The early life environment can strongly influence behavioural development. However, little is known about the underlying neurogenomic mechanisms. Using a half-sib design, threespine stickleback fish were either raised by their fathers or hand-reared ('orphaned') for 10 days before living in a common-garden environment. As offspring developed, they were tested in one of three behavioural assays: an open field assay with a simulated predator attack, a social behaviour assay with a simulated predator attack, and a light-dark box assay. Offspring that received paternal care behaved in ways that we interpret as indicating increased boldness and sociability. Fish in the open field assay had their brains sampled one hour following the simulated attack; brains were sampled at the same time from full-sib controls. These brains were processed for gene expression (via 3'Tag-seq) and chromatin accessibility (via ATAC-seq). Paternal care treatment and the predator attack affected brain gene expression, but sex was also a major factor, despite fish being reproductively immature. Sex, and to a lesser extent, paternal care treatment, also influenced chromatin accessibility at a whole-genome scale. Our findings further our understanding of the mechanisms by which the early life environment-including the environment provided by parents-influences offspring behavioural development. This article is part of the theme issue 'Ecological epigenetics at the intersection of behaviour and life history variation in non-model animals'.
Understanding how the brains structural architecture supports task-evoked functional activity is a fundamental goal of neuroscience. However, most predictive models rely on single-scale structural features, overlooking the brains intrinsically hierarchical organization. Here, we introduce the Collaborative Graph Attention Multi-Task Network (CoGA-MTN), a deep learning framework that integrates multi-scale structural features to jointly predict task-based functional connectivity (FC) and identify potential disease-related network alterations. CoGA-MTN employs a dual-branch graph attention network to extract complementary global statistical and local topological features from structural MRI, and a cross-modal task-coordinated learning mechanism that enables task-conditioned FC prediction alongside multi-disease classification. Validated on the Consortium for Neuropsychiatric Phenomics dataset (152 participants, three tasks, four diagnostic groups), CoGA-MTN outperforms single-scale baselines in task-conditioned FC prediction (PCC = 0.657 ± 0.02) and achieves macro F1 scores of 0.68-0.75 across three psychiatric disorders. Crucially, the model reconstructs a stable whole-brain connectivity architecture that is conserved across tasks, while simultaneously revealing diagnosis-related discrepancies that are consistent with established pathophysiological models. By modeling psychiatric conditions within a normative structure-function framework, this work provides a unified approach for characterizing the relationships between multi-scale brain structure, dynamic function, and psychopathology.
Growth-associated protein 43 (GAP-43), a synaptic protein involved in neuronal plasticity, has emerged as a potential biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI), with elevated levels linked to synaptic dysfunction. This dysfunction, in turn, has been associated with reduced cerebral glucose metabolism, which further exacerbates cognitive decline and accelerates disease progression. However, the link between CSF GAP-43 and cerebral glucose metabolism, measured by FDG-PET, remains less understood. This study aimed to investigate the relationship between CSF GAP-43 levels, cerebral glucose metabolism, and cognitive performance across different stages of cognitive impairment, specifically in individuals with AD (n = 83), MCI (n = 370), and cognitively normal (CN; n = 215). Cognitive function was assessed using the ADAS-Cog 13 scale, CSF GAP-43 levels were measured via ELISA, and cerebral glucose metabolism was analyzed with FDG-PET. The results showed that CSF GAP-43 levels were significantly elevated in the AD group compared to the CN and MCI groups (p < 0.001). In the MCI group, there was a modest but statistically significant negative association between CSF GAP-43 levels and cerebral glucose metabolism (β = -0.126, FDR p = 0.003), whereas this association was not significant in the CN (β = -0.031, FDR p = 0.612) or AD groups (β = 0.157, FDR p = 0.584). Mediation analysis, adjusted for age, sex, education, and APOE ε4 carrier status, showed that FDG-PET cerebral glucose metabolism partly and statistically mediated the association between CSF GAP-43 and cognitive performance only in the MCI group (β = 0.047, FDR-adjusted p = 0.009). These findings indicate that higher CSF GAP-43 was associated with lower cerebral glucose metabolism, which in turn was associated with worse cognitive performance in MCI. However, because of limitations, cross-sectional design, and modest magnitude of the effects, these results should be interpreted as statistical associations rather than evidence that CSF GAP-43 impairs glucose metabolism or cognition.
Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.
Imitation deficits after brain damage are commonly assessed with meaningless hand positions (HP) and finger configurations (FP). Previous studies on unilateral brain damage and callosotomy individuals revealed left-hemispheric specializations for HP and bilateral representation for FP, with a right-hemispheric dominance. This study examined hemispheric specialization for HP and FP imitation, as well as FP subtypes, in five hemispherectomy individuals (n = 3 with a remaining left (rLH); n = 2 with a remaining right hemisphere (rRH)). Imitation performance was analysed with the NEUROGES®-ELAN system, considering error types and reaction times. Bayesian analyses revealed no group differences in performance scores, error types and reaction times for HP or FP imitation. The qualitative analysis of error types revealed group differences, particularly for FP imitation, with rRH individuals showing predominantly self-corrections, whereas rLH individuals showed diverse error patterns (e.g., position errors). However, considerable interindividual variability was foremost observed across imitation tasks and subtypes. Overall, the findings do not support a strict hemispheric specialization for HP and FP imitation following hemispherectomy. Rather, they highlight the importance of individual variability.
AimMigraine substantially affects daily functioning, yet its impact on unpaid domestic labor, an essential and sex-structured component of home life, remains poorly characterized. Domestic tasks require sustained physical and cognitive effort and may be sensitive to illness-related functional limitations, particularly in households were gendered expectations shape baseline role allocation.MethodsAs part of the SMILE project, 675 adults with migraine (544 females and 131 males) and 232 non-migraine controls (186 females and 46 males) completed a survey including demographics, MIDAS, DASS-21, and a ten-domain domestic labor module adapted from the Who Does What questionnaire. Participants rated the current division of each task and their preferred redistribution of responsibilities. Analyses were stratified by sex. Group differences were quantified using standardized mean differences (SMDs). Associations between MIDAS and chore scores were examined using Spearman correlations and multivariable linear regression adjusted for age and DASS-21 subscales.ResultsParticipants with migraine had substantial disability (median MIDAS 30 [IQR 15-64]; 65% severe), and a median of 10 headache days in the preceding three months [IQR 5-20]. Females with migraine reported greater partner involvement in several female-dominated tasks compared with controls, including cleaning after meals (mean 4.12 vs 3.47; SMD 0.32), laundry (3.16 vs 2.59; SMD 0.27), and general cleaning (3.59 vs 3.18; SMD 0.19). Males with migraine showed increased involvement in a different subset of chores, most notably trash disposal (3.42 vs 5.18; SMD 0.87). Females with migraine also expressed stronger preferences for increased partner involvement across multiple domains. Among males, MIDAS correlated with greater partner involvement (r up to 0.29), whereas among females, MIDAS showed weaker, more variable associations; regression models confirmed task-specific relationships.ConclusionMigraine is associated with distinct sex-specific patterns in the structure and desired redistribution of domestic labor. These findings highlight household functioning as an overlooked dimension of migraine-related disability and fit within the SMILE Resource-Role Strain framework.
BackgroundThe mechanisms of early brain damage in cerebral amyloid angiopathy (CAA), a highly prevalent comorbid condition in Alzheimer's disease, are not completely understood. While current CAA diagnosis relies on late-stage MRI markers, impaired neurovascular coupling (NVC) has emerged as a promising early marker.ObjectiveTo investigate whether early vascular changes in CAA are associated with functional brain consequences, we examined the association between NVC and various functional connectivity metrics.MethodsWe analyzed MRI data from 93 older adults (71 ± 9 years old). A subgroup meeting Boston criteria v2.0 for possible or probable CAA (n = 46) was analyzed separately to investigate associations in confirmed CAA-related pathology. NVC (time to peak, time to baseline, and BOLD amplitude) was assessed in the occipital cortex using a visual stimulation task. Functional connectivity was assessed at multiple scales using resting-state fMRI, including within ten standard networks, between individual brain regions (edgewise analysis), and across the whole brain (graph theory).ResultsGeneral linear models, adjusted for age, sex, and clinical diagnosis, showed no significant associations between NVC and global connectivity metrics (networks and graph theory). Edgewise analyses revealed limited significant localized functional connections for each NVC measure. Findings were consistent across the total sample and the CAA subgroup.ConclusionsEarly CAA-related pathology is associated with localized rather than global functional connectivity. While large-scale connectivity remains preserved, edgewise analyses indicate subtle localized functional alterations. This suggests that functional connectivity disruption may originate as small-scale deficits that only progress into widespread, global impairment in advanced disease stages.
Health-related quality of life is a key secondary end point in stroke trials. Differential item functioning (DIF) occurs when individuals with the same underlying health-related quality of life interpret and respond differently to questionnaire items, potentially biasing treatment comparisons. This study evaluates DIF in the patient-reported 5-level EuroQOL questionnaire among patients with acute ischemic stroke across age, sex, and treatment groups. Data were from the AcT trial (Alteplase Compared to Tenecteplase), a registry-based randomized comparison of alteplase and tenecteplase conducted at 22 stroke centers across Canada (December 2019-January 2022). Patients with acute ischemic stroke presenting within 4.5 hours of symptom onset and eligible for thrombolysis completed the 5-level EuroQOL questionnaire at 90 days poststroke. DIF was assessed using multigroup graded response models with the Wald-based sweep procedure, which accounts for between-group differences in latent trait distributions. We quantified effect sizes using signed weighted area between curves (sWABC); |sWABC| <0.10=negligible. Of 1577 patients enrolled in the trial, 1264 survived to 90 days with complete 5-level EuroQOL questionnaire data (51.2% tenecteplase; 46.5% female; 30.1% aged ≥80). Omnibus testing revealed significant DIF only for age (χ2=86.9, P<0.001); neither sex (χ2=31.7, P=0.063) nor treatment (χ2=22.4, P=0.379) showed evidence of DIF. Four items flagged for age-related DIF: self-care, usual activities, pain/discomfort, and anxiety/depression. However, only self-care (sWABC=-0.46) and usual activities (sWABC=-0.34) showed moderate effects, while pain/discomfort (sWABC=-0.002) and anxiety/depression (sWABC=0.09) were negligible. Importantly, factor scores from models with and without DIF adjustment correlated (correlation coefficient=0.98). The 5-level EuroQOL questionnaire appears to function equivalently across sex and treatment groups in this stroke population. Age-related DIF, though statistically detectable in physical functioning items, had little practical consequence for individual scores, supporting the instrument's use for health-related quality of life comparisons in stroke trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.
BackgroundRecruitment for Alzheimer's disease and related dementias research remains challenging, particularly when reaching underrepresented groups such as Latin Americans.ObjectiveThis study aimed to (1) assess recruitment rates across strategies in the ReDLat study and (2) discuss lessons learned to inform future recruitment practices.MethodsThis retrospective study outlines the recruitment for ReDLat, a multi-partner consortium expanding dementia research in Latin America. Participants were recruited using: printed flyers, social media, word-of-mouth, and professional referrals. At initial contact, participants were asked how they learned about the study. Enrollment rates were calculated for each source, and differences across sources were examined using a Pearson chi-square test.ResultsBetween January 2023 and March 2025, 577 individuals expressed interest, of whom 69% (n = 397) were enrolled. Enrollment rates differed significantly across sources (χ2 (3) = 41.66, p < 0.001); professional referrals achieved a substantially higher rate (81%) than printed flyers (51%), social media (55%), and word-of-mouth (60%), which showed broadly comparable rates. Printed flyers and social media generated broad interest but lower enrollment conversion. Among the 180 individuals not enrolled, the most frequent reason for non-participation was failure to meet inclusion criteria (54%), particularly among those reached via social media and word-of-mouth. Loss of contact accounted for 36% of non-participation.ConclusionsProfessional referrals were associated with the highest enrollment rate for the ReDLat study. These findings highlight the importance of leveraging community trust and professional networks to improve recruitment outcomes for dementia research in underrepresented populations.
Individuals who survive acute respiratory distress syndrome (ARDS) often face prolonged cognitive impairments. Comparable consequences have been observed in chronic hypoxic conditions, like COPD and obstructive sleep apnea syndrome, which have been linked to reduced gray matter volume. We hypothesized that ARDS patients display similar cerebral findings, but those treated with extracorporeal membrane oxygenation (ECMO) show greater structural brain alterations than those treated conservatively, reflecting the severity of hypoxemia. Eighteen ARDS survivors, seven conservatively treated (ARDS-conv), and eleven treated with ECMO (ARDS-ECMO) were studied and compared with healthy controls. Structural magnetic resonance imaging (MRI) was analyzed using voxel-based morphometry (VBM). Total intracranial volume (TIV), gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) volumes were quantified and compared between groups. ARDS patients had lower TIV than healthy controls (1516.50 mL [95% CI 1380.85-1618.72] vs. 1664.07 mL [95% CI 1558.41-1776.06], P=0.008). While intracranial volumes of GM, WM, and CSF were not different between ARDS-conv and healthy controls, CSF volume of ARDS-ECMO was lower than in healthy controls, while GM and WM were comparable. Compared to ARDS-ECMO, ARDS-conv had lower GM volumes (ARDS-conv 37.9% [95% CI 36.3-39.2] vs. ARDS-ECMO 41.4% [95% CI 39.9-43.8]; P=0.036), WM and CSF were comparable. VBM also revealed distinct clusters of reduced GM in ARDS-conv patients compared to healthy controls (TFCE, FWE-corrected P<0.05). ARDS survivors exhibit structural brain changes suggestive of hypoxia-related injury. ECMO treatment may mitigate gray matter loss, supporting early initiation of ECMO in severe ARDS to reduce long-term neurological sequelae. Extracorporeal membrane oxygenation may prevent preterm cerebral atrophy in survivors of acute respiratory distress syndrome: a pilot trial.
BackgroundPrior work in preclinical late-onset Alzheimer's disease (LOAD) focused on neuritic plaque development suggested that intracellular ferritin expression in microglia and extracellular deposition of amyloid-β (Aβ) are innate neuroprotective mechanisms geared specifically towards limiting aging-dependent increases in intracerebral free iron which likely contribute to development of neurofibrillary degeneration (NFD).ObjectiveImprove understanding of LOAD pathogenesis.MethodsImmunohistochemical comparison of the extent of NFD with the intensity of ferritin expression and Aβ deposition in three brain regions, including temporal lobe (entorhinal cortex, hippocampus), frontal, and occipital cortex in 34 non-demented human subjects at Braak stages II-III.ResultsFerritin-positive microglia are present with similar quantity and intensity in the allo- and isocortices of every individual in the cohort. Extracellular Aβ deposition in the isocortex is observed before substantial NFD develops, but in the allocortex (temporal lobe) there are no Aβ deposits in 50% of subjects despite extensive NFD. Cytoskeletal lesions in the allocortex consist of atrophic grid cells, abundant pretangles, neuropil threads, neurofibrillary tangles, and neuritic plaques; isocortical sites show either no NFD at all or only minimal NFD presenting as solitary pretangles or tangles, neuropil threads, or droplet degeneration spheres from ferroptotic neurons. Presence of degenerating grid neurons in entorhinal cortex coincides with microglial apoptosis.ConclusionsNeuroprotection via ferritin expression and Aβ deposition is more effective in the isocortex than in allocortex. Findings support the hypothesis that degeneration or death of neuroprotective microglia promotes neuronal degeneration.
Self-assembly of L-phenylalanine (Phe) results in the formation of assemblies that are structurally and functionally related to amyloid-like fibrils. Recently, Phe assembly has been correlated with the elevated Phe levels observed in phenylketonuria (PKU) patients. The presence of Phe aggregates in the post-mortem brain sections of PKU patients and in transgenic mouse models suggests their plausible role in disease pathology. To inhibit Phe assembly, we hypothesized that gallic acid (GA), a known antioxidant, could interfere with the assembly process owing to its generic anti-amyloid activity. Here, using multiple biophysical techniques, we demonstrate the characteristic features of Phe assembly and its disassembly in the presence of GA. Owing to its natural occurrence in plants and its therapeutic potential, GA may serve as a promising molecule for future preclinical testing in PKU mouse models.
Neuronal intranuclear inclusion disease (NIID) pathogenesis has been strongly linked to uN2CpolyG translated from NOTCH2NLC transcript variant 1. However, emerging evidence suggests that NOTCH2NLC transcript variant 2 may also generate a disease-relevant protein, PolyGN2C-iso2, but isoform-discriminating and antibody-independent evidence remains incomplete. We characterize the aggregation propensity of PolyGN2C-iso2 in vitro, develop isoform-discriminating monoclonal antibodies for its detection in patient tissues, and perform targeted proteomic analysis of laser-microdissected p62-positive lesion cells. An AAV-mediated mouse model expressing PolyG(108×)N2C-iso2 is generated to assess its pathogenic potential, followed by behavioral, imaging, histopathological, proteomic, and functional analyses. NOTCH2NLC transcript variant 2 generates a distinct protein, PolyGN2C-iso2, which forms aggregates in vitro. Using developed monoclonal antibodies together with targeted proteomics, we provide evidence that PolyGN2C-iso2 is present within the pathognomonic intranuclear inclusions in NIID patient tissues, where it co-localizes with uN2CpolyG. The PolyG(108×)N2C-iso2 mouse model recapitulates key pathological hallmarks of NIID, including white matter abnormalities and cognitive deficits not fully captured by previous models. Mechanistically, PolyGN2C-iso2 expression is found to induce profound mitochondrial dysfunction. Our findings support the possibility that NIID involves a dual-protein pathogenic process involving both uN2CpolyG and PolyGN2C-iso2, which may have implications for therapeutic strategies targeting NOTCH2NLC-derived pathogenic proteins.
The space of human goals is tremendously vast; and yet, from just a few moments of watching a scene or reading a story, we seem to spontaneously infer a range of plausible motivations for the people and characters involved. What explains this remarkable capacity for intuiting other agents' goals, despite the infinitude of ends they might pursue? And how does this cohere with our understanding of other people as approximately rational agents? In this paper, we introduce open-ended sequential inverse plan search (SIPS), a sequential Monte Carlo model of open-ended goal inference. Open-ended SIPS combines top-down Bayesian inverse planning with bottom-up sampling based on the statistics of co-occurring subgoals. By proposing goal hypotheses related to the subgoals achieved by an agent, our model rapidly generates plausible goals without exhaustive search, then filters out goals that would be irrational given the actions taken so far. We validate this model in a goal inference task called Block Words, where participants try to guess the word that someone is stacking out of lettered blocks. In comparison to both heuristic bottom-up guessing and exact Bayesian inference over hundreds of goals, our model better predicts the mean, variance, efficiency, and resource rationality of human goal inferences, achieving similar accuracy to the exact model at a fraction of the cognitive cost, while exhibiting rational pruning of irrational goal hypotheses that cannot be captured by bottom-up sampling alone. Our experiments thus highlight the importance of uniting top-down and bottom-up models for explaining the speed, accuracy, and generality of human theory of mind.
The glymphatic system is a cerebrospinal fluid-interstitial fluid exchange pathway that clears metabolic waste and maintains brain fluid homeostasis. Aquaporin-4 (AQP4), a water channel at astrocytic endfeet along the neurovascular interface, supports perivascular water transport and glymphatic flow. Disruption of this glymphatic-AQP4 unit is implicated in conditions with altered fluid dynamics, including traumatic brain injury (TBI) and brain tumors. We reviewed experimental and clinical studies examining glymphatic pathways and AQP4 regulation in TBI and brain tumors, and synthesized evidence on glymphatic physiology, AQP4 polarization, and imaging-based assessment to compare mechanisms of disruption in injury versus tumor remodeling. Evidence shows reduced glymphatic transport in both conditions, commonly accompanied by altered AQP4 localization. In TBI, mechanical injury triggers astrocytic reactivity, blood-brain barrier disruption, and loss of perivascular AQP4 polarization, impairing clearance across phases of injury. In brain tumors, parenchymal remodeling, vascular compression, and vasogenic edema disrupt cerebrospinal fluid dynamics and glymphatic pathways. Across disease states, total AQP4 expression alone poorly predicts glymphatic function; instead, spatial localization and polarization of AQP4 at astrocytic endfeet more consistently correlate with clearance efficiency. Emerging imaging approaches, including diffusion-based MRI metrics and perivascular space quantification, offer potential noninvasive methods for assessing glymphatic alterations in vivo, although their reliability and biological specificity remain debated and under active investigation. Overall, the glymphatic-AQP4 system is a key neurovascular interface regulating brain fluid balance. Disrupted AQP4 polarization and glymphatic transport contribute to edema and impaired solute clearance in both TBI and brain tumors. Future work should prioritize standardized imaging biomarkers and time-dependent strategies to restore glymphatic function and perivascular AQP4 organization.
Alterations in circulating amino acid profiles have been observed in ischemic stroke patients; however, whether cerebral ischemia disrupts amino acid metabolism within brain tissue and whether this disruption contributes to cellular stress and cerebral injury remain unknown. This hypothesis-testing study investigates disrupted BCAA (branched-chain amino acid) catabolism as a key mechanism of ischemic brain damage and evaluates BCKDK (branched-chain α-keto acid dehydrogenase kinase) as a novel therapeutic target. Mouse primary cortical neurons subjected to oxygen-glucose deprivation and brain tissue from a mouse acute ischemic stroke model were used as experimental systems. Untargeted metabolomics and metabolic flux analysis were used to characterize BCAA metabolism in both models. In vivo pharmacological inhibition or in vitro knockdown of BCKDK was performed using BT2 treatment or RNA interference. Primary outcome variables included infarct volume, BCKDH (branched-chain α-keto acid dehydrogenase) enzyme activity, neuronal viability, and markers of energy metabolism and glutamate excitotoxicity. Between-group differences were evaluated using 1-way ANOVA; data are presented as mean ± SD with 95% CIs and corresponding P values. Metabolomics analysis of oxygen-glucose deprivation-exposed primary neurons revealed impaired BCAA catabolism and significant BCAA accumulation compared with normoxic controls. In ischemic mouse brain tissue, BCKDH activity was significantly suppressed, and BCKDK expression was markedly upregulated relative to sham-operated animals. Both pharmacological and genetic suppression of BCKDK substantially reduced cerebral ischemic injury, as evidenced by decreased infarct volume and improved neuronal survival (95% CI and P values per comparison). Mechanistically, ischemia-induced BCKDK expression via HIF-1α (hypoxia-inducible factor 1α)-mediated transcriptional activation, which inhibited BCAA conversion to tricarboxylic acid cycle substrates, thereby potentiating energy deficiency and glutamate excitotoxicity. These data identify BCKDK as a novel hypoxia-responsive factor whose upregulation drives disrupted BCAA catabolism as a key mechanism of ischemic neuronal injury. BCKDK represents a promising therapeutic target for cerebral ischemia, directly supported by both in vitro and in vivo experimental evidence presented here.
Spinal connectomics is increasingly shifting understanding of the spinal cord from a simple reflex relay toward an active system that contributes to sensorimotor integration and adaptive motor control. This narrative review summarizes recent advances in the study of spinal circuitry and examines how these networks may contribute to flexible, context-dependent motor behavior. We reviewed experimental and computational studies focusing on high-density electrophysiology, advanced imaging, circuit mapping, and computational modeling, with an emphasis on recent and landmark studies. Our review suggests that spinal circuits may implement principles consistent with predictive coding, Bayesian integration, and adaptive gain control, though much of the direct mechanistic evidence for these computations originates in cortical and psychophysics literature; spinal-specific empirical validation remains an active research frontier. High-density recording and imaging techniques permit laminar-specific analysis of spinal activity, while computational models link circuit organization to function and plasticity. These advances are beginning to inform the development of closed-loop neuromodulation, targeted rehabilitation strategies, and brain-machine interface approaches aimed at restoring movement and sensory feedback following spinal cord injury. Together, these findings are consistent with the emerging view of the spinal cord as a dynamic computational system rather than a passive relay. Integrating connectomic data with computational modeling and neuromodulation provides a framework for understanding spinal function and developing more precise therapeutic interventions. Continued progress in neural interface technologies and data-driven modeling has the potential to further advance spinal systems neuroscience and, over the coming years, to improve the treatment of neurological disorders.
Stroke is the second most common cause of death worldwide and predominantly affects individuals over 65 years old. Its prevalence is projected to increase in parallel with the aging global population. Nutrition is a modifiable risk factor for ischemic stroke. Folates, B-vitamins and choline play a central role in one-carbon metabolism (1 C), which is a key metabolic network that integrates nutritional signals with biosynthesis, redox homeostasis, epigenetics, regulation of cell proliferation, and stress resistance. Using preclinical models, our research group has previously shown that deficiencies in 1 C lead to worse stroke outcomes. However, the impact of ischemic stroke on 1 C enzymes in human brain tissue remains unexplored. The objective of this study is to investigate whether ischemic stroke contributes to a change in the levels of 1 C enzymes after ischemic stroke in male and female patients. Cortical brain tissue sections from ischemic stroke patients and controls were stained for enzymes involved in 1 C. All tissue was co-stained with neuronal nuclei (NeuN) and DAPI (4',6-diamidino-2-phenylindole). The colocalization of all three markers was evaluated by two individuals who were masked to the experimental groups. Ischemic stroke increased neuronal levels of the folate receptor and 1 C enzymes, methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and serine hydroxy methyltransferase (SHMT). In male stroke brain tissue was observed to have increased levels of MTHFR, TS, and SHMT. Female brain tissue had increases in the folate receptor and TS. The results suggest that ischemic stroke leads to changes in neuronal levels of FR and 1 C enzymes levels in penumbra. Further clinical investigation is required to determine whether there is increase enzymatic activity and how 1 C is impacted in other cells within the brain, such as glial and endothelial cells.
To examine sex differences in Alzheimer's disease and cognition with a focus on hormonal transitions, biomarker trajectory, and implications for diagnosis and treatment. Women account for nearly two-thirds of individuals with Alzheimer's disease and demonstrate important biological and clinical differences compared with men. APOE ε4 confers greater risk in women, while menopause, depression, chronic stress, adverse pregnancy outcomes, and metabolic dysfunction may further increase vulnerability. Biomarker studies suggest that amyloid trajectories are broadly similar between sexes, but women exhibit earlier or greater tau accumulation once amyloid pathology is present. Women may maintain verbal memory performance longer than men despite underlying pathology, potentially delaying diagnosis. Emerging plasma biomarkers, particularly p-tau217, may improve early detection, monitoring, and treatment. Alzheimer's disease in women reflects a complex interaction between sex-specific biology, hormonal transitions, psychosocial factors, and neurodegenerative processes. Recognizing these differences has important implications for cognitive assessment, biomarker interpretation, diagnosis, and application of disease-modifying therapies.
On January 1, 2024, Nebraska repealed its universal motorcycle helmet law for riders aged ≥21 years with a valid Class M license. We evaluated changes in helmet use, clinical outcomes, and short-term direct institutional costs following repeal. In this multicenter retrospective cohort study, motorcycle crash patients treated at five ACS-verified Level I-III trauma centers in eastern Nebraska before and after repeal were compared by law era and helmet status. Helmet-use trends were assessed using segmented binomial logistic regression. Cost analyses were restricted to patients with positive direct institutional costs using survivor-only and log-transformed models. Among 467 patients (241 pre-repeal, 226 post-repeal), helmet use declined from 84.2% to 20.4% after repeal (p<0.001). Segmented regression demonstrated an immediate reduction in helmet use after repeal (OR 0.17, 95% CI 0.06-0.44; p<0.001), consistent with adjusted individual-level analysis (aOR 0.04, 95% CI 0.03-0.07; p<0.001). Post-repeal, non-helmeted riders had greater unadjusted head-injury burden and more neurosurgical interventions. After adjustment, non-helmeted status remained independently associated with neurosurgical intervention (aOR 3.10, 95% CI 1.03-9.35; p=0.044), but not BIG score ≥2, severe traumatic brain injury composite, or mortality. Adjusted log-transformed analyses showed lower short-term direct institutional costs among non-helmeted riders (cost ratio 0.68, 95% CI 0.54-0.86; p=0.001), likely reflecting differences in injury patterns and procedural utilization rather than reduced economic burden. Nebraska's helmet-law repeal was associated with an immediate and sustained reduction in helmet use. Non-helmeted riders had higher adjusted odds of neurosurgical intervention despite similar adjusted severe brain injury and mortality outcomes. Lower short-term institutional costs should not be interpreted as economic neutrality because they exclude downstream rehabilitation, disability, productivity losses, and societal costs.