Joel Fundaun

Introduction: Whiplash-associated disorder grade II (WADII) is characterised by persistent pain in the absence of frank nerve injury, yet its molecular mechanisms remain unclear. Objectives: To identify molecular signatures of 2 recovery groups characterised by persistent moderate/severe and minimal symptoms in WADII using RNA-sequencing of blood samples 6 months postinjury. Methods: We performed bulk transcriptional analyses on blood samples collected from the primary cohort of individuals with WADII 6 months postinjury (n = 15/recovery group). Findings were replicated through meta-analyses using an independent cohort of chronic WAD. Blood cellular composition was estimated via deconvolution analyses across both cohorts. Results: Although there were no differentially expressed genes between recovery groups, we identified sex-specific gene expression signatures of recovery. In the primary WADII cohort, HLA-DQA1, HEBP1, and NECTIN2 showed lower expression in females with moderate/severe symptoms compared with minimal symptoms. SLC12A1 and MXRA7 showed lower expression in males with moderate/severe pain, whereas HLA-G was upregulated. Gene expression meta-analysis in females identified 6 differentially expressed genes, including replication of lower HLA-DQA1 expression from the primary cohort. There were no differentially expressed genes in the meta-analyses in males or between recovery groups. Deconvolution analyses revealed diverging trends between sexes for blood cell types and whiplash symptom severity scores. Ligand–receptor pair analyses further suggested distinct sex-specific recovery trajectories. Conclusion: Transcriptional profiling revealed sex-specific molecular blood signatures associated with persistent whiplash symptoms 6 months postinjury. Future research is needed to further characterise sex-specific mechanisms after whiplash injury to improve prognosis and targeted management strategies.

Background: Whiplash-associated disorders (WAD) are common after motor vehicle collisions and can result in persistent pain and disability. Most affected individuals are classified as WAD grade II (WADII) and frequently exhibit sensory disturbances suggestive of peripheral nerve involvement. Although peripheral neuroinflammation has been implicated, related microstructural changes remain unknown.Methods: Diffusion tensor imaging (DTI) was used to assess the brachial plexus roots, C5–C8 spinal nerve roots, and median nerve in 102 participants with WADII within 4 weeks of injury and 37 healthy controls. Fifty-one participants returned for follow-up at 6 months. Associations between DTI metrics, clinical measures, and recovery were examined.Findings: Acute WADII participants showed increased axial diffusivity (AD) in the bilateral C6–C7 brachial plexus roots, persisting at 6 months. In the median nerve, mean diffusivity (MD), AD, and radial diffusivity (RD) were elevated at both time points. Conversely, bilateral C6–C8 spinal nerve roots showed increased fractional anisotropy and reduced MD and RD acutely and at follow-up, with AD decreasing at 6 months. Acute DTI metrics did not predict recovery; however, higher median nerve AD and MD were associated with greater neuropathic pain severity at follow-up.Interpretation: WADII is associated with widespread, persistent alterations in peripheral nerve microstructure, consistent with altered axonal physiology and low-grade neuroinflammation rather than overt structural nerve injury. These findings support peripheral nervous system involvement in WADII and highlight the importance of evaluating neural contributions to persistent pain.

Background: Chronic pain is associated with impaired muscle health, but whether these changes reflect site-specific factors, broader systemic factors, or both remains unclear. The purpose of this study is to determine whether normative markers of muscle health derived from MRI show site-specific patterns in chronic pain. Methods: UK Biobank participants who underwent whole-body MRI from 2006 to 2010 were included in this retrospective cross-sectional study. The MuscleMap Toolbox quantified volume and intramuscular fat (IMF) in 42 muscles of the abdomen, pelvis, and thigh. Normative models trained on a no pain group generated muscle-specific deviations from normal (i.e., Z-scores) for single- and multi-site chronic and acute pain. Results: Of 17,843 participants, the primary site-specific analysis included 9,704 no pain, 885 single-site chronic back pain (CBP), 438 single-site chronic hip pain (CHP), and 1,315 single-site chronic knee pain (CKP) participants (n=12,342; mean age 63.7±7.5 years; 52.7% female). Additional analyses included single-site chronic neck/shoulder pain, acute pain, and multi-site chronic pain groups. In CBP, deviations were localized to abdominal muscles, with decreased volume in 6/8 and increased IMF in 6/8. In CHP, deviations were broad, with decreased volume in 3/8 of the abdominal and 14/26 of the thigh muscles, and increased IMF in 6/8 of the abdominal, 5/8 of the pelvic, and 4/26 of the thigh muscles. In CKP, deviations were localized to thigh muscles, with decreased volume in 8/26 and increased IMF in 6/26. Acute pain groups showed no significant differences except for decreased volume in one thigh muscle in acute knee pain. With each additional chronic pain site, volume decreased (β=−.078;IQR:−0.100−0.051), and IMF increased (β=.085;IQR:0.066−0.101). Combined Z-scores classified chronic pain groups better than chance (accuracy: 48.6%;p<.001), but not acute pain groups (accuracy: 39.0%;p=.20). Conclusions: Whole-body MRI combined with AI-driven muscle segmentation and normative modeling revealed site-specific patterns of muscle health in single-site chronic pain.

Introduction: Evidence increasingly shows small nerve fibre pathology in subsets of people with fibromyalgia through skin biopsy, corneal confocal microscopy, and microneurography. However, blood-based biomarkers of ongoing neuronal damage, particularly neurofilament light chain (NfL), an axonal structural protein, are not well established. Objectives: The aim of this study was to evaluate serum NfL concentrations in fibromyalgia compared with other chronic pain conditions and assess their relationship with neuropathic-like pain. Methods: We measured serum NfL using Simoa SR-X NF Light v2 digital-immunoassay in 60 participants with fibromyalgia, 61 with endometriosis (another traditionally considered non-neuropathic pain condition), 24 with small fibre neuropathy (a recognised neuropathic pain condition), and 30 healthy controls. Serum NfL concentrations were compared between the groups controlling for age and body mass index. Neuropathic-like pain was assessed using the painDETECT questionnaire for fibromyalgia and endometriosis and NeuPSIG grading criteria for small fibre neuropathy. Results: Compared with healthy controls (mean concentration = 6.77 pg/mL, Z-score = −1.15), serum NfL concentrations were significantly elevated in fibromyalgia (mean concentration = 8.52 pg/mL P = 0.048; Z-score = −0.30, and P = 0.006) and small fibre neuropathy (mean concentration = 8.98 pg/mL, P = 0.004; Z-score = 0.23, P = 0.0001), with endometriosis representing an intermediate phenotype (mean concentration = 5.57 pg/mL, P = 0.44; Z-score = −0.41, P = 0.024). Using PainDETECT, 44% of fibromyalgia and 26% of endometriosis participants met likely neuropathic pain criteria; using NeupSIG grading, 96% of small fibre neuropathy participants met probable/definite criteria. Conclusion: Our study provides serological evidence of nerve pathology in fibromyalgia at comparable levels with small fibre neuropathy, although this did not correlate with neuropathic-like pain presence or severity. These findings highlight the need for subgroup-specific treatment strategies.

Whiplash injuries cause considerable pain and disability. Most individuals are diagnosed with whiplash-associated disorder grade II (WADII), which is defined by the absence of frank nerve injury. However, studies indicate possible peripheral neuroinflammation in some individuals with WADII that may contribute to symptoms. The temporal changes of peripheral neuroinflammation in WADII remain unclear. This study aimed to investigate the course of peripheral neuroinflammation from acute to chronic stages and assess whether neuroinflammation in the acute stage predicts recovery 6 months postinjury. Sixty-two WADII participants, who were examined within 4 weeks of a whiplash injury, returned for a follow-up appointment at 6 months. Thirty-two percent (n = 20) of participants considered themselves to be all better at 6 months based on a global recovery question. Magnetic resonance imaging T2-weighted signal ratio of the C5 to C8 roots of the brachial plexus, associated dorsal root ganglia, and median nerve, were similar at both time points. Signs of heightened nerve mechanosensitivity reduced significantly at 6 months, as did mechanical and thermal hyperalgesia in the upper limb. Inflammatory mediator serum levels were unaltered at 6 months, except for tumour necrosis factor-α, which was reduced. Multivariable regression analysis indicated that heightened nerve mechanosensitivity (reduced elbow range of motion) in the acute stage was weakly prognostic for neuropathic pain classification at 6 months. Although many participants recovered at 6 months, the data show that peripheral neuroinflammation may persist in some individuals. These findings highlight the complexity of WADII and the contribution of neuroinflammation in both acute and chronic stages.

Background: Hand function is critical for daily activities and declines early in many diseases, conditions or disorders affecting the musculoskeletal and neurologic systems. Muscle health markers derived from clinically available magnetic resonance imaging (MRI) scans are strongly associated with functional capacity, may enhance clinical assessment and inform management options. However, traditional muscle MRI assessments require time‐intensive manual segmentations. Here, we aim to develop and test a computer‐vision model for automated forearm muscle segmentation and investigate associations between MRI‐derived muscle markers and age, sex, BMI, functional grip strength and dexterity measures. Methods: We recruited 42 healthy, right‐handed adults (54.8% female, median age 37.3 years, median BMI: 23.0). Grip strength and dexterity were measured using the NIH Toolbox motor battery. Dixon fat‐water MRI of the right forearm was acquired at 3.0 T, and forearm flexor and extensor muscle compartments were manually segmented for model training. A 2D U‐Net convolutional neural network model was trained and tested for segmentation of the forearm flexors and extensors for the assessment of muscle volume and intramuscular fat. Testing accuracy and reliability were assessed using Sørensen–Dice indices, intraclass correlation coefficients (ICCs) and Bland–Altman analyses. Associations between the MRI‐derived muscle markers, demographic factors, muscle metrics and hand function were evaluated using partial correlations and regression models. Results: The segmentation model showed high test accuracy, achieving mean Sørensen–Dice indices of 0.89 (flexors) and 0.85 (extensors) and ICCs of 0.75–0.99 for muscle volume and intramuscular fat. Muscle volume was positively correlated with BMI ( p < 0.001) but not age ( p > 0.249). Males had larger muscle volumes than females ( p < 0.001), with no sex differences in intramuscular fat ( p > 0.141), and no association between intramuscular fat and grip strength or dexterity ( p > 0.350). We observed strong positive correlations between grip strength and both flexor ( p = 0.004) and extensor ( p = 0.001) muscle volumes, while dexterity showed no significant associations. Conclusions: Our findings highlight the accuracy and reliability of automated forearm muscle segmentation using computer vision. BMI emerged as a key determinant of muscle volume, independent of age. The strong association between muscle volume and grip strength demonstrates the clinical relevance of these metrics, suggesting potential applications in therapeutic planning for conditions impairing hand function. Sex‐based differences in muscle volume underscore the importance of tailored assessments. Computer vision models integrated with Dixon fat‐water MRI enable efficient, accurate evaluation of forearm muscle health. Future research should explore these metrics in clinical populations and their utility in tracking functional outcomes.

Whiplash-associated disorders (WADs) affect 20–50 million individuals globally each year, with ≤50% developing persistent pain. WAD grade II (WADII) is the most common type and is characterized by neck symptoms and musculoskeletal signs without apparent nerve injury on routine diagnostic testing. However, emerging evidence suggests that nerve pathology might be present in some people with WADII. This longitudinal cohort study aimed to investigate comprehensively the presence, temporal patterns and prognostic value of nerve pathology and neuropathic pain in acute WADII. A prospective longitudinal cohort study was conducted with 129 acute participants with WADII (median age 36.0 years, 58% female) and 36 healthy controls (median age 39.0 years, 61% female). Participants with WADII were recruited within 4 weeks of injury from local emergency departments. Data collection included bedside neurological assessments, quantitative sensory testing, intraepidermal nerve fibre density and serum neurofilament light chain concentrations. Follow-up assessments were conducted 6 months after injury. Signs of neuropathic pain were present in 65% (84/129) acutely and persisted in 32% (21/66) 6 months post-injury. Bedside neurological assessment revealed that somatosensory loss-of-function was present in 54% (70/129) acutely, reducing to 25% (17/67) 6 months post-injury. Quantitative sensory testing demonstrated significantly reduced cold, warm, thermal sensory limen, mechanical and vibration detection thresholds in acute WADII compared with controls (d > 0.47). Acute loss-of-function in at least one quantitative sensory testing parameter was present in 67.6% (85/126) of WADII. At 6 months, participants with WADII showed persistent hypoaesthesia to warm, thermal sensory limen and mechanical detection thresholds, and decreased mechanical pain and pressure pain sensitivity compared with controls (d > 0.44). These functional neurological changes were accompanied by elevated serum neurofilament light chain levels in acute WADII compared with controls [d = −0.52 (95% confidence interval −0.94, −0.10)]. Intraepidermal nerve fibre densities at the index finger were not significantly different between groups. However, dermal myelin basic protein+/protein gene product+ myelinated nerve bundles at the index finger were reduced 6 months post-injury in WADII compared with controls [d = 0.69 (0.26, 1.11)]. Multivariable linear regression suggested that bedside tests for hypoaesthesia at the index finger were prognostic for whiplash-related upper quadrant pain 6 months post-injury (r2 = 0.13, P = 0.02). In conclusion, two-thirds of participants with acute WADII initially exhibited signs of neuropathic pain and nerve pathology. At the 6-month follow-up, neuropathic pain persisted in one-third of participants with WADII, and nerve pathology persisted in two-thirds. These findings challenge the traditional musculoskeletal classification of WADII and underscore the need for targeted neurological assessments and treatment.

Whiplash injury is associated with high socioeconomic costs and poor prognosis. Most people are classified as having whiplash-associated disorder grade II (WADII), with neck complaints and musculoskeletal signs, in the absence of frank neurological signs. However, evidence suggests that there is a subgroup with underlying nerve involvement in WADII, such as peripheral neuroinflammation. This study aimed to investigate the presence of neuroinflammation in acute WADII using T2-weighted magnetic resonance imaging of the brachial plexus, dorsal root ganglia and median nerve, and clinical surrogates of neuroinflammation: heightened nerve mechanosensitivity (HNM), raised serum inflammatory mediators, and somatosensory hyperalgesia. One hundred twenty-two WADII participants within 4 weeks of whiplash and 43 healthy controls (HCs) were recruited. Magnetic resonance imaging T2 signal ratio was increased in the C5 root of the brachial plexus and the C5-C8 dorsal root ganglia in WADII participants compared with HCs but not in the distal median nerve trunk. Fifty-five percent of WADII participants had signs of HNM. Inflammatory mediators were also raised compared with HCs, and 47% of WADII participants had somatosensory changes on quantitative sensory testing. In those WADII individuals with HNM, there was hyperalgesia to cold and pressure and an increased proportion of neuropathic pain. Many people with WADII had multiple indicators of neuroinflammation. Overall, our results present a complex phenotypic profile for acute WADII and provide evidence suggestive of peripheral neuroinflammation in a subgroup of individuals. The results suggest that there is a need to reconsider the management of people with WADII.