Journal of Neuroscience Research

Moderate-to-severe traumatic brain injury (msTBI) is recognized as a chronic and evolving neurological condition characterized by progressive structural brain changes and persistent cognitive impairment. While prior studies have demonstrated widespread atrophy following msTBI, less is known regarding the longitudinal trajectory of gray matter (GM) changes during recovery and post-rehabilitation. The current study used longitudinal voxel-based morphometry (VBM) to characterize GM volume changes over a period of 9 months, in individuals with msTBI relative to healthy controls (HC). Associations between regional GM volume and neuropsychological functioning were examined. Twenty-eight participants (14 msTBI, 14 HC) completed MRI and neuropsychological assessments across three timepoints spanning outpatient rehabilitation and follow-up. Longitudinal VBM analyses revealed significant group and time interactions within subcortical and limbic regions. Relative to HC, individuals with msTBI showed lower GM volume in these regions at baseline, with trajectories that converged toward HC values (right hippocampus) or increased relative to HC over the rehabilitation period (bilateral pulvinar), whereas the right amygdala and inferior cerebellar vermis remained persistently reduced. Significant longitudinal improvements in memory and psychomotor speed during the rehabilitation period were demonstrated in msTBI. Greater (preserved) GM volume within the right hippocampus, thalamus, and bilateral pulvinar was associated with better performance across measures of verbal memory, processing speed, executive functioning, and cognitive flexibility. These findings suggest that msTBI is associated with dynamic structural brain changes involving subcortical, limbic, and cerebellar networks, and that the rehabilitation period was accompanied by relative volumetric stabilization in these regions and by meaningful cognitive improvement.

Traumatic brain injury (TBI) is one of the leading causes of emergency room visits in children under 10. Children are potentially more vulnerable to the adverse effects of TBI, given that their brains are still developing at the time of injury. Indeed, early life TBI has been linked to cognitive, social, and mood-related impairments later in life. The neuroimmune system has been implicated in adult TBI mechanisms and plays numerous key roles in brain development, making it an interesting candidate for linking pediatric TBI and prolonged behavioral alterations. Here we establish a rat model of mild pediatric TBI to investigate the relationship between early life TBI, acute responses of neuroimmune cells, and chronic behavioral dysregulation. At postnatal day 15, which is roughly equivalent to toddler age, male and female rat pups received a TBI via lateral fluid percussion injury. At 3 days post injury, TBI increased microglia and astrocyte coverage locally in the Perilesional Cortex but not in more distant corticolimbic regions. However, the hippocampus and prefrontal cortex did exhibit increased expression of the phagocytic marker CD68 in microglia, suggesting widespread glial activation even in the absence of gross coverage change. TBI also impacted mast cells, early-response innate immune cells, increasing their number and degranulation in multiple regions. In the juvenile and early adult periods, TBI impaired cognitive function, reduced sociability, and increased avoidance, with no change in anxiety-like behavior. Later in adulthood, TBI continued to impact cognitive behavior, increasing risky decision-making and impairing optimization months after injury. Together, these results suggest that pediatric TBI causes lasting cognitive and social dysregulation, possibly via acute neuroimmune alterations following injury at a critical period of brain development.

Tau protein has been implicated as an important mediator of traumatic brain injury (TBI). Adult human brain expresses 6 tau isoforms expressing 3 (3R) or 4 (4R) microtubule binding sites; adult mouse brain expresses only 4R tau. A role for tau isoform expression on TBI disease course is tested using wild-type C57/BL6 mice (WT) and C57/BL6 with a knocked-in human tau coding region (MAPTKI). Uninjured WT and MAPTKI mice have similar brain histology and behavior as they age. At subacute times (14 days post-injury (DPI)), injured MAPTKI mice have less white matter damage with similar neuronal loss as WT. At chronic times (90DPI), MAPTKI mice demyelinate while WT mice remyelinate. At 14DPI, tau phosphorylation differs between WT and MAPTKI mice. At 90DPI, thioflavin-S+ protein aggregates in MAPTKI corpus callosum are higher than WT. At 14 or 90DPI, WT and MAPTKI mice acquire Barnes maze, WT retention is impaired at 14DPI and MAPTKI retention impaired at 90DPI. At 14DPI, only MAPTKI mice acquire and retain active place avoidance; at 90DPI, only WT mice acquire active place avoidance. At 14DPI, only injured MAPTKI mice acquire alternating T-maze. These data suggest that WT and MAPTKI differ in both subacute and chronic disease course. At 14DPI, WT mice have greater white matter damage and behavioral impairments than MAPTKI mice. At 90DPI, impairments in WT mice partially recover, yet worsen in MAPTKI mice. This data suggests that 3R tau isoform expression alters the disease course of head injury. HighlightsPost-injury disease course of MAPTKI mice expressing 3R and 4R tau differs from wild-type mice expressing only 4R tau. At subacute times post-injury, MAPTKI mice have less white matter, yet similar gray matter, injury than wild-type mice. At chronic times post-injury, white matter damage in MAPTKI worsens. At subacute times post-injury, MAPTKI mice have fewer behavioral deficits than wild type mice. At chronic times post-injury, MAPTKI mice develop behavioral deficits not present at subacute times.

Traumatic brain injury (TBI) induces rapid neuroinflammatory responses not only in the brain but also in anatomically and immunologically connected central nervous system (CNS) compartments, including the retina. In our study, we investigated retinal microglial activation, retinal ganglion cell (RGC) calcium dynamics, and caspase-3 activation in adult mice subjected to severe traumatic brain injury using the Marmarou impact-acceleration model at 24 and 48 h post-injury. Carrying out Ca{superscript 2}-imaging, immunohistochemistry, and ex vivo time-lapse microscopy, we found robust microglial activation in both the superficial and deep retinal layers following TBI, accompanied by increased microglial motility. RGCs exhibited a transient surge in degeneration-induced spontaneous activity at 24 h, followed by a marked reduction below control levels at 48 h, consistent with early degenerative changes. Activated caspase-3 levels were significantly elevated in both microglia and other retinal cell types at both time points, indicating ongoing apoptotic effects. Together, these findings demonstrate that TBI rapidly triggers inflammatory and apoptotic mechanisms in the retina, which are detectable within the first 48 hours. Our results highlight the retina as a sensitive indicator of early CNS pathology after traumatic injury and underscore the potential of retinal analysis for monitoring TBI-induced neurodegeneration for future clinical implementation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/734783v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@5bc694org.highwire.dtl.DTLVardef@14a4ce4org.highwire.dtl.DTLVardef@fe2d32org.highwire.dtl.DTLVardef@149419d_HPS_FORMAT_FIGEXP M_FIG C_FIG

Traumatic brain injury (TBI) is a characteristic feature of neurodegenerative diseases such as Alzheimers disease and chronic traumatic encephalopathy. Small animal models have been used to establish clinically relevant biomarkers of neuropathology, however, they show significant anatomical differences from humans and are affected by artificial experimental manipulations, making them often unsuitable for longitudinal study of repetitive mild TBI. Building on a previous study of neuropathology in headbutting bovids in the wild, this pilot study investigated whether freely headbutting domestic goats, which naturally engage in low-intensity, high-frequency head impacts, accumulate measurable biomarkers of neurodegeneration in cerebrospinal fluid (CSF) and brain tissue. Over a six-month period, three male goats (Capra hircus) were allowed to freely headbutt under continuous video surveillance. Monthly CSF samples were collected, and concentrations of key neurodegeneration biomarkers were measured via multiplex immunoassays, including amyloid {beta} ; peptides (A {beta} 40, A {beta} 42), total and phosphorylated tau (tTau and pTau), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neurofilament M (NF-M). Postmortem immunohistochemistry was conducted on prefrontal cortical tissues using antibodies targeting pTau, GFAP, and S100B. Head impact kinematics were quantified using horn-mounted accelerometer and inclinometer sensors that recorded linear acceleration, rotational velocity, and head orientation during naturally occurring headbutting events. Several notable trends were observed. Phosphorylated tau as well as reactive astrocytes were detected in the brain tissue, mirrored by elevated GFAP detected in the CSF. PET TSPO was unsuccessful, however, FDG PET revealed frontal-dominant activity in all goats, and one with asymmetrical activation. Overall, the goats sustained 5,000-7,000 head impacts each over six months, with forces up to 388 N and peak acceleration up to 16.5 g. This multi-modal observational study is the first to characterize neurodegeneration biomarkers and kinematics in headbutting goats. Even at one year old, the combination of pTau and gliosis in both the brain tissue and CSF indicates that the goat s repetitive head impacts begin to show neurodegenerative consequences early in life. Likely, the severity of these consequences increases with headbutts and age, eventually resulting in chronic neurodegeneration. This system shows promise as a large-animal model for the longitudinal study of the onset and progression of neurodegenerative disease.

The medial habenula (MHb) is an epithalamic structure involved in aversive processing and emotional regulation, notable for its marked cellular heterogeneity and high astrocyte density. This cellular composition suggests that astrocytes may play an important role in MHb structure and plasticity, potentially contributing to the regulation of emotional states. The aim of this study is to characterize sex-dependent astrocytic morphology in the MHb and determine how it is modulated by peripheral alterations and direct central manipulations. A high-fat diet (HFD) was used as a model of metabolic stress, and systemic lipopolysaccharide (LPS) administration was used to induce a peripheral inflammatory challenge. At the central level, a chemogenetic approach using Gi-DREADDs under the GFAP promoter allowed selective modulation of astrocytic intracellular signaling independently of peripheral influences. Preliminary results indicate sex-dependent morphological differences in MHb astrocytes across all these experimental conditions, supporting the idea that MHb astrocytes are sensitive to both peripheral and central disturbances and may represent a key cellular substrate linking body-brain interactions with emotional regulation.

Background: Norepinephrine (NE) released from locus coeruleus (LC) projections regulates astrocyte structure and function through adrenergic receptor signaling. We previously showed that increasing noradrenergic tone with the NE reuptake inhibitor desipramine increases astrocyte ramification in the molecular layer of the dentate gyrus. However, whether tonic LC-derived noradrenergic tone is required to maintain astrocyte morphological complexity in vivo, and whether {beta}-adrenergic receptor activation is the effector pathway, remained unclear. Methods: Adult male C57BL/6J mice received DSP-4 (50 mg/kg X 3 days i.p.), a selective LC neurotoxin, with or without concurrent isoproterenol that continued for 21 additional days post cessation of DSP-4 treatment (ISO; 2 mg/kg/day X 24 days), or saline (n = 4 mice per group). Animals were sacrificed 22 days after the final DSP-4 injection. Noradrenergic denervation was confirmed by dopamine {beta}-hydroxylase (DBH) immunostaining. GFAP-immunostained astrocytes in the molecular layer of the dentate gyrus were morphologically characterized using Sholl analysis. Astrocyte density was quantified by SOX9 immunostaining. Results: DSP-4 produced >83% reduction in DBH fiber coverage in the molecular layer. Sholl analysis revealed significant reductions in astrocyte branching complexity in both treatment groups, with the reductions concentrated at distances of 5-15 m from the soma. The maximum number of intersections was also significantly reduced in both groups. Unexpectedly, ISO did not rescue morphological complexity. While DSP-4 alone did not alter astrocyte density, as measured by the number of SOX9-expressing astrocytes, DSP-4+ISO increased SOX9-positive cell density, dissociating the effects of adrenergic signaling on morphology from those on cell numbers. Conclusions: LC-derived noradrenergic tone is required for the maintenance of astrocyte arbour complexity in the dentate gyrus molecular layer. {beta}-adrenergic receptor activation alone is insufficient to restore structural integrity following noradrenergic denervation, yet promotes astrocyte density independently of structural remodeling. These findings have implications for understanding how LC neurodegeneration in Alzheimer's disease and depression may compromise hippocampal astrocyte structure and function.

The main olfactory epithelium (MOE) is the primary site of olfaction and consists of multiple cell types including olfactory sensory neurons (OSNs), sustentacular cells, and immune cells. Neuroimmune interactions in epithelial tissues are critical in maintaining tissue function, but how OSNs and immune cells interact in the MOE in healthy and diseased states is largely unknown. Cellular responses in the MOE determine how and whether OSNs maintain olfactory function and are repaired or replenished following inflammatory environmental exposures. We hypothesized that acute nasal aeroallergen exposure alters immune cell function in the MOE to elicit a neuroprotective response, thereby preserving OSN function. We developed an environmental aeroallergen exposure consisting of one week of daily intranasal house dust mite extract (HDM) instillations. Spectral flow cytometry indicated only subtle changes in resident immune cells proportions and phenotypes in the MOE. Immunohistochemical evaluation did not reveal extensive changes in immune cell distribution in the sensory epithelium or lamina propria, but instead we observed increases in axonal olfactory marker protein (OMP) expression in the lamina propria, where resident immune cells are most abundant. To evaluate the effects of HDM exposure on OSN function, we performed live ex vivo Ca2+ imaging of MOEs from HDM- and sham-exposed transgenic mice using objective-coupled planar illumination (OCPI) microscopy. OSN responses to multiple odorants revealed increased chemosensory sensitivity and decreased across-trial adaptation in HDM-treated epithelia. These results indicate that short-term nasal aeroallergen exposure minimally alters immune cell phenotypes, and instead induces functional changes in OSN physiology that preserve olfactory function.

Background: Personality change is a debilitating consequence of traumatic brain injury (TBI), yet its prevalence, characteristics, and treatment remain poorly understood. Methods: We completed a pre-registered (CRD42023440990) systematic review and meta-analysis searching four databases (MEDLINE, PsycINFO, EMBASE and CINAHL) for primary studies assessing personality change after TBI. We synthesised conceptualisation, prevalence, longitudinal outcome, lesion location and treatment. Prevalence was estimated using a random effect meta-analysis using the Paule-Mandel estimator, with subgroup, meta-regression and robustness analyses. Results: 101 studies were included in this review, seventeen of which were suitable for meta-analysis. Personality change was defined inconsistently although common symptoms involved the emergence or increase of affective, behavioural, and social disturbances, including irritability, depression, emotional instability, anger outbursts, social withdrawal, anxiety, impulsivity, restlessness, aberrant motor behaviours, and aggression. The prevalence of secondary personality disorder was estimated as 29.1% (CIs 22.5% - 36.2%) and prevalence of broad personality change was 68.1% (CIs 53.4% - 81.2%). Robustness analyses showed that the estimate for broad personality change should be treated with caution as it was unstable when adjusted for risk of bias and potential publication bias. Follow-up studies, although of varying quality, consistently showed personality change remained stable over long follow-up periods. The relationship between personality change and specific lesion locations in TBI remains unclear, likely due to the poor methodological quality of studies examining this association. Perhaps most concerning, there is limited evidence and very few systematic studies addressing treatment. Conclusion: Personality change is a common and persistent consequence of TBI. Varying definitions, and the lack of high-quality lesion mapping studies and systematic investigations into treatment highlights critical gaps in understanding and management.

Background Chemotherapy-related cognitive impairment is a well-documented concern among cancer survivors, yet the neural mechanisms underlying deficits in cognitive control remain poorly understood. This study examined group differences in brain activation during a flanker task using functional MRI (fMRI) between chemotherapy-exposed participants and healthy controls. Methods Participants (21 survivors (24.9 years old; 71.4 % female; 15 years from diagnosis) and 21 healthy controls (26.7 years old; 61.9 % female) completed a flanker task during fMRI, with congruent and incongruent conditions. Reaction time, accuracy, and Flanker scores were collected. Whole-brain group comparisons were performed for congruent, incongruent, and incongruent > congruent contrasts. Associations between the incongruent > congruent contrast and cognitive performance were examined. Results Compared to controls, the Chemo group had longer reaction times in both congruent and incongruent conditions (p < .001) and lower NIH Flanker scores (p = .01), with no differences in accuracy. They showed reduced activation in the bilateral inferior frontal gyri, supplementary motor area, and bilateral caudate, but greater activation in the right inferior temporal and cerebellar regions. The incongruent > congruent contrast correlated with increased activation in the orbitofrontal cortex, inferior temporal gyri, and fusiform gyrus with cognitive performance. Conclusions Chemotherapy-exposed participants showed cognitive control deficits and altered neural activation during a flanker task, indicating disrupted recruitment of frontoparietal and subcortical regions key for conflict processing. These findings improve understanding of neural causes of chemotherapy-related cognitive impairment and may help identify at-risk survivors and guide personalized rehabilitation.

Background/Objectives: This systematic review examines how different mechanisms of Traumatic Brain Injury (TBI) influence post-injury functional independence and aims to clarify whether recovery patterns vary by injury type. A total of 105 studies (n = 59,621) involving adults with TBI were synthesized. These findings can guide clinicians and researchers in predicting outcomes and effectively customizing rehabilitation plans. Methods: A review following PRISMA standards analyzed English-language studies published from 1975 to 2025, assessed functional outcomes using the Functional Independence Measure (FIM) or the Glasgow Outcome Scale-Extended (GOSE), converted them to z-scores, and aggregated them via a random-effects model with inverse-variance weighting to demonstrate their relevance. Results: Recreational TBIs show the highest functional independence (z = +1.77), followed by MVAs (z = +1.56), with falls (z = +0.70) and assault-related TBIs (z = -0.12) showing moderate outcomes, and TBIs with penetrating trauma (z = -1.15) indicating the most adverse results. Conclusions: TBI mechanisms appear to meaningfully influence long-term post-injury functional independence. Highlighting this can inspire clinicians and researchers to trust these insights to improve prognosis and rehabilitation strategies, underscoring their crucial role in advancing patient care.

Background and Objectives: Are some brain regions intrinsically more vulnerable to metastatic colonization? We sought to characterize the spatial distribution of brain metastases and determine whether regional patterns vary according to primary tumor origin. Methods: We analyzed baseline MRI scans and expert tumor segmentations from 906 patients with 3,492 brain metastases treated with stereotactic radiosurgery. Lesions were normalized to MNI152 standard space and superimposed to generate probabilistic atlases of metastatic occurrence. Regional metastatic burden was quantified using anatomical and vascular atlases. Spatial distributions were additionally compared between lung cancer and melanoma metastases. Results: Metastatic burden was distributed nonuniformly throughout the brain. The cerebellum demonstrated the strongest enrichment relative to its anatomical volume (fold change 1.61, p < 0.001), accompanied by overrepresentation of the vertebrobasilar circulation (fold change 1.49, p < 0.001). Spatial distribution also varied by primary tumor type. Lung cancer metastases demonstrated greater infratentorial involvement than melanoma metastases (16.6% vs. 8.7%, p < 0.05), with a corresponding increase in cerebellar burden (14.8% vs. 6.8%, p < 0.05), whereas melanoma metastases were relatively concentrated within the frontal lobe (37.7% vs. 24.6%, p < 0.01). Infratentorial enrichment was observed across all carcinoma subgroups, with the greatest enrichment seen in gastrointestinal metastases (32.9% infratentorial). Conclusion: Brain metastases exhibit nonrandom spatial distributions, with preferential involvement of posterior and infratentorial structures. Regional patterns vary according to primary tumor origin, supporting the existence of region-specific vulnerability to metastatic disease.

Task-based precision mapping has become a promising technique in functional MRI (fMRI) to robustly characterize and map an individuals unique activity patterns. These experiments consist of acquiring extensive imaging data in one participant, ultimately improving the sensitivity and specificity of individual-specific functional localization. Despite its advantages, studies have primarily focused on understanding individual-specific cortical activation, preventing a holistic view of a systems-level functional response, and to date, best approaches for the statistical analysis of controlled task-based, densely sampled, whole-brain data have not yet been fully established. Therefore, in this study, we collected whole-brain (i.e. covering cortex, cerebellum, and brainstem) multi-echo densely sampled data of the auditory system, a system with major subcortical components, and evaluated activation sensitivity as well as activation stability across data subsets of commonly-used whole-brain and region-specific inference testing approaches. The whole-brain approaches involved standard voxel-level and cluster-level inference schemes with varying statistical thresholds and a non-parametric permutation inference approach. The region-specific approaches involved an exploratory top % t-statistics methods and non-parametric permutation inference approaches. We found that a whole-brain voxel-level approach with a false discovery rate (FDR) correction (p<0.05) presented highest sensitivity across regions and subjects as well as most consistent detection of expected auditory regions, even with lower scan duration. In addition, we found that a region-specific top % t-statistic approach may be a useful exploratory functional localization tool and a complementary method to standard inference testing approaches.

Traumatic brain injury (TBI) severity is typically classified using clinical indices that may have limited prognostic value. Objective measures of olfactory function depend on sensory, limbic, and memory networks and may provide a more specific marker of injury-related neural dysfunction. Seventy-nine individuals with TBI (48 mild, 31 moderate-to-severe) and 59 healthy controls completed an olfactory battery, including tests of odor percept identification (OPID9, OPID18), odor discrimination (OD10), and odor memory (POEM) ~4.04 (4.45) years after their most recent TBI. General linear models examined associations between olfactory outcomes and TBI severity, adjusting for age, age, sex, and education. Additional models examined the relationship between loss of consciousness (LOC) and olfactory functioning. The severity of the most recent TBI was significantly associated with all olfactory outcomes, after adjusting for age, sex, and education. Compared with controls, participants with moderate-to-severe TBI showed lower OPID9, OPID18, POEM, and OD10 performance, while participants with mild TBI showed lower OPID18 and POEM performance. LOC was associated specifically with odor memory in these models, as participants with prolonged (> 30min) LOC or LOC of unknown duration had lower POEM scores than those with no LOC. In TBI-only models, LOC remained associated with POEM after adjustment for TBI severity, whereas TBI severity was not associated with POEM after LOC was included. Long term olfactory functioning is sensitive to TBI severity, with generalized impairments across odor identification, discrimination, and odor memory. LOC characteristics appear especially relevant to odor memory, suggesting that olfactory memory may capture injury-related features beyond TBI severity classification alone.

Bergmann glia-like progenitors (BGLPs) are transient astroglial progenitors in the postnatal cerebellum, but how their lineage potential changes during development remains incompletely understood. Our previous electroporation-based study suggested that P0 BGLPs possess broader lineage potential than P6 BGLPs. Here, we performed recombination-based lineage tracing by cerebellar surface application of tamoxifen to Ai9/+; GlastCreERT2/+ mice and temporally analyzed the progeny of BGLPs labeled at P0, P3, P6, and P8. We found that BGLPs undergo progressive lineage restriction during postnatal development. P0 BGLPs gave rise to Bergmann glial cells (BGs), inner granule cell layer astrocytes (IGL astrocytes), white matter astrocytes (WM astrocytes), and molecular layer inhibitory neurons (ML-INs), confirming our previous electroporation-based findings. In contrast, P3 BGLPs generated BGs, IGL astrocytes, and WM astrocytes, whereas P6 BGLPs generated BGs and IGL astrocytes, and P8 BGLPs generated predominantly BGs. Thus, BGLP lineage output was progressively restricted from four progeny categories at P0 to a predominantly BG-restricted output by P8, suggesting that BGLPs dynamically adjust their cellular output during postnatal cerebellar maturation. Additional temporal analyses suggested that ML-INs are unlikely to be generated directly from P0 BGLPs, but may arise indirectly through astrocyte-like progenitors (AsLPs) and inhibitory neuron progenitors (INPs). These findings identify postnatal BGLPs as a useful in vivo model for studying progressive lineage restriction and stage-specific cellular supply during cerebellar development.

Importance: Neuroinflammation is a key component of the response to injury after concussion, but direct links between diffusion MRI metrics and specific plasma inflammatory pathways in human concussion have not been established. Objective: To examine associations between diffusion MRI metrics and pathway-level inflammatory proteomic signatures in adolescents during the subacute period after concussion. Design, Setting, and Participants: Cross-sectional analysis of data from the CARE4Kids Consortium, a six-site prospective study. Participants were English-speaking adolescents ages 11-17.99 with concussion and symptoms at 7-35 days post-injury. Data were collected between 2022-2024. Of 370 enrolled participants, 122 had both diffusion MRI and plasma proteomics available for analysis. Exposure: Advanced diffusion MRI metrics were converted to z-scores and participants were grouped by the spatial extent of outlier values (potholes and peaks) across 15 white matter regions of interest. Nine non-redundant groupings were selected for primary analysis. Main Outcomes and Measures: Pathway-level inflammatory profiles derived from gene set enrichment analysis (GSEA) of ~5,400 plasma proteins measured by Olink proximity extension assay, targeting nine hallmark inflammatory pathways spanning initiation through resolution. Persistent symptoms were assessed 64-115 days post-injury. Results: Diffusion metrics reflecting tissue disorganization were associated with upregulation of the coagulation pathway, consistent with hemostatic-inflammatory signaling. Metrics reflecting reduced tissue complexity and neurite density were associated with upregulation of interferon- and interferon-{gamma} response pathways, consistent with microstructural remodeling driven by cellular immune activation. Elevated free water content was associated with downregulation of most inflammatory pathways and trend-level transforming growth factor - {beta} upregulation, reflecting inflammatory resolution. Time since injury did not differ between groups based on free water (Kolmogorov-Smirnov p = 0.97), suggesting these differences reflect individual variability in recovery pace. Exploratory analyses showed a trend toward lower odds of persistent symptoms in the group with elevated free water content (odds ratio = 0.51, p = 0.18). Conclusions and Relevance: Multiple diffusion MRI metrics are differentially sensitive to distinct neuroinflammatory states in the subacute period after adolescent concussion. These findings suggest that diffusion imaging could serve as a non-invasive tool for inflammatory phenotyping, with potential implications for identifying patients who may benefit from targeted immunomodulatory intervention.

Background/Objectives: Traumatic Brain Injuries (TBIs) often cause profound functional impairments, yet the influence of TBI mechanisms on stair-climbing functional independence over extended timelines remains poorly understood. This study assesses whether Rasch-transformed FIM Stairs scores varied by TBI mechanism over follow-ups spanning 10 years or more. Methods: Data from the TBI Model Systems database were analyzed. The original 30,768 data entries were reduced to 6,226, corresponding to individuals with at least 10 years of data. Functional Independence Measure Stairs data were transformed to logit units via Rasch analysis before being evaluated with a linear mixed-effects regression, incorporating TBI mechanisms, age, follow-up time, and their interactions, with random effects accounting for the participant ID and pre-injury residence location. Results: TBI mechanisms meaningfully shape very long-term stair-climbing. Gunshot wounds and pedestrian-related accidents are associated with poorer performances, whereas motorcycles, bicycles, unclassified vehicular accidents, winter sports, other sports, and fall-related TBIs demonstrated relatively better function. Age, follow-up time, and their interaction also reached significance. Conclusions: Stair-climbing recovery trajectories over extended time significantly vary by TBI mechanism, with individuals with TBIs from gunshots and pedestrian-related accidents showing the most unfavorable recoveries. These findings support the development of mechanism-specific prognostic guidance and individualized rehabilitation strategies, thereby encouraging tailored approaches to improve outcomes.

Sex differences in brain disorders span age at onset, symptom profiles, disease course and treatment response, and may partly reflect underlying differences in cellular metabolism. Indeed, in vivo evidence of sex-related neurometabolic variation remains sparse, with heterogenous and conflicting findings. Using fast high-resolution whole-brain three-dimensional magnetic resonance spectroscopic imaging, we mapped five brain metabolites in three independent cohorts of healthy participants (total n = 114). In a discovery sample of adolescents scanned at 3 Tesla (3T) (n = 61), males showed higher total N-acetylaspartate (tNAA) across widespread gray matter regions. Regional analyses further revealed opposing sex patterns with a complementary higher total creatine (tCr) observed in females, motivating examination of their ratio as an integrative metabolic index. The tNAA/tCr ratio was consistently higher in males in the discovery sample and this finding was replicated across two independent young-adult samples (3T, n = 26; 7T, n = 27), with a widespread gray and white matter distribution. This tNAA/tCr ratio may link neuronal mitochondrial metabolism with cellular energy buffering, positioning it as a potential index of bioenergetic balance relevant for conditions showing both sex differences and altered neurometabolism, notably multiple sclerosis, Alzheimer disease, and psychosis. Together, these findings reveal a reproducible, distributed metabolic sexual dimorphism in the human brain, and underscore the importance of accounting for sex-specific neurometabolic profiles in studies of brain health and disease.

A recent study (Manjarrez et al., 2026) showed that the classification of cortical dendritic spines into stubby, thin, and mushroom subtypes is unstable under rotation. That result criticizes the categorical scheme but leaves an open question. What is the actual structure of spine morphology once the viewing angle is controlled? Here we answer it. We analyzed 228 spines from layer II pyramidal neurons in the H01 nanometer-resolution reconstruction of human temporal cortex. We first quantified the source of instability. We found that rotating dendritic segments by 90 degrees about their axes shifted the apparent spine height and head width in opposite directions across the population, thereby confirming orientation-dependent measurement error. Furthermore, to obtain measurements free of this artifact, we developed the Spine Morphometry Hub (SMH), a 12-point anatomical landmark framework that characterizes each spine in all three orthogonal planes and extracts geometric, voxel-based, and mesh-based metrics. All morphometric distributions were unimodal and right-skewed. Density-based clustering assigned most spines to noise, and a Monte-Carlo test against a discrete two-type null model confirmed that this pattern is incompatible with categorical subtypes. We also confirmed that apical and basal spines were statistically indistinguishable. Unlike previous reports of a spine continuum, all based on orientation-dependent measurements, our framework removes the viewing-angle confound itself, so the continuum we observe cannot be attributed to a projection artifact. Hence, our framework will be useful to quantify dendritic-spine remodeling in neurological disorders, in which spine shape has long been observed but never measured against an orientation-invariant morphometric standard. HighlightsO_LISpine Morphometry Hub (SMH) measures spines free of viewing-angle error C_LIO_LISMH was validated as an orientation-invariant morphometry framework C_LIO_LIRotating dendrites by 90{degrees} shifts spine height and head width oppositely C_LIO_LIAll morphometric distributions are unimodal and right-skewed, not categorical C_LIO_LISMH could be used to quantify dendritic-spine remodeling in neurological disorders C_LI

Working memory (WM) is a core cognitive function that supports goal-directed behavior by temporarily maintaining and manipulating information. One of the most widely used paradigms for investigating WM function is the N-back task, and numerous neuroimaging studies have examined load-dependent neural responses using a variety of analytical approaches. However, most previous studies have focused on low-to-moderate load ranges (primarily 0-3-back), and it remains unclear how whole-brain activity patterns reconfigure across a broader range of WM demands, including conditions approaching capacity limits. In the present study, we investigated behavioral performance and whole-brain activity patterns across an extended N-back task ranging from 0-back to 7-back. Behavioral analyses revealed that discrimination sensitivity (d') decreased nonlinearly with increasing WM load, whereas reaction time (RT) exhibited an inverted-U pattern, peaking at intermediate load conditions. To characterize load-dependent whole-brain activity patterns, we computed relative activation maps by subtracting the participant-wise mean activation map across all conditions from each condition-specific activation map. Spatial similarity analyses with the Yeo 7-network templates revealed that low-load conditions showed relatively high similarity to default mode network (DMN)-related patterns. Similarity to the dorsal attention network (DAN) and frontoparietal network (FPN) was maximal at intermediate load levels, indicating load-dependent changes in network similarity profiles. High-load conditions were characterized by partial re-emergence of DMN-related patterns, accompanied by reduced DAN/FPN similarity. In addition, semantic similarity analysis using Neurosynth-derived semantic maps revealed relatively high similarity to default mode-related and self-referential representations under low-load conditions. Intermediate-load conditions showed strong correspondence with working memory- and executive control-related representations, whereas high-load conditions exhibited increased similarity to salience-, aversive/interoceptive-, and inhibitory-control-related representations. Together, these findings suggest that increasing WM load is associated not merely with stronger activation, but with changes in whole-brain activity patterns accompanied by nonlinear changes in network similarity profiles across levels of cognitive demand. Furthermore, the relative activation map-based whole-brain pattern analysis used in this study may provide a useful approach for evaluating changes in whole-brain state representations associated with cognitive load.