Mutations in SHANK3 are a leading monogenic cause of autism spectrum disorder (ASD), often associated with profound sensory abnormalities. However, the impact of SHANK3 deficiency on olfactory processing and the underlying neural mechanisms remains unclear. Here, we identify a cross-species disruption of olfactory valence perception in individuals with SHANK3 mutations and in Shank3 mutant mice. Patients carrying SHANK3 mutations exhibited impaired valence-oriented sniffing and electroencephalography (EEG) responses, whereas Shank3B-/- mice displayed blunted behavioral responses to both attractive and aversive odors. In mice, these behavioral deficits were associated with attenuated odor-evoked calcium signals and reduced excitatory synaptic transmission in the cortical amygdala (CoA), a key node for olfactory valence processing. Acute CoA-specific Shank3 deletion recapitulated these deficits, whereas targeted restoration of CoA Shank3 expression rescued odor-induced appetitive and aversive behaviors. Our findings reveal a conserved function for SHANK3 in encoding olfactory valence and identify CoA dysfunction as a circuit mechanism in mice.

Variability-dominated auditory cortical dysfunction and targeted VNS modulation in a Mecp2+/- model of Rett syndrome.

T-cells infiltrate somatosensory ganglia in response to nerve damage, autoimmune disease, and infection, contributing to sensory abnormalities and pain. In naïve states, T-cells are rare in the rodent dorsal root ganglion (DRG) but have been reported in human and non-human primates without known relevant exposures. It remains unclear whether there are inherent evolutionary or species differences in DRG T-cell residence. Using a comparative biology approach, we investigated the frequency and distribution of T-cells in the mammalian DRG across humans, non-human primates, pigs, and rodents, and in humans investigated the contributions of sex and age. Spatial transcriptomics and immunofluorescence independently verified the robust presence of DRG T-cells at similar levels in humans, non-human primates, and pigs, but were fewer in rats and largely absent in mice. In humans, premenopausal females were more likely to have elevated DRG endoneurial T-cells than post-menopausal females or adult males. T-cells were detected in human dorsal root ganglion at as early as two months of age but were less abundant within the perineuronal niche. Most human DRG T-cells expressed distinct markers consistent with a resident memory (Trm) phenotype. We discuss the importance of studying the functional roles of DRG-resident T-cells and raise broader considerations for modelling peripheral nervous system disease.

We aim to comprehensively analyze how regional tumor and edema characteristics are associated with clinical presentations and survival outcomes in a large cohort of glioblastoma patients. Patients with IDH-wildtype glioblastoma who received brain MRI from 2010 to 2023 were included. The enhancing tumor, necrotic core, and edema/infiltration volumes were automatically segmented across brain regions. Multivariable regression assessed associations between regional volumes, presenting symptomatology, and survival outcomes. Of 526 patients analyzed, initial presentations included seizure (29%), aphasia (26%), confusion (25%), headache (24%), focal weakness (22%), memory problems (20%), ataxia (16%), visual field deficits (11%), personality change (10%), and focal sensory abnormalities (7%). Distinct regional tumor patterns emerged: seizures were associated with smaller overall tumor burden but with relatively greater cortical involvement, headache with increased subcortical volumes, confusion with left hemisphere and temporal involvement, personality changes with frontal-cingulate-basal ganglia involvement, and focal neurologic deficits with mostly predictable patterns. While no initial presentation correlated with survival, the presence of postoperative seizures was associated with improved overall survival. Increased volume of enhancing tumor, particularly in the insula and brainstem, was associated with worse overall survival. Anatomical tumor distribution provided prognostic information beyond overall tumor burden in glioblastoma. Regional patterns expand on the anatomical basis of symptoms. The survival benefit associated with postoperative seizures suggests distinct tumor biology or microenvironmental factors. Incorporating regional characteristics into clinical and prognostic models may improve risk stratification and inform treatment planning.

Mapping the neuropathic-sensory-affective pain axis in Sjögren's disease toward neuropsychological phenotyping.

Erythema Elevatum Diutinum (EED), an uncommon form of chronic leukocytoclastic vasculitis presents as reddish-brown plaques and papulonodules primarily affecting the extensor surface. It mimics various cutaneous disorders and hence poses diagnostic difficulties. EED is predominantly seen in middle-aged individuals between fourth and sixth decade. EED can also have various extracutaneous manifestations such as arthralgia, scleritis, panuveitis, ulcerative keratitis and neuropathy indicating circulating immune complexes deposition in several organs. Thereby thorough clinical and systemic examination for early diagnosis and comprehensive management of both skin and extracutaneous findings are essential to prevent complications and further progression. The authors hereby report a case of 47-year-old female with long standing diabetes mellitus presenting with asymptomatic papulonodular lesions over the extensor surface with sensory abnormalities, highlighting the diagnostic dilemma and emphasising the importance of histopathological correlation in arriving at appropriate diagnosis.

Anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) have emerged as a promising new class of analgesics, offering potential benefits in managing particular painful musculoskeletal (MSK) conditions. However, their long-term safety remains uncertain, leading to regulatory non-approval of these agents. This study aims to evaluate the efficacy and safety of individual anti-NGF mAbs compared to other analgesics when treating chronic MSK pain. Our literature search included PubMed, Scopus, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov through April 25th, 2025. Articles eligible for inclusion were randomized controlled trials (RCTs) comparing one of the human anti-NGF mAbs to other interventions in adults with chronic MSK pain. Primary outcomes evaluated were changes from baseline in pain, physical function, and patient global assessment (PGA) scores, as well as risks of adjudicated arthropathies (AAs) and abnormal peripheral sensation (APS). We used the Cochrane Risk of Bias 2 (RoB-2) tool to assess risk of bias. Pairwise and network meta-analyses were performed using random-effects models. Treatments were ranked using the cumulative ranking curve (SUCRA), and a multi-criteria decision analysis with Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) was applied to integrate all efficacy and safety outcomes. Statistical analyses were conducted in R (v4.3.1) using the meta, netmeta, gemtc, and Multi-Criteria Decision Aiding (MCDA) packages. A total of 29 studies, involving 27,747 patients with osteoarthritis or chronic low back pain, were included in this analysis. Compared to placebo, fasinumab showed the highest improvements in pain (standardized mean difference [SMD] - 0.40, 95% CI [- 0.52, - 0.29], p < 0.001) and physical function (SMD - 0.42, 95% CI [- 0.53, - 0.31], p < 0.001), followed by tanezumab (pain: SMD - 0.36, 95% CI [- 0.44, - 0.28], p < 0.001; function: SMD - 0.39, 95% CI [- 0.47, - 0.31], p < 0.001). For safety, both fasinumab and tanezumab demonstrated a significant risk for AAs (risk ratio [RR] 4.7, 95% CI [3.61, 6.13], p < 0.001; and RR 3.84, 95% CI [2.07, 7.14], p < 0.001, respectively) and APS (RR 1.99, 95% CI [1.49, 2.65], p < 0.001; and RR 2.46, 95% CI [1.93, 3.14], p < 0.001, respectively) relative to placebo. While fulranumab was less effective (pain: SMD - 0.25, 95% CI [- 0.42, - 0.07], p < 0.01; function: SMD - 0.25, 95% CI [- 0.43, - 0.07], p < 0.01), it showed better overall safety against placebo relative to both agents, demonstrating a significant risk only for APS events (RR 1.78, 95% CI [1.09, 2.92], p < 0.05). Anti-NGF mAbs, particularly fasinumab and tanezumab, are associated with the greatest levels of pain relief and functional improvement over placebo within this analysis. However, these benefits are counterbalanced by significant risks of joint-related adverse events. Implementation of strict safety protocols is essential when considering these agents for further evaluation. PROSPERO ID: CRD420251104612.

Near-infrared photobiomodulation can alleviate chemotherapy-induced peripheral neuropathy-associated sensory abnormalities.

Bortezomib (BTZ), the first-generation proteasome inhibitor, has been approved for the treatment of relapsed, refractory, and newly diagnosed multiple myeloma. Despite its remarkable antitumor efficacy, BTZ treatment is severely limited by a high incidence of systemic adverse reactions, primarily due to its non-selective cytotoxicity toward rapidly dividing normal cells and its potent neurotoxic effects on peripheral neurons. Bortezomib-induced peripheral neurotoxicity (BIPN) manifests as neuropathic pain and sensory abnormalities, affecting up to 31% to 64% of patients and limiting BTZ's clinical use. Currently, the underlying mechanisms of BIPN are poorly understood. To evaluate the effects of BTZ on the functions of peripheral nerves in mice, we administered an intraperitoneal injection treatment for four weeks. Results indicated that BIPN caused mechanical allodynia, gait abnormalities, and pathological changes in myelin and axons in mice. This study confirms that BTZ upregulates the expression of the activating transcription factor 3 (ATF3), which in turn mediates the increased expression of the copper transporter SLC31A1, causing dysregulation of intracellular copper ion homeostasis and subsequent copper accumulation, and ultimately inducing the development of peripheral neurotoxicity. Elevated intracellular copper concentration exerts a dual effect: it directly promotes the oligomerization of Dihydrolipoamide S-acetyltransferase (DLAT) and concurrently damages the iron-sulfur cluster protein ferredoxin 1 (FDX1), collectively triggering the onset of cuproptosis. Green tea has garnered attention for its rich content of catechins, with (-)-Epigallocatechin Gallate (EGCG) being the most abundant catechin present. This study uncovers the molecular mechanism by which EGCG inhibits BTZ-induced cuproptosis through targeted regulation of copper homeostasis. Analyses demonstrate that EGCG significantly downregulates the expression of the copper transporter SLC31A1, thereby effectively suppressing transmembrane influx of extracellular copper ions. This intervention markedly reduces intracellular copper overload, eliciting a dual regulatory effect: on one hand, the decreased copper concentration directly inhibits the oligomerization of DLAT; on the other hand, it effectively protects the iron-sulfur cluster protein FDX1 from damage. This study aims to systematically elucidate the molecular mechanisms underlying BIPN and to evaluate the therapeutic potential of EGCG in alleviating BIPN, offering a novel therapeutic strategy for the prevention and treatment of BIPN.

Fibromyalgia (FM) is a chronic pain disorder with a severe impact on a person's health-related quality of life. In addition to the characteristic widespread pain and fatigue, people with FM regularly experience sensory abnormalities and report lingering, often painful sensations after mechanical probing of the skin. The neurobiological changes which underlie the varied symptoms in FM are incompletely understood, but many symptoms and signs can be transferred from patients to mice by administration of patient IgG. The present study aimed to explore whether sensory afferents, including nociceptors, in rodents injected with FM patient IgG displayed ongoing firing after mechanical stimulation. Skin saphenous nerve recordings were retrospectively analyzed to assess the presence and quality of ongoing discharges following mechanical stimulation of sensory afferents in mouse skin after passive-transfer of FM patient IgG. Our analysis revealed that C-mechano and Aδ-mechano afferents innervating the skin in FM-IgG treated animals fired significantly more action potentials after, but not during, mechanical force steps compared to healthy control-IgG treated afferents. This sustained mechanically evoked activity mirrors the nociceptor hyperexcitability observed in people with FM, suggesting that autoreactive IgG might underly this phenomenon in patients. This adds to the growing body of evidence demonstrating that FM symptoms arise from changes in the peripheral nervous system generated by circulating autoreactive IgG. KEY POINTS: Passive transfer of fibromyalgia (FM)-IgG causes sensitization of mechano-sensitive afferents in the skin of mice. Aδ-mechano and C-mechano sensitive afferents in skin from mice injected with FM-IgG display more after-discharge following mechanical stimulation than mice injected with healthy control-IgG. Changes in the peripheral nervous system caused by circulating autoreactive IgG play a role in FM signs and symptoms.

This study examines the symptom clusters present in patients with oral cancer and assesses the impact of age, sex, tumor site, and clinical stage as four covariates on their longitudinal trajectories. This study collected data from 108 patients with oral cancer treated with surgery followed by chemoradiotherapy at a single center across six time points: 24h before surgery, 7days after surgery, 24h before discharge, 24h before initiation of CRT, within 24h after completion of CRT, and 2weeks after completion of CRT. PCA was performed on pooled observations from all time points to extract symptom clustersand LME modeled their temporal trajectories. The analysis accounted for age, sex, tumor site, and clinical stage as covariates, incorporating collinearity testing and model diagnostics. Five clusters were identified: Oropharyngeal-Systemic Discomfort (OSD), Upper GI-Sleep Disruption (USD), Oral Sensory Abnormality (OSA), Neuro-Constipation (NC), and Emotional-Somatic Reaction (ESR). OSD followed a quadratic (increase-then-decrease) trend, USD initially declined before rising, and OSA increased continuously. Clinical stage was significantly associated with OSD and USD trajectories, whereas age primarily related to OSA. Although change rates were comparable across clusters, higher baseline burdens predicted less improvement in USDand OSA, with a similar trend observed for NC. Diagnostics supported robust fit for OSD, USD, and OSA models, while NC and ESR findings warrant cautious interpretation. Combining PCA and LME effectively delineates symptom dynamics in oral cancer. Age and clinical stage serve as key factors, supporting the potential for early high-risk patient identification and personalized supportive care.

Microexons of 3 to 27 nucleotides selectively regulated in the vertebrate nervous system have attracted attention as new elements for modifying the function of neuronal proteins. Protein tyrosine phosphatase δ (PTPRD) is one of presynaptic hubs for neuronal synaptic organization. Alternative splicing (AS) of three microexons, meA3, meA6, and meB, encoding 3, 6, and 4 amino acid-peptides, respectively, imparts structural diversity to PTPRD, due to which the resulting eight splice variants exhibit distinct synaptogenic properties. However, the regulatory mechanisms of AS and physiological significance of the AS code for Ptprd gene remain largely unknown. Here, we report the AS of the three microexons is genetically regulated to generate spatiotemporally distinct expression pattern of eight Ptprd splice variants across brain regions and is modulated by neuronal activity. We identified both the intronic splicing enhancer region (ISE) for meB contributing to the spatiotemporal patterning of the AS and the neuronal activity-dependent intronic splicing silencer region for meB (ISS). Heterozygous deletion of the ISE in mice led to a decreased meB selection rate by ~25% with unaltered total amount of PTPRD protein and caused severe sensory, motor, social, and emotional behavioral abnormalities but no obvious changes in learning and memory, while heterozygous Ptprd knockout mice with unaltered meB selection rate and ~50% decrease in total PTPRD protein showed much fewer behavioral abnormalities. Interestingly, deletion of the ISS for meB caused selective impairments in motor learning and fear memory. Our findings demonstrate the spatiotemporal and activity-dependent AS code for Ptprd meB plays a crucial role in proper behavioral development.

Traumatic Brain Injury (TBI) patients may suffer from a number of long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here we investigate the effect of exercise on pain outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies employed the administration of noradrenergic (NA) and serotoninergic receptor blockers. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of the acute phase of pain from ∼5 weeks to 2-3 weeks in female and male TBI rats respectively, gains that could be reversed using the α 1 -adrenoceptor (α 1 AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT 7 receptor antagonist, SB-267790, the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Therefore, the transition from a noradrenergic to a serotonergic inhibitory pain pathway that we typically see in male TBI rats, was blocked by exercise. Assessment of neuropathology, acutely after TBI, reveals that both the astrocyte and microglial response to injury is significantly greater in male TBI compared to female TBI, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. In contrast, exercise significantly decreased the amount of axonal loss in the corpus callosum in both male and female TBI rats compared to sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups respectively. These results demonstrate that exercise is a promising treatment for chronic pain after TBI in both male and females. It also highlights that dysfunction of the endogenous pain modulatory pathways observed in male rats after TBI can be prevented by exercise, possibly by reducing axonal loss.

Different surgical techniques are used to treat idiopathic meralgia paresthetica. We analyzed the effect of neurolysis of the lateral femoral cutaneous nerve (LFCN) with intraoperative dynamic testing of the completeness of decompression. A retrospective single center study was conducted on a consecutive series of 109 procedures performed between January 2018 and January 2024. Five different postoperative outcome measures were used by an independent neurologist to assess specific meralgia symptoms and overall well-being: (1) pain and (2) skin sensation in the LFCN area, both rated on a 4-point ordinal scale (completely resolved, improved, unchanged, or worsened); (3) reduction of the area with abnormal skin sensation, measured on a 0-100 continuous scale; (4) the Global Perceived Effect, rated on a 7-point ordinal scale (much better, better, somewhat better, the same, somewhat worse, worse, or much worse); and (5) overall decrease in reported complaints rated on a 0-100 continuous scale. The correlation between outcome measures was assessed either by proportional odds model, or by linear-by-linear association test. The effect of time from onset of symptoms to surgery, body mass index, sex, and age on the reduction of complaints was evaluated using a Beta mixed effect regression model. Most of the interventions resulted in either complete or marked overall reduction of complaints (mean 87.9, SD: 17.9). The overall reduction was positively associated with the Global Perceived Effect and strongly associated with greater improvements in postoperative pain and sensory scores (P < .001). No significant impact was found of baseline covariates on the reduction of symptoms. Neurolysis of the LFCN with intraoperative dynamic testing to assess the completeness of decompression yields excellent pain reduction and improvement of sensation in the majority of idiopathic meralgia paresthetica patients. Whether dynamic testing contributes to outcomes requires a comparative study with static decompression alone.

Sleep disturbances and sensory processing and integration in children and adolescents with autism spectrum disorder: a systematic review.

Multiple chemotherapeutic agents exhibit neurotoxicity. For example, bortezomib (BTZ)-induced peripheral neuropathy (BIPN) is characterized by sensory abnormalities and pain, and effective treatment strategies are currently lacking. This study aimed to investigate the alleviating effects of gastrodin (GAS) on BIPN and its potential mechanisms. Behavioral tests were used to assess changes in pain thresholds across all groups of mice. Hematoxylin-eosin staining, transmission electron microscopy, and immunofluorescence were used to evaluate peripheral nerve injury and the activation of spinal glial cells. ELISA was used to measure the levels of inflammatory cytokines. Proteins associated with the NF-κB/NLRP3 pathway were examined using Western blot. GAS significantly improved thermal and mechanical hyperalgesia in BIPN mice. Moreover, BTZ can cause loss of intraepidermal nerve fibers, microstructural damage to the dorsal root ganglia, a disorganized arrangement of sciatic nerve fibers, and demyelination, all of which were effectively reversed by GAS treatment. Further investigation revealed that GAS significantly suppressed the upregulation of IBA-1 and GFAP in the spinal cord of BIPN mice, and the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were concurrently reduced. IBA-1/IL-1β and IBA-1/TNF-α double-labeled positive cells were significantly increased in BIPN mice, and GAS intervention reduced the number of these double-labeled cells. In addition, GAS significantly inhibited aberrant NF-κB signaling and upregulation of NLRP3 inflammasome-related proteins of BIPN mice. GAS may alleviate BIPN by suppressing microglia-mediated neuroinflammatory responses, and the NF-κB/NLRP3 inflammasome signaling pathway appears to be involved in this process.

ABSTRACT Seizure is a neurological disorder characterized by the abnormal discharge of electricity in some or all of the brain, leading to motor, sensory, or psychomotor abnormalities. In the present study, the Antiepileptic effect of the puerarin flavonoids was evaluated against the PTZ‐induced seizure in animals. The puerarin administration evidently increased the duration of seizure onset as compared to the only PTZ‐treated group. Similarly, administration of the puerarin dose dependently reduced the seizure duration and seizure severity using the Racine scale; however, the maximum dose produced a pronounced Antiepileptic effect. Following in vivo activities, computational studies were conducted to assess the mechanism and dynamic stability of the complexes. The molecular docking analysis showed maximum binding energies of the puerarin with the 2OKK and 2W8O target proteins and interactions via multiple hydrogen and hydrophobic bonds. Following the docking analysis, molecular dynamic (MD) simulations were performed, and post‐MD analysis showed that all complexes remained stable during the entire 100 ns simulation. The MD analysis was followed by Molecular Mechanics–Poisson–Boltzmann Surface Area and Molecular Mechanics–Generalized Born Surface Area (MM‐PBSA, MM‐GBSA) calculations for both complexes, that is, 2OKK and 2W8O. The results showed the energy of the system remains negative, and favorable bonding interactions have been observed in both ligand‐protein systems.

Spinal cord injury (SCI), which is a severe complication of spinal fractures, often causes the dysfunction of the spinal cord and results in sensory and motor abnormalities. Current clinical treatments-including medication, decompression surgery, and bed rest-remain insufficient for complete functional recovery. It is necessary to reduce the early inflammatory reactions, rebuild the connections of neurons, and reduce the formation of the glial scar in order to restore spinal cord function. With the development of biomaterials discipline, hydrogel tissue engineering has become an effective and feasible method. Injectable and highly biocompatible hydrogel can directly fill the injured site as a scaffold material that can provide physical support to reduce scar formation and promote axon growth. In addition, hydrogels have the ability to regulate pathophysiological events. For example, it can reduce inflammatory reactions, inhibit glial scar formation, and promote axonal growth, so as to achieve the recovery of motor function after SCI. This review systematically correlates the four pathological phases of SCI with the stage-specific biological functions of hydrogels. It summarizes the current state of research in SCI and hydrogel-based tissue engineering, and discusses the key challenges and future directions in this evolving field.

Advances in the study of Parkinson's disease-related salivation and associated mechanisms.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviours. Sensory processing abnormalities are now recognized as a core feature of ASD and have been extensively studied. While differences in sensory profiles between individuals with and without ASD are well established, the genetic underpinnings of sensory variability within the ASD population remain unclear. The opioid system is believed to play a role in processes such as social behaviours, pain, addiction, reward, mood, cognition and perception. This study aimed to investigate the relationship between ASD, sensory differences and prodynorphin (PDYN) gene polymorphisms. This was a case-control study that included 45 children aged 3 to 7 years diagnosed with ASD and 45 neurotypical children matched for age and gender. The parents of all participating children were administered the Sociodemographic Data Form, the Autism Behaviour Checklist and the Dunn Sensory Profile-Parent Questionnaire. The ASD clinical severity of the cases was assessed using the Childhood Autism Rating Scale. Venous blood samples were collected from all the children for the analysis of PDYN gene polymorphisms. Prodynorphin gene variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism methods. No significant differences were found between the ASD and control groups in terms of PDYN gene polymorphisms. While there were no differences in scores related to endurance and tone sensory processing, low endurance-tone and inactivity between the groups, all other subtest scores were significantly lower in the ASD group. In children with ASD, a significant difference was observed in the number of individuals showing atypical performance in the oral sensory processing and regulation of visual inputs influencing emotional responses and activity level subtests for the prodynorphin rs1022563 polymorphism. Due to the preliminary nature of this investigation and the relatively small sample size, these findings should be interpreted with caution and require validation in larger cohorts. These preliminary findings suggest a potential modulatory role of PDYN gene variants in sensory processing characteristics among children with ASD. These novel findings warrant replication in larger cohorts to validate the influence of PDYN polymorphisms on sensory phenotypes and to further clarify their neurobiological relevance.