Pathophysiology of Mild TBI: Implications for Altered Signaling Pathways

In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 4.


Concussions and mild traumatic brain injury (TBI) represent a substantial portion of the annual incidence of TBI aided by the increased reporting of concussions in youth sports, and the increased exposure of soldiers to blast injuries in the war theater. The pathophysiology of concussions and mild TBI consist predominantly of axonal injury at the cellular level and working memory deficits at the behavioral level. Importantly, studies in humans and in animals are making it clear that concussions and mild TBI are not merely a milder form of moderate-severe TBI but represent a separate disease/injury state. Therefore, acute and chronic treatment strategies, both behavioral and pharmacological, need to be implemented based on thorough pre-clinical assessment. The review in this chapter focuses on two under-studied components of the pathophysiology of mild TBI—the role of the c-Jun N-terminal kinase pathway in axonal injury, and the role of the dopaminergic system in working memory deficits.

The growing awareness of the incidence of concussion in contact sports, coupled with the emergence of blast-related injuries in combat fighting, has heightened the urgency to understand the underlying mechanisms of mild brain trauma and devise potential therapeutic interventions. TBI in general, and mild TBI in particular, is considered a “silent epidemic” because many of the acute and enduring alterations in cognitive, motor, and somatosensory functions may not be readily apparent to external observers. Moderate to severe TBI is a major cause of injury-induced death and disability with an annual incidence of approximately 500 in 100,000 people affected in the United States (Sosin et al., 1989; Kraus and McArthur, 1996; Rutland-Brown et al., 2006). However, approximately 80% of all TBI cases are categorized as mild head injuries (Bazarian et al., 2005; Langlois et al., 2006). It is important to note that these approximations are underestimates because they do not account for incidents of TBI in which the person does not seek medical care (Faul et al., 2010). Recent estimates to correct for this underreporting have placed the annual incidence at approximately 3.8 million (Bazarian et al., 2005; Ropper and Gorson, 2007; Halstead and Walter, 2010). The Glasgow Coma Scale (GCS) score, which measures level of consciousness, has been the primary clinical tool for assessing initial brain injury severity in mild (GCS 13–15), moderate (GCS 9–12), or severe (GCS < 8) cases (Teasdale and Jennett, 1974). Although this scoring system serves as a reliable predictor of patient survival (Steyerberg et al., 2008), particularly in the acute phase of trauma and for those patients with more severe head injury (Saatman et al., 2008), it does not necessarily reflect the underlying cerebral pathology because different structural abnormalities can produce a similar clinical picture.

Concussions are a frequent occurrence in contact sports such as football, hockey, lacrosse, and soccer, and increasing evidence suggests that athletes may sustain multiple concussions throughout their career (Bakhos et al., 2010; Bazarian et al., 2005; Grady, 2010; McCrory et al., 2009). Another significant population is soldiers suffering from blast-related injuries, with one in six soldiers returning from combat deployment in Iraq meeting the criteria for concussion (Wilk et al., 2010). Gender factors may also play a role in the epidemiology of concussion. Comparisons of similar sports have yielded the observation that females have nearly twice the rate of concussion compared with males (Dick, 2009; Lincoln et al., 2011). It is important to note that concussed high school males and females self-report different symptoms, with females more often complaining of drowsiness and noise sensitivity, whereas males complain of cognitive deficits and amnesia (Frommer et al., 2011). Furthermore, females also have a higher postconcussion symptom score 3 months postinjury (Bazarian et al., 2010). Two primary complications of concussion are the postconcussion syndrome and second impact syndrome. The postconcussion syndrome is the persistence of concussion-induced symptomatology for greater than 3 months postinjury, presumably because of both neurophysiological and neuropathological processes secondary to the initial concussion (Silverberg and Iverson, 2011).

Second impact syndrome is a condition in which a second head impact is sustained during a “vulnerable period” before the complete symptomatic resolution of the initial impact leading to profound engorgement, massive edema, and increased intracranial pressure within minutes of the impact and resulting in brain herniation, followed by coma and death (Cantu, 1998; Field et al., 2003). It is believed that this vulnerable period is the duration of an injury-induced failure of cerebral blood flow autoregulation (Lam et al., 1997), which can leave the patient highly vulnerable to drastic fluxes and extremes of blood pressure. Second impact syndrome has a morbidity rate of 100% and a mortality rate of 50%, and it is important to note that as of 2001, all reported cases of second impact syndrome had occurred in athletes younger than 20 years of age (McCrory, 2001).

Neurobehavioral symptoms, which often correlate with severity of the TBI, vary in type and duration and are manifested as somatic and/or neuropsychiatric symptoms (reviewed in Riggio and Wong, 2009). Somatic symptoms refer to the physical changes associated with TBI and include headache, dizziness/nausea, fatigue or lethargy, and changes in sleep pattern. Headache is the most commonly reported somatic symptom after mild TBI and is considered acute if resolved within 2 months or chronic if headaches persist for longer than 2 months. Dizziness is another commonly reported symptom of TBI and generally resolves within 2 months but may continue in patients with moderate or severe TBI. Another particularly debilitating symptom is fatigue, likely due to difficulty in initiating or maintaining sleep. Neuropsychiatric sequelae after TBI comprise cognitive deficits and behavioral disorders and are identified in almost all TBI patients for up to 3 months, with a small percentage exhibiting persistent (months—years) symptoms. Cognitive deficits are characterized by impaired attention, memory, and/or executive function and may cause the patient to become irritable, anxious, or depressed. Cognitive deficits in cases of mild TBI generally resolve within days and do not have to be associated with loss of consciousness and posttraumatic amnesia. Behavioral manifestations after TBI include personality changes, depression, and anxiety. Personality changes describe aggression, impulsivity, irritability, emotional lability, and apathy. Major depression is one of the most frequently reported behavioral sequelae of TBI, accounting for approximately 25% to 40% of cases of moderate-to-severe TBI (Riggio and Wong, 2009).

Collectively, these observations underscore the need to develop age-, sex-, and injury severity—appropriate animal models of mild TBI and concussions. The following review describes the current state of knowledge of the pathophysiology of mild TBI/concussions, with particular attention to axonal injury and cognitive deficits.

Publication types

  • Review