Abstract
Traumatic brain injury-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines, especially epinephrine, although few ...preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury. Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate, blood pressure, and blood flow to the hindlimb muscles. Therefore, the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in several function-specific central nervous system regions in rats. Following three repeated blast injuries at three-day intervals, the hippocampus, motor cortex, locus coeruleus, vestibular nuclei, and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector coupled with high-performance liquid chromatography. Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age- and sex-matched sham controls. In other function-specific central nervous system regions, although the epinephrine levels were slightly altered following blast-induced traumatic brain injury, they were not statistically significant. These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function. This is the first report to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.
Spasticity and gait impairments are two common disabilities after cervical spinal cord injury (C-SCI). In this study, we tested the therapeutic effects of early treadmill locomotor training (Tm) ...initiated at postoperative (PO) day 8 and continued for 6 weeks with injury site transcranial magnetic stimulation (TMSsc) on spasticity and gait impairments after low C6/7 moderate contusion C-SCI in a rat model. The combined treatment group (Tm+TMSsc) showed the most robust decreases in velocity-dependent ankle torques and triceps surae electromyography burst amplitudes that were time locked to the initial phase of lengthening, as well as the most improvement in limb coordination quantitated using three-dimensional kinematics and CatWalk gait analyses, compared to the control or single-treatment groups. These significant treatment-associated decreases in measures of spasticity and gait impairment were also accompanied by marked treatment-associated up-regulation of dopamine beta-hydroxylase, glutamic acid decarboxylase 67, gamma-aminobutyric acid B receptor, and brain-derived neurotrophic factor in the lumbar spinal cord (SC) segments of the treatment groups, compared to tissues from the C-SCI nontreated animals. We propose that the treatment-induced up-regulation of these systems enhanced the adaptive plasticity in the SC, in part through enhanced expression of pre- and postsynaptic reflex regulatory processes. Further, we propose that locomotor exercise in the setting of C-SCI may decrease aspects of the spontaneous maladaptive segmental and descending plasticity. Accordingly, TMSsc treatment is characterized as an adjuvant stimulation that may further enhance this capacity. These data are the first to suggest that a combination of Tm and TMSsc across the injury site can be an effective treatment modality for C-SCI-induced spasticity and gait impairments and provided a pre-clinical demonstration for feasibility and efficacy of early TMSsc intervention after C-SCI.
Traumatic brain injury (TBI) can produce life-long disabilities, including anxiety, cognitive, balance, and motor deficits. The experimental model of closed head TBI (cTBI) induced by weight ...drop/impact acceleration is known to produce hallmark TBI injuries. However, comprehensive long-term characterization of comorbidities induced by graded mild-to- mild/moderate intensities using this experimental cTBI model has not been reported. The present study used two intensities of weight drop (1.0 m and 1.25 m/450 g) to produce cTBI in a rat model to investigate initial and long-term disability of four comorbidities: anxiety, cognitive, vestibulomotor, and spinal reflex that related to spasticity. TBI and sham injuries were produced under general anesthesia. Time for righting recoveries post-TBI recorded to estimate duration of unconsciousness, revealed that the TBI mild/moderate group required a mean of 1 min 27 sec longer than the values observed for noninjured sham animals. Screening magnetic resonance imaging images revealed no anatomical changes, mid-line shifts, or hemorrhagic volumes. However, compared to sham injuries, significant long-term anxiety, cognitive, balance, and physiological changes in motor reflex related to spasticity were observed post-TBI for both TBI intensities. The longitudinal trajectory of anxiety and balance disabilities tested at 2, 4, 8, and 18 weeks revealed progressively worsening disabilities. In general, disability magnitudes were proportional to injury intensity for three of the four measures. A natural hypothesis would pose that all disabilities would increase incrementally relative to injury severity. Surprisingly, anxiety disability progressed over time to be greater in the mildest injury. Collectively, translational implications of these observations suggest that patients with mild TBI should be evaluated longitudinally at multiple time points, and that anxiety disorder could potentially have a particularly low threshold for appearance and progressively worsen post-injury.
Post-traumatic headache (PTH) following TBI is a common and often persisting pain disability. PTH is often associated with a multimodal central pain sensitization on the skin surface described as ...allodynia. However, the particular neurobiology underlying cTBI-induced pain disorders are not known. These studies were performed to assess trigeminal sensory sensitization and to determine if sensitization measured behaviorally correlated with detectable changes in portions of the trigeminal sensory system (TSS), particularly trigeminal nucleus, thalamus, and sensory cortex. Thermal stimulation is particularly well suited to evaluate sensitization and was used in these studies. Recent advances in the use of reward/conflict paradigms permit use of operant measures of behavior, versus reflex-driven response behaviors, for thermal sensitization studies. Thus, to quantitate facial thermal sensitization (allodynia) in the setting of acute TBI, the current study utilized an operant orofacial pain reward/conflict testing paradigm to assess facial thermal sensitivity in uninjured control animals compared with those two weeks after cTBI in a rodent model. Significant reductions in facial contact/lick behaviors were observed in the TBI animals using either cool or warm challenge temperatures compared with behaviors in the normal animals. These facial thermal sensitizations correlated with detectable changes in multiple levels of the TSS. The immunohistochemical (IHC) studies revealed significant alterations in the expression of the serotonin (5-HT), neurokinin 1 receptor (NK1R), norepinephrine (NE), and gamma-aminobutyric acid (GABA) in the caudal trigeminal nucleus, thalamic VPL/VPM nucleus, and sensory cortex of the orofacial pain pathways. There was a strong correlation between increased expression of certain IHC markers and increased behavioral markers for facial sensitization. The authors conclude that TBI-induced changes observed in the TSS are consistent with the expression of generalized facial allodynia following cTBI. To our knowledge, this is the first report of orofacial sensitization correlated with changes in selected neuromodulators/neurotransmitters in the TSS following experimental mild TBI.
•cTBI induced significant orofacial allodynia.•This orofacial allodynia was accompanied by significant alterations in the expression of the 5-HT, NK1R, NE, and GABA throughout the trigeminal sensory pathway.•These neuromodulators in primary, secondary, and tertiary levels of the trigeminal sensory pathway may contribute generalized facial allodynia and/or headache-like pain behavior following TBI.•These observations suggest potentially multiple targets for intervention to addresses changes as an effective strategy to control orofacial pain after TBI.•Facial allodynia is one of the major outcomes in headache or trigeminal injury related pain following TBI patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Successful therapy for TBI disabilities awaits refinement in the understanding of TBI neurobiology, quantitative measurement of treatment-induced incremental changes in recovery trajectories, and ...effective translation to human TBI using quantitative methods and protocols that were effective to monitor recovery in preclinical models. Details of the specific neurobiology that underlies these injuries and effective quantitation of treatment-induced changes are beginning to emerge utilizing a variety of preclinical and clinical models (for reviews see (Morales et al., Neuroscience 136:971-989, 2005; Fujimoto et al., Neurosci Biobehav Rev 28:365-378, 2004; Cernak, NeuroRx 2:410-422, 2005; Smith et al., J Neurotrauma 22:1485-1502, 2005; Bose et al., J Neurotrauma 30:1177-1191, 2013; Xiong et al., Nat Rev Neurosci 14:128-142, 2013; Xiong et al., Expert Opin Emerg Drugs 14:67-84, 2009; Johnson et al., Handb Clin Neurol 127:115-128, 2015; Bose et al., Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects, CRC Press/Taylor & Francis, Boca Raton, 2015)). Preclinical models of TBI, essential for the efficient study of TBI neurobiology, benefit from the setting of controlled injury and optimal opportunities for biometric quantitation of injury and treatment-induced changes in the trajectories of disability. Several preclinical models are currently used, and each offer opportunities for study of different aspects of TBI primary and secondary injuries (for review see (Morales et al., Neuroscience 136:971-989, 2005; Xiong et al., Nat Rev Neurosci 14:128-142, 2013; Xiong et al., Expert Opin Emerg Drugs 14:67-84, 2009; Johnson et al., Handb Clin Neurol 127:115-128, 2015; Dixon et al., J Neurotrauma 5:91-104, 1988)). The closed-head, impact-acceleration model of TBI designed by Marmarou et al., 1994 (J Neurosurg 80:291-300, 1994), when used to produce mild to moderate TBI, produces diffuse axonal injuries without significant additional focal injuries of the brain (Morales et al., Neuroscience 136:971-989, 2005; Foda and Marmarou, J Neurosurg 80:301-313, 1994; Kallakuri et al., Exp Brain Res 148:419-424, 2003). Accordingly, use of this preclinical model offers an opportunity for (a) gaining a greater understanding of the relationships of TBI induced diffuse axonal injuries and associated long term disabilities, and (b) to provide a platform for quantitative assessment of treatment interactions upon the trajectories of TBI-induced disabilities. Using the impact acceleration closed head TBI model to induce mild/moderate injuries in the rat, we have observed and quantitated multiple morbidities commonly observed following TBI in humans (Bose et al., J Neurotrauma 30:1177-1191, 2013). This chapter describes methods and protocols used for TBI-induced multiple morbidity involving cognitive dysfunction, balance instability, spasticity and gait, and anxiety-like disorder.
Spasticity is a major health problem for patients with traumatic brain injury (TBI). In addition to spasticity, TBI patients exhibit enduring cognitive, balance, and other motor impairments. Although ...the use of antispastic medications, particularly ITB, can decrease the severity of TBI-induced spasticity, current guidelines preclude the use of ITB during the first year after TBI. Therefore, the present study was performed to quantitate disability in an animal model of closed-head TBI (cTBI; Mararou's model) after ITB treatment. After cTBI, significant deficits in spasticity and gait, cognitive, balance, and anxiety-like behaviors were detected. ITB (Lioresal(®)) or saline was administered using Alzet pumps (0.8 μg/hour for 4 weeks). Spasticity measures using velocity-dependent ankle torque and ankle extensor muscle electromyography recordings, footprints (gait), balance performance tests, serial learning, and anxiety-like behaviors were performed at multiple post-treatment and -withdrawal of ITB time points. Our data indicated that 1 month of ITB treatment initiated at post-TBI week 1 blocked the early onset of spasticity and significantly attenuated late-onset spasticity and anxiety-like behavior with no significant adverse effects on cognitive and balance performance. This improved spasticity outcome was accompanied by marked up-regulation of gamma-aminobutyric acid (GABA)/GABAb, norepinephrine, and brain-derived neurotrophic factor expression in spinal cord tissue. Early intervention with ITB treatment was safe, feasible, and effective in this cTBI animal model. Collectively, these data provide a strong molecular footprint of enhanced expression of reflex regulation by presynaptic inhibition. The possibility that acute ITB treatment may decrease maladaptive segmental and descending plasticity is discussed. The data provided by the present animal model initiates a pre-clinical platform for safety, feasibility, and efficacy of early ITB intervention after TBI.
Traumatic brain injury (TBI) leads to enduring cognitive disorders. Although recent evidence has shown that controlled cortical impact in a rodent may induce memory deficits with prolonged cell death ...in the dentate gyrus (DG) of the hippocampus, few studies have reported long-term chronic hippocampal cell death following 'closed-head' TBI (cTBI), the predominant form of human TBI. Therefore, the aim of this study was to quantify terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)(+) apoptotic hippocampal cells as well as hippocampal cells with hallmark morphological features of degenerating cells in a chronic setting of cTBI in rats. TUNEL assays and Cresyl violet staining were performed using 6-month post-TBI fixed hippocampal sections. Evidence of prolonged hippocampal cell death was shown by the presence of a significantly increased number of TUNEL(+) cells in the cornu ammonis 1-3 (CA1-CA3) and DG of the hippocampus compared with intact controls. In addition, Cresyl violet staining indicated a significantly elevated number of cells with the degenerative morphological features in all hippocampal subregions (CA1-CA3, hilus, and DG). These results suggest that prolonged cell death may occur in multiple regions of the hippocampus following cTBI.
As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research ...and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.
Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain ...response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.
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