Neurotherapeutics

Neuropathic pain (NP) affects approximately 60% of individuals with spinal cord injury (SCI). Existing pharmacological treatments provide only modest relief and are often limited by adverse effects, while non-pharmacological options show small effects at best. As such, there remains a need for accessible, mechanism-informed treatments for SCI-NP. This protocol describes a trial evaluating two promising home-based neuromodulatory interventions for SCI-NP - electroencephalography neurofeedback (EEG-NF) and transcranial direct current stimulation (tDCS) - tested both independently and when applied in combination. We will employ a partially double-blinded (i.e. 1 treatment blinded, the other not), 2x2 factorial randomised controlled trial. Adults with chronic SCI-NP (N=192) will be randomised to: (1) EEG-NF + active tDCS, (2) EEG-NF + sham tDCS, (3) active tDCS alone, or (4) sham tDCS alone, in addition to treatment as usual. Participants will complete 20 home-based sessions over 5 weeks. The primary outcome is change in overall pain severity with the primary endpoint being 6 weeks post-randomisation, with secondary endpoints at 16, 26 and 52 weeks post-randomisation. Secondary outcomes (worst pain intensity, pain interference, sleep, depressive symptoms, health-related quality of life) will be assessed at 6 weeks, 16 weeks, 26 weeks and 52 weeks post-randomisation. This will be the first large-scale trial of home-based EEG-NF and tDCS for SCI-NP. If found to be effective, these scalable interventions could be integrated into routine care and inform further optimisation of neuromodulation strategies for managing SCI-NP.

Parkinsons disease (PD) is the second most common neurodegenerative disease, resulting from accumulation of -synuclein (-syn) in midbrain dopaminergic neurons and progressive neuronal loss. The most relevant species of -syn, oligomers, may exert neurotoxicity in a variety of mechanisms. Accumulation of misfolded -syn in the endoplasmic reticulum (ER) lumen induces ER stress conditions that leads to activation of the Unfolded Protein Response (UPR) and its main sensor PKR-like ER kinase (PERK). PERK is critical for cell fate determination - under prolonged ER stress, it may direct cell towards pro-apoptotic pathways. Targeting of -syn aggregation or UPR by genetic and pharmacological approaches proved effective in preclinical models of PD by previous research. Thus, in the present study, we aimed to determine the potential effect of combination of small-molecule inhibitors of -syn aggregation and ER stress-mediated PERK signaling (namely anle138b and AMG44) in a novel, 3D in vitro model of PD. We demonstrate that combination of both anti-aggregation and ER stress-targeting approaches amplifies neuroprotection against PD in organoid model in terms of increased neuronal metabolic activity, decreased -syn phosphorylation and aggregation, reduced dopaminergic cell death, and restoration of proteostasis.

Background: Chronic pain affects millions of patients globally and remains therapeutically chal-lenging. While conventional pharmacological approaches have limitations and side effects, pulsed electromagnetic field (PEMF) therapy represents a non-invasive biophysical approach. However, the biological mechanisms underlying PEMF efficacy remain poorly understood. Objective: This study starting from a multi-center post-market surveillance (PMS) data of 81 patients treated with Synth&eacuteXer (a CE-marked Class IIa PEMF device) proposes a mechanistic framework that links ob- served clinical effects to epigenetic modulation via the histone demethylase KDM6B. Materials and Methods: Patients with inflammatory and degenerative disorders causing chronic pain were treated with Synth&eacuteXer across four Italian rehabilitation centers. Pain was assessed using the Numerical Pain Rating Scale (NPRS) before and after treatment. Statistical analysis included descriptive statistics, ANOVA, correlations, and Cohen d effect size. Proposed mechanisms were based on and extrapolated from molecular and biochemical studies demonstrating KDM6B-dependent epigenetic changes in response to specific PEMF sequences. Results: Mean NPRS score decreased significantly from 8.07 {+/-} 1.65 (PRE) to 1.79 {+/-} 1.67 (POST), representing a 6.28-point reduction (p < 0.001; Cohen d = 3.1). Ninety-eight percent of patients showed pain reduction [&ge;] 2 points. No adverse effects were reported. Subset analysis revealed consistent responses across inflammatory (n=19) and degenerative (n=62) pathologies. Discussion: While the observational nature of these data precludes definitive causal attribution, the magnitude of clinical response combined with emerging evidence of KDM6B-mediated epigenetic remodeling suggests a plausible biological basis for PEMF efficacy. Specifically, sequence-depend- ent electromagnetic stimulation may promote the production of and release of anti-inflammatory cytokines and pain resolution through histone demethylation and chromatin remodeling ultimately acting on the expression modulation of such regulatory cytokines. Conclusions: These post-market surveillance data provide clinical evidence of PEMF effects in chronic pain management. The proposed epigenetic mechanism, while requiring further experimental validation and mechanistic confirmation, offers a science-based framework for understanding PEMF biological action and guiding future investigations.

Background-Synuclein (-Syn) plays a central role in Parkinsons disease (PD). Under pathological conditions, -Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This -Syn-microglia axis creates a self-perpetuating cycle of neuroinflammation and neurodegeneration, accelerating dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and contributing to motor deficits. Moreover, -Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting -Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD. MethodsThis study investigates the therapeutic potential of 3-monothiopomalidomide (3MP), a novel thalidomide derivative designed to reduce neuroinflammation with a potentially better safety profile than Pomalidomide (POM). The neuroprotective and anti-inflammatory effects of 3MP were evaluated in rat primary mesencephalic mixed neuron-microglia cultures exposed to human -Syn oligomers (H-SynOs). Anti-aggregation activity was assessed via Thioflavin T (ThT) assays and Thioflavin S (ThS) staining in SH-SY5Y cells. Finally, the anti-aggregation, anti-inflammatory, and neuroprotective effects of 3MP were evaluated in vivo in a rat model of PD induced by intracerebral infusion of H-SynOs. ResultsIn primary cell cultures, 3MP dose-dependently reduced -Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited -Syn aggregation in vitro in the ThT assay and in SH-SY5Y cells exposed to -Syn protofibrils, outperforming POM. When chronically administered in vivo, 3MP preserved dopaminergic neurons within the SNpc and yielded functional benefits on motor and cognitive readouts. Notably, 3MP markedly attenuated -Syn aggregates induced by the H-SynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129--Syn+ and reduced pSer129-Syn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-SynOs-infusion, were significantly dampened by 3MP. ConclusionsOverall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and -Syn aggregation and thereby disrupting the -Syn-driven inflammatory cycle. Its neuroprotective effects and favourable safety profile support its potential as a disease-modifying therapy for PD, with promising implications for clinical translation.

IntroductionThe exploration of alternative strategies for neural tissue regeneration and repair is giving rise to a novel paradigm in neurosurgery: fusogenic therapy. This approach promises rapid restoration of peripheral nerve and spinal cord function by circumventing Wallerian degeneration and eliminating the delay associated with axonal regrowth. Its potential stems from the capacity of fusogens to induce axonal fusion and achieve immediate membrane sealing, complemented by their pronounced neuroprotective properties. However, experimental data on fusogens and their effects are inconsistent, often contentious, and derived using heterogeneous methodologies. MethodsWe present the first comprehensive systematic review covering nearly four decades of research on fusogens for axonal membrane repair and 26 years of their experimental and clinical application in mammalian and human models for peripheral and central nervous system restoration. The review includes a meta-analysis of fusogen efficacy following traumatic spinal cord and peripheral nerve injuries. ResultsConducted in accordance with the PRISMA 2020 flow protocol and PICO criteria, our analysis incorporates 86 sources, 20 of which were included in the meta-analysis. DiscussionIn summary, we have systematized the prevailing approaches and methods for fusogen application, delineated key contentious issues, and identified promising directions for the development of axonal fusion technology.

Chronic low back pain (CLBP) is persistent and refractory, affecting 20-30% of population worldwide. Neurofeedback has been explored as a potential non-pharmacological intervention for chronic pain, although evidence in CLBP remains limited. This study evaluated PainWaive, a consumer-grade digitally-delivered neurofeedback intervention targeting multiple pain-related frequency bands recorded over the sensorimotor cortex in individuals with CLBP. In a multiple-baseline experimental design, four participants completed daily assessments of pain severity and pain interference during randomly-assigned baseline phases of 7, 10, 14, and 20 days, followed by 20 sessions of the PainWaive intervention over four weeks. Daily pain assessments continued during the post-intervention and follow-up phases. Participants rated PainWaive's usability and acceptability at post-intervention. Anxiety, depression, wellbeing, and sleep disturbance were assessed at three timepoints. Aggregated Tau-U analyses indicated a large effect (-0.67) on pain severity from baseline to intervention and very large from baseline to post-intervention (-0.92) and follow-up (-0.92) phases. Large effects (-0.63, -0.62, and -0.70) were also observed for pain interference. Individual-level analyses showed significant reductions across all participants, with visual inspection confirming progressive decreases over time. The intervention was rated usable and acceptable by all participants, while psychological outcomes were mixed and varied across participants. The findings provide promising evidence that the PainWaive neurofeedback intervention may reduce pain severity and pain interference in some individuals with CLBP. By prioritising accessibility, usability, and self-administration, PainWaive supports a foundation for more patient-centred, technology-enabled approaches to chronic pain management. Further evaluation of this approach in randomised trials is required to establish efficacy.

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses. Most serotonergic compounds also increased synaptogenesis and induced c-Fos and Egr-2 expression, although ligand-specific differences were evident, particularly for psilocin and the phenethylamines DOI and Ariadne. Uncoupling of Gq/11 or Gi/o protein-dependent signaling differentially modified neuroplastic and transcriptional responses, indicating a ligand and endpoint dependent contribution of both pathways. Serotonergic psychedelics further induced a 5-HT2A receptor dependent lactate response that was generally sensitive to disruption of either Gq/11 or Gi/o protein coupling. Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network with distinct structural, transcriptional and metabolic outputs, and establish this neural stem cell-derived system as a valuable platform for screening and dissecting the signaling basis of psychedelic action.

BackgroundSpinal cord injury (SCI) triggers persistent neuroinflammation, gliosis, neuronal loss, and demyelination, leading to motor deficits and neuropathic pain. Botulinum neurotoxin type A (BoNT/A) has shown anti-inflammatory and neuroprotective effects in acute SCI, but its potential in the chronic phase remains unclear. This study investigates whether combining BoNT/A with electrical muscle stimulation (EMS) enhances recovery in chronic SCI. MethodsAdult mice with severe thoracic SCI (paraplegic) underwent EMS (30 min/day for 10 non-consecutive days starting 3 days post-injury) or no stimulation. Fifteen days after SCI, animals received a single intrathecal injection of BoNT/A (15 pg/5 L) or saline. Functional recovery was assessed up to 60 days as well as in moderate and mild SCI mice, neuropathic pain onset and maintenance were evaluated. Spinal cord tissue was analysed for astrocytic and microglial morphology, neuronal and oligodendroglia survival, myelin protein expression, and in vitro effects on oligodendrocyte precursor cells (OPCs). The phenotype of hindlimb muscles was evaluated through morphological and gene expression analyses. ResultsEMS was able to counteract muscle atrophy and fibrosis, and when combined with BoNT/A, also denervation. Moreover, the combination restored hindlimb motor function in chronic SCI, whereas BoNT/A or EMS alone were ineffective. Neuropathic pain, a common comorbidity associated with SCI, was mitigated by BoNT/A treatment even when administered in the chronic phase. BoNT/A reduced astrocytic hypertrophy and excitatory synapse association and was associated with a morphology-based redistribution of microglial profiles toward a resting-like classification, decreased apoptosis, and increased neuronal and oligodendroglia survival. Myelin basic protein expression was significantly elevated in vivo. In vitro, BoNT/A promoted OPC differentiation into myelinating oligodendrocytes, increased process complexity, and upregulated Myelin basic protein, galactocerebroside C, proteolipid protein, and myelin oligodendrocyte glycoprotein under both proliferative and differentiating conditions. Cleaved SNAP25 colocalization with OPC confirmed direct BoNT/A internalization and activity. ConclusionsBoNT/A exerts multi-cellular neuroprotective actions in chronic SCI, supporting neuronal and oligodendroglia survival, reducing neuroinflammation, enhancing remyelination and the combination with EMS promotes substantial recovery of muscle homeostasis within a permissive microenvironment shaped by early stimulation. Its efficacy depends on a permissive microenvironment achieved through EMS. These results provide strong rationale for the clinical evaluation of BoNT/A as a therapeutic strategy for chronic SCI.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to develop a logistic regression-based risk stratification tool for interventional pain medicine. Methods: We searched PubMed, Scopus, and Cochrane Library through March 2026 for studies reporting adjusted odds ratios for associations between (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, (4) preoperative opioid use/polypharmacy, and chronic pain chronification or treatment failure. Random-effects meta-analyses (DerSimonian-Laird) were performed for each loop. Effect sizes were translated into a composite logistic regression model, the Pain Amplifier Loop Framework (PALF), using ln(OR) as first-order coefficient approximations. Results: Forty-four studies with over 500,000 participants were included. Pooled odds ratios were: sleep disturbance OR=1.80 (95% CI 1.65-1.96; k=16), pain catastrophizing OR=2.11 (95% CI 1.71-2.61; k=8), metabolic/fat mass OR=2.02 (95% CI 1.32-3.09; k=7), preoperative opioid use OR=4.48 (95% CI 2.87-6.97; k=6), and opioid-benzodiazepine co-prescription OR=2.62 (95% CI 1.76-3.89; k=7). All four loops converge on TLR4/NF-kB microglial signaling. The PALF model produces a probability of interventional failure enabling stratification into low, moderate, and high risk categories. Conclusions: Four amplifier loops independently increase chronic pain risk. The PALF provides a transparent, clinically actionable risk score requiring prospective validation.

Major depressive disorders (MDD) are predicted to become the first cause of burden of disease worldwide in 2030, but 30% of patients still do not respond to antidepressants. Current rodent models of MDD mainly result either from one genetic or one environmental risk factor exposure, not recapitulating the multifactorial and polygenic nature of MDD. We recently generated a polygenic mouse model of MDD from selective breeding after mild stress in the Tail Suspension Test (TST), named H-TST. Here, we selected animals exhibiting high immobility during the Forced Swim Test (FST) to generate a new stable polygenic model of MDD, called H-FST. Unlike our previous H-TST model, H-FST mice did not exhibit any anxiety-or anhedonia-like behaviors, nor did they display any sleep disturbances. Moreover, H-TST and H-FST mice showed opposite response after administration of various antidepressant treatments. The gene expression level in the prefrontal cortex of H-TST and H-FST mice revealed little overlap in genes and biological pathways associated with depressive-like behaviors and opposite dysregulation of excitatory/inhibitory synaptic imbalance. Finally, these two models allowed in humans the identification biomarkers of treatment response specific of clinical subgroup of patients.

Background Chronic pain is associated with structural and functional brain alterations, particularly within prefrontal, insular, and cingulate cortices. The dorsolateral prefrontal cortex (DLPFC) shows consistent structural abnormalities across chronic pain conditions, whereas findings on intrinsic functional connectivity (FC) remains inconsistent. Anchoring FC analyses to structural alterations may help identify consistent patterns across chronic pain conditions. Methods We employed a voxel-based morphometry (VBM)-guided, seed-based resting-state FC approach. Structural and functional MRI data were obtained from patients with chronic neck pain (CNP; n=21) and healthy controls (HC; n=25). Regions showing significant gray matter volume (GMV) differences were used as seeds for whole-brain FC analysis. Associations with pain intensity and pain-related fear were examined. Findings were further evaluated in an independent cohort with chronic primary pain (CPP; n=38). Results VBM revealed reduced GMV in the left DLPFC in CNP compared with HC, replicated in CPP. Seed-based FC analysis demonstrated reduced connectivity between the left DLPFC and the right hippocampus in CNP, with a similar pattern in CPP. In CNP, GMV in the DLPFC was positively associated with DLPFC-hippocampal connectivity (r = 0.45, 95% CI 0.02 to 0.74, p = 0.043). Reduced DLPFC-hippocampal connectivity was associated with higher activity avoidance (r = -0.50, 95% CI -0.77 to -0.09, p = 0.021), whereas no associations were observed with pain intensity. Conclusions These findings indicate consistent structural and functional alterations across chronic pain cohorts. Reduced DLPFC-hippocampal connectivity may reflect altered interactions between prefrontal and hippocampal circuits involved in pain-related cognitive and affective processes.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to propose a composite meta-analytic risk index for interventional pain medicine requiring prospective validation. Methods: We searched PubMed/MEDLINE, Scopus, and the Cochrane Library through March 2026 for studies reporting adjusted odds ratios linking (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, and (4) preoperative opioid use/polypharmacy to chronic pain chronification or treatment failure. DerSimonian-Laird random-effects meta-analyses were performed per loop. Publication bias was assessed via Egger's test (k>=8). Effect sizes were integrated into a logistic regression model--the Pain Amplifier Loop Framework (PALF). Neurobiological convergence on TLR4/NF-kB microglial signaling was examined. Results: Forty-four studies (>500,000 participants) were included. Pooled odds ratios: sleep disturbance 1.80 (95% CI 1.65-1.96; k=16; I2=51%), pain catastrophizing 2.11 (1.71-2.61; k=8; I2=0%), metabolic/fat mass 2.02 (1.32-3.09; k=7), preoperative opioid use 4.48 (2.87-6.97; k=6; I2=84%), and opioid-benzodiazepine co-prescription 2.62 (1.76-3.89; k=7; I2=79%). Egger's test showed no significant asymmetry for sleep (p=0.21) or catastrophizing (p=0.84). All loops converge on TLR4/NF-kB microglial signaling. The PALF yields a Systemic Load Score and failure probability P=1/(1+e^-theta), enabling low (<0.30), moderate (0.30-0.60), and high (>=0.60) risk stratification. Conclusions: Four biopsychosocial amplifier loops independently and substantially increase chronic pain risk. The PALF proposes a transparent, hypothesis-driven composite risk index anchored in meta-analytic evidence from >500,000 participants. As a meta-analytic synthesis rather than a fitted prediction model, the PALF requires prospective multicenter validation with individual patient data before clinical application.

BackgroundMutations in the E3 ubiquitin ligase Parkin (encoded by PRKN) are the most frequently known cause of recessively inherited Parkinsons disease. In addition to the loss of dopaminergic neurons, microglial activation is another pathological feature observed in Parkinsons disease. While postmortem brain samples show the end stage of the disease, neurons and glia derived from patients induced pluripotent stem cells (iPSCs) provide a model for detecting early pre-degenerative disease trajectories. However, mixed cell populations often confound these cultures, leading to heterogeneous disease phenotypes. MethodsHere, we tease apart the cell type-specific phenotypes underlying Parkin-linked Parkinsons disease by performing single-nucleus RNA sequencing in iPSC-derived co-cultures of dopaminergic neurons and microglia from PRKN mutation carriers and healthy controls. We validated our transcriptomic key findings through inflammatory cytokine profiling and live-cell calcium imaging. ResultsSingle-nucleus RNA sequencing identified seven major cell types composed of neuronal, glial, and precursor cells, with dopaminergic neurons accounting for the largest cell population. Pathway analysis revealed cell type-specific dysregulated biological processes in Parkin-deficient cells, including gene expression differences in dopaminergic neurons that control mitophagy and dopamine homeostasis, whereas microglia showed changes in calcium homeostasis and inflammatory signaling. Functional analysis verified elevated secretion of monocyte chemotactic protein 1 in PRKN-mutant co-cultures compared with controls, linking Parkin deficiency to increased microglial chemotactic signaling. Furthermore, lower intracellular calcium levels and diminished calcium release following treatment confirmed impaired calcium homeostasis in PRKN-mutant microglia. ConclusionsProfiling at the single-cell level resolved distinct cell subpopulations, enabling us to identify cell type-specific pathway disturbances underlying Parkin deficiency. This unique dataset provides a basis for understanding the impairment of individual cell types and the impact of cellular crosstalk in Parkinsons disease pathology.

Cognitive dysfunction is increasingly recognized as an important feature of chronic pain (CP). However, subjective cognitive complaints and objectively measured cognitive performance frequently diverge. Whether and how these two aspects of cognitive functioning differentially relate to the broad symptomatology and brain function in CP remains unclear. Here, 114 individuals with CP completed patient-reported outcome measures on cognitive functioning and multidimensional CP symptoms, as well as a visuospatial working memory task, and resting-state EEG. Bayesian correlations, network analyses, and Bayesian regression models examined how subjective and objective cognitive functioning relate to multidimensional CP symptoms and EEG activity/connectivity, while controlling for age and sex. Additional models tested whether EEG associations were independent of broader symptom burden. Results indicated that subjective and objective cognitive functioning were uncorrelated. Subjective cognitive functioning was strongly associated with psychosocial symptoms, whereas objective cognitive functioning was largely independent of broader symptom burden. EEG revealed associations between subjective cognitive functioning and bilateral frontotemporal beta connectivity; however, these relationships were substantially attenuated after accounting for broader CP symptom burden. Objective cognitive functioning showed no robust associations with EEG. These findings indicate a dissociation between subjective cognitive complaints and objective cognitive performance in CP. Subjective cognitive complaints were primarily associated with psychosocial symptom burden and beta-band hypoconnectivity. In contrast, objective cognitive performance was unrelated to the broader symptomatology of CP and EEG measures. This dissociation may inform more targeted interventions, optimize the allocation of cognitive assessment resources, and ultimately improve long-term functional outcomes in CP.

High-impact chronic pain (HICP), defined as persistent pain that substantially limits daily activities, affects millions of adults and poses a public health challenge. Yet relatively little is known about how HICP manifests in people's daily lives. To address this gap, this study used the comprehensive Ecological Momentary Assessment of pain (cEMAp) to assess pain-related experiences four times per day over 7 days in individuals with chronic low back pain. Based on the classification using the Graded Chronic Pain Scale-Revised, we compared individuals with HICP (n = 66) with those in the next most severe pain category, bothersome chronic pain (n = 41), defined as having similar pain frequency but less frequent interference with daily activities. On each prompt, participants completed 2-hour assessments of pain intensity, interference, catastrophizing, behaviors, coping strategies, and pain characteristics. In line with prior research, both groups reported similar pain intensity levels, but the HICP group reported more frequent interference with physical, mental, and social activities. There were no group differences in daily mood or catastrophizing. Exploratory analyses suggested that many daily experiences were similar across groups, with differences observed in selected pain qualities, coping strategies, and pain behaviors. Additional analyses of response distributions showed some similarity across groups in many experiences. Overall, although individuals with HICP on average experience higher pain interference in daily life, levels of many day-to-day experiences are similar between the two groups. Data obtained with cEMAp complement traditional retrospective assessment by providing a detailed view of chronic pain in everyday life.

Adeno-associated viral (AAV)-mediated overexpression of human wildtype -synuclein (-syn) in the substantia nigra (SN) is a widely used approach to model Parkinsons disease (PD) in rodents. However, variability in the ability of AAV-based systems to induce nigrostriatal pathology and motor deficits has limited reproducibility across studies, especially in mice. Here, we systematically optimized key vector features - AAV serotype, promoter, viral titer - to establish a highly efficient and reliable mouse model of PD. We compared the tropism and expression efficiency of mixed AAV2/1 and AAV2/rh10 serotypes combined with three promoters - CMV enhancer/chicken {beta}-actin (CBA), human Synapsin (hSYN), and rat Tyrosine Hydroxylase (TH) - to drive human -syn gene (SNCA) expression in nigral dopaminergic neurons. The AAV.TH.SNCA vector, delivered at an optimized titer, achieved selective and sustained -syn overexpression in nigral neurons, resulting in nigro-striatal neurochemical changes and progressive motor deficits preceding overt neuronal loss. Fine tuning -syn expression proved critical for detecting early disease processes: lower AAV.TH.SNCA titer induced early pathological signatures, including -syn hyperphosphorylation and neuroinflammation, whereas higher titers produced robust nigrostriatal degeneration not achieved with other promoter constructs. Notably, we demonstrate that motor and neurochemical impairments can occur prior to dopaminergic cell death, implicating microglial activation and -syn pathology as primary drivers of dysfunction. This observation is consistent with human genetic evidence showing that triplication of the wild-type SNCA gene alone can cause Parkinsonian pathology, highlighting that our model enables the use of a single experimental reagent to investigate the molecular, cellular, and behavioral consequences of controlled increases in -syn expression. This novel AAV.TH.SNCA model provides a powerful and versatile platform for investigating mechanisms of a -syn-mediated neurotoxicity and for evaluating disease modifying interventions targeting early, pre-degenerative stages of PD. HighlightsO_LITitrated -syn expression uncouples early dysfunction from dopaminergic neuron loss C_LIO_LIAAV2/rh10-TH-SNCA model captures prodromal and degenerative PD stages C_LIO_LIMotor deficits arise from -syn pathology and nigral molecular changes before neurodegeneration. C_LI

Repeated exposure to hypoxia (oxygen levels below sea-level atmospheric conditions, [~]21%) alternated with regular voluntary exercise, known colloquially as Living High, Training Low, or simply High-Low, is used by elite athletes to boost exercise benefits and athletic performance. While paradigms of High-Low training have been utilized by Olympic athletes for decades, the therapeutic potential of a High-Low regimen in the context of neurotrauma has yet to be investigated. This long-term experiment evaluated the independent and combined effects of repeated hypoxic exposure and voluntary exercise on functional outcomes within the context of preclinical spinal cord injury (SCI). We hypothesized that combinatorial High-Low training enhances functional recovery, beyond either exercise or repeated exposures to hypoxia alone, to improve outcomes after SCI. Adult female rats (n=62) underwent a high-cervical hemisection (LC2H) to model spinal cord injury. At 6 weeks post-SCI, treatment (access to exercise wheel, repeated exposure to normobaric hypoxia at rest, or alternation of both) began in the surviving subjects (n=49). Despite initiation of treatment beyond the acute post-injury phase, High-Low therapy significantly improved respiratory function and prevented the development of SCI-associated anxiety-like behaviors. Notably, repeated in vivo exposure to normobaric hypoxia induced a shift in peripheral T cell profiles, characterized by increased CD4+ and reduced CD8+ expression. These findings indicate that combining repeated exposure to hypoxia with voluntary exercise as a therapy could promote recovery in the existing spinal cord-injured population. Collectively, this work provides a foundational first step for further investigation of High-Low training as a rehabilitation therapy for individuals living with SCI.

Study ObjectivesIdiopathic hypersomnia (IH) is a central nervous system hypersomnia frequently accompanied by autonomic symptoms, yet objective physiological data are limited. We sought to characterize autonomic nervous system (ANS) dysfunction in IH using nocturnal heart rate variability (HRV) and diurnal autonomic reflex testing (ART), compared to individuals with type 1 narcolepsy (NT1) and healthy controls (HCs). MethodsTwenty-four adults with IH, 10 with NT1, and 14 HCs underwent overnight video polysomnography with HRV analyses in time and frequency domains during stable slow-wave sleep and REM sleep. Comprehensive ART included sympathetic adrenergic (head-up tilt (HUT), Valsalva BP responses), parasympathetic cardiovagal (HRV to deep breathing, Valsalva ratio), and sudomotor (Q-Sweat) measures. ResultsIH participants were predominantly female, with over half reporting long sleep duration. Compared to NT1 and HC, participants with IH demonstrated a greater magnitude of orthostatic tachycardia on tilt ({Delta}HR 41.0 {+/-} 16.3 vs. 26.3 {+/-} 9.3 vs. 30.8 {+/-} 9.3 bpm, p = 0.0086), as well as frequent sudomotor dysfunction (64.3%). IH participants demonstrated greater nocturnal and REM HR with reduced parasympathetic indices during REM, indicating diminished vagal modulation compared with HCs ConclusionsIH is characterized by a distinct pattern of autonomic dysfunction, including pronounced orthostatic tachycardia, frequent sudomotor abnormalities, and reduced parasympathetic activity during sleep. These findings provide objective physiological evidence of ANS involvement in IH and delineate features that distinguish IH from NT1 and HCs.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

Chronic pain is often accompanied by cognitive complaints, but evidence for global working memory problems is mixed. We tested whether working memory performance differences in chronic pain are global or task-specific and whether model-based analysis could help distinguish differences in processing efficiency, response caution or sensory/motor speed. In a preregistered online case-control study, 99 adults with mixed chronic pain conditions and 87 pain-free controls completed visuo-verbal, visuo-spatial and auditory-temporal n-back tasks at low (0/1-back) and high (2-back) load. Accuracy and reaction times were analysed with mixed effects models. Drift diffusion modelling decomposed performance into processing efficiency (drift rate), response caution (threshold separation) and non-decision (sensory/motor) time. Higher load reduced accuracy and slowed responses in both groups. There was no evidence of a global working-memory deficit in the chronic pain group. The clearest group difference was a larger load-related drop in accuracy in the auditory-temporal task (odds ratio 0.64, 95% CI 0.56 to 0.73), persisting after adjustment for mood, sleep and fatigue. Load-related slowing in visuo-verbal (6.7% slower, 5.1% to 8.2%) and auditory-temporal tasks (3.6% slower, 1.7% to 5.4%) were attenuated after adjustment. Diffusion modelling showed no evidence for sensory/motor slowing, but rather greater response caution in the auditory-temporal task and small efficiency (drift rate) reductions in low-load visual conditions. The results do not support a global working-memory capacity loss account in this mixed chronic pain sample. Rather, they suggest task-specific performance differences, most evident in auditory-temporal processing, with response caution as a plausible contributor.