Brain Research Bulletin

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood, debilitating multisystem condition. Converging evidence implicates impaired cellular bioenergetics, neuroinflammation and defective neurovascular coupling that may manifest as "virtual hypoxia" only under physiological stress. Methods We performed a single-session multimodal 3T MRI study combining brain volumetry, arterial spin labelling (ASL) and multivoxel proton magnetic resonance spectroscopy under normoxia and two controlled hypoxic challenges (oxygen saturation 87 {+/-} 3%) in 26 ME/CFS patients and 27 age- and sex-matched healthy controls. Results After intracranial-volume normalization, patients showed a reduced brainstem volume (1.46 0.14 vs. 1.55 {+/-} 0.18 % of eTIV; p = 0.013, FDR-p = 0.039), whereas deep grey matter and whole-brain parenchymal fraction did not differ between groups. Whole-brain cerebral blood flow (CBF) rose under hypoxia in both groups (controls +4.8 {+/-} 13.0%, patients +3.7 {+/-} 11.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p = 0.001). Thalamic lactate-to-creatine (Lac/tCr) ratios increased with hypoxia in controls (FDR-p = 0.028) but were already elevated at normoxia in patients (0.171 vs. 0.135; FDR-p = 0.021) and did not rise further (FDR-p = 0.38). In exploratory analyses, patients showed exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF. Conclusions These findings provide in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and highlighting candidate imaging markers for stratification that warrant validation.

Background: Chronic pain affects hundreds of millions worldwide and remains a major clinical challenge, despite numerous available treatments. Advances in brain imaging offer a promising path toward identifying neural signatures of chronic pain, potentially enhancing diagnosis and guiding treatment. However, while a core set of brain regions, including the insula, cingulate, and somatosensory cortices, has been repeatedly implicated, findings regarding other regions and connectivity patterns involved remain inconsistent, with limited robust replication. Objective: To address these gaps, the present work characterizes resting-state functional connectivity and gray matter volume differences between chronic pain patients and pain-free controls. Methods: In this secondary analysis of publicly available data, anatomical and resting-state functional MRI were analyzed from 56 patients with chronic knee pain due to osteoarthritis and 20 pain-free controls. Group comparisons used Network-Based Statistic (NBS) and Bayesian multivariate regression models, controlling for demographic covariates. Results: In the pain group, about 75% of parcellated brain regions exhibited increased functional connectivity compared to controls. The 30 highest degree centrality regions in the NBS network were concentrated in regions consistent with prior pain neuroimaging findings. Additionally, chronic pain patients exhibited reduced gray matter volume (-3.98%; SD 1.2%) across 33% of parcellated brain regions, including key regions implicated in pain processing. Conclusions: These findings demonstrate widespread functional and anatomical neural alterations in chronic pain, revealing a global pattern of reorganization extending beyond previously reported network-pair effects. Characterizing such alterations may contribute to ongoing efforts to identify neuroimaging markers of chronic pain, with potential translational relevance.

Despite its high prevalence and socioeconomic costs, the condition of tinnitus shares with related neuropsychiatric disorders the characteristic that, to this day, it cannot be cured. Two contradictory views of the origin of tinnitus (peripheral hyperexcitability and central brain oscillation changes linked to prediction error) are currently discussed without any regard for one another. We now firstly used a compact 64 sensor optically pumped magnetometer (OPM)-MEG system to study a group of tinnitus subjects without co-morbidity of hyperacusis. This new technology provided an unprecedented opportunity for analyzing hemisphere-specific brain activity changes with high spatial resolution in response to pure-tones with a pitch within or outside the tinnitus frequency. We observed in tinnitus smaller ABR amplitudes (reflecting reduced cochlear output synchrony) linked with reduced alpha and enhanced gamma activity at rest (reflecting elevated excitement of intracortical circuits). In tinnitus, reduced alpha and enhanced gamma brain activity at rest were associated with reduced evoked alpha, beta, and gamma in response to pure-tones within tinnitus frequencies (reflecting low signal-to-noise ratios in auditory target regions). Furthermore, elevated gamma activity in key regions in the brain involved in attention control was observed in tinnitus subjects: hypergamma activity was seen in posterior/frontal regions, that -when hyperactive - are predicted to trigger excessive attention to irrelevant stimuli. Weakened cochlear output synchrony, possibly through lowering tonic inhibitory strength in the ascending auditory pathway, can thus reduce alpha activity (default-mode network) and unleash cortical regions that control attention to irrelevant stimuli -- tracing tinnitus to perception.

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Background: Hearing loss is a potentially modifiable risk factor for brain health, but whether it acts as a causal lever remains unclear. Methods: We constructed an ear-disease comorbidity network from NHANES 2011-2020 (N=18,939, 16 nodes, 62 edges), performed bidirectional Mendelian randomization (MR) across 24 exposure-outcome pairs, and triangulated evidence with longitudinal data from CHARLS (N=17,101). Results: Subjective hearing symptoms (prevalence 6.1%) occupied hub positions in the comorbidity network, whereas objective hearing impairment (8.0%) was sparsely connected. All forward MR estimates were null after multiple-testing correction (IVW P>.05 for 9 of 9 pairs). Reverse MR showed one nominally significant association (cognition to objective hearing beta=-0.15, P=.013) that did not survive correction. Longitudinal analysis yielded HR=1.57 (P=.00004) for subjective hearing symptoms predicting incident depression. Conclusions: Perceived hearing symptoms organize the ear-disease comorbidity network but are not a causal lever for brain health. These findings support a "flag, not lever" framework: subjective hearing symptoms warrant clinical attention as markers of systemic multimorbidity rather than intervention targets for dementia prevention.

Objective: Impaired understanding of noisy or degraded speech is a central feature of listening difficulties (LiD), but the possible causes of these symptoms are wide-ranging. Accordingly, recent research underscores the need to study these deficits using a test battery approach. Event-related potentials are useful objective metrics for studying LiD, but probing function across the speech processing hierarchy using traditional protocols is sequential and unrealistic in clinical settings. The novel chirped speech (Cheech) method combines natural speech with acoustic chirps to overcome these limitations. This study examines its utility for profiling childhood LiD. Methods: Twenty-eight children (15 typically developing, 13 with LiD), aged 8-17 years old, listened to a 17-minute Cheech story and detected a target word within the story via button press while EEG data were collected from 53 scalp sites. Results: Cheech successfully evoked responses from the auditory brainstem response through to the brain's language centers, as reflected by the N400 effect. Unlike TD children, those with LiD demonstrated N400 effects with atypical distributions that favored frontal rather than the typical parietal sites. A trend towards a delayed and reduced amplitude Wave V was also observed. Conclusions: Hierarchical examination of speech processing using Cheech primarily implicates altered language processing as a contributing factor to LiD, with the frontal topography of the N400 effect for those with LiD potentially suggesting a greater reliance on deliberate memory retrieval during the speech perception task. Significance: LiD could arise due to auditory and/or cognitive factors. The present results demonstrate the feasibility of objective, parallel measurement across this hierarchy and point to impaired language processing as a possible mechanism.

Objectives: To develop and externally validate a wall-focused deep learning framework for identifying composite unstable intracranial aneurysm phenotypes on dual-phase high-resolution vessel wall imaging (HR-VWI), and to visualize model attention on the aneurysm wall surface. Methods: This retrospective multicenter study included patients with intracranial aneurysms who underwent both non-contrast and contrast-enhanced HR-VWI. Center 1 was used for model development and patient-level five-fold out-of-fold assessment, whereas Centers 2 and 3 served as independent external validation cohorts. For each aneurysm, dual-phase local wall patches and larger spatial context patches were generated. The Wall-Constrained Encoding Network (WCE-Net) extracted mask-constrained local wall features, and a transfer-learning U-Net with Nested Transformers (UNesT) branch extracted spatial context information. Branch outputs were fused by logit-level stacking. Model performance was evaluated using discrimination, calibration, and decision curve analysis. Three-dimensional gradient-weighted class activation mapping (Grad-CAM) responses were projected onto the reconstructed aneurysm wall surface and compared with HR-VWI surface signal intensity. Results: A total of 629 patients with 773 aneurysms were included. The final fusion model achieved areas under the receiver operating characteristic curves (AUCs) of 0.908, 0.857, and 0.855 in Center 1, external Center 2, and external Center 3, respectively. Corresponding Brier scores were 0.119, 0.153, and 0.150. Surface Grad-CAM showed partial spatial overlap between model-attention hotspots and high-signal HR-VWI regions. Conclusions: Dual-phase wall-focused local-context fusion showed feasibility for identifying composite unstable intracranial aneurysm phenotypes across centers. Surface Grad-CAM provided anatomically referenced visualization of model attention.

Background. Dynamic susceptibility contrast MRI with capillary-function post-processing exports a relative maximum cerebral metabolic rate of oxygen, formed from blood flow and a transit-time-derived extraction term. The share each contributes to an observed contrast is unquantified. Methods. In a retrospective single-centre cohort with untreated glioblastoma, six perfusion maps normalised to normal-appearing white matter were sampled in automatically segmented enhancing tumour and peritumoral brain. The paired compartment contrast in the oxygen-metabolism index was partitioned into flow, extraction and residual terms and examined against tumour-core volume. Results. Of 131 patients, 122 were analysable. Flow-linked maps were about twice as high in enhancing tumour, the transit and extraction maps only modestly (all q < 0.05). Flow accounted for 92.6% (95% CI 85.9-98.8) of the contrast and extraction for 6.6% (0.7-12.9). Across volume tertiles the flow share rose from 67.8% to 104.0%, a gradient arising peritumorally: every map changed with volume there, none in enhancing tumour. Conclusion. The compartment contrast in the oxygen-metabolism index is largely accounted for by blood flow and varies with lesion size, that dependence originating peritumorally. It should be read within the complete perfusion panel, not as independent metabolic evidence.

Objective: To evaluate the clinical efficacy of non-invasive electrical pulsed radiofrequency (PRF) stimulation on diagnostic thresholds and subjective pain in chronic, pedal diabetic peripheral neuropathy (DPN). Methods: A randomized, single-blind, placebo-controlled trial (ClinicalTrials.gov: NCT07725419) enrolled 92 patients with pedal DPN naive to PRF and scoring [&ge;] 4/10 on the Douleur Neuropathique 4 (DN4) test. Participants received either active PRF stimulation (n = 46) or a non-stimulating placebo (n = 46) applied bilaterally to the sciatic nerve in the popliteal fossa for 10 minutes per limb, once weekly for three weeks. The primary outcome was clinical neuropathic resolution (DN4 < 4). Secondary outcomes included subjective pain tracking via the Brief Pain Inventory-Short Form (BPI-SF) Worst Pain scale over a 6-month follow-up window. Missing data were handled via Non-Responder Imputation (NRI). Longitudinal continuous trajectories were modeled using Linear Mixed-Effects Models (LMMs) adjusted for age, gender, and baseline medication use. Results: In the Intention-to-Treat population (N = 92), a significant diagnostic responder effect occurred at 3 months, with 39.1% of active patients dropping below the diagnostic threshold for neuropathy (DN4 < 4) versus 19.6% of placebo controls (p = 0.039). For subjective pain, 47.7% of active patients achieved a Minimally Clinically Important Difference ([&ge;] 3-point reduction) in BPI Worst Pain at 1 month compared to 19.4% of placebo controls (p = 0.008). Multivariable logistic regression identified active treatment as a significant independent predictor of clinical response (Adjusted OR = 4.86; 95% CI: 1.56 to 17.53; p = 0.010). Continuous LMM tracking confirmed a statistically significant treatment-by-timepoint interaction for BPI Worst Pain at 1 month (p = 0.046). Conclusion: A brief, three-week course of non-invasive PRF stimulation serves as a safe, effective, non-pharmacological adjunct that aids in managing the diagnostic presentation of neuropathic pain and mitigates worst pain experiences in patients suffering from pedal DPN.

Accurate prediction of individual medical outcomes is essential for optimizing treatment allocation amid rising costs, coverage denials, and limited clinical resources. Traditional predictive models, including regression and neural networks, rely on average effects and cannot tailor predictions to the specific circumstances of individual cases. We present relevance-based prediction (RBP), a model-free method that predicts outcomes as weighted averages of observed cases, with weights determined by a rigorously defined measure of relevance. Unlike model-based methods that rely on fixed calibrated parameters, RBP revisits the original data for each prediction and customizes both the cases and variables used. Applied to opioid treatment, RBP provides case-specific insights unavailable from conventional models, including how each prior case informs a prediction, how each variable affects its reliability and value, and how reliable the prediction is before it is made. These individualized insights may prevent misleading average-based decisions and reduce harmful or suboptimal treatment.

Chronic widespread pain (CWP) is highly prevalent among minoritized adults with clinical obesity, and symptom management is challenging. Weight loss via bariatric surgery is often recommended to improve musculoskeletal pain. However, there is significant variation in pain trajectories following bariatric surgery, and the impact of weight loss on movement-evoked pain is largely unknown. The current study aims to systematically characterize and quantify longitudinal changes in pain at rest and movement-evoked pain up to 6 months post-surgery, and to determine whether pain modulatory mechanisms, joint motion, and mechanical loading biosignatures mediate the relationship between weight loss and pain change. This study protocol details the research methodologies and procedures for a prospective observational cohort study of 60 individuals undergoing bariatric surgery for weight loss. Participants will complete questionnaires, anthropometric measurements, clinical and experimental pain testing, functional testing, and a standardized movement testing battery to assess joint motion and mechanical loading using camera-based motion capture before and at 3 and 6 months post-bariatric surgery. Generalized linear mixed models to assess the significance of changes in PAR, MEP, and all patient-reported outcome measures. Reduced models will treat the main effect of time as a fixed factor, and intra-individual repeated measures as random effects. Ethics and dissemination: This study protocol has been registered as an observational study with ClinicalTrials.gov (NCT0675386) in the United States and has been approved by the NYU Langone Health Institutional Review Board (IRB#: i21-01652) and the New York City Health + Hospitals/Bellevue Research Office (Bellevue Study ID #: STUDY00003739). Study results will be published in peer-reviewed journals and presented at national and international conferences and community events.

Introduction The superior longitudinal fasciculus (SLF) is a major association fiber bundle implicated in cognition, visuospatial attention, language, and motor control, and its impairment is linked to several neurological and neuropsychiatric disorders. This proof-of-concept study was performed with three main objectives in healthy adults. First, to fuse whole brain spectroscopic (WBSI) and diffusion MRI (dMRI) derived parametric maps along the SLF I and II segments to quantify their spatial concordance, second, to evaluate regional metabolite concentrations and microstructural properties along these trajectories and finally, to determine the relationships between the WBSI and dMRI parameters within these segments. Methods Ten healthy adults (4F, 6M; mean age 31.4 {+/-} 7.53 years) underwent 3T MRI including multi-shell high angular resolution diffusion imaging and WBSI. After preprocessing and non-linear co-registration, WBSI-derived white matter metabolite maps and neurite orientation dispersion and density imaging (NODDI) / diffusion tensor imaging (DTI) derived parametric maps were spatially aligned and projected along the centroid of reconstructed SLF I and II segments divided into 20 discrete, anatomically contiguous sections. Results A strong spatial alignment between WBSI and dMRI imaging modalities was confirmed by mutual information and Pearson's correlation analyses. Intra-subject repeatability, as assessed from a single participant scanned three times, demonstrated high tract reconstruction reliability (mean Dice similarity coefficients >0.79; track density-weighted Dice >0.97) and acceptable intra-subject coefficients of variation. Inter-subject coefficients of variation were within acceptable ranges ({approx}3-17%) for most parameters, with free water fraction (fiso) exhibiting relatively higher variability. Single and multivariate regression analyses revealed significant associations between WBSI and dMRI tract profiles: choline/creatine (Cho/Cr) and choline/ N-acetyl aspartate (Cho/NAA) ratios showed positive linear associations with intra-cellular volume fraction (ficvf) and fractional anisotropy (FA), and negative associations with mean diffusivity (MD) along bilateral SLF I, with ficvf and MD identified as the strongest combined predictors of metabolite ratios. Conclusion Co-localization/fusion of WBSI and NODDI/DTI data into one framework offers a reliable, user-independent way for mapping regional metabolite and microstructural alterations along the path of SLF. Moving forward, this image processing pipeline has the potential to enhance diagnosis and clinical assessment of neurological disorders linked to SLF damage.

Cognitive impairment affects up to 80% of patients with drug resistant epilepsy (DRE), yet the basis for this impairment in patients with otherwise comparable disease characteristics remains poorly understood. Prior work has largely focused on identifying focal nodes responsible for cognitive decline, leaving the broader network reorganization associated with cognitive preservation poorly characterized. In this study, we hypothesized that the brain's capacity to reorganize its functional network hubs, rather than the degree of underlying pathology, distinguishes cognitively resilient from cognitively impaired patients. We studied a retrospective cohort of 105 DRE patients and 60 healthy controls who underwent resting-state functional neuroimaging. DRE patients were stratified into epilepsy cognitively neutral (ECN) and epilepsy cognitively impaired (ECI) subgroups based on comprehensive neuropsychological profiling spanning both domain-general and domain-specific levels. The subgroups did not differ in key disease characteristics including epilepsy duration, age of onset, seizure lateralization, and lesion status (p>0.05). We characterized hub organization across the whole brain, canonical functional networks and subcortical levels and summarized each subject's functional reorganization using the hub disruption index. We found that whole brain topology is preserved in both groups whereas disruption concentrates in the salience network and dissociates within subcortical structures with reduced hippocampal node strength in both groups and increased thalamic node strength, with the latter more pronounced with cognitive burden. Inter-network connectivity shifted from focal, selective up-regulation in ECN to diffuse hyperconnectivity in ECI. Critically, the hub disruption index (HDI) for centrality separated the groups where the ECN group showed the greatest redistribution of centrality from canonical hubs towards alternative relay regions whereas ECI demonstrated comparatively little reorganization (ECN vs ECI: d=0.52, p=0.029; Bonferroni corrected). The same pattern held within individual domains, with greater hub reorganization in patients whose language and memory function was preserved. These cross-sectional findings link cognitive impairment in epilepsy to a reduced capacity for adaptive hub reorganization rather than to pathology alone. Because the HDI for centrality is computable at the individual level, it may offer an objective imaging biomarker to complement neuropsychological testing, aid identification of patients at risk for cognitive decline, and inform prognostic counseling and surgical planning in DRE.

Interindividual differences in fear acquisition and extinction have been related to variation in specific brain correlates. However, variability in experimental setups complicates the integration of findings. Here, we present a combined fear acquisition (n = 101) and extinction (n = 88) study from which we obtained distinct microstructural, macrostructural, and connectivity brain properties with magnetic resonance imaging in healthy, young participants. The properties included regional brain volume, cortical surface area and thickness, neurite density and orientation dispersion, and nodal efficiency of structural and functional connectivity. Fear responses were quantified as changes in skin conductance. Data from 360 cortical and 16 subcortical brain regions as well as the efficiency of network connections between them were used as independent variables in bootstrapped and cross-validated regularized regression models. Results show that numerous brain regions, spanning the so-called 'fear and extinction network' and extending beyond it, contribute to fear acquisition, to extinction, or dynamically shift between both phases. For several brain regions, data from multiple imaging modalities showed a high degree of concordance for several brain regions. These findings call for further research to examine the potential interplay between brain correlates shaping fear acquisition and extinction, as opposed to studying the imaging modalities in isolation.

Rib-cage morphology is a determinant of thoracic biomechanics, ventilation, and injury response, yet statistical shape models (SSMs) of the rib cage have relied on small cohorts (~100s of individuals) imaged by clinical computed tomography, which over-represents injury and disease. We constructed a surface-based SSM of the complete 24-rib cage from 26,275 standardised whole-body magnetic resonance imaging (MRI) scans of adults aged 19-74 years from the population-based German National Cohort (NAKO). Ribs were segmented with a deep-learning pipeline (a rib-extended SPINEPS model), reconstructed as per-rib surface meshes, and brought into dense vertex-wise correspondence by Gaussian-process morphable registration in Scalismo; the aligned ensemble was summarised by generalised Procrustes analysis and principal component analysis (PCA). Fourteen per-rib geometric descriptors provided a quantitative cross-walk between the abstract PCA modes and named shape features, and associations with sex, age, body size and composition (including body-fat percentage), and smoking exposure were estimated by multivariable regression with Benjamini-Hochberg false-discovery-rate control. Shape variation was strongly concentrated: 28 modes captured 95% of the total variance, and the first three alone accounted for 69.4% (PC1, 42.6%; PC2, 16.3%; PC3, 10.5%) and admitted consistent anatomical readings - a sexually dimorphic axis (PC1), a slender-versus-stout body-habitus contrast (PC2), and a free-rib-size axis at ribs 11-12 (PC3). The sexes were nearly fully separated along PC1 (Cohen's d = 2.52). Body mass and body-fat percentage were the dominant modifiable correlates of rib-cage shape, whereas the association with cumulative smoking exposure was comparatively small. The model is released as a population-representative geometric reference for benchmarking and morphing donor-derived finite-element human-body models and for further large-cohort shape analysis.

Functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) both rely on the phenomenon of neurovascular coupling (NVC) to probe brain activity through their sensitivity to cerebral blood oxygenation. However, the relationship between fNIRS chromophores (oxy- and deoxyhaemoglobin, HbO and HbR), and fMRI (Blood Oxygen Level Dependent and Arterial Spin Labeling, BOLD and ASL) measurements, and whether this relationship remains consistent across subjects and physiological conditions, has only been partially characterised.. We acquired concurrent continuous-wave fNIRS and gradient-echo (GE) and spin-echo (SE) BOLD-ASL fMRI in healthy adults (n = 10) during visual stimulation. By applying calibrated fMRI methodology, we examined the relationships between fNIRS-derived haemoglobin modulations and fMRI-derived modulations in macrovascular (GE-) and microvascular (SE-) BOLD signals, cerebral blood flow (CBF), and oxygen metabolism (CMRO2). Group-level results showed strong temporal cross-modal agreement, with HbO and HbR tightly mirroring all fMRI signal time-courses (|r| > 0.8). A quantitative analysis of trial-by-trial modulations revealed distinct state-dependent behaviours: HbO maintained a stable relationship with the fMRI-derived metrics across conditions, whereas cross-modal relationships between HbR and fMRI-derived metrics substantially strengthened at higher flow-metabolism coupling (FMC), the ratio of CBF to CMRO2 change, an index of the strength of NVC. Both HbO and HbR were more strongly associated with GE-BOLD than with SE-BOLD. These findings provide a rigorous physiological grounding for fNIRS signal interpretation, demonstrating its utility as a surrogate marker for specific haemodynamic and metabolic parameters.

Chronic pain is highly heterogeneous, with individuals varying substantially in symptoms. pain severity, disability, affective distress, cognitive functioning, and trauma-related symptoms. This study examined whether working memory, post-traumatic stress symptoms (PTSS), trauma exposure, and pain modulation explain distinct or shared dimensions of chronic pain variability. Individuals with chronic pain completed clinical, cognitive, trauma-related, and behavioural pain modulation measures, as well as resting-state functional magnetic resonance imaging. Multivariate regressions were used to determine whether working memory, PTSS, trauma exposure, and pain modulation independently predicted chronic pain outcomes. Principal component analysis was used to identify latent dimensions of chronic pain, and mediation analyses tested whether behavioural pain modulation explained relationships between dlPFC to vlPAG resting-state functional connectivity and clinical pain outcomes. PTSS independently predicted affective outcomes, including depression, state anxiety, and trait anxiety, whereas working memory independently predicted pain severity and pain interference. Trauma exposure was associated with greater PTSS and poorer working memory, but did not independently predict core pain outcomes after accounting for these more proximal factors. Principal component analysis identified partially distinct affective and sensory-disability dimensions, while trauma exposure loaded primarily on a separate component characterized by greater PTSS and poorer working memory. Behavioural pain modulation showed broader relationships across symptom dimensions and was associated with dlPFC to vlPAG connectivity. Exploratory mediation analyses demonstrated that pain modulation mediated relationships between dlPFC to vlPAG connectivity and both pain severity and affective distress. These findings support an integrated model where PTSS and working memory are more proximal predictors of affect and severity respectively, and trauma exposure represents a more distal vulnerability factor that predicts both. Thus, pain modulation represents a shared mechanism linking cortico-brainstem connectivity to chronic pain intensity and affect. These variables need further testing for phenotyping people with chronic pain based on their specific clinical needs.

Cerebral aneurysms are abnormal outpouchings of arteries within the brain and occur in [~]1 in 30 adults. Their initiation, growth, and rupture have been linked to focal blood flow abnormalities--often termed "disturbed" or "hostile" hemodynamics--but commonly-used hemodynamic metrics yield conflicting associations with pathology and lack a unifying mechanistic interpretation. Building on a theoretically-grounded link between wall shear stress and near-wall vorticity, we hypothesized that a topology-based description of near-wall flow can operationalize the concept of hostile hemodynamics in a reproducible way. Inspired by atmospheric tornadic phenomena, we sought a principled taxonomy of coherent near-wall fluid structures with potential mechanobiological and clinical implications. Using high-fidelity computational fluid dynamics simulations in anatomically realistic geometries, we identified coherent near-wall fluid structures whose organization mirrors well-studied atmospheric phenomena: tornado-like columnar rotating cores; downburst-like nonrotating wall-impinging jets with tangential outflow, roll-cloud-like tangential vortices; and mixed configurations. These tornadic events on the aneurysm luminal surface were identified from wall shear stress topology, consistent with its theoretical connection to near-wall vorticity kinematics. The presence of tornadic phenomena--and their imprints on the aneurysm wall--was independently observed in vivo using 4D flow magnetic resonance imaging. By translating concepts from atmospheric physics into vascular biomechanics, this topology-based framework yields a unified mechanistic language for describing near-wall hemodynamics, resolving blood flow complexity into interpretable and reproducible coherent fluid structures, enabling standardized hemodynamic phenotyping, and supporting hypothesis-driven studies of aneurysms and other cardiovascular diseases where greater fluid-mechanical specificity and interpretability may strengthen links between mechanobiology and clinical risk.

Background: Large language models have been proposed to improve patient comprehension of radiology reports. However, whether they improve objective understanding remains unproven. Purpose: To evaluate the effect of appending an LLM-generated lay summary to brain MRI reports on objective and subjective patient comprehension in a randomized controlled trial. Materials and Methods: In this randomized controlled trial, 2,727 adult participants from the ComPaRe e-cohort were randomly assigned to interpret six standardized brain MRI reports for headache, presented either in their native format (control; n = 1,401) or appended with a lay summary generated by an open-weights LLM (Mistral Small 3.2) (intervention; n = 1,326). The primary outcome was objective comprehension, defined as the rate of correct classification of whether the report provided a probable explanation for the headache, with ground truth established by four-radiologist consensus. Secondary outcomes included satisfaction, subjective comprehension, anxiety, and willingness to contact a healthcare professional. Generalized estimating equations accounted for repeated within-participant observations. Results: A total of 2,727 participants (mean age, 52 years +/- 15; 75.2% women) were evaluated. Objective comprehension did not differ between arms (58.3% vs 59.4%; odds ratio (OR) 0.97; 95% CI: 0.90-1.06; P = .54). The intervention significantly improved overall satisfaction (64.9% vs 36.7%; OR 3.26; 95% CI: 2.93-3.64; P < .001) and subjective comprehension (50.3% vs 24.0%; OR 3.17; 95% CI: 2.82-3.56; P < .001). High anxiety was modestly reduced (25.1% vs 26.6%; OR 0.92; P = .037). The effect on objective comprehension varied by report type (P for interaction < .001): summaries improved comprehension of symptom-explaining reports (42.4% vs 37.4%; P < .001) but reduced it for normal reports (72.5% vs 76.6%; P = .001). Conclusion: LLM-generated lay summaries appended to brain MRI reports improved patient satisfaction and subjective comprehension but did not improve objective comprehension, indicating a gap between perceived and actual understanding that should be addressed before clinical integration.

Background: Homeless individuals are disproportionately affected by limited access to primary care and pain management services. While community-based organizations frequently conduct outreach, few have ethical, standardized, or replicable methods for assessing pain and distributing referrals in field settings. Existing models range from passive, meals-only outreach, to costly mobile clinics with limited reach. This leaves a critical gap that a low-resource, agile framework is designed to address. Objective: The aim of this quality-improvement initiative was to implement and iteratively refine a standardized, field-based pain assessment and response pathway for adults experiencing homelessness and to evaluate its feasibility, fidelity, safety, and operational barriers during routine outreach. Methods: A cross-sectional quality improvement needs assessment was conducted during homeless outreach activities in San Francisco and Sacramento using convenience sampling. The intervention framework incorporated volunteer training, cognitive capacity screening, verbal informed consent, vital sign collection, and predefined criteria for emergency escalation. Participants were unsheltered adults with adequate decisional capacity to provide voluntary informed consent. Results: The dataset included 193 encounters, with valid pain scores for 175 participants. Mean pain was 3.79 plus or minus 2.78, with a median of 3. Cold packs were used for acute discomfort and foot or ankle pain, while hot packs were used for joint pain. Some participants declined comfort measures. No supply shortages, referral confusion, or emergency-escalation delays were documented. Telephone access remained a barrier to referral completion. Conclusion: This framework demonstrates a replicable and ethically grounded model for field-based pain assessment and referral during homeless outreach. The pathway was feasible and safe to implement, expanded care options beyond default emergency-department referral by directing stable nonemergent pain toward primary care, and identified limited telephone access as a major barrier to completing follow-up.