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... results support this pathophysiology as the cause of loss of consciousness and visual dysfunction in mild TBI. The dorsal raphe nucleus (DRN) is also a midline structure of the dorsal midbrain and is located very near the oculomotor and Edinger-Westphal nuclei ( Figure 2). According to the collision injury analysis, the DRN is likely highly affected in mild TBI as well. ...
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Background
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Citations
... Repetitive head impacts (RHI) progressively reduce the structural integrity of the white matter within the midbrain (i.e., axonal tract damage) [15], and TBI results in significant midbrain diffuse axonal injury that correlates to states of unconsciousness [13]. Further, clinical imaging studies and post-mortem analyses of affected individuals have corroborated preclinical observations denoting the midbrain as being preferentially impacted by RHI and mTBI [16,17], making the midbrain and the cellular populations that comprise the midbrain a relevant research target. Cumulatively, these clinical studies indicate that the dorsal zone of the midbrain raphe nuclei, a region with diverse serotonergic neuron populations, is preferentially impacted by mild TBI, with implications for the development of mood disturbances like depression following injury induction. ...
... Specifically, physical interactions between the parenchyma of the human brain and the environment that occur during acceleration/deceleration events associated with whiplash can be computationally constructed using a human head finite element modeling system [17]. Though diffusion tensor imaging (DTI) is the most sensitive imaging modality for visualizing minute damage to white matter tracts, up to half of patients with head injuries do not have positive DTI results measured by changes in fractional anisotropy and mean diffusivity [17,18]. ...
... Specifically, physical interactions between the parenchyma of the human brain and the environment that occur during acceleration/deceleration events associated with whiplash can be computationally constructed using a human head finite element modeling system [17]. Though diffusion tensor imaging (DTI) is the most sensitive imaging modality for visualizing minute damage to white matter tracts, up to half of patients with head injuries do not have positive DTI results measured by changes in fractional anisotropy and mean diffusivity [17,18]. To circumvent the limitations of modern imaging techniques, the Total Human Model for Safety (v.5) 50th percentile adult male model was utilized to simulate acceleration/deceleration events associated with car crashes at various speeds [17]. ...
Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.
... SSRIs have been shown to improve common depressive symptoms post-TBI, which arise partly due to decreased serotonergic signaling (153). Increasing extracellular serotonin after damage has been shown as beneficial for improving mood disturbances, however it is ineffective in improving cognition (155). Therefore, it is important to use a pharmacological approach that addresses both mood and cognitive symptoms that arise from TBI. CBD also antagonizes the G protein-coupled receptor GPR55 (156), which results in enhanced GABAergic neurotransmission in the mouse hippocampus due to increases in inhibitory neuron excitability, and ultimately decreases the excitation/inhibition ratio (120). ...
Cannabidiol (CBD) has numerous pharmacological targets that initiate anti-inflammatory, antioxidative, and antiepileptic properties. These neuroprotective benefits have generated interest in CBD's therapeutic potential against the secondary injury cascade from traumatic brain injury (TBI). There are currently no effective broad treatment strategies for combating the damaging mechanisms that follow the primary injury and lead to lasting neurological consequences or death. However, CBD's effects on different neurotransmitter systems, the blood brain barrier, oxidative stress mechanisms, and the inflammatory response provides mechanistic support for CBD's clinical utility in TBI. This review describes the cascades of damage caused by TBI and CBD's neuroprotective mechanisms to counter them. We also present challenges in the clinical treatment of TBI and discuss important future clinical research directions for integrating CBD in treatment protocols. The mechanistic evidence provided by pre-clinical research shows great potential for CBD as a much-needed improvement in the clinical treatment of TBI. Upcoming clinical trials sponsored by major professional sport leagues are the first attempts to test the efficacy of CBD in head injury treatment protocols and highlight the need for further clinical research.
