Current neurocritical care relies on fixed, population-based intracranial pressure (ICP) thresholds, which fail to account for inter-individual variability or the dynamic nature of cerebral physiology. Individualized ICP (iICP) thresholds have emerged as a potential personalized alternative but have largely relied on complete recording periods, limiting their derivation to post-hoc calculations and preventing continuous real-time estimation. Recently, a novel algorithm capable of continuously deriving iICP was developed; however, this algorithm has not yet been validated beyond a single-center cohort, and its prognostic utility remains uncertain. Therefore, the goals of this study were to externally validate the performance of this continuous iICP algorithm and to evaluate the prognostic utility of continuously derived iICP compared with current guideline-based ICP thresholds. A retrospective multicenter study was conducted using high-resolution physiologic datasets from the CAHR-TBI collaborative. iICP was derived using the recently developed continuous iICP algorithm. Algorithm performance was externally validated by assessing derivation yields and associated quality metrics and comparing with those reported in the original study that introduced the algorithm. Outcome associations were evaluated using mean hourly dose of ICP above iICP and guideline-based thresholds. Logistic regression models were used to assess and compare prognostic performance, with discrimination quantified using optimism-corrected area under the receiver operating characteristic curve and added predictive value assessed using Nagelkerke's R2. Finally, intensity-duration heatmaps were generated to characterize the relationship between iICP-based insult burden and clinical outcomes. The continuous iICP algorithm demonstrated consistent performance across parameter settings compared with the original study, supporting its external validity. Select hybrid iICP configurations, defaulting to 20 mmHg or 22 mmHg during periods where iICP could not be identified, outperformed guideline-based ICP thresholds in prognostic models. Heatmap analyses demonstrated a graded relationship between iICP-defined insult burden and outcome, with greater burden of ICP above iICP associated with poorer outcomes. Overall, iICP represents a promising adjunct to conventional guideline-based ICP management in neurocritical care. The findings of this study suggest potential clinical benefit from iICP-supplemented ICP management; however, prospective randomized controlled trials will be required to determine whether such an approach translates into meaningful improvements in patient outcomes.
Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality, yet metabolic responses in the injured brain remain incompletely understood. Metabolomic profiling of pericontusional tissue may enable the identification of acute-phase biomarkers and reveal novel therapeutic targets. Using a controlled cortical impact (CCI) model, we performed targeted metabolomic analysis of tricarboxylic acid (TCA) cycle intermediates, amino acids, and acylcarnitines at multiple time points within the first 72 h postinjury. We hypothesize that there is time-dependent mitochondrial dysfunction and impaired β-oxidation in the acute and sub-acute time points after injury. CCI was performed in adult male C57BL6/J mice (velocity 5 m/s, depth 1.2 mm) under isoflurane anesthesia. Pericontusional tissue was harvested at 2, 6, 24, and 72 h postinjury following transcardial saline perfusion (n = 8/group). Naïve and anesthesia-only sham animals served as controls; sham animals received isoflurane exposure without craniotomy to isolate anesthetic effects from surgical injury. Relative quantification of TCA cycle intermediates, amino acids, and acylcarnitines was performed by liquid chromatography-high resolution mass spectrometry; metabolite abundances were normalized to protein content. Data were analyzed by Student's t-test, and p value < 0.05 determined significance. Enrichment analysis of metabolite profiles was conducted and visualized in MetaboAnalyst 6.0. Pericontusional tissue demonstrated time-dependent changes across the three metabolite classes, with two distinct temporal phases identified by dimensionality reduction: an acute phase (2-6 h) and a subacute phase (24-72 h). TCA cycle intermediates and glycolytic metabolites were broadly and progressively depleted, consistent with sustained mitochondrial dysfunction and energy failure. Acylcarnitines accumulated across multiple chain lengths, indicating impaired fatty acid β-oxidation. Amino acid profiles showed broad accumulation of essential and branched-chain amino acids-notably leucine and valine-alongside depletion of glutamate, alanine, and GABA, contrasting with prior reports of branch-chain amino acids depletion after TBI. Ingenuity Pathway Analysis confirmed broad suppression of amino acid catabolism, carbohydrate metabolism, and lipid oxidation pathways after CCI. Tryptophan catabolism via the kynurenine pathway was the sole upregulated metabolic pathway, consistent with indoleamine 2,3-dioxygenase 1-mediated neuroinflammatory signaling. We identified TBI-dependent alterations in key metabolic pathways within pericontusional tissue that may have implications for the development of biomarkers or metabolism-targeted therapies. Future investigations should explore cell type-specific metabolic changes and assess their correlation with clinically measurable metabolite levels.
The management of traumatic brain injury (TBI) involves various strategies, with sedation playing a pivotal role. Historically, ketamine has been discouraged in TBI management due to concerns regarding its negative impact on cerebral physiology. However, emerging evidence is challenging this perspective. This narrative review was conducted through a comprehensive literature search utilizing key terms such as "ketamine" and "traumatic brain injury." This investigation involved querying multiple medical and scientific databases. Data on the effects of ketamine on intracranial pressure (ICP), cerebral perfusion pressure, systemic hemodynamics, neuroprotection, and neuroinflammation in TBI conditions were collected. Current evidence suggests that ketamine does not significantly affect cerebral hemodynamics compared with other sedatives. Furthermore, preclinical studies have indicated that ketamine exhibits neuroprotective and anti-neuroinflammatory effects. Research endeavors are warranted to explore the effects of ketamine on patients with high-risk ICP and the dose-dependent and combination responses. Moreover, the investigation of the neuroprotective properties of ketamine is encouraged to elucidate its full potential. Reevaluation of ketamine's use is recommended, as it demonstrates comparable efficacy to other sedatives.
Concussions are one of the most common causes of neurological morbidities in children. In addition to physical, cognitive, and emotional symptoms, a common complaint after concussion is the presence of sleep disturbances, such as trouble falling asleep. The present study sought to longitudinally assess the nature of sleep changes and their association with symptom recovery following concussion in a pediatric sample. Secondary analyses were conducted on a prospective, longitudinal, multicenter cohort study involving 2,991 children and adolescents (5-17 years) who presented to an emergency department within 48 h of a head trauma and who met diagnostic criteria for concussion consistent with the consensus statement prevailing at the time of data collection. Ratings of post-concussive symptoms and sleep disturbances were obtained at 5 pre-defined time points following concussion (weeks 1, 2, 4, 8, and 12), using the Post-Concussion Symptom Inventory (PCSI) and the sleep item of the Pediatric Quality of Life Inventory, respectively. Linear mixed models were fitted separately for the PCSI total score and the physical, cognitive, and emotional symptom subscales, adjusting for random participant effects. Model predictors included sleep, time, and time x sleep interaction. The model accounted for age, sex, maximum duration of previous concussion symptoms for individuals who had a previous concussion, prior diagnosis of developmental disorder, depression, and anxiety, and prior diagnosis of sleep disorders, as they are known risk factors for prolonged recovery. There was significant improvement in both sleep quality ratings (mean values per time point: week 1 = 76.3, SD = 30.1; week 2 = 81.6, SD = 28; week 4 = 82.4, SD = 27.4; week 8 = 86.6, SD = 24.2; week 12 = 89, SD = 22.8) and post-concussive symptoms across time points (mean delta values per time point: week 1 = 0.40, SD = 0.77; week 2 = 0.39, SD = 0.76; week 4 = 0.38, SD = 0.76; week 8 = 0.38, SD = 0.76; week 12 = 0.38, SD = 0.76) (all p < 0.001). Significant sleep*time interactions showed that better sleep was significantly associated with reduced global (β = 0.003, p = 0.030, 95% CI [0.00003, 0.0006]) and physical post-concussion symptoms (β = 0.007, p = 0.035, 95% CI [0.0005, 0.01]) after the injury relative to pre-injury levels, especially in early phases of recovery. Better sleep, regardless of the recovery period, was associated with greater reductions in patient-reported cognitive (β = -0.26, p = 0.0001, 95% CI [-0.34, -0.18]) and emotional symptoms (β = -0.28, p = 0.0001, 95% CI [-0.35, -0.20]) after concussion. The present findings indicate that better sleep is linked to more favorable post-concussion recovery as reflected by different clusters of symptoms. These results highlight the importance of investigating whether safeguarding sleep in children and adolescents with concussion may facilitate recovery.
The Open Data Commons for Traumatic Brain Injury (ODC-TBI.org) was launched in 2018 to support data sharing in pre-clinical TBI. As data science and artificial intelligence continue to advance, open sharing of high-quality, FAIR (Findable, Accessible, Interoperable, and Reusable) data has assumed critical importance to propel discovery science and as a countermeasure to some of the rigor and reproducibility problems plaguing translational research across biomedicine. Researcher-led specialist repositories such as ODC-TBI serve as important hubs through which biomedical communities come together to define data sharing requirements for their respective domains in support of new requirements by funders and journals for routine data sharing. ODC-TBI is now the recognized data repository for pre-clinical TBI research, listed on the National Library of Medicine-recommended repository listing, and is supported by the National Institute on Neurological Disorders and Stroke. ODC-TBI forms one of the critical infrastructure components of the PRE C linical I nteragency re S earch resourc E -TBI (PRECISE-TBI) project, an interagency effort to promote and support data sharing, rigor, and reproducibility in pre-clinical TBI research. Through PRECISE-TBI, the ODC-TBI has conducted broad outreach, starting in 2022, resulting in a significant increase in the number of users, datasets uploaded and public data releases. PRECISE-TBI has facilitated the establishment of an Editorial Board providing community oversight of ODC-TBI policies and recommendations, for example, the use of standards such as common data elements (CDEs). Here we describe the current state of the ODC-TBI, including its organization, operation, and governance. We perform a detailed overview of public datasets to provide insight into data sharing practices, including the use of CDEs and ancillary practices such as providing links to publications and citing data. We examine the impact of the ODC-TBI by providing statistics on downloads per datasets and reuse of ODC-TBI data in published studies. The results not only provide insight into the growth trajectory of ODC-TBI and data sharing behaviors in pre-clinical TBI, but also point to areas where increased outreach, communication, and training are needed to firmly establish a culture of data sharing.
Repetitive, nonconcussive head impacts in collision sports are associated with lasting neurophysiological effects. This study investigates region-specific changes in neocortical mean diffusivity (MD) and resting-state functional magnetic resonance imaging (fMRI) power spectral density (fMRI-PSD) that correlate with cumulative nonconcussive linear risk-weighted exposure (RWE-Lin) sustained over one high school football season. Pre- to postseason percent changes in MD (%ΔMD) and fMRI-PSD (%ΔfMRI-PSD) were calculated for football players without diagnosed concussions during the season of observation (n = 87 player-seasons). Voxelwise linear regression analyses examined relationships between RWE-Lin with neocortical %ΔMD and %ΔfMRI-PSD. False discovery rate-corrected alpha thresholds of 0.0125 accounted for multiple comparisons and directionality within each test. While controlling for age, body mass index, days between scans, position group (skill vs. line), level (junior varsity vs. varsity), and concussion history, RWE-Lin was significantly positively correlated with %ΔMD (p = 1.12 × 10-5) and inversely correlated with %ΔfMRI-PSD in the frontal cortex (p = 7.36 × 10-4). Football players were stratified into high RWE-Lin (n = 13) and low RWE-Lin (n = 37) groups using the Jenks natural breaks algorithm. Noncollision athletes (NCAs, n = 11) served as external controls. When comparing imaging measures across the three groups, the high RWE-Lin football group showed significant differences from both NCA and low RWE-Lin football groups in frontal %ΔMD and %ΔfMRI-PSD (p < 0.05). No significant imaging differences were observed between NCA and low RWE-Lin football groups. Biomechanical modeling localized high-risk impact regions that have high spatial correspondence to the observed imaging abnormalities. Exploratory post hoc voxelwise analyses of magnetoencephalography spectral power detected no significant voxelwise associations with RWE-Lin. In the absence of diagnosed concussion, high-impact football players exhibit abnormal structural and neurovascular changes in the frontal cortex. These regions overlap with those identified to be at greatest risk from biomechanical modeling and those implicated in the pathogenesis of chronic traumatic encephalopathy. Importantly, these imaging abnormalities were not generally observed in football players with lower RWE-Lin. These findings suggest that limiting the number and severity of head impacts may be an effective strategy to mitigate subclinical brain injury in American football.
Neuromodulation has recently garnered attention as a potent approach to improve sensorimotor function following neural injury. After spinal cord injury, electrical stimulation targets sensorimotor circuitry to enhance volitional movement; however, motor neurons are located in the ventral gray matter. Previously, we developed a versatile wireless stimulation system and surgical approach to selectively activate motor neurons caudal to a cervical spinal cord injury. Here, we empirically tested if ventral epidural stimulation is sufficient to promote lasting recovery of skilled motor function. Ventrally stimulated animals exhibited significantly improved forelimb function associated with electrically stimulated motor pathways. Further, stimulation produced increases in neuronal Nr4a1 expression, a subacute reduction in microglia Nr4a1 expression, and a shift from activated toward ramified microglial morphologies in the stimulated ventral gray matter. This study reports the first successful application of ventral spinal stimulation to improve function in an animal model and the first sustained improvement in skilled forelimb reaching when behavioral testing was decoupled from the stimulation.
In the current study, we aimed to determine whether adults with a history of moderate-to-severe traumatic brain injury (TBI) carry a greater burden of modifiable dementia risk factors than demographically matched healthy controls. This was a cross-sectional observational study. Participants were recruited from a pre-existing database of individuals who had previously undergone inpatient rehabilitation at a private hospital in Melbourne, Australia. The study included 106 individuals with a history of moderate-to-severe TBI and 106 demographically matched healthy controls with no TBI history. Participants in the TBI group were at least 1-year post-injury. The groups were matched on age, sex, and years of education. Self-report measures were used to assess a range of modifiable dementia risk factors, including sensory (hearing), mental health (depressive symptoms), lifestyle (social engagement, physical activity, smoking, sleep quality), and cardiometabolic factors. A 14-item composite score was calculated to index the overall modifiable-risk burden. Compared to controls, the TBI group reported significantly poorer hearing, greater depressive symptoms, lower social engagement, higher lifetime smoking prevalence, and poorer sleep quality. However, vascular and metabolic health profiles were similar between groups. The overall composite risk score did not significantly differ between the TBI group and the control group. Individuals with a history of moderate-to-severe TBI demonstrate a distinct profile of modifiable dementia risks rather than a globally elevated risk burden. These findings suggest a need for targeted post-injury surveillance and interventions that focus on auditory health, mental well-being, social participation, smoking cessation, and sleep to help mitigate future dementia risk.
Traumatic brain injury (TBI) is a significant global health issue, causing cognitive, motor, and psychological impairments while increasing neurodegenerative disease risk. Essential oil extracted from Pelargonium graveolens (Pg), also known as geranium oil, is Food and Drug Administration (FDA)-approved and classified as generally recognized as safe for use in the food industry. Pg oil contains low molecular weight lipophilic compounds, which potentially traverse the blood-brain barrier and modulate brain functions. We have previously demonstrated that Pg oil exhibits anti-inflammatory and neuroprotective effects. Given the significant role of these processes in TBI pathophysiology and the absence of FDA-approved treatments, our goal in this study was to investigate the therapeutic potential of Pg oil in the closed-head injury (CHI) model for TBI. For this purpose, male C57BL/6JOlaHsd mice (8-9 weeks old, 20-25 g) underwent CHI using a modified weight-drop device and were treated orally with Pg oil for 2 weeks; 56 mice served as controls. Treatment group assignment was randomized based on neurological severity score (NSS) evaluation at 1-hour postinjury. Mice were monitored for 1 month following injury using a comprehensive behavioral battery administered in a blinded manner, then sacrificed for histopathological assessment. Pg was obtained from the Newe Ya'ar Research Center MAP Germplasm collection and prepared via steam distillation. The essential oil composition was characterized using gas chromatography-mass spectrometry (GC-MS). The therapeutic efficacy of Pg oil was demonstrated through multiple behavioral assessments, including the Barnes Maze, Y-maze, and novel object recognition test. Pg oil significantly enhanced cognitive performance in the injured mice, with effects persisting for at least 1-month post-injury. Histopathological evaluation revealed that Pg oil reduced axonal damage and increased neuronal survival in cortical and hippocampal regions. Additionally, Pg oil treatment significantly improved brain tissue preservation, as evidenced by reduced cortical and corpus callosum atrophy and decreased ventricle enlargement. The therapeutic benefits stemmed from anti-inflammatory and antioxidant activities, evidenced by reduced tumor necrosis factor-α, interleukin-1β, and lipid peroxidation levels, along with M2 phenotype immunomodulation, and elevated phosphorylated cyclic-AMP response element binding protein levels. The exclusive use of male mice in this study necessitates future investigation of Pg effects in female subjects. Our findings support the potential applications of Pg oil as a novel nutraceutical and a therapeutic candidate for TBI treatment and improvement of cognitive outcomes, warranting further translational research in TBI patients.
The acute management of traumatic spinal cord injury (SCI) continues to lack a universally accepted pharmacological intervention. We developed a novel therapeutic strategy, intrathecal administration of pharmaceutical recombinant human hepatocyte growth factor (KP-100), based on translational research using a non-human primate model of cervical SCI. A Phase I/II trial (multi-center, randomized, double-blind study including subjects with cervical SCI with modified Frankel grade A/B1/B2 at 72 h post-injury) demonstrated the safety and efficacy of intrathecal KP-100. A greater proportion of Frankel grade A subjects achieved ≥1 point improvement on their lower-extremity motor score (33.3% [KP-100] vs. 6.3% [placebo]). This study aimed to confirm these findings by including only subjects with the American Spinal Injury Association (ASIA) impairment scale (AIS) grade A. This open-label, non-randomized, single-group interventional Phase III study enrolled subjects with AIS grade A at 72 h post-injury. KP-100 was administered intrathecally immediately after enrollment. Subsequent doses were given once weekly, for a total of five administrations. Subjects were followed up for 168 days after the first administration. The primary end-point was the proportion of subjects who demonstrated improvement from AIS grade A at baseline to C or higher at day 168, compared with subjects with AIS grade A at 72 h post-injury in the General Spinal Cord Injury Center Data Bank in Japan (n = 81, the DB group). Additionally, we utilized data from modified Frankel grade A subjects in the PI/II study (n = 16, the PI/II Placebo group; n = 15, the PI/II KP-100 group) for post hoc analyses of therapeutic effects. Of the 31 pre-registered participants, 6 were excluded due to ineligibility, and 25 were included in the efficacy analysis (the PIII group). The primary end-point was not achieved (8.6% [DB, 95% confidence interval [CI]: 4.2-16.8] vs. 12.0% [PIII, 95% CI 4.2-30.0]). However, in post hoc exploratory comparisons, the PIII group tended to have greater proportion of subjects who improved to AIS grade B or higher (56.0% [37.1-73.3]) than the DB group (19.8% [12.5-29.7]). Whereas SCIs without fracture at the C3/4 level were more common in the PI/II KP-100 group, the PIII group tended to have more SCIs with fractures or dislocations and below C3/4. Accordingly, in exploratory comparisons, the proportion of subjects who improved to modified Frankel grade C1 or higher tended to be highest in the PI/II KP-100 group (6.3% in the PI/II Placebo, 26.7% in the PI/II KP-100, 12.0% in the PIII group). Conversely, ≥5 points of improvement on the upper-extremity motor score tended to be most frequent in the PIII group (31.3% in the PI/II Placebo, 20.0% in the PI/II KP-100, 56.0% in the PIII group). These results showed exploratory signals of neurological recovery in this highly impaired population, providing supportive evidence for potential biological activity of KP-100.
Performance of currently available prognostic models for predicting incomplete functional recovery following mild traumatic brain injury (mTBI) is only modest. Blood-based biomarkers may improve model performance. In this study we aimed to assess the incremental discriminative value of promising biomarkers reflecting activation of relevant pathophysiological processes (mechanistic markers), interleukin (IL) -6, -8, and -10 (inflammation), free thiols (FTs, oxidative stress), and tryptophan (Trp; kynurenine pathway [KP]), to prognostic models containing pertinent clinical predictors. Established mTBI biomarkers, glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light were also included to compare prognostic performance with the less well characterized mechanistic markers. In a prospective longitudinal cohort study (Acute Injury Markers for mild traumatic brain injury), 257 patients with mTBI were recruited. Blood was sampled within 24 h of injury at the emergency department (ED) and again 4-6 weeks later. All participants underwent acute head CT scans. Two models were used as reference models: (1) ED model, including only predictors obtained at the ED, and (2) ED+ model, including additional predictors obtained through symptom questionnaires 2 weeks after injury. The primary outcome was the Glasgow Outcome Scale Extended (GOS-E) at 6 months. The incremental prognostic value of biomarkers, relative to the ED or ED+ model, was assessed via optimism-corrected differences (Δ) in the area under the receiver operating curve (AUC) and Nagelkerke's R2. Outcome data was available for 208 patients, with 49% having incomplete recovery (GOS-E < 8). Plasma IL-6 was the only individual biomarker to improve ED model performance (ΔAUC 0.039 (95% confidence interval, 0.017, 0.057), and ΔR2 4.3% (1.2%, 6.7%), albeit modestly. UCH-L1 was the best-performing established marker (ΔAUC 0.005 [-0.008, 0.027] and ΔR2 0.1% [-3.8%, 2.1%]). Combining IL-6 with plasma Trp resulted in the largest ED model improvement (ΔAUC 0.041 [0.021, 0.065], ΔR2 4.2% [0.0%, 8.1%]). While individual biomarkers provided negligible improvement to the ED+ model, the combination of IL-6, Trp, and plasma FTs resulted in improved performance of the ED+ model (ΔAUC 0.034 [0.012, 0.055] and ΔR2 5.4% [-8.2%, 12.4%]). Blood-based mechanistic markers marginally improve performance of prognostic models for incomplete functional recovery following mTBI. The findings of this study highlight the need for further assessment of mechanistic markers, and especially IL-6, in the context of mTBI prognosis.
Immune dysregulation is a central component of secondary injury processes following spinal cord injury (SCI). Cell adhesion molecules (CAMs) play key roles in leukocyte-endothelium interactions and neuroimmune communication after neurotrauma; however, their potential as clinically accessible peripheral blood biomarkers reflecting immune alterations after SCI remains insufficiently defined. Transcriptomic datasets derived from peripheral blood of individuals with SCI and healthy controls (GSE151371 and GSE226238) were analyzed to identify CAM-related genes associated with post-injury immune dysregulation. Integrated differential expression analysis, weighted gene co-expression network analysis, and least absolute shrinkage and selection operator regression were applied for feature selection. Discriminative performance was evaluated using receiver operating characteristic analysis. Functional enrichment and immune cell deconvolution analyses were conducted to characterize immune associations. Key findings were validated in an independent transcriptomic cohort and further confirmed by quantitative RT-PCR using serum samples from individuals with SCI. Integrative bioinformatics analyses identified 99 CAM-associated candidate genes, which were further refined to six feature genes. Among these, SBK 1, ADGRG 5, and TCF 7 were consistently downregulated in SCI across independent datasets. SBK 1 and ADGRG 5 demonstrated good discriminative performance, with area under the curve values of 0.85 and 0.83, respectively. Immune deconvolution revealed significant alterations in peripheral immune cell composition, including resting natural killer (NK) cells and naïve CD4 + T cells. Expression levels of SBK 1 and ADGRG 5 positively correlated with these immune cell populations. Serum-based RT-quantitative real-time PCR validation confirmed significant downregulation of SBK 1 and ADGRG 5 in SCI individuals compared with healthy controls. SBK 1 and ADGRG 5 were identified as CAM-related genes that were downregulated in peripheral blood after SCI and associated with distinct alterations in peripheral immune cell profiles, particularly involving CD4 + T cells and resting NK cells. These findings suggest that SBK 1 and ADGRG 5 may serve as accessible peripheral transcriptional biomarkers associated with post-SCI neuro-immune dysregulation and may support immune monitoring and patient stratification following SCI.
Post-traumatic amnesia (PTA), recently conceptualized as part of the broader syndrome known as post-traumatic confusional state (PTCS), marks a critical phase of recovery following traumatic brain injury (TBI). Indeed, this state is characterized not only by anterograde memory impairment but also by disorientation, agitation, and attention deficits. Given the phenotypic overlap between PTA/PTCS and delirium—both marked by fluctuating cognitive and attentional disturbances—electroencephalography (EEG) represents a promising tool for elucidating shared pathophysiological mechanisms. While delirium is typically associated with diffuse EEG slowing and the presence of slow-wave activity (SWA), thought to reflect underlying global cortical disruption, it remains unclear whether PTCS exhibits similar EEG underpinnings. In this prospective longitudinal study, we assessed dynamic EEG correlates of PTCS using the grand total EEG (GTE) score, a composite measure that incorporates background slowing and superimposed SWA. We enrolled 42 consecutive TBI patients (mean age = 40.3 ±15 years) classifying them at baseline (T0) into two groups based on the Confusion Assessment Protocol (CAP): those in PTA/PTCS ( N = 22; median time from injury 24 days; median CAP total score 5) and those already emerged from PTA/PTCS (i.e., TBI controls, N = 20; median time from injury 24 days; median CAP total score 0). At T0, patients with PTA/PTCS exhibited significantly higher baseline GTE scores compared with TBI controls, 16.6 ± 4.5 versus 5.1 ± 2.8; t (35.75) = 10.04, p < 0.0001; d = 3.04, reflecting severe EEG abnormalities characterized by diffuse slowing and disrupted rhythmic activity, as captured by the GTE subdomains. Longitudinal follow-up (T1) at emergence from PTCS revealed a significant EEG improvement paralleling clinical recovery, with GTE scores dropping from 16.5 (interquartile range [IQR]: 6.5) to 8, IQR: 3.75; t (21) = 8.03, p < 0.0001; d = 1.71, confirming EEG’s sensitivity to dynamic clinical changes. Furthermore, the severity of EEG abnormalities at follow-up (T1) significantly correlated with the total duration of PTA/PTCS (ρ = 0.56, p < 0.0001), underscoring EEG’s potential as an objective biomarker for disease burden and for monitoring recovery trajectories. Notably, these findings were independent of pharmacological confounders, as medication regimens were not significantly different across groups and time points. Our results support a reconceptualization of PTA/PTCS as a functional (i.e., non-structural) encephalopathy that shares key clinical and neurophysiological features with delirium, with EEG slowing reflecting widespread, often reversible cortical dysfunction. By capturing these transient yet clinically critical changes, clinical EEG—quantified via the granular, multifaceted GTE—offers a novel tool for diagnosing PTA/PTCS, stratifying its severity, and objectively monitoring its evolution in intensive care unit and subacute rehabilitation settings.
Traumatic brain injury (TBI) increases the risk for infection, and urinary tract infection (UTI) is commonly reported in patient populations that require additional medical intervention. UTIs are one of the most prevalent bacterial infections worldwide, reflecting a significant public health threat that disproportionately affects females. UTIs are most often caused by uropathogenic Escherichia coli (UPEC) and can cause delirium-like symptoms in vulnerable patients, but the specific neuroimmune and cognitive effects of post-injury UTI remain underexplored. To address this gap in knowledge, we present a unique combination of pre-clinical models of TBI and UTI to define the biological effects of bladder infection after brain injury. We hypothesize that UTI after TBI worsens the long-term outcome of brain injury. Female mice received either a sham injury or lateral fluid percussion TBI, and 3 days post-injury (DPI), mice were inoculated transurethrally with vehicle or UPEC to recapitulate a post-injury infection. Y-maze and open-field behavioral tests were administered 6 DPI and 8 DPI, respectively. Brains and blood were collected for flow cytometry and enzyme-linked immunosorbent assay from a subset of mice 6 DPI. Brains and urinary bladders were collected for immunohistochemistry from the remaining mice 10 DPI. TBI mice displayed spatial memory deficits, which were exacerbated following UTI; however, no differences in exploratory behavior were observed after TBI or UTI. TBI significantly elevated plasma interleukin-6, but strikingly, UTI following TBI dampened this response 6 DPI. Flow cytometry revealed no significant differences in circulating immune cells 6 DPI but confirmed that TBI elevated microglial reactivity and monocyte infiltration to the brain, independent of infection. TBI and UTI differentially modulated Glial Fibrillary Acidic Protein (GFAP) and Ionized Calcium-binding Adapter Molecule 1 (Iba1) expression in the hippocampus and cortex, reflecting additive and interaction-based effects. UTI after TBI elevated microglia CD68 expression in a brain region-specific manner further demonstrating that post-injury infection alters the neuroimmune landscape. Together, these data offer novel insight into the effects of UTI after TBI, showing that UTI after TBI is detrimental to overall outcome and warrant further investigation into the signaling mechanisms between bladder infection and neuroinflammation.
It is becoming increasingly recognized that high-level spinal cord injury (SCI) is associated with altered heart structure and function, as well as a significantly elevated risk for heart disease. Despite this knowledge, we know remarkably little about the temporal molecular changes that occur in the heart following SCI and how these relate to functional decline. In the present study, we addressed this shortcoming by combining bulk RNA sequencing (RNA-seq) of left ventricle (LV) tissue with matching in vivo cardiac function assessments (i.e., pressure-volume loops obtained via LV catheterization) from the same animals. We studied rats at either the acute (1 and 3d post-SCI) or chronic (12wk post-SCI) stage of SCI to establish temporal patterns and compared findings to sham-injured rats. We found that SCI induces marked, time-dependent changes in cardiac gene expression and function. Acute (1-3d) and chronic (12w) SCI display distinct, often opposing transcriptomic signatures, with thousands of genes differentially expressed versus SHAM. Acute SCI is characterized by suppressed immune, inflammatory, cell cycle, and stress-response pathways with altered metabolism. Chronic SCI shows upregulated immune signaling, impaired oxidative phosphorylation, extracellular matrix remodeling, and stress responses. Functionally, cardiac systolic dysfunction occurs early post-SCI and persists to the chronic phase. Reduced systolic function is strongly correlated with changes in immune, hypoxia, and cholesterol-related genes at the acute timepoints and with immune and hormone-signaling pathways at the chronic timepoint. Collectively, our data provide novel insight into the cardiac transcriptome post-SCI and identify the molecular pathways that most strongly correlate with functional decline.
Falls are the primary cause of mild traumatic brain injury (mTBI) among older adults, yet limited research has examined patterns of clinical care, mobility, and subsequent fall risk in this population. The objective of this study was to evaluate outpatient physical or occupational therapy (PT/OT) referral patterns and assess physical function and fall risk status of older adults with mTBI. We analyzed acute care and 2-week post-mTBI assessment data from a prospective cohort study of adults aged 65 and older with mTBI treated at a level 1 trauma center and six affiliated hospitals 2023-2025 and meeting eligibility criteria. Of 625 that were confirmed eligible, 155 consented to participate in the study. Of these, five were missing the 2-week assessment and nine were missing PT/OT referral information, leaving 141 in the current study. The exposure of interest was referral to PT/OT at discharge, obtained from medical records. Two-week post-mTBI assessments included the Short Physical Performance Battery (SPPB) and the Four-Square Step Test (FSST). Statistical comparisons between exposure groups were made using Fisher's exact test, Student's t-test or the Wilcoxon rank-sum test. Participants (n = 141) were on average 76.1 (standard deviation 7.3) years old and 56.0% female. Falls were the primary cause of mTBI (89%). At the 2-week assessment, participants demonstrated poor physical performance: 53% had impaired SPPB (<10), 62% had impaired FSST (>15 sec), and 65% had slow gait speeds (<0.80 m/s), all indicative of elevated fall risk. Only 34 (24%) were referred to PT/OT at discharge. Those referred were more likely to have received an inpatient PT/OT consultation (97% vs. 22%, p < 0.001). Among participants not referred to PT/OT, 46% had impaired SPPB, 58% had impaired FSST, and 60% had slow gait speed, indicating high fall risk. Less than a quarter of older adults with primarily fall-related mTBI received any discharge PT/OT referral despite clear mobility and balance deficits. This critical gap in post-discharge rehabilitation underscores a disconnect between fall-prevention guidelines and clinical practice, leaving many older adults at high risk of recurrent falls and injuries.
