Systemic gene expression profiles according to pain types in individuals with chronic spinal cord injury.

Pain affects most individuals with traumatic spinal cord injury (SCI). Major pain types after SCI are neuropathic or nociceptive, often experienced concurrently. Pain after SCI may be refractory to treatments and negatively affects quality of life. Previously, we analyzed whole blood gene expression in individuals with chronic SCI compared to able-bodied (AB) individuals. Most participants with SCI reported pain (N = 19/28). Here, we examined gene expression of participants with SCI by pain status. Compared to AB, participants with SCI with pain had 468 differentially expressed (DE) genes; participants without pain had 564 DE genes (FDR < 0.05). Among DE genes distinct to participants with SCI with pain, Gene Ontology Biological Process (GOBP) analysis showed upregulated genes were enriched in categories related to T cell activation or inflammation; downregulated genes were enriched in categories related to protein proteolysis and catabolism. Although most participants with pain reported multiple pain types concurrently, we performed a preliminary comparison of gene expression by worst pain problem type. Compared to AB, participants with SCI who ranked neuropathic (N = 9) as worst had one distinct DE gene (TMEM156); participants who ranked nociceptive (N = 10) as worst had 61 distinct DE genes (FDR < 0.05). In the nociceptive group, the GOBP category with the lowest P-value identified among upregulated genes was "positive regulation of T cell activation"; among downregulated genes it was "receptor tyrosine kinase binding". An exploratory comparison of pain groups by principal components analysis also showed that the nociceptive group was enriched in T-cell related genes. A correlation analysis identified genes significantly correlated with pain intensity in the neuropathic or nociceptive groups (N = 145, 65, respectively, Pearson's correlation r > 0.8). While this pilot study highlights challenges of identifying gene expression profiles that correlate with specific types of pain in individuals with SCI, it suggests that T-cell signaling should be further investigated in this context.

Riding the wave into wellbeing: A qualitative evaluation of surf therapy for individuals living with acquired brain injury.

Nature has long demonstrated the capacity to facilitate wellbeing. Interventions involving the natural environment such as surf therapy, are increasingly being used to facilitate aspects of wellbeing in clinical populations. However, explorations of how nature-based interventions such as surf therapy may be used to promote wellbeing in the context of neurorehabilitation are missing from the peer-reviewed literature. Here we characterize the experience of a five-week surfing intervention involving fifteen adults living with the psycho-social and cognitive sequelae of acquired brain injury. Insights were analysed using reflexive thematic analysis, which highlighted the importance of seven overarching themes, including: 1) Connection to Nature, 2) Facilitating Trust and Safety, 3) Managing and Accepting Difficult Emotions, 4) Facilitating Positive Emotion, Meaning and Purpose, 5) Building Community through Social Connection, and 6) Positive Change. Barriers and opportunities (theme 7) were also identified as components on which clinical services may be improved. We present a theoretical model for the benefits of surf therapy in people living with acquired brain injury (ABI) based on these themes and reflections on findings from the wider literature. Findings emphasise the importance of leveraging community partnerships to augment the holistic model of neurorehabilitation and potential implications for service redesign are discussed, focusing on recent developments in wellbeing science.

Elevated levels of IgA and IgG2 in individuals with chronic spinal cord injury.

OBJECTIVES: To determine circulating levels of antibodies (IgA, IgM, IgG1-4) in individuals with SCI as compared to uninjured individuals. STUDY DESIGN: Prospective, observational study. SETTING: Outpatient clinic of a Department of Physical Medicine and Rehabilitation and research institute in an academic medical center. PARTICIPANTS: Individuals with chronic (≥ 1 year from injury) SCI and uninjured individuals. OUTCOME MEASURES: Serum antibody titers were determined by commercial multiplex ELISA. RESULTS: Blood samples were collected from individuals with chronic SCI (N = 29, 83% males) and uninjured individuals (N = 25, 64% males). Among participants with SCI, the distribution of American Spinal Injury Association Impairment Scale (AIS) grades was: A (n = 15), B (n = 2), C (n = 4), D (n = 8). Neurological levels of injury were: cervical (n = 17), thoracic (n = 10), and lumbar (n = 2). IgA levels were significantly elevated in participants with SCI compared to uninjured participants (median: 1.98 vs. 1.21 mg/ml, P < 0.0001), with levels most elevated in individuals with motor complete injuries compared to uninjured participants (P < 0.0003). IgG2 antibodies were also significantly elevated in participants with SCI compared to uninjured participants (median: 5.98 vs. 4.37 mg/ml, P < 0.018). CONCLUSIONS: To our knowledge, this study provides the first evidence of elevated IgA, the antibody type most prevalent at respiratory, genitourinary and gastrointestinal tracts, common sites of infections in individuals with SCI. IgG2 levels were also elevated in individuals with SCI. These data support further investigations of IgA and other antibody types in individuals with chronic SCI, which may be increasingly important in the context of emerging novel infectious diseases such as SARS-CoV-2.

Assessment of pain symptoms and quality of life using the International Spinal Cord Injury Data Sets in persons with chronic spinal cord injury.

Introduction: Traumatic spinal cord injury (SCI) triggers complex changes that can negatively impact health and quality of life. The International SCI Data Sets were developed to enable more comparable data collection on the complex sequelae of SCI across studies. This should facilitate progress in mechanistic understanding and improving treatments of SCI. Study design: Prospective observational pilot study. Objectives: To collect data on pain symptoms and quality of life (QoL) in adults living with chronic SCI. Setting: Academic medical center, New York, USA. Methods: The International SCI Basic Pain and Qol Data Sets were used to collect data from participants with chronic SCI (N = 31) at 2 study visits held 6 months apart. The QoL Data Set was also used to collect data from able-bodied persons of similar age and gender distribution (N = 28). Results: Most participants with SCI had multiple types and locations of pain problems at both study visits, despite reported being treated for pain. At both visits, the worst pain problem type was nociceptive, followed by neuropathic, which was typically rated of higher intensity. QoL scores were significantly lower across all domains of the data set in persons with SCI than able-bodied persons. Persons with pain tended to have lower QoL scores, although this trend was not significant. Conclusions: This study demonstrates the presence, complexity and stability of pain symptoms refractory to treatment and lower quality of life ratings in persons with chronic SCI. Sponsorship: Grants from the Craig H. Neilsen Foundation, New York Empire Clinical Research Program, New York State Spinal Cord Injury Research Board.

Persons with Chronic Spinal Cord Injury Have Decreased Natural Killer Cell and Increased Toll-Like Receptor/Inflammatory Gene Expression.

Infections are the leading cause of death for individuals with traumatic spinal cord injury (SCI). Along with increased infection rates, inflammation is often also observed in persons with chronic SCI. Together, immunological changes post-SCI are also poised to impede neurological recovery and mediate common medical consequences of SCI, including atherogenesis and neuropathic pain. The molecular mechanisms contributing to increased infection susceptibility and inflammation in persons living with SCI are poorly understood. Here, we used tools of functional genomics to perform a pilot study to compare whole-blood gene expression in individuals with chronic SCI (≥1 year from initial injury; N = 31) and uninjured individuals (N = 26). We identified 1815 differentially expressed genes in all SCI participants and 2226 differentially expressed genes in persons with SCI rostral to thoracic level 5, compared to uninjured participants. This included marked downregulation of natural killer cell genes and upregulation of the proinflammatory Toll-like receptor signaling pathway. These data provide novel mechanistic insights into the causes underlying the symptoms of immune dysfunction in individuals living with SCI.

Age and Other Risk Factors Influencing Long-Term Mortality in Patients With Traumatic Cervical Spine Fracture.

OBJECTIVE: To identify clinical or demographic variables that influence long-term mortality, as well as in-hospital mortality, with a particular focus on the effects of age. SUMMARY AND BACKGROUND DATA: Cervical spine fractures with or without spinal cord injury (SCI) disproportionately impact the elderly who constitute an increasing percentage of the US population. METHODS: We analyzed data collected for 10 years at a state-designated level I trauma center to identify variables that influenced in-hospital and long-term mortality among elderly patients with traumatic cervical spine fracture with or without SCI. Acute in-hospital mortality was determined from hospital records and long-term mortality within the study period (2003-2013) was determined from the National Death Index. Univariate and multivariate regression analyses were used to identify factors influencing survival. RESULTS: Data from patients (N = 632) with cervical spine fractures were analyzed, the majority (66%) of whom were geriatric (older than age 64). Most patients (62%) had a mild/moderate injury severity score (ISS; median, interquartile range: 6, 5). Patients with SCI had significantly longer lengths of stay (14.1 days), days on a ventilator (3.5 days), and higher ISS (14.9) than patients without SCI (P < .0001 for all). Falls were the leading mechanism of injury for patients older than age 64. Univariate analysis identified that long-term survival decreased significantly for all patients older than age 65 (hazard ratio [HR]: 1.07; P < .0001). Multivariate analysis demonstrated age (HR: 1.08; P < .0001), gender (HR: 1.60; P < .0007), and SCI status (HR: 1.45, P < .02) significantly influenced survival during the study period. CONCLUSION: This study identified age, gender, and SCI status as significant variables for this study population influencing long-term survival among patients with cervical spine fractures. Our results support the growing notion that cervical spine injuries in geriatric patients with trauma may warrant additional research.

High-Mobility Group Box 1 (HMGB1) Is Elevated Systemically in Persons with Acute or Chronic Traumatic Spinal Cord Injury.

Inflammation in traumatic spinal cord injury (SCI) has been proposed to promote damage acutely and oppose functional recovery chronically. However, we do not yet understand the signals that initiate or prolong inflammation in persons with SCI. High-Mobility Group Box 1 (HMGB1) is a potent systemic inflammatory cytokine-or damage-associated molecular pattern molecule (DAMP)-studied in a variety of clinical settings. It is elevated in pre-clinical models of traumatic spinal cord injury (SCI), where it promotes secondary injury, and strategies that block HMGB1 improve functional recovery. To investigate the potential translational relevance of these observations, we measured HMGB1 in plasma from adults with acute (≤ 1 week post-SCI, n = 16) or chronic (≥ 1 year post-SCI, n = 47) SCI. Plasma from uninjured persons (n = 51) served as controls for comparison. In persons with acute SCI, average HMGB1 levels were significantly elevated within 0-3 days post-injury (6.00 ± 1.8 ng/mL, mean ± standard error of the mean [SEM]) or 4-7 (6.26 ± 1.3 ng/mL, mean ± SEM), compared with controls (1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.001 and p ≤ 0.01, respectively). In persons with chronic SCI who were injured for 15 ± 1.5 years (mean ± SEM), HMGB1 also was significantly elevated, compared with uninjured persons (3.7 ± 0.69 vs. 1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.0001). Together, these data suggest that HMGB1 may be a common, early, and persistent danger signal promoting inflammation in individuals with SCI.

Circulating T cell subsets are altered in individuals with chronic spinal cord injury.

Traumatic spinal cord injury (SCI) induces changes in the immune system, both acutely and chronically. To better understand changes in the chronic phase of SCI, we performed a prospective, observational study in a research institute and Department of Physical Medicine and Rehabilitation of an academic medical center to examine immune system parameters, including peripheral immune cell populations, in individuals with chronic SCI as compared to uninjured individuals. Here, we describe the relative frequencies of T cell populations in individuals with chronic SCI as compared to uninjured individuals. We show that the frequency of CD3+ and CD3+ CD4+ T cells are decreased in individuals with chronic SCI, although activated (HLA-DR+) CD4+ T cells are elevated in chronic SCI. We also examined regulatory T cells (Tregs), defined as CD3+ CD4+ CD25+ CD127lo and CCR4+, HLA-DR+ or CCR4+ HLA-DR+. To our knowledge, we provide the first evidence that CCR4+, HLA-DR+ or CCR4+ HLA-DR+ Tregs are expanded in individuals with SCI. These data support additional functional studies of T cells isolated from individuals with chronic SCI, where alterations in T cell homeostasis may contribute to immune dysfunction, such as immunity against infections or the persistence of chronic inflammation.