Search Results (1,731)

Depression is often associated with functional disturbances in the visual system. However, the fundamental features underlying these visual system aberrations in depression remain to be fully elucidated. In particular, in the first stage of visual processing, how different retinal output neuron types change their intrinsic properties and output features in response to specific light stimulation remains unclear. Here, by adopting a mouse model of depression induced by chronic unpredictable stress (CUS), we found that depression is associated with reduced blood perfusion in the retinal inner plexiform layer (IPL). The hypoperfusion in the IPL is paralleled by a remarkable reduction of retinal ganglion cell (RGC) density, with more cell loss in ipRGCs than in the general RGCs. The surviving RGCs—particularly, ipRGCs—changed their intrinsic electrical properties, exhibiting decreased membrane input resistance, more depolarized resting membrane potential, and altered spiking properties. Additionally, these cells showed stimulus-size-dependent increases in light-evoked responses. Together, our findings demonstrate that depression is associated with the retinal IPL hypoperfusion and RGC impairments (particularly ipRGCs) and suggest retinal layer- and RGC-type-specific susceptibilities, furthering our understanding of retinal pathophysiology in depression. Full article

Chronic heart failure (CHF) is a growing global health concern characterized, in part, by progressive sympathetic overactivation, which exacerbates this condition. Accumulating evidence identifies oxidative stress as a key driver of sympatho-excitation, mediated by excess reactive oxygen species (ROS) and impaired antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) is a central regulator of antioxidant gene expression, but its role in the peripheral sympathetic nervous system, particularly in the stellate ganglia, remains unclear. We hypothesized that Nrf2 signaling is disrupted in the stellate ganglia in CHF and that modulation of Nrf2 alters ROS levels and sympathetic responses. In rats, six weeks post myocardial infarction (MI), the stellate ganglia exhibited increased ROS levels in tyrosine hydroxylase-positive neurons along with reduced Nrf2 protein and mRNA expression; both changes were inversely associated with ejection fraction (EF). To determine the functional role of Nrf2, lentiviral vectors encoding GFP or GFP-Nrf2 were delivered to the stellate ganglia three weeks after MI. Nrf2 upregulation attenuated heart rate responses to stellate stimulation in sham rats but augmented responses in CHF rats. The increase in plasma norepinephrine levels was reduced following stellate stimulation in CHF rats that overexpressed Nrf2, while β1-adrenergic responsiveness to dobutamine was unchanged. This study demonstrates that CHF is associated with increased oxidative stress and reduced Nrf2 expression in the stellate ganglion. Nrf2 overexpression significantly modulated sympathetic regulation, altering heart rate responses and reducing plasma norepinephrine in CHF rats. These findings support the concept that impaired Nrf2 signaling contributes to ganglionic redox imbalance and dysregulated sympathetic nerve activity in CHF. Full article

Adult optic nerve axon regeneration has traditionally been framed as a problem of limited intrinsic growth capacity in central nervous system neurons. However, growing evidence suggests that intrinsic factors alone cannot account for regenerative failure: restrictive extrinsic environmental factors largely govern optic nerve regeneration, dictating the intrinsic capacity axons can express. In this review, we frame the extrinsic optic nerve environment as a dynamic regenerative niche, in which vascular, immune, glial, matrix, and metabolic compartments are spatially co-localized and temporally coordinated rather than acting as independent barriers. These compartments follow a shared trajectory, broadly protective in the acute phase, then inhibitory once the underlying response fails to resolve, while also actively driving one another, such as reactive astrocytes promoting the matrix remodeling that subsequently restricts axon regrowth. Consequently, the niche’s overall permissiveness for regeneration reflects the aggregate and interdependent state of these compartments rather than the action of any single barrier. This review integrates current evidence on extrinsic barriers, intervention opportunities, and disease-specific variability relevant to RGC axon regeneration after injury. These interventions must incorporate the spatial, temporal, and metabolic factors that shape the goal of functional recovery and vision restoration. Full article

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Background/Objectives: Retinal imaging has considerable potential for monitoring Alzheimer’s disease (AD) neurodegeneration, as retinal ganglion cell dendritic atrophy within the inner plexiform layer (IPL) is an early event. We tested whether quantitative optical coherence tomography (OCT) speckle texture analysis combined with supervised machine learning could discriminate AD-related IPL alterations without exogenous contrast agents in a mouse model. Methods: Retinal explants from triple-transgenic AD mice (n = 7, aged 12 months) and C57BL/6 controls (n = 3, aged 15 months) were imaged ex vivo using a custom 1040 nm spectral-domain OCT system. Five grey-level co-occurrence matrix (GLCM) features were extracted from IPL volumes of interest (VOIs) and classified using a linear support vector machine (SVM). Results: AD and control IPL textures formed two completely separable clusters in a two-dimensional feature space defined by contrast and entropy (0°), achieving 100% VOI-level classification accuracy (95% CI: 96.4–100%). However, given the small sample size, VOI-level rather than animal-level validation, lack of histological confirmation, non-interleaved image acquisition, and differences in age/strain between groups, these results represent exploratory dataset separability rather than a validated diagnostic test. Conclusions: These findings demonstrate the feasibility of the ligand-free, texture-based OCT discrimination of IPL alterations, indicating a strong underlying optical signal. Adequately powered, in vivo longitudinal studies with matched controls, interleaved acquisition, animal-level cross-validation, and histological validation are required before any clinical translation. Full article

Introduction: The fetal ganglionic eminence (GE) is a transient brain structure involved in interneuron development; its abnormalities may be associated with malformations of cortical development (MCD). This systematic review evaluated the feasibility and clinical value of transvaginal neurosonography for fetal GE assessment. Material and Methods: PubMed, Scopus, and Web of Science were searched from January 2015 to June 2026. Human in vivo ultrasound studies of the fetal GE were included. Results: Thirteen studies comprising 890 fetuses were included. GE visualization ranged from 71% to 100%, with highest rates using dedicated three-dimensional transvaginal neurosonography at 9–22 weeks. Measurement reproducibility was good to excellent. GE cavitation and enlargement were associated with MCD in selected high-risk cohorts, but reported frequencies varied substantially. Conclusions: Transvaginal neurosonography permits feasible and reproducible visualization of the fetal GE in experienced hands. Small studies, heterogeneous protocols, and limited long-term outcome data preclude routine GE assessment at present. Full article

Sudden sensorineural hearing loss (SSNHL) carries unpredictable recovery, and adjunctive therapies beyond systemic corticosteroids are limited. Stellate ganglion block (SGB) and hyperbaric oxygen therapy (HBOT) have each been proposed as adjuncts, yet their combined effect remains poorly characterized. A retrospective three-arm cohort study (IRB No. 202401644B0) enrolled 75 SSNHL patients: Control (standard corticosteroid, n = 39), SGB (n = 21), and SGB+HBOT (n = 15). PTA4 improvement and Siegel recovery categories were assessed at two weeks, one month, and two months. Subgroup analyses stratified patients by baseline PTA4 < 70 dB and ≥70 dB. Groups differed significantly in overall baseline PTA4 (Kruskal–Wallis p = 0.044; SGB group worst at 80.4 ± 17.3 dB) and in diabetes mellitus (DM) prevalence (Control 44% vs. 7% in SGB+HBOT; p = 0.018). Within the ≥70 dB subgroup, baseline PTA4 was balanced across groups (Control 86.5 ± 13.0 dB, SGB 88.2 ± 14.2 dB, SGB+HBOT 90.9 ± 15.3 dB; p = 0.748). In this balanced stratum, SGB+HBOT achieved the greatest two-month PTA4 improvement (+23.6 ± 27.2 dB) and the highest complete recovery rate (43%, 3/7), versus 27% (3/11) in Control and 9% (1/11) in SGB. No statistically significant between-group differences were identified. However, SGB+HBOT demonstrated the numerically greatest audiometric improvement and the highest complete recovery rate in the severe–profound subgroup despite baseline disadvantages, suggesting a possible therapeutic benefit for this population. These exploratory findings support prospective evaluation in an adequately powered randomized controlled trial. Full article

Background/Objectives: Regional anesthesia techniques are increasingly being incorporated into multimodal analgesia for septorhinoplasty. This study compared the postoperative analgesic efficacy and recovery profiles of infraorbital–infratrochlear (ION–ITN) nerve block and transnasal sphenopalatine ganglion (SPG) block techniques. Methods: In this prospective, randomized, double-blind trial, 93 patients undergoing septorhinoplasty received bilateral ION–ITN block (n = 45) or transnasal SPG block (n = 48). The primary outcome was postoperative pain assessed using the Numerical Rating Scale (NRS). Peak postoperative NRS scores at the predefined assessment intervals were evaluated with a linear mixed-effects model adjusted for relevant covariates. Continuous variables are presented as medians (first quartile–third quartile [Q1–Q3]), and categorical variables as numbers (percentages). Secondary outcomes included emergence agitation (Riker Sedation–Agitation Scale (RSAS)), rescue tramadol use, patient satisfaction, and adverse events. Results: Pain scores decreased significantly over time in both groups (p < 0.001). No significant group effect was observed (p = 0.726), and adjusted between-group differences were not significant at any postoperative interval (all p > 0.05). Although the group-by-time interaction showed a trend toward statistical significance (p = 0.053), no meaningful differences in postoperative pain trajectories were observed between the two groups. Median RSAS scores were lower in the SPG group (3 [2,3,4] vs. 4 [3,4], p = 0.04), whereas emergence agitation incidence, tramadol use, patient satisfaction, and adverse events were similar. Conclusions: Within the multimodal analgesic regimen, no statistically significant differences in postoperative pain outcomes were detected between ION–ITN and transnasal SPG block. Because this study was not designed as an equivalence or non-inferiority trial, these findings should be interpreted as an absence of detected differences rather than proof of equivalent analgesic efficacy. Although SPG block was associated with lower agitation scores, this finding suggests reduced agitation severity rather than superior overall analgesic efficacy. Full article

Primary sensory neurons of the dorsal root ganglion (DRG) express mu-type opioid receptors and undergo plasticity that can contribute to both analgesia and maladaptive outcomes such as opioid tolerance and opioid-induced hyperalgesia. Most mechanistic work has relied on rodent models, which may not fully capture the repertoire of opioid-responsive pathways present in humans. In this study, we tested whether morphine exposure reshapes gene expression programs in human nociceptors. Human induced pluripotent stem cell (hiPSC)-derived nociceptors were exposed to morphine (3.5 μM) acutely (1h, 16h) or repeatedly (2–3 days; daily 16h exposure separated by 8h washout) and profiled by time-series RNA sequencing. The transcriptional response to morphine included the induction of a small set of genes across exposure paradigms. P2RY11, encoding the purinergic G protein-coupled receptor P2Y11, was the most robustly induced transcript across the time course, and genes involved in purinergic signaling pathways exhibited coordinated expression dynamics. Since P2RY11 lacks a mouse/rat ortholog, its contribution to nociceptor biology and opioid responses has remained largely underexplored. Using human DRG tissue and primary human DRG cultures from organ donors, we detected P2RY11 mRNA and P2Y11 protein in neuronal populations. We observed increased P2Y11 expression in peripherin-positive neurons after morphine exposure in vitro, corroborating our sequencing results. These findings identify P2RY11/P2Y11 as a morphine-responsive purinergic receptor in DRG neurons and nominate purinergic signaling as a candidate pathway contributing to opioid-driven peripheral plasticity. Full article

The global prevalence of myopia is increasing, and the combination of myopia and glaucoma is widely expected to become an important clinical and public health issue. Myopic eyes undergo axial elongation and posterior pole remodeling, leading to optic disc tilt, peripapillary deformation, choroidal thinning, and altered spatial relationships between the optic nerve head and its vascular supply. Glaucomatous optic neuropathy is associated with retinal ganglion cell damage, lamina cribrosa deformation, and ocular blood flow impairment. Recent advances in optical coherence tomography angiography and laser speckle flowgraphy have enabled noninvasive assessment of retinal, peripapillary, choroidal, and optic nerve head circulation. These modalities have revealed reduced radial peripapillary capillary density, choroidal microvasculature dropout, and reduced optic nerve head tissue blood-flow signal in glaucomatous eyes. In eyes with myopia and glaucoma, myopia-related structural deformation and glaucoma-associated perfusion abnormalities may coexist and show sectoral correspondence with neural damage, particularly in regions related to the central visual field. This review summarizes the anatomical background of ocular blood flow, myopia-induced structural and vascular changes, glaucoma-associated blood flow impairment, and their interaction in eyes with myopia and glaucoma. Potential therapeutic approaches targeting ocular blood flow are also discussed, although evidence beyond intraocular pressure reduction remains limited. Full article

Background and Clinical Significance: Proliferative fasciitis (PF) is an infrequent benign fibroblastic/myofibroblastic proliferation that may closely resemble a soft tissue sarcoma, creating a diagnostic dilemma out of proportion to its biological behaviour. Because no single clinical, histological or immunohistochemical feature is diagnostic, accurate classification depends on the integration of complementary findings. We describe a challenging case of PF involving the lower leg and present a practical clinicopathological approach to its evaluation. Case Presentation: A 34-year-old man presented with a painless subcutaneous nodule on the lateral aspect of the left lower leg, discovered incidentally. Clinical examination suggested a benign superficial soft-tissue lesion, and because no features raised suspicion for malignancy, complete excision was performed without preoperative imaging. Gross examination revealed a 1.9 × 1.6 × 0.7 cm fascial-based lesion composed of spindle cells and scattered ganglion-like cells within a variably myxoid stroma. Focal nuclear pleomorphism, typical mitotic activity (2 mitoses/10 high-power fields), and limited extension into adjacent adipose tissue broadened the differential diagnosis. Immunohistochemistry demonstrated focal SMA positivity, weak focal desmin and S100 expression, absence of CD31 and CD34 staining, and a low Ki-67 proliferative index (approximately 2–3%). Negative surgical margins, together with integration of the clinical presentation, gross findings, histomorphology, and immunophenotype, supported the diagnosis of proliferative fasciitis. The patient remains free of local recurrence four months after surgery. Conclusions: PF should be considered in the differential diagnosis of superficial spindle-cell proliferations showing deceptively aggressive histological features. Careful clinicopathological correlation remains the cornerstone of diagnosis and helps distinguish this benign entity from its malignant mimics. The clinicopathological framework proposed in this report may assist pathologists in the systematic evaluation of similar diagnostically challenging lesions. Full article

Disruptions in folate (vitamin B9) and vitamin B12 metabolism, including nutritional deficiency, folate receptor alpha (FRα) autoantibodies, and MTHFR/DHFR polymorphisms, impair one-carbon metabolism and produce measurable retinal structural, microvascular, and functional changes, offering a non-invasive window into systemic and cerebral metabolic dysfunction, particularly cerebral folate deficiency (CFD). This review synthesizes peer-reviewed evidence on retinal alterations linked to folate/B12 deficiency, hyperhomocysteinemia, FRα autoantibody syndromes, and MTHFR/DHFR variants, alongside artificial intelligence (AI) and machine learning (ML) approaches applied to retinal imaging for metabolic, anemic, and nutritional optic neuropathy detection. Three convergent phenotypes emerge: structural changes (retinal nerve fiber layer and ganglion cell complex thinning, optic disc pallor, chorioretinal atrophy), microvascular abnormalities (reduced vessel density, foveal avascular zone enlargement, capillary dropout), and functional deficits (centrocecal scotoma, dyschromatopsia, reduced contrast sensitivity); they arise from homocysteine-mediated endothelial toxicity, mitochondrial impairment, and eNOS uncoupling. Existing AI/ML models for anemia and optic neuropathy establish technical feasibility but do not target folate-specific phenotypes. We propose a dedicated multimodal ML framework integrating structural, perfusion, functional, and biochemical/genetic data as a research agenda for automated, non-invasive CFD detection. Given the established folate–autism spectrum disorder (ASD) risk association reported in FRAA-positive cohorts, such a framework, once validated, could support prenatal and neonatal screening in FRAA-positive or genetically high-risk pregnancies, enabling earlier leucovorin treatment and reducing neurodevelopmental risk. Full article

N-methyl-D-aspartate (NMDA) excitotoxicity drives mitochondrial dysfunction and retinal ganglion cell (RGC) loss in blinding retinal disorders. Ciliary neurotrophic factor (CNTF) is neuroprotective, but its short half-life limits long-term therapy. Here, we investigated whether mitochondrial homeostasis mediates the sustained protection of a CNTF-loaded chitosan hydrogel. In vitro, free CNTF and the hydrogel equally protected RGCs against NMDA, effects completely abolished by the mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). In vivo, free CNTF provided only transient rescue, whereas the hydrogel sustained RGC survival, mitochondrial integrity, and visual function for 28 days, with persistent upregulation of mitochondrial biogenesis genes. Adeno-associated virus-mediated DRP1 overexpression-induced mitochondrial fission fully reversed the hydrogel’s benefits, mirroring CCCP inhibition. Collectively, intact mitochondrial homeostasis is essential for the long-term neuroprotection of the CNTF-chitosan hydrogel, which extends CNTF retention without altering its mitochondrial-dependent mechanism. This hydrogel represents a promising long-acting treatment for retinal excitotoxicity. Full article

Glaucoma is the leading cause of irreversible blindness worldwide and a paradigmatic age-related neurodegenerative disease in which retinal ganglion cells (RGCs) are selectively lost through mechanisms that extend beyond intraocular pressure. Age-dependent NAD⁺ depletion in RGCs, compounded by the progressive impairment of NAD⁺ biosynthesis and by the hyperactivation of NAD⁺-consuming enzymes under oxidative stress, defines a metabolic vulnerability that current pressure-lowering therapy does not address. Pyrroloquinoline quinone (PQQ) is a tricyclic ortho-quinone present in plant-derived foods that acts on the NAD⁺ pool through a mechanism distinct from that of conventional precursors. Rather than expanding the pool by net synthesis, PQQ binds lactate dehydrogenase and oxidizes NADH to NAD⁺ through catalytic redox cycling, raising NAD⁺ availability without altering the total dinucleotide content and independently of the two biosynthetic enzymes selectively impaired in glaucomatous RGCs. The resulting increase in NAD⁺ availability activates sirtuin-dependent programs that drive mitochondrial biogenesis. PQQ additionally engages an NRF2-dependent antioxidant response, addressing molecular deficits directly implicated in glaucomatous RGC degeneration. In retinal cell models, PQQ preserves ATP content and viability under mitochondrial stress. In vivo, it protects RGC density in optic nerve degeneration models and elevates NAD⁺ along the visual pathway. A randomized clinical trial demonstrated functional improvement in glaucoma patients receiving a PQQ-containing combination. The redox biochemistry of PQQ places it at a mechanistic intersection with the NAD⁺ deficit that characterizes glaucomatous neurodegeneration. Its complementarity with conventional NAD⁺ precursors and neuroprotective compounds acting on distinct molecular targets supports the design of combination regimens addressing multiple dimensions of RGC vulnerability. Critical questions regarding bioavailability, molecular target characterization, and clinical validation in dedicated trials remain open. Full article

Background/Objectives. Headache and migraine were exacerbated by light during an episode, with light also serving as a diathesis for pain between episodes. Such interictal photosensitivity has been hypothesized to reflect heightened sensitivity to blue-cyan (BC) light, due to activation of melanopsin-based intrinsically photosensitive retinal ganglion cells (ipRGCs). This study examined evidence for wavelength-selective photosensitivity and its relation to headaches/migraine and accompanying functional sequelae. Methods. Individuals with persistent post-traumatic headache (N = 325) were assessed for photosensitivity with an analysis of filtered wavelengths that resulted in relief. A subsample (n = 209) wore precision tinted lenses that matched their individual wavelength photosensitivity profile for over a 1–3-month follow up period and were assessed on a variety of persistent functional complaints. Results. Analysis of wavelengths associated with photosensitivity did not support differential sensitivity to the BC range, revealing greater sensitivity to light below 440 nm and less sensitivity above 680 nm, but with a coefficient of variation of 94.7%, consistent with extremely high individual variation. Individuals who showed near elimination of photosensitivity (97.9%) had decreased self-reported headache frequency (92.6%), as well as reported diminished physical, emotional and cognitive complaints, with these functional outcomes unrelated to the magnitude of BC filtering. Conclusions. These results suggested (1) wavelengths evoking photosensitivity were highly individually variable and (2) interictal exposure to a variety of wavelengths may have contributed to post-traumatic head pain and associated impaired global function, pointing toward common central origins. Full article