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.

Objective: To evaluate the efficacy, engagement, and usability of Tune Out, an unguided, self-paced online tinnitus management program, for reducing tinnitus severity in adults with tinnitus. Design: A two-arm, parallel-group randomised controlled trial was conducted with Australian adults reporting diagnosed or self-reported tinnitus. Participants were randomised to immediate access to Tune Out or a waitlist control group. Outcomes were assessed at baseline, 6 weeks, and 12 weeks. The primary outcome was tinnitus severity measured using the Tinnitus Functional Index (TFI). Secondary outcomes included tinnitus handicap, psychological symptoms, program engagement, self-efficacy, and usability. Results: Eighty-eight participants were randomised: 43 to the intervention group and 45 to the waitlist control group. The primary outcome analysis included 63 participants at 12 weeks. A significant Group x Time interaction was observed for TFI total score, indicating greater reductions in tinnitus severity over time in the intervention group compared with waitlist control, F(2, 102.57) = 5.95, p = .004, partial 2= .104. Significant effects were also observed for tinnitus handicap, F(2, 106.76) = 4.12, p = .019, partial 2 = .072. Effects on psychological symptoms were less consistent, although anxiety showed a significant Group x Time interaction, F(2, 116.85) = 3.63, p = .030, partial 2 = .059. At 12 weeks, 23.1% of intervention participants achieved a clinically meaningful reduction in tinnitus severity compared with 5.4% of controls. Program use was highly variable, with a median use of 1.10 hours, and 25.6% of intervention participants recording no use. Usability ratings were favourable among respondents, with a mean System Usability Scale score of 73.13. Conclusions: Tune Out demonstrated preliminary efficacy for reducing tinnitus severity and tinnitus handicap compared with waitlist control. Effects on broader psychological symptoms were less consistent. Although usability was rated positively, low and variable engagement highlights the need for strategies to support uptake and sustained use in unguided digital tinnitus interventions.

Abstract Background: Long COVID frequently includes post-exertional malaise, neuromuscular fatigue, internal vibrations, tremor-like symptoms, orthostatic intolerance, sleep disturbance, cognitive dysfunction, and autonomic instability. Neuroimaging studies in Long COVID and post-infectious ME/CFS have identified abnormalities across limbic, thalamic, mesiotemporal, brainstem, cerebellar, and white-matter systems, but no single established circuit accounts for this clinical phenotype. We examined whether abnormalities cluster at the mammillary body-fornix-superior tuberal hypothalamic interface and within connected brainstem-cerebellar pathways. Methods: Structural MRI and diffusion tensor imaging were analysed in 88 participants with clinician-diagnosed Long COVID and 34 healthy controls (total N = 122). Thirty-three patients were classified as bedridden. Volumetric and diffusion analyses focused on the mammillary bodies, superior tuberal hypothalamic region, fornix, dorsal and median raphe, midbrain reticular formation, and cerebellar peduncles. Fractional anisotropy was used as an index of white-matter microstructural organisation. Exploratory clinical associations included motor impairment, proprioceptive dysfunction, autonomic symptoms, fatigue, internal vibrations, and tremor-like symptoms. Results: Three mammillary-body volume phenotypes were identified: reduced, enlarged, and control-range. Left and right mammillary-body volumes differed across groups, with large effect estimates. Segmentation showed narrowing or loss of a visible internal passage at the superior tuberal-mammillary interface, while the fornix showed altered diffusion measures and reduced tract coherence in the hypothesised gate region. Additional findings included lower superior cerebellar peduncle volume, lower middle cerebellar peduncle fractional anisotropy, and lower dorsal raphe and midbrain reticular formation volumes in Long COVID. Conclusions: The findings support an exploratory mammillary body-fornix gate model in which a vulnerable periventricular hypothalamic-limbic interface may contribute to network dysfunction in a subgroup of patients with severe Long COVID. The data do not establish direct viral invasion, a coronavirus entry route, axonal destruction, or a single causal pathway. Prospective replication with standardised acquisition, preregistered regions of interest, correction for multiple comparisons, objective movement and autonomic measures, and longitudinal follow-up is required. Keywords: Long COVID; post-COVID condition; ME/CFS; mammillary body; fornix; hypothalamus; diffusion tensor imaging; internal vibrations; tremor-like symptoms; neuromuscular fatigue; dysautonomia; brainstem

Chiari I malformation (CM-I) is conventionally defined by cerebellar tonsil position, yet tonsil position is an indirect surrogate for the anatomic obstruction that impairs cerebrospinal fluid (CSF) flow across the craniocervical junction (CCJ). We hypothesized that CCJ crowding, quantified as subarachnoid space narrowing at the foramen magnum and C1, would explain CSF flow impairment more directly than tonsil position. Using non-invasive low b-value diffusion-weighted MRI (low-b dMRI), we quantified effective CSF motility, indexed by mean pseudo diffusivity (M{psi}), across the upper cervical spine, CCJ, and posterior fossa. Voxel-wise CCJ CSF pseudo-diffusion spatial statistics were integrated with CSF Waterways atlas-based regional analyses. We applied this approach in 81 pediatric and adult participants with CM I to determine how CCJ structural features shape regional CSF dynamics and clinical outcomes. Voxel wise analyses revealed that crowding at the foramen magnum was the dominant structural determinant of reduced intracranial CSF effective motility across the CCJ, basilar cisterns, and fourth ventricular outflow pathways (family-wise error corrected p < 0.05). While lower tonsil position and C1 level crowding were also associated with reduced CSF effective motility across the CCJ and fourth ventricular outflow pathways, but their associations within the basilar cisterns were spatially restricted to regions adjacent to the Liliequist membrane. Atlas-based region-of-interest analyses confirmed that greater foramen magnum crowding was associated with lower M{psi} across multiple basilar cisterns, but with higher M{psi} in the ventral spinal CSF compartment. Mediation analyses indicated that CCJ crowding at the foramen magnum and C1 accounted for the majority of the relationship between tonsil position and reduced CSF motility in the basilar cisterns. Multivariate M{psi} profiles across the CSF regions identified data-driven foramen magnum crowding thresholds of 69.5% and 77.5%, stratifying patients into mild, moderate, and severe physiological crowding groups. Exploratory analyses linked lower pre-operative CSF M{psi} to greater pain-related functional impairment, reduced cognitive function, and a higher likelihood of subsequent decompression surgery. Together, these findings demonstrate that CCJ crowding, particularly at the foramen magnum, exerts a quantifiable, region specific impact on CSF effective motility in CM I, and that low b dMRI provides a sensitive, complementary marker of CSF flow impairment. This integrative CCJ structural and CSF flow imaging framework establishes a mechanistic link between CCJ anatomy, CSF dynamics, and symptom burden, offering a scalable tool for phenotyping CM I and informing clinical decision making.

Nociplastic pain represents a major burden across immune-mediated inflammatory diseases (IMIDs). It is hypothesised, but not yet demonstrated, that peripheral inflammation promotes nociplastic pain by bottom-up sensitisation of the central nervous system (CNS). In rheumatoid arthritis (RA), a prototypic IMID, we used ultra-high field (7T) brain resting-state functional MRI to evaluate whether peripherally targeted anti-inflammatory therapies alter a biomarker of bottom-up CNS sensitisation: inferior parietal lobule (IPL)--insula connectivity. In discovery and replication cohorts, JAK-STAT pathway inhibitors significantly shifted IPL--insula connectivity toward a normalised pattern. This effect was not seen with placebo or anti-TNF therapy. Moreover, after performing an agnostic whole-brain multivariate analysis of functional connectivity change related to JAK-STAT inhibition, the posterior cingulate cortex (PCC) was identified; like the IPL, a major hub of the default mode network (DMN). We then probed the DMN with transcranial magnetic stimulation in an independent RA cohort. Active, but not sham, stimulation altered DMN connectivity and reduced peripheral blood monocyte pSTAT3 function, a surrogate of immune inactivation, suggesting a bi-directional brain-immune circuit. Together, these findings provide the first human experimental evidence that peripheral JAK-STAT pathways contribute to nociplastic pain in IMIDs.

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.

Background: Sleep, pain, affect, cognition and energy (SPACE) has been described as a latent symptom-severity construct in chronic overlapping pain conditions. Its population-level structure and associations with chronic pain interference and functional disability remain uncertain. Methods: We conducted a cross-sectional analysis of UK Biobank participants. Prespecified standardised symptom domains were examined using correlation analysis, principal component analysis, exploratory factor analysis and k-means clustering. Associations with chronic pain interference, current work disability, poor self-rated health and longstanding illness or disability were assessed using covariate-adjusted logistic regression. A four-domain score excluding pain tested whether associations extended beyond the pain domain. Secondary analyses examined convergence with actigraphy, biomarkers, polygenic risk scores and brain magnetic resonance imaging phenotypes. Results: Of 501,935 eligible participants, 475,134 had complete domain data. Domains were modestly intercorrelated (r=0.04-0.46). Clustering identified lower- and higher-burden phenotypes comprising 70.5% and 29.5% of participants; current work disability occurred in 1.3% and 10.3%, respectively. Adding the four non-pain domains increased the area under the curve for chronic pain interference from 0.593 to 0.672 and for work disability from 0.748 to 0.850. Inclusion of pain increased the work-disability area under the curve to 0.863. Multimodal measures added smaller increments. Conclusions: A multidimensional symptom profile was identifiable at population scale and was concurrently associated with chronic pain interference and work disability, with non-pain domains contributing information beyond pain burden alone.

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.

Placebo analgesia varies substantially across individuals, yet the sources of this heterogeneity remain incompletely understood. Pain-reporting variability may represent an underrecognized predictor of placebo responsiveness. This study examined whether variability and reliability of pain reporting predict placebo analgesia in an experimental pain setting. Eight hundred and three participants (401 individuals with temporomandibular disorder and 400 healthy controls) completed a standardized thermal pain paradigm involving calibration, placebo conditioning, and testing phases. We obtained repeated heat temperatures (four) during thermal calibration and pain ratings during conditioning test (24 trials). We used these measurements to quantify within-person pain-reporting variability using standard deviation (SD) and coefficient of variation (CoV), and reliability using intraclass correlation coefficients (ICC). Placebo analgesia was calculated as the difference in pain ratings between control and placebo cue trials during testing. Regression models examined associations between reporter characteristics and placebo analgesia controlling for age, sex, race and experimenters. Variability of thermal pain responses during calibration did not predict placebo analgesia. Greater pain-reporting variability during conditioning was associated with reduced placebo analgesia (higher SD and CoV), and this effect was mediated by slower acquisition of the cue pain contingency. Conditioning-phase reliability was not associated with placebo analgesia, whereas three clusters of learning profiles predicted placebo effects. Thus, individual differences in pain-reporting variability during conditioning, rather than baseline sensory variability, contribute to heterogeneity in placebo analgesia. These findings suggest that variability during acquisition processing matters more than general sensory variability influencing the magnitude of placebo effects.

Moderate-to-severe traumatic brain injury (msTBI) is recognized as a chronic and evolving neurological condition characterized by progressive structural brain changes and persistent cognitive impairment. While prior studies have demonstrated widespread atrophy following msTBI, less is known regarding the longitudinal trajectory of gray matter (GM) changes during recovery and post-rehabilitation. The current study used longitudinal voxel-based morphometry (VBM) to characterize GM volume changes over a period of 9 months, in individuals with msTBI relative to healthy controls (HC). Associations between regional GM volume and neuropsychological functioning were examined. Twenty-eight participants (14 msTBI, 14 HC) completed MRI and neuropsychological assessments across three timepoints spanning outpatient rehabilitation and follow-up. Longitudinal VBM analyses revealed significant group and time interactions within subcortical and limbic regions. Relative to HC, individuals with msTBI showed lower GM volume in these regions at baseline, with trajectories that converged toward HC values (right hippocampus) or increased relative to HC over the rehabilitation period (bilateral pulvinar), whereas the right amygdala and inferior cerebellar vermis remained persistently reduced. Significant longitudinal improvements in memory and psychomotor speed during the rehabilitation period were demonstrated in msTBI. Greater (preserved) GM volume within the right hippocampus, thalamus, and bilateral pulvinar was associated with better performance across measures of verbal memory, processing speed, executive functioning, and cognitive flexibility. These findings suggest that msTBI is associated with dynamic structural brain changes involving subcortical, limbic, and cerebellar networks, and that the rehabilitation period was accompanied by relative volumetric stabilization in these regions and by meaningful cognitive improvement.

BACKGROUND: Myofascial Pain Syndrome (MPS) is a common musculoskeletal pain condition associated with myofascial trigger points that has been reported to occur in 30-93% of patients who present with musculoskeletal pain. The current pharmacologic treatments (such as nonsteroidal anti-inflammatory drugs [NSAIDs], muscle relaxants, and tricyclic antidepressants) are only partially effective and have side effects. Shilajit, a mineral-organic exudate from the Himalayas, has antioxidant, anti-inflammatory, mitochondrial bioenergetic, and central analgesic effects and has not previously been examined as an analgesic in any musculoskeletal pain condition. METHODS: This was an exploratory pilot clinical trial with open-label design in a single arm for an 18-month period at All India Institute of Medical Sciences (AIIMS), Rishikesh, India. Patients aged 18 to 65 years with clinically diagnosed MPS (Simons et al. 1999 criteria) and a baseline visual analog scale (VAS) score >4 were enrolled. Native Himalayan Shilajit 250 mg daily was administered as add-on therapy for 49 days. The main outcome was the percentage of participants with more than or equal to 30% VAS reduction at Day 49. The intensity of pain, the dose of analgesics consumed, and the number of trigger points were evaluated at five time points (Day 0, 12, 24, 36, 49). Throughout, adverse events were monitored. RESULTS: Of 80 enrolled participants, 76 (95.0%) completed the per-protocol analysis. Mean age was 41.25 (SD 9.05) years; 52.6% were male. A total of 56 of 76 participants (73.7%; 95% CI: 62.1-82.8%) achieved the primary endpoint. Mean VAS score declined from 6.63 (SD 1.08) at baseline to 3.63 (SD 1.72) at Day 49 (mean reduction 45.3%; Friedman Chi-square= 278.5, p<0.001). The first signs of pain reduction were seen at Day 24. The number of analgesic doses consumed decreased by 75.5% during the study period (chi-square = 126.1, p<0.001). There was a significant reduction in trigger point count from baseline to Day 49 (p=0.031) of 23.4%. One Grade 2 adverse event (gastrointestinal irritation, Day 28, resolved within 24 hours, no drug discontinuation) occurred; no serious adverse events were reported. Trial registration: CTRI/2025/06/088636. The study was not funded by any external sources. CONCLUSIONS: Native Himalayan Shilajit 250 mg/day for 49 days was associated with clinically and statistically significant reductions in pain intensity, analgesic consumption, and trigger-point burden in patients with MPS, with a favorable safety profile. These findings warrant confirmation in a larger, randomized, placebo-controlled trial.

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.

ABSTRACT IMPORTANCE Childhood obesity is a growing global health concern associated with adverse physical, psychiatric, and neurodevelopmental outcomes. Although previous neuroimaging studies have linked obesity to widespread alterations in brain structure and function, it remains unclear how well multimodal neuroimaging measures and genetic markers can predict future weight gain and inform early intervention strategies. OBJECTIVE To evaluate the predictive utility of multimodal MRI measures and polygenic risk scores for obesity in estimating proportional body weight at baseline and predicting weight gain over one year in preadolescent children. DESIGN, SETTING, AND PARTICIPANTS This study used data from the Adolescent Brain Cognitive Development (ABCD) Study, a large-scale, multisite longitudinal cohort of children aged 9 to 10 years (N = 11,880). Analyses included baseline data collected between 2016 and 2018, and one-year follow-up data collected between 2018 and 2020 across multiple imaging sites. MAIN OUTCOMES AND MEASURES Elastic net regression models were applied to structural MRI (including diffusion tensor imaging) and resting-state functional MRI data to predict baseline triponderal mass index (TMI), a weight-for-height measure that more accurately reflects adiposity in children than body-mass index (BMI). Longitudinal classification models were developed to predict excess weight gain relative to normative developmental trajectories at one-year follow-up. Models were evaluated with and without the inclusion of polygenic risk scores and other non-imaging covariates. Generalizability was assessed using leave-one-site-out cross-validation. RESULTS Structural MRI measures predicted baseline TMI with an R^2 of 0.21, whereas resting-state functional MRI measures predicted TMI with an R^2 of 0.08. Classification models predicted one-year weight gain with area under the receiver operating characteristic curve (AUC) values of 0.73 for structural MRI and 0.60 for resting-state functional MRI. Including polygenic risk scores and other covariates improved model performance (structural MRI: R^2 = 0.25, AUC = 0.75; resting-state functional MRI: R^2 = 0.15, AUC = 0.69). Leave-one-site-out cross-validation revealed reduced generalizability across imaging sites (structural MRI R^2 = 0.13-0.17; resting-state functional MRI R^2 = 0.02-0.09; structural MRI AUC = 0.73-0.74; resting-state functional MRI AUC = 0.60-0.67). CONCLUSIONS AND RELEVANCE Multimodal MRI measures were associated with proportional body weight and demonstrated modest predictive utility for future weight gain in preadolescent children, explaining up to one fifth of the variance in weight-related outcomes. The addition of genetic and non-imaging variables improved prediction accuracy, underscoring the multifactorial nature of childhood obesity. However, the observed decline in performance under site-wise cross-validation highlights the need to address site-related variability to enhance reproducibility and generalizability in neuroimaging-based predictive models of pediatric obesity.

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.