Journal of Neurotrauma

Traumatic Brain Injury (TBI) patients may suffer from a number of long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here we investigate the effect of exercise on pain outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies employed the administration of noradrenergic (NA) and serotoninergic receptor blockers. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of the acute phase of pain from [~]5 weeks to 2-3 weeks in female and male TBI rats respectively, gains that could be reversed using the 1-adrenoceptor (1AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT7 receptor antagonist, SB-267790, the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Therefore, the transition from a noradrenergic to a serotonergic inhibitory pain pathway that we typically see in male TBI rats, was blocked by exercise. Assessment of neuropathology, acutely after TBI, reveals that both the astrocyte and microglial response to injury is significantly greater in male TBI compared to female TBI, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. In contrast, exercise significantly decreased the amount of axonal loss in the corpus callosum in both male and female TBI rats compared to sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups respectively. These results demonstrate that exercise is a promising treatment for chronic pain after TBI in both male and females. It also highlights that dysfunction of the endogenous pain modulatory pathways observed in male rats after TBI can be prevented by exercise, possibly by reducing axonal loss.

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.

BackgroundPrognostication after moderate-to-severe traumatic brain injury (TBI) rarely captures long-term functional recovery, despite its importance to patients, families, and clinicians. Large trauma registries such as the Trauma Quality Improvement Program (TQIP) dataset contain detailed clinical data but lack systematic follow-up, limiting their ability to study longer-term functional outcomes. MethodsWe developed and externally validated a machine learning model to predict favorable six-month functional outcome (GOS "MD"/"GR" or GOSE [≥]5) using harmonized data from two randomized clinical trials: CRASH (training) and ROC-TBI (validation). Five candidate classifiers (random forest [RF], linear discriminant analysis, k-nearest neighbors, naive Bayes, and support vector machine) were trained using seven shared clinical predictors. Models were evaluated using ROC-AUC, calibration metrics, and performance at the Youden optimal threshold and a high-sensitivity secondary threshold. The final model was applied to patients with moderate-to-severe TBI in the national TQIP registry (2017-2022) to estimate population-level recovery patterns. ResultsThe RF model demonstrated the highest overall performance after recalibration, achieving strong discrimination (AUC internal and external, 0.887 and 0.784), good calibration, and high sensitivity (0.890) and negative predictive value (0.909). Applied to 63,289 patients from TQIP, the model estimated that 45% would achieve favorable six-month outcomes at the Youden optimal threshold and 57% at the high-sensitivity threshold, with predicted recovery aligning with established clinical correlates such as younger age, higher admission GCS, and lower rates of penetrating or brainstem injuries. ConclusionA machine learning model trained on high-quality trial data can generate clinically plausible estimates of long-term functional recovery when applied at scale to national trauma registries that lack systematic follow-up. This approach enables imputation of functional outcomes in datasets lacking follow-up, supports benchmarking and quality improvement across trauma systems, and provides a foundation for future models incorporating physiologic time-series, imaging, and biomarker data.

PurposePrevious research has demonstrated effects of head impact exposure on cortical neurophysiology, which may help with understanding variability in clinical sequelae. In separate lines of research, neurochemical and gene transcription markers of vulnerability to traumatic brain injury (TBI) have been established. The purpose of this study was to examine whether these cortical neurochemical and gene transcription gradients are spatially aligned with neurophysiological effects. Methods and MaterialsMagnetoencephalography (MEG) data was collected at a total of 278 pre- and post-season timepoints from 91 high school football players across up to four seasons of play. Of the 91 football players, 10 experienced a concussion, and of the remaining 81 non-concussed players, 71 met the criteria for complete imaging and kinematic data, with post-season evaluations less than six weeks after the end of the season. Head impacts were tracked over the course of the season with helmet-mounted sensors. MEG data underwent source-imaging, frequency-transformation, spectral parameterization, and linear modeling to examine the effects of concussive and non-concussive head impact exposure on pre-to-post-season changes in rhythmic and arrhythmic neurophysiological activity. To determine clinical effects, parent reported Post-Concussive Symptom Inventory scores related to cognitive symptoms were correlated with cortical neurophysiological changes. Multi-atlas data of neurochemical system densities from neuromaps and gene expression from the Allen Human Brain Atlas were examined for alignment with head impact-related alterations in neurophysiology via nonparametric spin-tests with autocorrelation-preserving null models (5,000 Hungarian spins; pFDR <.05). ResultsConcussion-related reductions in cortical excitability (i.e., aperiodic exponent slowing) were aligned with atlas-based norepinephrine transporter (NET) and alpha-4 beta-2 nicotinic receptor (4{beta}2) densities, and with apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) expression levels. More severe cognitive symptoms associated with concussion-related slowing of aperiodic neurophysiology were also aligned with atlas-based NET and 4{beta}2 receptor densities. Similar changes in cortical excitability related to non-concussive head impact exposure were colocalized with serotonin receptor (5-HT1A) density maps and APOE and BDNF expression. Rhythmic alpha activity was reduced by concussion and colocalized with histamine (H3) and mu-opioid (MOR) receptors, among others, as well as with gene transcription atlases of APOE and C-C chemokine receptor 5 (CCR5). ConclusionsThese findings extend our previous work to show that the effects of head impact exposure on neurophysiology are strongest in cortical areas with specific neurochemical and genetic profiles that are known to signal vulnerability to traumatic brain injury, and that these spatial alignments are also associated with self-reported symptom severity. Clinical Relevance / ApplicationChange in cortical excitability, as measured here by MEG, has potential value as a clinical tool for concussion diagnosis and prognosis. We provide genetic and neurochemical contextualization for these changes that may extend their clinical applications, for example to concussion risk assessment and pharmacotherapies.

Ankle clonus is a sustained, involuntary, rhythmic muscle contraction frequently observed in humans with spinal cord injury (SCI). Although its pathophysiology remains incompletely understood, converging evidence suggests a role for brainstem systems in its generation. Following SCI, brainstem neuromodulatory inputs partially compensate for the loss of descending motor pathways by regulating motoneuron excitability during involuntary contractions, suggesting their involvement in the generation of clonus. To test this hypothesis, motoneuron excitability in response to Ia synaptic input was quantified using the soleus H reflex and maximal motor response (H/M ratio), and brainstem involvement was probed using the long lasting component of the cutaneous reflex (LLR) in the tibialis anterior and soleus muscles, as well as the StartReact response-an involuntary release of a movement triggered by a startling stimulus thought to engage the reticulospinal tract. We studied individuals with chronic SCI, both with and without ankle clonus, using standardized clinical tests across two days. Participants with clonus showed elevated H/M ratios, indicating increased motoneuron excitability, whereas those without clonus exhibited lower values than controls. Additionally, individuals with clonus exhibited longer LLR duration and greater LLR magnitude in both muscles, along with shorter reaction times to startle stimuli, consistent with enhanced monoaminergic and reticulospinal contributions. Notably, LLR duration was positively correlated with both StartReact response and H/M ratio. Together, these findings support a role for descending brainstem systems-particularly monoaminergic and reticulospinal pathways-in the maintenance of clonus in chronic SCI.

Background: Spinal cord injury (SCI) is associated with widespread reorganisation of cortical sensorimotor circuits. Persistent complications such as spasticity and neuropathic pain suggest that homeostatic plasticity, which normally helps stabilise and constrain activity-dependent changes in sensorimotor circuits, may be disrupted after SCI. Homeostatic plasticity can be probed using repeated blocks of transcranial direct current stimulation (tDCS); in healthy individuals, two closely spaced excitatory blocks typically leads to an inhibitory response, reflected as a reduction in corticomotor excitability. Objective: To determine whether individuals with SCI show reduced homeostatic suppression of corticospinal excitability in response to repeated anodal tDCS, compared with healthy controls. Methods: Twenty adults with thoracic or below SCI and 20 healthy controls completed three counterbalanced sessions. Each session comprised two 10-minute blocks of 2 mA tDCS separated by 5 minutes, with the second block always being anodal tDCS over left primary motor cortex. The first block was either anodal, cathodal, or sham tDCS, yielding 3 condition types: anodal-anodal, cathodal-anodal, and sham-anodal. To assess corticomotor excitability, transcranial magnetic stimulation-evoked motor evoked potentials (MEPs) were elicited at baseline, after priming, and every 5 minutes for 60 minutes after the second block. The primary outcome was percent change in MEP amplitude from baseline. Results: In the anodal-anodal condition, the SCI group showed greater facilitation than controls over 0-30 minutes (estimate = 83.09, 95% CI 49.75 to 116.43, p < 0.001), suggestive of a weaker homeostatic response. The cathodal-anodal condition led to a significant overall facilitatory effect with no between-group difference, while the sham-anodal condition showed no change in MEP amplitude relative to baseline. Within the SCI group, exploratory subgroup analysis suggests that those with neuropathic pain and a traumatic injury showed greater facilitation in the anodal-anodal condition than those without these features, indicative of a weaker homeostatic response. Conclusions: SCI is associated with impairment in the homeostatic regulation of corticomotor excitability following repeated excitatory brain stimulation. Disrupted plasticity stabilisation may be relevant to persistent symptoms such as neuropathic pain.

Traumatic brain injury (TBI) is a condition of high incidence worldwide, but remains mostly undertreated. Previous observations in preclinical studies pointed to a beneficial effect of insulin-like growth factor 1 (IGF-1) in TBI. As brain injury is associated to loss of IGF-1 sensitivity, we tested the therapeutic potential of AIK3a305 (AIK3), a novel IGF-1 sensitizer. Twenty-four hours after mild TBI induced by controlled impact, mice received daily intraperitoneal injections of AIK3 during 4 weeks. We found that TBI-associated sensorimotor disturbances measured with the adhesive-removal test were reverted by AIK3 treatment. In addition, neurological and cognitive disturbances measured by the neurological severity score and Y maze respectively, were also ameliorated by treatment with the IGF-1 sensitizer, whereas increased anxiety after mild TBI was also normalized by AIK3. Circulating levels of IGF-1 were increased after AIK3 treatment in TBI mice, while serum IL-6 levels, a biomarker of inflammation associated to TBI were similar to control mice treated with AIK3. Transcriptomic analysis determined that treatment with AIK3 widely affected gene expression in TBI brains, showing a general reduction in both up- and down-regulated genes. Collectively, these data support the use of IGF-1 sensitizers such as AIK3 for treatment of TBI.

Persistent pain is a common but poorly understood outcome of traumatic burn injury. With increasing numbers of patients surviving their burn injuries, ongoing pain presents a growing complication to patient healing and quality of life. Despite more women reporting chronic pain post-burn than men, preclinical burn research rarely includes female animals. To address this gap, this study examined a diverse set of behavioral outcomes in male and female rats after a unilateral full-thickness burn to the hind paw. Utilizing traditional methods to assess evoked pain behaviors, new technology to assess gait abnormalities, and established techniques to evaluate comorbid anxiety-like behavior, we determined that male and female rats have divergent pain-related behaviors post-burn. Both sexes experienced mechanical allodynia after burn injury, but only males experienced thermal hyperalgesia. In contrast, female rats were acutely resistant to noxious thermal stimulation. While both sexes demonstrated gait abnormalities post-burn when freely ambulating, female rats exhibited a wider range of abnormal gait features, which were more severe and longer-lasting than those in males. However, despite both sexes demonstrating symptoms of persistent pain, only males displayed anxiety-like behavior on the Elevated Zero Maze. In conclusion, our study found that male and female Sprague Dawley rats displayed divergent, sex-specific evoked pain responses, gait dysfunction, and anxiety-like behavior after full-thickness burn injury. Future studies should examine the underlying mechanisms behind these behavioral sex differences. PerspectiveThis article takes a novel approach to pain behavior testing after full-thickness burn injury, capturing behaviors beyond traditional reflexive ("evoked") behaviors. The results of this article provide evidence that preclinical research must expand behavioral testing to capture the full animal pain experience and better model human patient outcomes.

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.

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

Background: Acute treatments for patients with spinal cord strokes (SCS), including lumbar drain, blood pressure augmentation, corticosteroids, antiplatelets, and anticoagulants, are largely extrapolated from literature on cerebral infarcts or based on suspected SCS physiology. This study adds to the knowledge of symptomatology and management of SCS. Methods: This retrospective cohort study included patients from one medical system from 2000-2025. Multivariate ordinal logistic regressions were performed to evaluate associations of SCS treatments with the primary outcome of ambulatory status (independently ambulatory, ambulatory with assistance, non-ambulatory) at first follow-up, as well as secondary outcomes of modified Rankin Scale (mRS) and modified Japanese Orthopedic Association (mJOA) scores. SCS severity by American Spinal Injury Association impairment scale (AIS) with grade A as the comparator, age, sex, and whether SCS was spontaneous/periprocedural were covariates. Odds ratios (OR) greater than 1 were associated with better ambulatory status, lower mRS, and higher mJOA. Results: 130 SCS patients were included. Median age at SCS onset was 62 years, 42% were female, and 39% were periprocedural. Median first follow-up was 57 days. AIS grade was A for 28%, B for 25%, C for 28%, and D for 26%. SCS severity had significant associations with outcomes. For ambulatory status, AIS B OR 2.78, 95% CI 1.03-7.69, p-value 0.045; AIS C OR 16.7, 95% CI 5.56-50.0, p-value <0.01; AIS D OR 125, 95% CI 33.3-500, p-value <0.01. Corticosteroids were associated with improved ambulatory status and mJOA at follow-up (OR 2.38, 95% CI 1.15-5, p-value 0.023 and OR 2.27, 95% CI 1.09-4.76, p-value 0.030, respectively). No treatment had a significant association with mRS. Conclusion: Initial SCS severity had the strongest association with outcomes. Corticosteroids were associated with a better ambulatory status and mJOA. This study can help guide clinician management of patients with SCS.

The impact of social parameters on brain health among people with traumatic brain injury (TBI) has been extensively documented. However, translation of this evidence into policy and clinical practice remains limited. This may reflect a lack of coordinated and equity-driven approaches to brain health that integrate diverse stakeholder perspectives, limiting progress toward equity-oriented research and service delivery models. We conducted a convergent parallel mixed-methods study guided by the REporting guideline for PRIority SEtting of health research (REPRISE). We utilized the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and context-specific parameters) to ensure systematic consideration of social parameters in the study. For Objective 1, we synthesized existing evidence on social parameters and brain health outcomes. For Objective 2, we surveyed people with lived experience of TBI, family members/friends, clinicians, researchers, and community leaders across the globe to assess their prioritization of social parameters relevant to brain health. For Objective 3, we integrated evidence synthesis and stakeholder input through a structured Round Robin consensus activity to prioritize actionable areas for feasibility and impact. The activity culminated in the development of a knowledge mobilization agenda designed to inform equity-centred policy, research, and clinical practice. In Objective 1, we identified 59 publications with evidence on the effect of PROGRESS-Plus parameters on brain health outcomes following TBI. Meta-research highlighted that education, age, and country-level indicators are prognostic for brain health after TBI. In Objective 2, the highest-ranked priorities of 113 stakeholders across four continents (North America, Europe, Africa, and Oceania) were education, access to benefits, and income. These priorities were at the centre of discussion in Objective 3, which comprised idea sharing, refinement and thematic clustering, and a final prioritization poll. The resulting final 15 priorities were organized into two tracks: Track A, actions feasible in the short term, and Track B, longer-term implementation priorities. Building on this priority-setting process, co-created with stakeholders around the globe, the findings provide a roadmap for integration of social parameters in TBI research, knowledge exchange, policy, and practice.

The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres and is anatomically divided into three major subregions along the anteroposterior axis: the genu, midbody, and splenium. The splenium is frequently affected in traumatic head impacts, yet the biomechanical basis for this selective vulnerability remains poorly understood. Clinical studies have long hypothesized that the falx cerebri contributes to the splenial susceptibility because of its close anatomical relationship with the posterior corpus callosum, although direct verification is lacking. To address this, a high-resolution finite element head model with explicit representations of the genu, midbody, and splenium was employed. Two model variants, differing only in the presence or absence of an anatomically and mechanically detailed falx, were used to simulate ten head impacts covering a range of loading directions and severities. Peak strain, strain rate, and shear stress were quantified in each corpus callosum subregion and compared using linear mixed-effects models. The results showed that inclusion of the falx altered the regional distribution of mechanical responses within the corpus callosum. Across the simulated impacts, the splenium consistently exhibited greater strain, strain rate, and shear stress than the genu and midbody when the falx was present. In contrast, these preferentially larger splenial deformation were not consistently observed when the falx was absent. Statistical analyses demonstrated significant region-dependent effects of the falx, with falx-induced increases in strain, strain rate, and shear stress being significantly greater in the splenium than in the genu and midbody (p < 0.05). These findings verified the hypothesis that the falx selectively amplified mechanical loading within the splenium, thereby contributing to its heightened vulnerability to injury. This work provides a plausible biomechanical explanation for the frequent involvement of the splenium in brain trauma patients and highlights the heterogeneous influence of the falx on mechanical responses across corpus callosum subregions.

Introduction: Adults with spinal cord injury (SCI) often experience reduced or lost sensation and movement, impairing the ability of the brain to locate paralyzed body parts, which, in turn, compromises sensorimotor recovery. This disruption of the internal body map of the brain, or mental body representations (MBR), also contributes to neuropathic pain in about 69% of adults with SCI. Medications for neuropathic pain are often ineffective and can cause adverse reactions. Our previous pilot clinical trial showed that Cognitive Multisensory Rehabilitation (CMR), a physical therapy that restores MBR, produced significant, lasting reductions in neuropathic pain, improved sensorimotor function, and enhanced brain function. Building on these results, we examined whether 8 weeks of CMR or adaptive fitness (1) improved sensorimotor function and reduced pain; (2) greater brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Sixteen participants (52+/-8 years old, 13+/-10 years post-SCI) were randomized to 8 weeks of CMR or adaptive fitness (45 min, 3x/week). Ten participants had neuropathic pain of 3/10 or greater. Pain and sensorimotor function were assessed at baseline, post-intervention, and 3-month follow-up using the Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS). Functional MRI included resting-state and 4 tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR, participants improved on AIS with large effect sizes (touch: d=1.54; pinprick: d=1.83; lower limb motor function: d=1.32), while adaptive fitness had small/moderate effects (touch: d=0.49; pinprick: d=0.53; lower limb motor function: d=0.74). CMR also showed larger effect sizes for NRS (core: d=2.19; upper limb: d=0.69; lower limb: d=0.74) than fitness (core: d=0.73; upper limb: d=0.34; lower limb: d=0.00). Benefits persisted at follow-up. Highest neuropathic pain intensity reduced post-CMR and at 3-month follow-up (d=0.48; d=0.63). Pain increased slightly after fitness (n=6; d=-0.19; d=-0.41). CMR increased brain connectivity and activation during the leg imagery task. Increased activation during whole-body imagery was greater after CMR than fitness. Discussion: These preliminary results support the potential of CMR to improve function and reduce neuropathic pain in adults with SCI, warranting larger confirmatory trials. Clinicaltrial.gov: NCT05167032

BackgroundNeurodevelopmental impairment remains common in neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with the standard of care, therapeutic hypothermia (TH). The complement response activates at reperfusion and is known to exacerbate neuroinflammation and injury, though its full role and interaction with hypothermia are incompletely defined. We hypothesized that modulating the complement response could improve structural and functional outcomes in HIE, and tested a novel complement therapy (CT), consisting of C3a peptides and the C5a-receptor antagonist PMX205, as both a stand-alone treatment and as an adjuvant to TH. MethodsWistar rat pups were randomized to the following treatment groups: Sham (uninjured control), NT (uninjured, normothermia/not treated control), or injured and treated with either TH, CT, or CT+TH. At term-equivalence, mild-moderate hypoxic-ischemic injury was induced by Vannuccis method. To capture the short and long-term effects of the treatments, cohorts were harvested 3 or 66-72 days post-injury, respectively. Cerebral injury was measured by quantifying levels of inflammatory markers and cerebral tissue loss, and functional outcomes were assessed in a series of behavioral tests. The data were stratified to detect sexual dimorphisms. ResultsCT and TH treatments demonstrated test and sex-dependent differences in improvement compared to untreated, injured rats. In male rats, TH treatment worsened long-term hippocampal and thalamic brain injury and functional measures of ataxia and attention. CT-treatment worsened long-term thalamic loss in females. Combining the two treatments (CT+TH) demonstrated additive improvement in both sexes, including short and long-term cortical loss and ataxia. ConclusionsComplement modulation enhances the neuroprotective effects of TH after neonatal hypoxic-ischemic injury, with sex-specific effects on inflammation and behavior. Combining complement modulation with the standard of care often demonstrated synergistic improvement in both sexes, supporting complement-targeted therapy as a promising adjunct to hypothermia in neonatal HIE. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/717097v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1025d1forg.highwire.dtl.DTLVardef@2fa4e5org.highwire.dtl.DTLVardef@1f2c1c4org.highwire.dtl.DTLVardef@8f3410_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender. Saadat, A. (2026) https://BioRender.com/siwm825.

Background Chronic subdural hematoma (cSDH) recurrence requiring reoperation occurs in 5-33% of cases, representing a substantial clinical and economic burden. The ability to predict recurrence could enable risk-stratified surveillance protocols, potentially reducing imaging burden in low-risk patients while maintaining close monitoring for high-risk individuals. We evaluated whether machine learning algorithms could achieve clinically actionable recurrence prediction using routinely available clinical and radiographic variables. Methods This retrospective single-center study included 564 consecutive patients who underwent surgical evacuation of cSDH between 2015 and 2023. Data were randomly divided into training (75%, n=422) and test (25%, n=142) sets. We developed and compared three machine learning models--regularized logistic regression, Random Forest, and XGBoost--using 31 predictor variables including demographics, comorbidities, medications, laboratory values, hematoma characteristics, and postoperative features. Model development and hyperparameter tuning were performed exclusively on the training set using 10-fold cross-validation. The best-performing model was selected and evaluated on the held-out test set. The primary outcome was postoperative recurrence requiring reoperation. Results Postoperative recurrence occurred in 170 patients (30.1%). Within the training set, XGBoost achieved the highest cross-validated ROC AUC of 0.713 (SE=0.024), outperforming regularized logistic regression (0.686) and matching Random Forest (0.713). Variable importance analysis identified hematoma volume, coagulation parameters (INR, platelets, aPTT), and disease severity markers (ICU admission, GCS) as the most influential predictors, though absolute effect sizes remained modest. On the held-out test set, the final XGBoost model achieved ROC AUC 0.688 (95% CI: 0.590-0.772) with excellent calibration. However, at the clinically relevant 90% sensitivity threshold, test set specificity was only 30.3%, allowing potential imaging reduction in approximately one-third of non-recurrence patients. The consistency between training and test performance confirmed that limitations stem from inherent predictor information content rather than overfitting. Conclusions Machine learning models using routinely available clinical and radiographic variables cannot achieve clinically actionable risk stratification for cSDH recurrence. Despite rigorous methodology and internal validation, discriminative capacity remained insufficient to identify a low-risk patient subgroup suitable for de-escalated surveillance. These findings suggest that recurrence is driven by factors not captured in standard clinical assessment, and support either uniform surveillance protocols or symptom-driven imaging strategies rather than risk-stratified approaches.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

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.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

BackgroundAs therapeutic options emerge for hereditary spastic paraplegias (HSP), clinical trials require outcome measures that reflect disease aspects most important to patients. Patient priorities in HSP remain poorly defined. This study aimed to develop a regulatory-compliant framework of patient-prioritised health domains to evaluate treatment response in clinical trials. MethodsPatient-reported data on health impacts were collected via two multinational, multilingual online surveys conducted sequentially, including 616 and 504 patients across the clinical and genetic spectrum of HSP. Using a staged approach, we examined prevalence, relevance, and severity, focusing on health impacts that were (i) common (ii) sensitive to disease progression, (iii) highly relevant to patients, and (iv) showed strong severity-relevance correlation. Patient representatives contributed centrally to study design and prioritisation. FindingsOur patient-focused analysis yielded five highly prevalent and relevant core health domains: mobility, lower body function, autonomic dysregulation, pain, and psychosocial aspects. Ambulation and lower body function ranked highest across all disease stages. Among non-motor impacts, reduced ability to work, bladder incontinence, and fatigue were most relevant. In mild disease stages, reduced walking distance, reduced walking speed, and the urgency to empty the bladder were the most frequent and most relevant health impact. InterpretationThis work provides the most comprehensive patient-reported and disease stage specific profiling of HSP health impacts to date. It lays the necessary groundwork for developing patient-focused outcome tools capable of capturing treatment effects in future trials.