The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review

Abstract

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals' recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer's disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI.

Keywords: Alzheimer’s; concussion; dementia; headache; microglia; neuroinflammation; pain; sleep; traumatic brain injury.

Figure 1

The putative role of neuroinflammation in the acquired traumatic injuries and related sleep disturbances. Traumatic brain injuries (TBI) and orthopedic traumas (OT) both lead to a downstream pathophysiological cascade that includes peripheral inflammation, blood–brain barrier (BBB) dysfunction, and neuroinflammation. In turn, chronic neuroinflammation plays a role into the development of poor long-term outcomes. At each step of the way, sleep and sleep disturbances interact bidirectionally with traumatic pathological mechanisms and neuroinflammation. Poorer sleep exacerbates peripheral inflammation, BBB dysfunction, neuroinflammation, and worsen long-term outcomes. On the other hand, the trauma itself, its comorbidities, or neuroinflammation affect sleep regulation, which leads to a positive feedback loop, where neuroinflammation and sleep interact together to affect long-term outcomes following an injury.