Traumatic spinal cord injury (tSCI) causes immediate mechanical damage followed by a secondary cascade of excitotoxic, oxidative, metabolic, and inflammatory events that expands tissue loss. Connexin (Cx) and pannexin (Panx) channels are increasingly recognized as potential amplifiers of this secondary injury. This focused review summarizes the structural and biophysical properties of these channels that are relevant to the injured spinal cord, their cellular localization, and the experimental evidence linking Cx43 and Panx1 activity to ATP release, calcium dysregulation, neuroinflammation, tissue loss, neuropathic pain, and functional recovery after tSCI. We also review genetic and pharmacologic studies of channel inhibition and discuss the limited but emerging evidence for Cx-mediated signaling in paralyzed skeletal muscle. Evidence is strongest for astrocytic Cx43 hemichannels, whereas the contribution of Panx1 after tSCI remains promising but less completely defined. Throughout, we distinguish findings demonstrated directly after tSCI from mechanisms inferred from other tissues or disease models and identify priorities for translational research.

Following traumatic brain injury (TBI), changes in proteins, metabolites, and gene expression are highly dynamic and are influenced by genetic and environmental factors, circadian rhythms, and injury characteristics, including injury type (focal or diffuse), severity (mild to severe), and stage of recovery (acute, subacute, and chronic). These molecular alterations are accompanied by epigenetic modifications that regulate gene expression and contribute to injury progression and recovery. In this review, we integrate and summarize preclinical and clinical studies examining DNA methylation, histone methylation and acetylation, microRNA (miRNA)-mediated regulation, RNA epigenetic modifications, and mitochondrial epigenetic (mitoepigenetic) changes following TBI. Most studies have focused on DNA methylation, histone modifications, and miRNAs in experimental models, providing important insights into cell type-specific epigenetic responses after injury. We also review studies evaluating therapeutic strategies, including DNA methyltransferase and histone deacetylase inhibitors, that target epigenetic mechanisms to improve TBI outcomes.

Circulating biomarkers of brain perturbation are rarely evaluated against anatomically localized in vivo imaging measures, limiting biological interpretation. We tested whether perioperative changes in candidate biomarkers were associated with diffusion tensor imaging (DTI)-defined microstructural changes in a controlled human perioperative model. In a paired cohort of 75 patients undergoing left-sided encephaloduroarteriosynangiosis, we obtained matched pre- and postoperative DTI and blood samples. Six biomarkers (ubiquitin C-terminal hydrolase-L1 [UCH-L1], glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B [S100B], neurofilament light chain, neuron-specific enolase, and protein tau) were quantified. Analyses included paired comparisons, region-of-interest-based cross-modal correlations, sparse canonical correlation analysis (sCCA) with bootstrap stability assessment, and patient-grouped regularized logistic regression for state discrimination. DTI showed perioperative changes in bilateral temporal-limbic regions and connected white matter, with the largest effects in left hippocampal and amygdalar territories on the operated side. UCH-L1, GFAP, and S100B showed the clearest paired increases and dominated internal perioperative-state discrimination. Blood-DTI associations were heterogeneous across biomarkers and states, and paired-change associations were not confined to these three markers. An observed three-biomarker panel discriminated perioperative state with an area under the receiver operating characteristic curve of 0.914 in the test set. Several circulating biomarkers covaried with regional DTI measures in this exploratory perioperative cohort. UCH-L1, GFAP, and S100B were the most perioperatively responsive and state-discriminative markers, but the DTI-association pattern was not specific to this trio. The findings support a structure-associated framework for evaluating blood biomarkers against regional imaging changes; they do not validate these biomarkers for traumatic brain injury, and relevance to traumatic brain injury (TBI) remains hypothesis-generating.

There are currently no available effective pharmacological therapies for treating chronic cognitive deficits after traumatic brain injury (TBI). Psychoplastogens, including atypical psychedelics, classical serotonergic psychedelics, and neuroplastogens, are a class of small molecule drugs that can enhance neuroplasticity by inducing rapid and sustained effects on neuronal architecture and function, with the potential to have broad therapeutic effects. Ketamine, psilocybin, and dimethyltryptamine (DMT) have demonstrated therapeutic efficacy for treating multiple psychiatric conditions, and their ability to enhance neuroplasticity is hypothesized to be the primary mechanism. However, the administration of psychoplastogens for the treatment of cognitive impairments in TBI and other neurodegenerative diseases is nascent. In this review, we discuss the following: (1) relevant TBI pathologies and how neuroplasticity is impaired following TBI, (2) psychoplastogens and their use in neural repair models, and (3) the potential of psychoplastogens as treatments for TBI to alleviate various pathologies and improve cognitive behavioral outcomes. The underlying pathologies observed after TBI, including impaired neuroplasticity, synaptic dysfunction, neuronal atrophy, altered neurotransmission, and cellular dysfunction, are shared with several psychiatric disorders. Based on the multiple pathophysiological targets, there is a critical unmet need to investigate psychoplastogens as therapeutic interventions during the chronic phase of TBI for cognitive outcomes and underlying impact on neuroplasticity.

Caregivers of individuals admitted to inpatient rehabilitation following traumatic brain injury (TBI) often experience high burden and unmet needs after hospital discharge. Transitional periods are challenging, and standard discharge planning with referrals to outpatient care is typically not enough support for this critical phase. We sought to evaluate the impact of a post-inpatient rehabilitation patient/caregiver intervention (rehabilitation transition planning; RTP) on caregiver burden and quality of life, compared to standard rehabilitation discharge planning (RDP). Of 925 randomized patient participants at six inpatient rehabilitation centers, 591 had caregivers who enrolled in the study. Patients and caregivers in the RTP group (N = 295) received up to 12 remote follow-up support contacts for 6 months post-discharge. The RDP control group (n = 296) received standard discharge planning. Caregiver outcomes (Bakas, Zarit, PROMIS, SF-12 Physical/Mental) were assessed at 6 and 12 months. Data analysis used intention-to-treat principles. No significant differences were observed in any caregiver outcome measures at 6 or 12 months between RTP and RDP groups. In exploratory analyses, greater functional impairment, need for assistance, and a history of prior mental health problems on the part of the patient were associated with greater burden and reduced quality of life for caregivers irrespective of treatment assignment. Female caregivers, White caregivers, and those with greater education tended to show greater burden on some measures. No patient or caregiver attributes were consistently associated with a differential response to the intervention. Future research should explore alternative or more targeted interventions for this vulnerable population using both intervention-sensitive and global measures of outcome.

Spinal cord injury (SCI) initiates a complex secondary injury cascade characterized by neuroinflammation, astrocyte reactivity, neuronal loss, and glial scar formation, all of which influence endogenous repair and functional recovery. Emerging evidence identifies microRNAs (miRNAs) as post-transcriptional regulators of these processes, yet their integrated role in astrocyte-associated pathology and their translational relevance remain incompletely defined. Experimental studies indicate that miRNAs can modulate conserved signaling pathways, including NF-κB, MAPK, PI3K/AKT/mTOR, and JAK/STAT, with reported effects on astrocyte reactivity, inflammatory responses, neuronal survival, axonal regeneration, and blood-spinal cord barrier (BSCB) integrity. Additionally, miRNAs have been implicated in epigenetic regulation and mitochondrial function, which may influence glial proliferation and scar formation. In parallel, human studies of acute SCI demonstrate dynamic, severity-associated changes in circulating and cerebrospinal fluid miRNA profiles. Some of these human miRNA signatures overlap with inflammatory, apoptotic, and metabolic pathways identified in experimental models, although the biological sources and functional significance of these circulating signals remain incompletely defined. Human data remain largely descriptive and have not yet been fully integrated with mechanistic insights from preclinical astrocyte-focused studies. This review consolidates preclinical and human evidence to define a pathway-level framework in which miRNAs may contribute to astrocyte-associated pathology, glial scar dynamics, and neurorepair after SCI. By relating experimentally defined miRNA mechanisms to human biofluid signatures, miRNA networks represent potential translational targets for biomarker development and future therapeutic investigation. This framework provides a rationale for further evaluation of miRNA-based strategies in traumatic SCI, with potential future relevance to SCI occurring in the setting of spinal surgery.

The hospital-to-home transition is a heightened period of psychological vulnerability after acquired brain injury (ABI) and spinal cord injury (SCI), during which individuals draw on internal resources such as resilience to cope. However, the stability of resilience during the first 12 months post-discharge is largely unknown. This study aimed to examine trajectories of resilience and depressive symptoms and associations with levels of hope during the first 12 months post-discharge after ABI and SCI. Individuals with ABI and SCI were recruited between June 2023 and July 2024 from specialist inpatient rehabilitation units and were administered measures of resilience, depressive symptoms, and hope at discharge and at 3 and 12 months post-discharge. In total, 125 individuals with ABI (n = 70) and SCI (n = 55) were recruited at discharge, with longitudinal data available for 107 of these participants. Latent Class Growth Mixture Modeling identified four trajectories of resilience over 12 months post-discharge, including two stable (high-stable n = 27; moderate-stable n = 67) and two changing (stable-decreasing n = 6; decreasing-stable n = 7). Four depression trajectories were also identified, including low-stable (n = 70), moderate-fluctuating (n = 25), decreasing-increasing (n = 7), and increasing-stable (n = 5). In terms of group membership across trajectories, individuals with high-stable resilience typically had low-stable depression (85%), whereas other resilience trajectories had more variable membership across depression trajectories. Levels of hope were significantly higher and more stable for the high-stable resilience trajectory than for other resilience trajectories. However, levels of hope significantly decreased for the low-stable depression trajectory. Overall, patterns of resilience post-discharge after SCI and ABI were related to, but distinct from, depressive symptoms and hope. While resilience was largely stable over time, depressive symptoms increased for nearly one-third of individuals, and hope often decreased in the context of stable levels of resilience and depression, thus informing priorities for clinical management.

Concern is growing that subconcussive blast exposure during military exercises such as heavy weapons training (HWT) may adversely affect brain function. HWT involves firing shoulder-mounted weapons that can expose the gunner, assistant gunner, and instructors (range safety officers [RSOs]) to blast overpressure >4.0 psi. Every HWT participant sustains repeated blast exposure: gunner and assistant alternate firing within an event, and instructors supervise multiple firings at approximately 12 HWTs over two years. This five-year study was designed to quantify blast exposure and serially assess a broad array of brain function measures in HWT participants and corresponding controls. Two hundred and twenty-four participants were prospectively assessed: 104 exposed special operators (SOs) firing live rounds in HWT; 47 SOs completing land warfare training without firing live rounds during HWT (training controls); 36 conventional active duty controls (ADCs); and 37 instructors. Assessments were conducted at baseline and at 30 min, 6, 24, and 72 h, 2 weeks, and 3 months post-HWT. Instructors were also assessed 9 and 18 months after their first HWT, with repeat of all acute assessments (30 min through 3 months) after their 18-month HWT. Blast exposure was measured with the Black Box Biometrics Generation 7 Blast Gauge System. Assessments included blood biomarkers, symptom scales, memory, cerebrovascular reactivity, electroencephalography (EEG), oculomotor function, gait, tactile discrimination, and hearing acuity. SOs exhibited significant alterations in short-term memory, complexity of electroencephalographic signals, and the blood biomarkers tau and ubiquitin C-terminal hydrolase L1 within minutes after HWT, while gait and oculomotor function were measurably altered within hours. More than 20% of the exposed had at least one significant change in a hearing threshold on audiologic assessment, though this, as well as changes in levels of the blood biomarker neurofilament-light, were observed two weeks after HWT. Instructors who experienced repeated HWT exposure over two-year duty tours demonstrated greater magnitude and duration alterations in memory and gait toward the end of those tours. The blood biomarker glial fibrillary acidic protein, vasomotor reactivity of the middle cerebral arteries, and seven cognitive tests comprising the Automated Neuropsychological Assessment Metrics Version 4 showed no significant changes in association with subconcussive blast exposure in this setting. Blast exposure during HWT is associated with acute changes in some blood biomarker levels and measures of brain function such as short term recall memory and gait. The effects appear to be short in duration, but recovery may be delayed after repeated exposure.

Mild traumatic brain injury (mTBI) accounts for around 80-90% of TBI cases, is increasing in incidence, and represents a major public health concern. Despite its high incidence, mTBI lacks reliable molecular biomarkers for diagnosis or prognosis. Metabolomics, the profiling of small-molecule metabolites (≤1 kDa), has emerged as a promising approach to characterize acute neurometabolic perturbations in mTBI and identify candidate biomarkers. However, metabolomic changes in mTBI have not yet been comprehensively characterized. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines, we conducted a scoping review of studies from 2010 to 2025 on acute-phase (24-72 h post-injury) serum/plasma metabolomics in adult mTBI (Glasgow Coma Scale 13-15). Systematic searches of PubMed, Scopus, and Embase identified 11 eligible studies. Seven metabolites were consistently reported as altered in ≥2 studies: glucose and the ketone body 3-hydroxybutyrate were elevated in mTBI, whereas five amino acids (valine, isoleucine, glycine, methionine, and tryptophan) were decreased. Pathway analysis revealed branched-chain amino acid biosynthesis as the most enriched pathway, while one-carbon folate-mediated metabolism and energy metabolism were also implicated. Preliminary evidence indicates that acute mTBI also perturbs lipid metabolism, with increases in phospholipid breakdown products and sphingomyelins, reflecting membrane disruption and altered energy utilization. This metabolic signature aligns with known acute mTBI pathophysiology, including hypermetabolism, excitotoxicity, and neuroinflammation, and may reflect compensatory responses to increased energy demand and oxidative stress. These changes show promise as candidate biomarkers and therapeutic targets but require validation in larger cohorts to establish their utility in mTBI diagnosis, prognosis, and management.

In traumatic brain injury (TBI) patients, therapeutic drug monitoring of midazolam and its metabolites can help to assess residual sedation. Based on previous literature in non-TBI patients, it is assumed that concentrations of <100 ug/L of midazolam are non-sedative. The objective of this study was to assess the threshold sum concentration of midazolam and metabolites for residual sedation after cessation of midazolam infusion in critically ill TBI patients. We performed a retrospective study at the adult ICU of Erasmus University Medical Center between 07-2017 and 03-2024. TBI patients were included for analysis if sequential Glasgow Coma Scale (GCS) scores and at least one midazolam plasma concentration <100 ug/L was available. Residual sedation was evaluated based on improvement in the sum of the Eye and Motor scores from the GCS according to a decision rule. Among 51 patients, 75% (n = 38) had residual sedation. Median sum midazolam concentrations in the residual sedation versus no residual sedation group were 14 ug/L (3-32) and 7 ug/L (3-31), respectively. In the patients with residual sedation an improved EM score of 3 (2-5) was observed within 3 days (2-4) and 22 patients (58%) scored M6 within 4 (2-5) days. Finally, in the residual sedation and no residual sedation group we observed in hospital mortality rates of 5% and 46%, respectively. In TBI patients the threshold concentration for a residual sedative effect of midazolam appears to be much lower than previously described in non-TBI populations. Therefore, clinicians should be reluctant to make withdrawal or limitation of care decisions too early based on low GCS in TBI patients, even in the presence of very low plasma concentrations of midazolam and metabolites.