This session was built from submitted abstracts and pairs laboratory with clinical studies to identify and intervene in the treatment of traumatic brain injury. The talks will focus on pain, inflammation, and nutrition as chronic co-morbidities, with mention of mechanisms that can be targeted for therapeutic interventions. The six 12-minute talks will be followed by an integrated and moderated discussion by the panel co-chairs.

This session was built from submitted abstracts and pairs laboratory with clinical studies to identify and intervene in the treatment of traumatic brain injury. The talks will focus on pain, inflammation, and nutrition as chronic co-morbidities, with mention of mechanisms that can be targeted for therapeutic interventions. The six 12-minute talks will be followed by an integrated and moderated discussion by the panel co-chairs.

BACKGROUND: Chronic pain is a remarkably frequent outcome of mild TBI (mTBI). Common syndromes include headache, backache, limb pain and prolonged pain in the context of other injuries. Chronic pain after TBI leads to personal suffering, suboptimal functional recovery and increases exposure to opioids. Recent human and laboratory data suggest that dysfunctional endogenous pain control circuits, particularly those centered in the brainstem, may contribute to these pain problems. We hypothesized that descending pain modulatory circuits and aberrant serotonergic signaling are involved.

METHODS: To address the effects of mTBI on descending pain modulation, both rat lateral fluid percussion and mouse closed head models were employed. Pain-related changes were measured using tests of mechanical allodynia in the facial region and hindlimbs. The bright light stress model of headache was used as were injury models including hindpaw incision and tibial fracture. Pharmacologic tools involved systemic, intrathecal and stereotactically targeted injections of selective adrenergic and serotonergic agents as well as neurotoxins such as dermorphin-saporin to eliminate cells expressing mu-opioid receptor. To control the activity of the locus coeruleus and periaqueductal gray matter, virally encoded Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were administered. Finally, running wheel equipped enclosures were used to study the effects of exercise on endogenous pain control systems after TBI.

RESULTS: We observed that TBI leads to an acute but transient period of pain sensitization characterized by facial and hindlimb allodynia supported by descending signaling through spinal 5-HT3 receptors. After recovery from this sensitization, however, the mice and rats showed profound disruption and plasticity of descending noradrenergic and serotonergic circuits. Maintenance of normal pain thresholds after TBI required the activity of endogenous opioid signaling. In this chronic setting, treatment of the mice or rats with serotonin selective reuptake inhibitors (SSRIs) was effective in restoring endogenous pain control systems and in reducing sensitization after limb injuries. Augmenting descending pain modulation through DREADD stimulation in the locus coeruleus or periaqueductal gray matter provided analgesia in the TBI animals. Finally, exercise beginning days after TBI could restore normal endogenous pain control systems.

CONCLUSIONS: Even mild TBI leads to a state of profound and long-lasting disruption of endogenous pain control systems. Pain control centers in the brainstem are central to this phenomenon. The augmentation of serotonergic signaling using clinically available SSRI drugs or exercise seem to be viable options for the restoration of normal endogenous pain control, and translational studies are indicated.

The objective of this secondary analysis was to examine the relationship between extreme pain phenotypes (based on pain interference and perceived improvement) and psychosocial outcomes among persons with chronic pain after moderate-to-severe traumatic brain injury (TBI). In total, 1762 TBI Model Systems (TBIMS) participants 1 to 30 years postinjury reporting chronic pain were recruited as part of a multisite, cross-sectional, observational cohort TBIMS addendum study on Chronic Pain. Extremely low and high pain phenotypes were identified by the Brief Pain Inventory (BPI) interference scale, and the Patient’s Global Impression of Change (PGIC). Clinical outcomes of interest included life satisfaction, posttraumatic stress, depression and anxiety symptoms, sleep and participation. Generally, extreme phenotypes based on interference had greater association with psychosocial outcomes compared to improvement-based phenotypes. Those identified as extremely high pain interference phenotype had poorer psychosocial outcomes compared to the extremely low phenotype group. After controlling for covariates, large effect sizes (ES) related to pain interference were observed for posttraumatic stress symptomatology (ES = -1.14), sleep quality (ES = -1.10), depression (ES = -1.08), anxiety (ES = -0.82), and life satisfaction (ES = 0.76); effect sizes for participation outcomes, although significant, were relatively small (ES = 0.21-0.36). Effect sizes related to perceived improvement were small for life satisfaction (ES = 0.20) and participation (ES = 0.16-0.21) outcomes. Pain intensity was identified as a meaningful confounding factor of the relationships between extreme phenotypes and posttraumatic stress, depression, anxiety, and sleep quality. Results suggest that the relationships among a variety of characteristics of the person, their experience with pain, and treatment of pain are complex. However, examination of subgroups defined by extreme phenotypes of interference (and to an extent, perceived improvement) were able to identify pronounced differences in the psychosocial experience of individuals living with chronic pain and TBI. Further research is needed to better understand these complex relationships and how differences in pain interference and perceived improvement from treatment can assist in assessment and treatment of chronic pain after TBI.

Traumatic brain injury (TBI) affects millions of individuals annually, resulting in reduced quality of life in patients and substantial financial costs. TBI impacts learning and memory functionality and is a recognized risk factor for the development of Alzheimer’s disease (AD). A key component of the immune response in TBI and AD is activation of the inflammasome. The inflammasome is a multi-protein complex that activates pro-inflammatory cytokines interleukin (IL)-1β and IL-18, through the recruitment of caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Activation results in pyroptotic cell death through cleavage and formation of the GSDM-D pore. We have previously demonstrated that genetic predisposition to AD, utilizing the 3XTg mouse model, significantly exacerbates inflammasome activation in the acute injury phase of TBI and leads to greater cognitive impairment. Furthermore, we showed that inhibition of the inflammasome through use of an anti-ASC therapeutic monoclonal antibody (IC100), was effective in reducing inflammasome activated IL-1β in 3xTg mice after TBI. Our current work investigates the chronic inflammatory response of TBI pathology in familial AD. 5-month-old wild-type (WT) and 3xTg (AD) mice underwent either sham surgery or moderate controlled cortical impact (CCI). At 3-months after surgery, animals were sacrificed and the ipsilateral cortex was dissected, homogenized, and immunoblotted for inflammasome proteins and IL-1β. A Simple Plex assay was completed using cortical lysates to assess neurodegeneration and astroglia reactivity by probing for neurofilament-light (NfL) and glial fibrillary acidic protein (GFAP), respectively. Histology and immunohistochemistry was also conducted on whole brain sections blotted for ASC, NfL, and GFAP. Sections were used to assess cortical and hippocampal tissue loss after injury using volumetric analysis. Our results demonstrate that IL-1β protein remains significantly elevated in the chronic stages after injury in AD animals compared to WT. We also observed a persistent elevation of the inflammasome proteins NLRP3, caspase-8, and ASC in injured AD mice which was not present in injured WT animals. Moreover, there is a chronic increase in NfL expression after TBI, with evidence of ASC co-localization after injury. Interestingly, only injured AD mice demonstrated continued elevation of GFAP. GFAP+ cells additionally demonstrated ASC co-localization in the injured AD mice. Finally, there was a significant loss in total cortical volume and total hippocampal volume in injured AD mice compared to the injured WT mice. In conclusion, we provide evidence that genetic predisposition to AD leads to chronic inflammasome activation and pro-inflammatory cytokine release after TBI leading to even greater neurodegeneration. Importantly, our results indicate that the inflammasome could be a promising therapeutic target for TBI with AD.

Managing concussions and TBI remains a complex challenge in sports medicine and healthcare. A one-size-fits-all approach isn’t going to work. While current standard of care primarily involves rest and symptomatic management, emerging research suggests that active recovery and specific nutritional strategies may expedite concussion recovery. Therapies targeting the inflammasome are essential to maintain or regain brain health after injury. Presented here is a comprehensive overview of the potential efficacy of targeted nutritional interventions in ameliorating the effects of concussions and diminishing the risk of recurring injuries.

There exists a complex interplay between omega-3s and omega-6s and the endocannabinoid system. The endocannabinoid system has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are essential for optimal brain development and function with and through the cannabinoid system. Omega long-chain polyunsaturated fatty acids (LCPUFA), including ARA, DHA, and EPA (eicosapentaenoic acid), are essential components of membrane phospholipids and precursors to a number of bioactive lipid mediators. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. Yet, DHA and EPA supplementation reduce AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules, docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA). Dietary enrichment with DHA and EPA have shown beneficial effects on learning and memory, neuroinflammatory processes, synaptic plasticity, and neurogenesis.

This review contributes to the evolving landscape of concussion management by highlighting the pivotal role of targeted nutritional therapy as a therapeutic approach. These interventions can modulate neuroinflammation, enhance neuroprotection, and facilitate neurorepair following a concussion. Furthermore, practical considerations for implementing targeted nutritional interventions across diverse populations, from athletes to military personnel and individuals at risk of recurrent head injuries, are to be addressed. This underscores the importance of acknowledging nutrition as a complementary strategy in the multifaceted domain of concussion management and prevention. As we persist in our endeavors to augment patient outcomes and alleviate the societal burden of concussions and TBI, the application of targeted nutritional interventions warrants further exploration and clinical integration within the field of traumatic brain injury.

Acute traumatic brain injury (TBI) exerts damage to the brain through an external force that activates a cerebral inflammatory response. In some cases, maladaptive inflammation may result in chronic inflammatory conditions and/or changes to the gut microbiome. Inflammation and the gut microbiome have a complex bidirectional relationship that plays a part in neurogenerative processes, behavior, and cognition. Currently few treatment options exist for TBI patients, therefore a better understanding of biological responses that are connected to physical and mental health outcomes is needed in human studies. In this study, longitudinal sampling was conducted from emergency department patients with post-acute mild TBI (mTBI). Samples included the fecal microbiome within 48 hours of admission (baseline) and at monthly intervals for up to 12 months in 23 participants for 167 total fecal samples (mean >7 samples per participant). Plasma was collected at baseline for all participants and at 12 months for a subset of 11 participants and analyzed for changes in inflammatory markers (i.e., C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor). Data regarding psychological histories/symptoms were obtained at baseline and each month of participation. Preliminary analysis was conducted to explore the microbiome and inflammatory changes post-acute mTBI. In a linear mixed model to account for related samples from the same participants, the overall microbial community was significantly divergent across the sampling time when compared to baseline. A rapid reduction in abundance, with no long-term recovery, of the potentially anti-inflammatory genus Akkermansia partially explained the trend. Akkermansia muciniphila promotes intestinal barrier function, in part by enhancing mucus production. A similar trend was not observed in other genera commonly associated with anti-inflammatory effects (e.g. Bacteroides, Faecalibacterium, Lactobacillus). Plasma concentrations of IL-6 were significantly reduced from baseline to 12 months, consistent with previous studies documenting elevated plasma concentrations of IL-6 immediately after a TBI. Findings support previous work highlighting relationships between TBI, inflammatory response, and the gut microbiome. Analysis of the factors associated with changes in the gut microbiome and/or biomarkers of inflammation is ongoing, including analysis of associations of physiologic responses with mental health outcomes subsequent to post-acute mTBI.