ABSTRACT
The clinical burden of traumatic brain injury (TBI) continues to grow worldwide, with patients often developing chronic neurological, behavorial, and cognitive deficits. Treatment and management strategies remain a key challenge, given that they target the symptoms and not the underlying pathological response. To advance pre-clinical research and therapeutic developments, there is a need to study treatment strategies that improve brain injury recovery. Cranial osteopathic manipulative medicine (cOMM) is a non-invasive and non-pharmacological strategy that has been shown to improve quality of life for several medical conditions and injuries, and may be able to treat TBI and reduce subsequent symptoms. In this study, we aimed to evaluate the neurobiological effect of cOMM on the injury response and its potential to alleviate symptoms. We investigated the ability of cOMM to enhance fluid transport by quantifying fluorescent tracer clearance throughout the brain. Further, using an in vivo TBI model, male rats were exposed to a repeated blast overpressure that was followed by cOMM treatment 24 h later. Our findings indicated that cOMM treatment attenuated acute and subacute anxiety-like behaviors. Post-mortem pathological examination in the hippocampus, pre-frontal, and motor cortices indicated improvements in glial pathology in cOMM-treated animals compared to the untreated injury group. Overall, this is the first study to explore cOMM as a treatment option for brain injury, demonstrating its capability to improve TBI outcomes.
ABSTRACT
Long-term neuropsychiatric impairments have become a growing concern following blast-related traumatic brain injury (bTBI) in active military personnel and Veterans. Neuropsychiatric impairments such as anxiety and depression are common comorbidities that Veterans report months, even years following injury. To understand these chronic behavioral outcomes following blast injury, there is a need to study the link between anxiety, depression, and neuropathology. The hippocampus and motor cortex (MC) have been regions of interest when studying cognitive deficits following blast exposure, but clinical studies of mood disorders such as major depressive disorder (MDD) report that these two regions also play a role in the manifestation of anxiety and depression. With anxiety and depression being common long-term outcomes following bTBI, it is imperative to study how chronic pathological changes within the hippocampus and/or MC due to blast contribute to the development of these psychiatric impairments. In this study, we exposed male rats to a repeated blast overpressure (~17 psi) and evaluated the chronic behavioral and pathological effects on the hippocampus and MC. Results demonstrated that the repeated blast exposure led to depression-like behaviors 36 weeks following injury, and anxiety-like behaviors 2-, and 52-weeks following injury. These behaviors were also correlated with astrocyte pathology (glial-fibrillary acid protein, GFAP) and dendritic alterations (Microtubule-Associated Proteins, MAP2) within the hippocampus and MC regions at 52 weeks. Overall, these findings support the premise that chronic glial pathological changes within the brain contribute to neuropsychiatric impairments following blast exposure.
ABSTRACT
Vestibular impairment has become a frequent consequence following blast-related traumatic brain injury (bTBI) in military personnel and Veterans. Behavioral outcomes such as depression, fear and anxiety are also common comorbidities of bTBI. To accelerate pre-clinical research and therapy developments, there is a need to study the link between behavioral patterns and neuropathology. The transmission of neurosensory information often involves a pathway from the cerebral cortex to the thalamus, and the thalamus serves crucial integrative functions within vestibular processing. Pathways from the thalamus also connect with the amygdala, suggesting thalamic and amygdalar contributions to anxiolytic behavior. Here we used behavioral assays and immunohistochemistry to determine the sub-acute and early chronic effects of repeated blast exposure on the thalamic and amygdala nuclei. Behavioral results indicated vestibulomotor deficits at 1 and 3 weeks following repeated blast events. Anxiety-like behavior assessments depicted trending increases in the blast group. Astrogliosis and microglia activation were observed upon post-mortem pathological examination in the thalamic region, along with a limited glia response in the amygdala at 4 weeks. These findings are consistent with a diffuse glia response associated with bTBI and support the premise that dysfunction within the thalamic nuclei following repeated blast exposures contribute to vestibulomotor impairment.
