Brain最新文献

{"title":"Variant-specific deep phenotyping as a tool to develop precision therapies.","authors":"Rita Horvath, Hanns Lochmüller","doi":"10.1093/brain/awaf264","DOIUrl":"10.1093/brain/awaf264","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"148 9","pages":"3021-3022"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144941990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive spinal neuromodulation enables stepping in children with complete spinal cord injury.","authors":"Kathryn Lucas, Goutam Singh, Luis R Alvarado, Molly King, Nicole Stepp, Parth Parikh, Beatrice Ugiliweneza, Yury Gerasimenko, Andrea L Behrman","doi":"10.1093/brain/awaf115","DOIUrl":"10.1093/brain/awaf115","url":null,"abstract":"<p><p>Paralysis is assumed permanent in persons with motor-complete spinal cord injury (SCI). However, spinal epidural stimulation combined with activity-based locomotor training (ABLT) and cognitive intent enabled two adults with motor-complete SCI to walk with a walker. Transcutaneous spinal stimulation (scTS), also capable of promoting a cyclic step-like pattern, might be a viable alternative in children with SCI. These findings prompted our investigation into multimodal neuromodulation training using ABLT (enhancing afferent input), spinal stimulation (scTS) and descending (intent) drive to restore voluntary stepping in children with chronic motor-complete SCI. Five non-ambulatory children (9.6 ± 2.5 years old, three female, four thoracic and one cervical injury) with chronic (>1 year, 5.2 ± 2.5 years), complete SCI underwent 60 sessions of combined ABLT and scTS training with cognitive intent to step and returned for a 3- to 6-month follow-up. During the first training session in a gravity-neutral position, all five children made small reciprocal cycles of the hips/knees in a flexion/extension step-like pattern with stimulation, with increased excursion at session 20 for five of five children (right hip excursion increased from 10.1° ± 15.1° to 25.9° ± 21.3° and right knee excursion increased from 9.3° ± 13.9° to 39.6° ± 29.2°, P = 0.02). The children stepped overground at sessions 50 [Participant (P)15], 60 (P34) and 20 (P32, P14, P240), voluntarily initiating and alternating left/right leg swings on the treadmill and overground with and without scTS. Three to six months post-training, all children maintained the capacity to step. The parents and children reported unanticipated improvements in sensation, bladder function, proprioception, assist to stand, transfers and dressing. In children with chronic, motor-complete SCI, multimodal neuromodulation training can potentiate the intrinsic stepping capacity of the spinal locomotor centres to enable voluntary stepping. Remarkably, these enhancements are durable and observed even in the absence of spinal stimulation.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3290-3299"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of focal brain damage on political behaviour across different political ideologies.","authors":"Shan H Siddiqi, Stephanie Balters, Giovanna Zamboni, Shira Cohen-Zimerman, Jordan H Grafman","doi":"10.1093/brain/awaf101","DOIUrl":"10.1093/brain/awaf101","url":null,"abstract":"<p><p>Intense political behaviour is associated with brain regions involved in emotional and cognitive processing. However, it remains unclear if this neuroanatomy is causal, compensatory or otherwise correlated. We employed lesion network mapping in a cross-sectional study of 124 male military veterans with penetrating head trauma. Approximately 40-45 years after the injury, participants reported current political behaviour and recollection of political behaviour pre-injury. Using a normative connectome database (n = 1000), we mapped the circuitry functionally connected to lesions associated with changes in intensity of political involvement, ideological polarity and party affiliation. No significant neuroanatomical circuit was associated with political ideology or party affiliation, but a distinct circuit was associated with intensity of political involvement. Political involvement was more intense after lesions connected to the left dorsolateral prefrontal cortex and posterior precuneus, in the full sample and in conservative-leaning participants. Political involvement was less intense after lesions connected to the amygdala and anterior temporal lobe, in the full sample and in liberal-leaning participants. These effects survived cross-validation in the full sample (P = 0.01) and in both conservative-leaning and liberal-leaning participants. These findings may inform cognitive mechanisms of political behaviour as well as clinical assessment after brain lesions.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3280-3289"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent Na+ current couples spreading depolarization to seizures in Scn8a gain-of-function mice.","authors":"Isamu Aiba, Yao Ning, Jeffrey L Noebels","doi":"10.1093/brain/awaf120","DOIUrl":"10.1093/brain/awaf120","url":null,"abstract":"<p><p>Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. Although SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (IKM) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes in the awake mouse cortex. Here we find that enhanced persistent Na+ current attributable to gain-of-function mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic direct-current (DC)-band EEG recording detected spontaneous bilateral seizure-SD complexes accompanied by seizures with a profound tonic motor component, which occur predominantly during the light phase and were detected at ages between postnatal Days 33 and 100. Laser speckle contrast imaging of cerebral blood flow dynamics resolved SD evoked by an injection of pentylenetetrazol as a bilateral wave of hypoperfusion and subsequent hour-long hypoperfusion in Scn8aD/+ cortex in awake head-restrained mice. Subcortical recordings in freely moving mice revealed that approximately half of the spontaneous cortical seizure-SD complexes arose with a concurrent SD-like depolarization in the thalamus and delayed depolarization in the striatum. In contrast, SD-like DC potential shifts were rarely detected in the hippocampus or upper pons. Consistent with the high spontaneous incidence in vivo, cortical slices from Scn8aD/+ mice showed a raised SD susceptibility, and pharmacological inhibition of persistent Na+ current (INaP), which is enhanced in Scn8aD/+ neurons, inhibited SD generation in cortical slices ex vivo and in head-fixed mice in vivo, indicating that INaP contributes to SD susceptibility. Ex vivo Ca2+-imaging studies using acute brain slices expressing a genetic Ca2+ sensor (Thy1-GCAMP6s) demonstrated that pharmacological activation of IKM suppressed Ca2+ spikes and SD, whereas an IKM inhibitor strongly increased the frequency of hippocampal Ca2+ spikes in Scn8aD/+ but not wild-type slices, suggesting that IKM restrains the Scn8a gain-of-function hyperexcitability. Our study identifies a cortical SD phenotype in Scn8a gain-of-function mice shared with the Kcnq2 conditional knockout model of developmental epileptic encephalopathy and reveals that an imbalance of non-inactivating inward and outward tonic membrane currents modulates spatiotemporal SD susceptibility bidirectionally.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3325-3339"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.","authors":"","doi":"10.1093/brain/awaf189","DOIUrl":"10.1093/brain/awaf189","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e85"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The presence and prognosis of nerve pathology following whiplash injury: a prospective cohort study.","authors":"Joel Fundaun, Colette Ridehalgh, Soraya Koushesh, Alex Novak, Macarena Tejos-Bravo, Stephen Bremner, Georgios Baskozos, Andrew Dilley, Annina B Schmid","doi":"10.1093/brain/awaf088","DOIUrl":"10.1093/brain/awaf088","url":null,"abstract":"<p><p>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 tar","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3392-3406"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking polygenic risk scores to dopaminergic neuron loss using neuromelanin-sensitive imaging.","authors":"Aymeric Lanore, Rahul Gaurav, François-Xavier Lejeune, Aymeric Basset, Christelle Tesson, Gatepe Cedoine Kodjovi, Sara Sambin, Graziella Mangone, Isabelle Arnulf, Marie Vidailhet, Louise-Laure Mariani, Alexis Brice, Suzanne Lesage, Stephane Lehericy, Jean-Christophe Corvol","doi":"10.1093/brain/awaf184","DOIUrl":"10.1093/brain/awaf184","url":null,"abstract":"<p><p>Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), and neuromelanin-sensitive MRI provides a biomarker to track this neuronal loss. Isolated REM sleep behaviour disorder (iRBD), associated with cognitive decline, may represent a distinct subtype of synucleinopathy. Polygenic risk scores for these conditions may be associated with neuronal degeneration. This study investigates whether genetic risk scores for Parkinson's disease (PGS000903) or iRBD (PGS003414) are associated with neuromelanin signal loss in the SNc in the ICEBERG cohort. The analysis included 123 individuals with Parkinson's disease, 37 with iRBD and 48 healthy individuals. Neuromelanin signal intensity was analysed through linear mixed models by status and genetic risk, adjusted for age and sex. Compared with healthy controls, patients with Parkinson's disease had higher genetic risk scores for both disorders, while patients with iRBD had higher genetic risk scores only for RBD. Both patient groups showed significant signal loss over time (P < 0.001). In Parkinson's disease, higher genetic risk for the condition was associated with greater neuromelanin signal decline (P = 0.008), particularly in sensorimotor (P = 0.04) and limbic (P = 0.02) regions. No significant association was found in iRBD. In Parkinson's disease, genetic susceptibility was linked to neuromelanin signal loss, indicating genetic susceptibility to neuronal degeneration. The absence of a significant effect in iRBD may be due to a lack of power. These results should be replicated in independent studies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3095-3101"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCR3-mediated natural killer cell infiltration exacerbates white matter injury after intracerebral haemorrhage.","authors":"Anson C K Ng, Cuiting Zhang, Tsz Lung Lam, Karrie M Kiang, Vaness N C Ng, Zhiyuan Zhu, Jiaxin Liu, Wenwei Tu, Wanjun Tang, Katrina C W Chau, Kwan Man, Gilberto K K Leung","doi":"10.1093/brain/awaf108","DOIUrl":"10.1093/brain/awaf108","url":null,"abstract":"<p><p>Intracerebral haemorrhage (ICH), a subtype of stroke, carries a grim prognosis. The inflammatory response during the early phase of ICH is a major perpetuator of neurological damage. Recent clinical studies suggest possible participation of the CXC chemokine receptor 3 (CXCR3)-chemokine system in mediating neuroimmune crosstalk, which exacerbates neurological dysfunction and might serve as a potential therapeutic target in the management of ICH. CXCR3 is expressed by natural killer (NK) cells, which are known to be pathogenic in ICH. However, whether and how CXCR3 promotes NK cell infiltration and functioning in ICH and whether the attenuation of CXCR3 might affect neurological outcome have not been delineated. The present preclinical study has demonstrated, for the first time, the role of CXCR3 in facilitating the ingress of NK cells from the systemic compartment into the haemorrhagic brain and in causing ICH-related neurological injury. CXCR3 expression was found to be upregulated in the peri-haematomal region including the white matter tracts, with CXCR3+ leucocytes being the main contributor. When compared with wild-type mice, CXCR3 knockout mice showed splenic pooling of NK cells, suggestive of impaired systemic recruitment. Adoptive intravenous transfer of NK cells obtained from wild-type mice resulted in significantly greater cerebral homing of NK cells than after the transfer of NK cells obtained from CXCR3 knockout mice, confirming the pivotal role of CXCR3. Global CXCR3 deficiency was associated with reduced recruitment of NK cells expressing interferon-gamma (IFN-γ), the prototypic cytokine responsible for NK cell-induced inflammatory responses, in addition to better corticospinal tract integrity in the cervical spinal cord and improved neurological outcomes in terms of gross and fine motor functions. Systemic administration of AMG487, a CXCR3 antagonist, achieved the same effects. In conclusion, CXCR3, NK cells and IFN-γ operate in concert in ICH pathogenesis, and the attenuation of CXCR3 has important translational potential. Our findings present a new research direction in identifying novel strategies for mitigating the detrimental neuroinflammatory responses found in ICH and, possibly, in other neurological conditions.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3121-3136"},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.","authors":"Hannes Erdmann, Annalisa Schaub, Morghan C Lucas, Veronika Scholz, Anna Benet-Pages, Kerstin Becker, Christine Dineiger, Veronika Mayer, Inga van Buren, Eva Breithausen, Karl Akbari, Isabell Cordts, Mayra Sauer, Christine Schneider, Rosanna Krakowsky, Franziska Schnabel, Konstanze Dunker, Lena Fabritius, Johannes Gerb, Denis Grabova, Ken Möhwald, Marius Näher, Karoline Steinmetz, Franziska Thiessen, Alexander Jäck, Christiane Schneider-Gold, Simone Zittel, Christina Petersen, Isolde Schreyer, Larissa Mämecke, Sibylle Wilfling, Gilbert Wunderlich, David Brenner, Yorck Hellenbroich, Kirsten Muhle, Tessa Huchtemann, Inga Claus, Thomas Klopstock, Michael Strupp, Johannes Levin, Günter Höglinger, Doreen Huppert, Sandra Becker-Bense, Filipp Filippopulos, Fabian Kilpert, Elsa Leitão, Sabine Kaya, Christel Depienne, Florian Schöberl, Teresa Neuhann, Elke Holinski-Feder, Andreas Zwergal, Angela Abicht","doi":"10.1093/brain/awaf318","DOIUrl":"10.1093/brain/awaf318","url":null,"abstract":"<p><p>Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich's ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occuring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters besides repeat length to improve diagnostic precision of repeat analysis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144941867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aβ low threshold mechanoreceptors contribute to sensory abnormalities in fibromyalgia.","authors":"Mathilde R Israel, Richard Berwick, Nisha Vastani, Qin Zheng, Warren Moore, Margot Maurer, Clive Gentry, Anne Marshall, Haoyue Sun, Harvey Neiland, James Dunham, Otmane Bouchatta, Katy Plant, Saad S Nagi, Håkan Olausson, Uazman Alam, Xinzhong Dong, Stuart Bevan, Andrew Marshall, Andreas Goebel, David A Andersson","doi":"10.1093/brain/awaf321","DOIUrl":"10.1093/brain/awaf321","url":null,"abstract":"<p><p>Fibromyalgia syndrome (FM) is characterized by widespread pain and fatigue. People living with FM also experience tactile allodynia, cold-evoked pain, paresthesia and dysesthesia. There is evidence of small fiber neuropathy and hyperexcitability of nociceptors in FM, however the presence of other sensory abnormalities suggests involvement of large diameter sensory fibers. The passive-transfer of FM IgG to mice causes cold and mechanical hyperalgesia associated with changes in A- and C-nociceptor function. However, whether FM IgG also confers sensitivity to light touch and whether large diameter sensory fibers contribute to symptoms evoked by cold is unknown. Here we demonstrate that the presence of sensory abnormalities such as tingling, correlate with the impact of FM, and that people with FM describe the sensation of cutaneous cooling with neuropathic descriptors such as tingling/pins and needles. We find a causal link between circulating FM IgG and the sensitization of large diameter, Aβ low threshold mechanoreceptors (Aβ-LTMR) to mechanical and cold stimuli in mice ex vivo and in vivo. In keeping with our experimental observations, a larger proportion of Aβ-LTMRs respond to cold stimulation in people with FM, but in contrast to our results ex vivo, the same fibers display reduced responses to mechanical stimuli. These results expand the pathophysiological role of IgG in FM, and will inform future studies of sensory symptoms and pain in people with FM. .</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144942284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}