWI) in draining veins of intracranial arteriovenous malformations (AVMs) may be associated with disease progression and development of venous stenosis. The aim of this study was to investigate the relationship between vessel wall enhancement and hemodynamic stressors along AVM draining veins. Eight AVM patients with 15 draining veins visualized on VWI were included. Based on MR venography data, patient-specific 3D surface models of the venous anatomy distal to the nidus were segmented. The enhanced vascular wall regions were manually extracted and mapped onto the venous surface models after registration of image data. Using image-based blood flow simulations applying patient-specific boundary conditions based on phase-contrast quantitative MR angiography, hemodynamics were investigated in the enhanced vasculature. For the shear-related parameters, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) were calculated. Velocity, oscillatory velocity index (OVI), and vorticity were extracted for the intraluminal flow-related hemodynamics. Visual observations demonstrated overlap of enhancement with local lower shear stresses resulting from decreased velocities. Thus, higher RRT values were measured in the enhanced areas. Furthermore, nonenhancing draining veins showed on average slightly higher flow velocities and TAWSS. Significant decreases of 55% (p = 0.03) for TAWSS and of 24% (p = 0.03) for vorticity were identified in enhanced areas compared with near distal and proximal domains. Velocity magnitude in the enhanced region showed a nonsignificant decrease of 14% (p = 0.06). Furthermore, increases were present in the OSI (32%, p = 0.3), RRT (25%, p = 0.15), and OVI (26%, p = 0.3) in enhanced vessel sections, although the differences were not significant. This novel multimodal investigation of hemodynamics in AVM draining veins allows for precise prediction of occurring shear- and flow-related phenomena in enhanced vessel walls. These findings may suggest low shear to be a local predisposing factor for venous stenosis in AVMs.

Decoding and reconstructing disease relations between dry eye and depression: a multimodal investigation comprising meta-analysis, genetic pathways and Mendelian randomization

IntroductionThe clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined. ObjectivesTo this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP. MethodsA meta-analysis comprising 26 case−control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP. ResultsOur meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (rG = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein−protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained. ConclusionWith the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.