Traumatic brain injury treatment using a rodent model of homelessness

Introduction: Traumatic brain injury (TBI) is a common diagnosis among veterans secondary to combat experiences. TBI is also rampant among those experiencing homelessness, possibly due to veterans making up 12.3% of the homeless population (Tsai and Rosenheck, 2015), or due to the high risk of violence or trauma among those experiencing homelessness. TBI is up to 10× more prevalent among those experiencing homelessness (Stubbs et al., 2020; Dell et al., 2021). In a study involving 1215 patients, 58% of patients discharged from trauma centers without stable housing were diagnosed with TBI compared to 48% of those discharged to a home (Dell et al., 2021). In a meta-analysis of 9702 homeless or unstably housed individuals, the lifetime prevalence of TBI was 53.1% (Stubbs et al., 2020). TBI has known underlying neuroinflammatory changes, and the chronic stressors of homelessness may further contribute to systemic inflammation (Brisson et al., 2020). Our research team questioned whether the additional stress associated with homelessness may exacerbate the functional deficits and pathophysiological changes in TBI.

Our recent work: We found that homelessness may further complicate TBI impairments by perpetuating white matter degeneration in the corpus callosum (Monsour et al., 2023). Our laboratory introduced a novel model of homelessness using adult, male Sprague-Dawley rats. Rats were assigned to four groups, TBI only, homelessness only, TBI and homelessness, or control (n = 9 per group). Over 5 weeks, animals (two animals per cage) were exposed to soiled beddings as a simulation of homelessness. While our unique design is new, previous models of homelessness have manipulated bedding by providing sparse bedding or frequent cleaning to disrupt animals marking their territory (Castelhano-Carlos and Baumans, 2009). By disturbing this “home base” (Sanders and Brown, 2015), our model of homelessness mimics the feeling of discomfort of unstable and occasionally precarious or unclean housing. Subsequently, animals were introduced to TBI by using the moderate controlled cortical impact model, then underwent 4 consecutive days of behavioral testing (beam walk, elevated body swing test, forelimb akinesia, paw grasp, rotarod, and elevated T-maze). Behavioral testing confirmed motor function was significantly impacted by TBI, with the TBI only and TBI and homeless rats having additional deficits in motor function (TBI rats: beam walk 85.0%, forelimb akinesia 104.7%, and paw grasp 100% greater deficits compared to controls). Homeless and TBI rats had greater deficits than TBI only rats (beam walk 93.3%, forelimb akinesia 40.5%, and paw grasp 50% greater deficits compared to TBI only). Two-way ANOVA further demonstrated significant group differences in beam walk (F_(4,160) = 31.69, P < 0.0001), forelimb akinesia (F_(4,160) = 13.71, P < 0.0001), paw grasp (F_(4,160) = 3.873, P = 0.005), and EBST (F_(4,160) = 6.929, P < 0.0001) performances. T-maze (F_(4,160) = 9.529, P = 0.9952) and rotorod (F_(4,160) = 1.116, P = 0.3507) showed insignificant differences between the groups.

To further analyze the underlying pathophysiology of these changes, we performed nissl staining and measured cell survival in the peri-impact area and corpus callosum area. TBI only and TBI and homeless rats exhibited expectedly greater cortical impact damage (F_(3,95) = 51.75, P < 0.0001) and peri-impact cell loss (F_(3,238) = 47.34, P < 0.0001) compared to the control group. While there were no significant differences between the corpus callosum area in TBI and homeless and TBI only groups, the TBI only group did not differ significantly in corpus callosum area compared to controls or homeless only groups, while TBI and homeless did. TBI and homeless rats showed significant alterations in white matter area (measured via the corpus callosum) compared to homeless only groups (P < 0.05).

Considering these findings, we propose that the corpus callosum allows for regenerative signals to be transmitted between hemispheres following TBI, aiding in subsequent functional recovery. However, it is likely that TBI pathology is further perpetuated by cellular and molecular mechanisms that promote inflammation and oxidative changes. Ultimately, this research stresses the vitality of personalizing TBI treatments with special attention to patients' socioeconomic situations. Further research on the underlying mechanisms and possible socioeconomic confounders is needed to optimize TBI treatments.

Future research and treatment considerations: When considering therapeutics for addressing the exacerbation of TBI pathology by homelessness, preclinical translational research initiatives should include stress biomarkers and sensitive anxiety functional tests that can capture the physiological, cellular and behavioral abnormalities associated with social stressors that may exacerbate TBI (Figure 1). Clinically-relevant biomarkers tested in TBI that may extend to homelessness-induced stress include structural imaging modalities and molecular biospecimens, such as blood and cerebrospinal fluid, altogether providing proteomic, genomic, or metabolomic signature of TBI pathology (Agoston and Kamnaksh, 2015). Such specific signature-stress biomarkers may reveal key pathological processes in guiding therapeutics development for TBI. A reliable stress biomarker that can be validated in the preclinical model may provide some insights into the clinical manifestation of anxiety in TBI, especially in these homeless patients. Furthermore, our behavioral tests mainly have focused on functional mobility. Regarding the mental health repercussions of homelessness and TBI, however, it is imperative to conduct studies that specifically measure anxiety and depression responses in animal models.

Figure 1.

TBI and homelessness.

This figure exemplifies our unique design and recent findings regarding white matter changes and motor function following TBI in the homeless simulation using rats as subject. We then illustrate future initiatives that may advance this field, such as light therapy, melatonin, sleep, enriched environment, anxiety and depression behavioral tests, stress biomarkers, and more sensitive animal models of homelessness. Created with BioRender.com. TBI: Traumatic brain injury; WM: white matter.

In addition, when considering treatment interventions for those experiencing homelessness, it is important to consider physical barriers, social barriers, or psychological trauma that may contribute to non-adherence. Anti-inflammatory pharmaceutical interventions may be beneficial for a select TBI patient population; however, if a patient has to walk to a physician's office or has to choose between buying medications and feeding their family, it is unlikely that pharmaceutical treatments will be a priority for that unique patient. It is necessary to consider options that provide sustainable, long-term benefits, depending on each patient's priorities and barriers to care. With this regards, enrichment interventions, such as exercise, adequate housing, and social interaction, have been shown to reduce neuroinflammation in animal models. In the clinic, trials of innovative treatment interventions to address stress, anxiety, and depression in TBI may be extended to homeless TBI patients. Improvements in physical and social environments, such as the use of bright light (Elliott et al., 2022), and sleep hygiene treatments (Makley et al., 2020), are currently being explored in TBI patients. These non-pharmaceutical interventions may negate some of the added pathophysiological changes in TBI patients experiencing homelessness by lessening social stressors. The use of enriched environment approach as a therapeutic may reduce homelessness-induced stress in TBI as shown in many preclinical studies on TBI (Tapias et al., 2022). In tandem, over-the-counter and easily accessible drugs that specifically target general stress, such as melatonin (Bekala et al., 2022), may work in alleviating homelessness-induced stress in TBI.

Future animal model research initiatives may alternate simulating homelessness prior to TBI with subsequent enriched environmental conditions to better establish the benefit of these interventions in unique populations. Considering our findings and future research revealing possible increased inflammation in TBI patients that experience homelessness, it may be necessary to increment anti-inflammatory treatments to appropriately cover both stressors. Regardless, the ultimate treatment regimens and goals should focus on patients' unique socioeconomic hurdles and consider additional stressors that contribute to neuroinflammatory changes.

Conclusion: Our recent research exemplifies how homelessness impacts functionality following TBI, as evidenced by behavioral tests, including paw grasp, forelimb akinesia, and beam walking. We suggest that white matter changes within the corpus callosum partially explain these behavioral discrepancies, while inflammatory and oxidative changes likely perpetuate these changes and may also contribute to the white matter damage itself. To optimize therapeutics for TBI in all patient populations, stress biomarkers or sensitive anxiety functional tests may allow for comprehensive analysis of factors that affect social stressors and TBI.